[Material basis and mechanism of Bletillae Rhizoma for melasma, gastrointestinal hemorrhage, lung cancer and bronchoplumonary inflammation as "homotherapy for heteropathy" based on UHPLC-Q-Exactive Orbitrap HRMS coupled with network pharmacology and molecular docking].

Based on UHPLC-Q-Exactive Orbitrap HRMS coupled with the network pharmacology and molecular docking, the common material basis and molecular mechanisms of Bletillae Rhizoma for melasma, gastrointestinal hemorrhage, lung cancer and bronchoplumonary inflammation as "homotherapy for heteropathy" were explored. The fingerprint of 17 batches of Bletillae Rhizoma from different areas was established using HPLC, and the similarity analysis was carried out. The common chemical components of the 17 batches of Bletillae Rhizoma were identified using UHPLC-Q-Exactive Orbitrap HRMS. Depending on the bioavailability and drug-like properties of the common components, the active chemical components were screened, and then their protein targets were collected using the Traditional Chinese Medicine Database and Analysis Platform(TCMSP) and SwissTargetPrediction database. The protein targets related to diseases were retrieved from the databases DrugBank, TTD and GeneCards to produce a Venn diagram. The shared targets were obtained between drugs and diseases as "homotherapy for heteropathy" targets. The protein-protein interaction(PPI) was analyzed with the STRING database, and KEGG and GO analyses of the "homotherapy for heteropathy" targets were performed using the Bioconductor database. Cytoscape 3.7.2 software was employed to construct the "chemical components of Bletillae Rhizoma-homotherapy for heteropathy targets" network and PPI network, and topological analysis was conducted to screen out the key active chemical components and core targets. Finally, the affinity between the active components and core targets was evaluated using the molecular docking by AutoDock Vina 4.2.6, which verified the interaction between them. Thirteen common peaks were identified by fingerprint chromatography, and the similarity between different batches was 0.941-0.998. Fifty-three chemical components were identified by mass spectrometry in Bletillae Rhizoma, and 18 common chemical constituents were obtained in the 17 batches of Bletillae Rhizoma. Network pharmacologic screening showed that the pharmacodynamic substances of Bletillae Rhizoma for melasma, gastrointestinal hemo-rrhage, lung cancer and bronchoplumonary inflammation with "homotherapy for heteropathy" were 11 compounds, such as polysaccharides, biphenanthrenes, dihydrophenanthrenes and bibenzyls. There were 42 common targets identified for the treatment of different diseases. These targets were involved in biological processes such as cell response to chemical stress, reactive oxygen species and positive regulation of protein kinase B signal transduction. They were also involved in 121 signaling pathways, encompassing vital pathways such as PI3K-Akt, ErbB, Rap1, FoxO, MAPK and estrogen. Molecular docking results showed a strong affinity between the key active components and the core targets. This study provides a preliminary explanation of how Bletillae Rhizoma exerts its therapeutic effect on chloasma, gastrointestinal hemorrhage, lung cancer, and bronchopneumonic lesions as "homotherapy for heteropathy" through a combined action involving multiple components, targets, and pathways. These findings offer a certain theoretical basis for the further deve-lopment and application of Bletillae Rhizoma.

Image features and clinical analysis of retroperitoneal pelvic schwannoma: a case report.

BACKGROUND: Schwannomas are benign usually encapsulated nerve sheath tumors derived from the Schwann cells, and affecting single or multiple nerves. The tumors commonly arise from the cranial nerves as acoustic neurinomas but they are extremely rare in the pelvis and the retroperitoneal area. Retroperitoneal pelvic schwannomas often present with non-specific symptoms leading to misdiagnosis and prolonged morbidity. CASE PRESENTATION: We report the case of a 59-year-old woman presenting with a feeling of heaviness in the lower abdomen who was found to have a retroperitoneal pelvic schwannoma originating from the right femoral nerve. She had a history of two resections of peripheral schwannomas at four different sites of limbs. After conducting magnetic resonance imaging, this pelvic schwannoma was misdiagnosed as a gynecological malignancy. The tumor was successfully removed by laparoscopic surgery. Pathological analysis of the mass revealed a benign schwannoma of the femoral nerve sheath with demonstrating strong, diffuse positivity for S-100 protein. CONCLUSIONS: Although retroperitoneal pelvic schwannoma is rare, it should be considered in the differential diagnosis of pelvic masses, especially in patients with a history of neurogenic mass or the presence of neurogenic mass elsewhere.

Derived from fangchinoline, LYY-35 exhibits an inhibiting effect on human NSCLC cancer A549 cells.

Although fangchinoline has been widely used as an adjunct therapy for a variety of inflammatory and cancerous diseases, its mechanism of action on tumor cells remains unclear. Fangchinoline derivative LYY-35 reduced the number of A549 cells, deformed cell morphology and increased cell debris. Cell viability was significantly reduced, while the same concentration of LYY-35 had little effect on BEAS-2B viability of normal lung epithelial cells. In addition, LYY-35 can also reduce the migration, proliferation and invasion ability of A549 cells. Levels of ß-catenin, ZO-1 and ZEB-1 proteins, biomarkers of cell adhesion and epithelial mesenchymal transformation, were significantly reduced. The levels of superoxide dismutase and lactate dehydrogenase decreased gradually, while the levels of glutathione, malondialdehyde and intracellular and extracellular ROS increased significantly. At the same time, LYY-35 induced increased apoptosis, increased expression of Bax, cleaved caspase3, cleaved PARP1, and decreased expression of Bcl-xl, which blocked the cell cycle to G0/G1 phase. The expressions of cell cycle checkpoint proteins Cyclin B1, Cyclin E1, CDK6, PCNA and PICH were significantly decreased. With the increase of LYY-35 concentration, the trailing phenomenon was more obvious in single cell gel electrophoresis. DNA damage repair proteins: BLM, BRCA-1 and PARP-1 expression decreased gradually.LYY-35 can inhibit the proliferation of non-small cell lung cancer A549 cells, block cell cycle, promote apoptosis, increase ROS production, cause DNA damage and interfere with DNA replication. LYY-35 is promising for the treatment of non-small cell lung cancer in the future.

A novel L-shaped ortho-quinone analog suppresses glioblastoma progression by targeting acceleration of AR degradation and regulating PI3K/AKT pathway.

Glioblastoma (GBM) is a primary intracranial malignant tumor with the highest mortality and morbidity among all malignant central nervous system tumors. Tanshinone IIA is a fat-soluble active ingredient obtained from Salvia miltiorrhiza, which has an inhibitory effect against various cancers. We designed and synthesized a novel L-shaped ortho-quinone analog TE5 with tanshinone IIA as the lead compound and tested its antitumor activity against GBM. The results indicated that TE5 effectively inhibited the proliferation, migration, and invasion of GBM cells, and demonstrated low toxicity in vitro. We found that TE5 may bind to androgen receptors and promote their degradation through the proteasome. Inhibition of the PI3K/AKT signaling pathway was also observed in TE5 treated GBM cells. Additionally, TE5 arrested the cell cycle at the G2/M phase and induced mitochondria-dependent apoptosis. In vivo experiments further confirmed the anti-tumor activity, safety, and effect on androgen receptor level of TE5 in animal models of GBM. Our results suggest that TE5 may be a potential therapeutic drug to treat GBM.

Tanshinone analog inhibits castration-resistant prostate cancer cell growth by inhibiting glycolysis in an AR-dependent manner.

Androgen receptor (AR) is one of the key targets for the treatment of castration-resistant prostate cancer (CRPC). Current endocrine therapy can greatly improve patients with CRPC. However, with the change of pathogenic mechanism, acquired resistance often leads to the failure of treatment. Studies have shown that tanshinone IIA (TS-IIA) and its derivatives have significant antitumor activity, and have certain AR-targeting effects, but the mechanism is unknown. In this study, the TS-IIA analog TB3 was found to significantly inhibit the growth of CRPC in vitro and in vivo. Molecular docking, cellular thermal shift assay, and cycloheximide experiments confirmed that AR was the target of TB3 and promoted the degradation of AR. Furthermore, TB3 can significantly inhibit glycolysis metabolism by targeting the AR/PKM2 axis. The addition of pyruvic acid could significantly alleviate the inhibitory effect of TB3 on CRPC cells. Besides, the knockdown of AR or PKM2 also could reverse the effect of TB3 on CRPC cells. Taken together, our study suggests that TS-IIA derivative TB3 inhibits glycolysis to prevent the CRPC process by targeting the AR/PKM2 axis.

Applying image features of proximal paracancerous tissues in predicting prognosis of patients with hepatocellular carcinoma.

BACKGROUND: Most of the methods using digital pathological image for predicting Hepatocellular carcinoma (HCC) prognosis have not considered paracancerous tissue microenvironment (PTME), which are potentially important for tumour initiation and metastasis. This study aimed to identify roles of image features of PTME in predicting prognosis and tumour recurrence of HCC patients. METHODS: We collected whole slide images (WSIs) of 146 HCC patients from Sun Yat-sen Memorial Hospital (SYSM dataset). For each WSI, five types of regions of interests (ROIs) in PTME and tumours were manually annotated. These ROIs were used to construct a Lasso Cox survival model for predicting the prognosis of HCC patients. To make the model broadly useful, we established a deep learning method to automatically segment WSIs, and further used it to construct a prognosis prediction model. This model was tested by the samples of 225 HCC patients from the Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC). RESULTS: In predicting prognosis of the HCC patients, using the image features of manually annotated ROIs in PTME achieved C-index 0.668 in the SYSM testing dataset, which is higher than the C-index 0.648 reached by the model only using image features of tumours. Integrating ROIs of PTME and tumours achieved C-index 0.693 in the SYSM testing dataset. The model using automatically segmented ROIs of PTME and tumours achieved C-index of 0.665 (95% CI: 0.556-0.774) in the TCGA-LIHC samples, which is better than the widely used methods, WSISA (0.567), DeepGraphSurv (0.593), and SeTranSurv (0.642). Finally, we found the Texture SumAverage Skew HV on immune cell infiltration and Texture related features on desmoplastic reaction are the most important features of PTME in predicting HCC prognosis. We additionally used the model in prediction HCC recurrence for patients from SYSM-training, SYSM-testing, and TCGA-LIHC datasets, indicating the important roles of PTME in the prediction. CONCLUSIONS: Our results indicate image features of PTME is critical for improving the prognosis prediction of HCC. Moreover, the image features related with immune cell infiltration and desmoplastic reaction of PTME are the most important factors associated with prognosis of HCC.

Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 2: Modulation of hypoxia, redox status, and mitochondrial protection in a neuroblastoma cell line, SH-SY5Y.

OBJECTIVE: To examine the mitochondrial protective effects of icariin, naringenin, kaempferol, and formononetin, potentially active agents in Bu-Shen-Jian-Pi formula (BSJP) identified using network pharmacology analysis. MATERIALS AND METHODS: Mitochondrial protection activity was determined using a hypoxia-reoxygenation in vitro model based on the neuroblastoma cell line SH-SY5Y and measurements of anti-ferroptotic activity. RESULTS: Icariin, naringenin, kaempferol, and formononetin showed mitochondrial protective activity involving diverse signaling pathways. The cytoprotective effects of formononetin depended on the inhibition of ferroptosis. Hypoxia-reoxygenation stimulation induced ferroptosis in SH-SY5Y cells. DISCUSSION: Ferroptosis is a key mechanism in nervous system diseases and is associated with hypoxia-reoxygenation injury. Naringenin and kaempferol were devoid of anti-ferroptotic activity. CONCLUSION: Evidence has been obtained showing that the core components: icariin, naringenin, kaempferol, and formononetin in BSJP formula have anti-hypoxic and mitochondrial protective activity of potential clinical importance in the treatment of amyotrophic lateral sclerosis and patients with symptoms of hypoxia.

New clerodane diterpenoids from Callicarpa pseudorubella and their antitumor proliferative activity.

Six previously undescribed clerodane diterpenes, cardorubellas A-F (1-6), along with seven known ones (7-13), were isolated from the aerial parts of Callicarpa pseudorubella. Their chemical structures were established by analysis of 1D and 2D NMR, HR-ESI-MS, X-ray diffraction, and electronic circular dichroism (ECD) data. Notably, cardorubella B (2) represented the first examples of naturally occurring succinic anhydride-containing clerodane diterpenes derivatives. The anti-proliferative activities of these compounds were assessed. Remarkably, compound 2 exhibited comparable inhibitory activity against HEL cell lines, surpassing the positive control with an IC50 value of 14.01 ± 0.77 µM, compared to 17.02 ± 4.70 µM for 5-fluorouracil.

Discovery of tricyclic PARP7 inhibitors with high potency, selectivity, and oral bioavailability.

PARP7 has been recently identified as an effective drug target due to its specific role in tumor generation and immune function recovery. Herin, we report the discovery of compound 8, which contained a tricyclic fused ring, as a highly selective PARP7 inhibitor against other PARPs. In particular, compound 8 strongly inhibits PARP7 with an IC50 of 0.11 nM, and suppresses the proliferation of NCI-H1373 lung cancer cells with an IC50 of 2.5 nM. Compound 8 exhibits a favorable pharmacokinetic profile with a bioavailability of 104 % in mice, and 78 % in dogs. Importantly, daily treatment of 30 mg/kg of 8 induced 81.6 % tumor suppression in NCI-H1373 lung xenograft mice tumor models, which is significantly better than the clinical candidate, RBN-2397. These intriguing features highlight the promising advantages of 8 as an antitumor agent.

Radiomics-based machine learning and deep learning to predict serosal involvement in gallbladder cancer.

OBJECTIVE: Our study aimed to determine whether radiomics models based on contrast-enhanced computed tomography (CECT) have considerable ability to predict serosal involvement in gallbladder cancer (GBC) patients. MATERIALS AND METHODS: A total of 152 patients diagnosed with GBC were retrospectively enrolled and divided into the serosal involvement group and no serosal involvement group according to paraffin pathology results. The regions of interest (ROIs) in the lesion on all CT images were drawn by two radiologists using ITK-SNAP software (version 3.8.0). A total of 412 features were extracted from the CT images of each patient. The Mann‒Whitney U test was applied to identify features with significant differences between groups. Seven machine learning algorithms and a deep learning model based on fully connected neural networks (f-CNNs) were used for radiomics model construction. The prediction efficacy of the models was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Through the Mann‒Whitney U test, 75 of the 412 features extracted from the CT images of patients were significantly different between groups (P < 0.05). Among all the algorithms, logistic regression achieved the highest performance with an area under the curve (AUC) of 0.944 (sensitivity 0.889, specificity 0.8); the f-CNN deep learning model had an AUC of 0.916, and the model showed high predictive power for serosal involvement, with a sensitivity of 0.733 and a specificity of 0.801. CONCLUSION: Radiomics models based on features derived from CECT showed convincing performances in predicting serosal involvement in GBC.

A novel L-shaped ortho-quinone analog as PLK1 inhibitor blocks prostate cancer cells in G2 phase.

Prostate cancer is the most common malignant tumor among men worldwide. Currently, the main treatments are radical prostatectomy, radiotherapy, chemotherapy, and endocrine therapy. However, most of them are poorly effective and induce side effects. Polo-like kinase 1 (PLK1) regulates cell cycle and mitosis. Its inhibitor BI2536 promotes the therapeutic effect of nilotinib in chronic myeloid leukemia, enhances the sensitivity of neural tube cell tumors to radiation therapy and PLK1 silencing enhances the sensitivity of squamous cell carcinoma to cisplatin. Therefore, the aim of this study was to evaluate the effect of the PLK1 inhibitor L-shaped ortho-quinone analog TE6 on prostate cancer. In vitro on prostate cancer cells showed that TE6 inhibited PLK1 protein expression and consequently cell proliferation by blocking the cell cycle at G2 phase. In vivo on a subcutaneous tumor model in nude mice confirmed that TE6 effectively inhibited tumor growth in nude mice, inhibited PLK1 expression and regulated the expression of cell cycle proteins such as p21, p53, CDK1, Cdc25C, and cyclinB1. Thus, PLK1 was identified as the target protein of TE6, these results reveal the critical role of PLK1 in the growth and survival of prostate cancer and point out the ability of TE6 on targeting PLK1, being a potential drug for prostate cancer therapy.

Limonoids from the Branches and Leaves of Aglaia lawii and Their Cytotoxic Activities.

Three undescribed limonoids (1-3), named aglaians G-I, and one new natural product azedaralide (4), together with nine known analogues (5-13) were isolated from the branches and leaves of Aglaia lawii by RP C18 column, silica gel column, Sephadex LH-20 column chromatography and preparative HPLC. The structures of the new compounds were elucidated by IR, HRESIMS, 1D, 2D NMR, electronic circular dichroism (ECD) calculations and X-ray crystallography diffraction analysis. The results of bioassay showed that the compound 12 exhibited potential inhibitory activity against six human tumor cell lines (MDA-MB-231, MCF-7, Ln-cap, A549, HeLa and HepG-2) with IC50 values as 8.0-18.6 µM.

Bisbenzylisoquinoline alkaloid fangchinoline derivative HY-2 inhibits breast cancer cells by suppressing BLM DNA helicase.

The high expression of BLM (Bloom syndrome) DNA helicase in tumors involves its strong association with cell expansion. Bisbenzylisoquinoline alkaloids own an antitumor property and have developed as candidates for anticancer drugs. This paper aimed to study the antitumor effect of fangchinoline derivative HY-2 by targeting BLM642-1290 DNA helicase, and then explore its inhibitory mechanism on proliferation of MDA-MB-435 breast cancer cells. We confirmed that the mRNA and protein levels of BLM DNA helicase in breast cancer were higher than those in normal tissues. HY-2 could inhibit the DNA binding, ATPase and DNA unwinding of BLM642-1290 DNA helicase with enzymatic assay. HY-2 could also inhibit the DNA unwinding of DNA helicase in cells. In addition, HY-2 showed an inhibiting the MDA-MB-435, MDA-MB-231, MDA-MB-436 breast cancer cells expansion. The mRNA and protein levels of BLM DNA helicase in MDA-MB-435 cells increased after HY-2 treatment, which might contribute to HY-2 inhibiting the DNA binding, ATPase and DNA unwinding of BLM DNA helicase. The mechanism of HY-2 inhibition on BLM DNA helicase was further confirmed with the effect of HY-2 on the ultraviolet spectrogram of BLM642-1290 DNA helicase and Molecular dynamics simulation of the interacting between HY-2 and BLM640-1291 DNA helicase. Our study provided some valuable clues for the exploration of HY-2 in the living body and developing it as an anticancer drug.

The m7G Reader NCBP2 Promotes Pancreatic Cancer Progression by Upregulating MAPK/ERK Signaling.

PDAC is one of the most common malignant tumors worldwide. The difficulty of early diagnosis and lack of effective treatment are the main reasons for its poor prognosis. Therefore, it is urgent to identify novel diagnostic and therapeutic targets for PDAC patients. The m7G methylation is a common type of RNA modification that plays a pivotal role in regulating tumor development. However, the correlation between m7G regulatory genes and PDAC progression remains unclear. By integrating gene expression and related clinical information of PDAC patients from TCGA and GEO cohorts, m7G binding protein NCBP2 was found to be highly expressed in PDAC patients. More importantly, PDAC patients with high NCBP2 expression had a worse prognosis. Stable NCBP2-knockdown and overexpression PDAC cell lines were constructed to further perform in-vitro and in-vivo experiments. NCBP2-knockdown significantly inhibited PDAC cell proliferation, while overexpression of NCBP2 dramatically promoted PDAC cell growth. Mechanistically, NCBP2 enhanced the translation of c-JUN, which in turn activated MEK/ERK signaling to promote PDAC progression. In conclusion, our study reveals that m7G reader NCBP2 promotes PDAC progression by activating MEK/ERK pathway, which could serve as a novel therapeutic target for PDAC patients.

Red Room-Temperature Phosphorescence Supramolecular Assemblies Based on Cucurbit[7]uril: Reversible Temperature Stimulation Response and Cell-Specific Silver Ion Imaging.

Solid-state materials with efficient room-temperature phosphorescence (RTP) emission have been widely used in materials science, and organic RTP-emitting systems with heavy-metal doping in aqueous solutions have attracted much attention in recent years. A novel supramolecular interaction was induced by host-guest assembly using cucurbit[7]uril (Q[7]) as the host and brominated naphthalimide phosphor as the guest. This interaction was further enhanced through synergistic chelation stimulated by analytical silver ion complexation. This approach facilitated the system's structural rigidity, intersystem crossing, and oxygen shielding. We achieved deep red phosphorescence emission in aqueous solution and ambient conditions along with quantitative determination of silver ions. The new complex exhibited good reversible thermoresponsive behavior and was successfully applied for the first time to target phosphorescence imaging of silver ions in the mitochondria of A549 cancer cells. These results are beneficial for constructing novel RTP systems with stimulus-responsive luminescence in aqueous solution, contributing to future research in bioimaging, detection, optical sensors, and thermometry materials.

Unusual triterpenoids and steroids from Cipadessa baccifera and their biological activities.

Five undescribed triterpenoids and steroids (1-5), as well as ten known compounds, were purified from the branches and leaves of Cipadessa baccifera. Notably, 1 and 2 are rare cipadesin-type limonoids with an unusual 8,30-epoxide ring and 1,8-ether linkage, respectively. Compound 5 possessed pregnane steroid skeleton with an uncommon 5/6/6/6/5-fused ring system. Their structures were constructed by extensive spectroscopic analysis (NMR, IR, UV, and HRESIMS), and their absolute configurations were confirmed by ECD calculations and quantum chemical calculations. All the isolates were in vitro assayed for their antimicrobial potentials against 6 pathogenic microorganisms and antiproliferation activities against five human cancer cell lines. As a result, compounds 5, 12, 13, and 14 exhibited moderate antibacterial activities (MIC: 25-50 µg/mL). Moreover, 5 showed cytotoxicity against five cancer cell lines with IC50 values ranging from 8.0 to 19.9 µM.

Probing Transcriptional Crosstalk between Cryptochromes and Iron-sulfur Cluster Assembly 1 (MagR) in the Magnetoresponse of a Migratory Insect.

Many organisms can sense and respond to magnetic fields (MFs), with migratory species in particular utilizing geomagnetic field information for long-distance migration. Cryptochrome proteins (Crys) along with a highly conserved Iron-sulfur cluster assembly protein (i.e., MagR) have garnered significant attention for their involvement in magnetoresponse (including magnetoreception). However, in vivo investigations of potential transcriptional crosstalk between Crys and MagR genes have been limited. The brown planthopper, Nilaparvata lugens, is a major migratory pest insect and an emerging model for studying MF intensity-related magnetoresponse. Here, we explored in vivo transcriptional crosstalk between Crys (Cry1 and Cry2) and MagR in N. lugens. The expression of Crys and MagR were found to be sensitive to MF intensity changes as small as several micro-teslas. Knocking down MagR expression led to a significant downregulation of Cry1, but not Cry2. The knockdown of either Cry1 or Cry2 individually did not significantly affect MagR expression. However, their double knockdown resulted in significant upregulation of MagR. Our findings clearly indicate transcriptional crosstalk between MagR and Crys known to be involved in magnetoresponse. This work advances the understanding of magnetoresponse signaling and represents a key initial step towards elucidating the functional consequences of these novel in vivo interactions.

A Self-Assembly Nano-Prodrug for Combination Therapy in Triple-Negative Breast Cancer Stem Cells.

Triple-negative breast cancer (TNBC) displays a highly aggressive nature that originates from a small subpopulation of TNBC stem cells (TNBCSCs), and these TNBCSCs give rise to chemoresistance, tumor metastasis, and recurrence. Unfortunately, traditional chemotherapy eradicates normal TNBC cells but fails to kill quiescent TNBCSCs. To explore a new strategy for eradicating TNBCSCs, a disulfide-mediated self-assembly nano-prodrug that can achieve the co-delivery of ferroptosis drug, differentiation-inducing agent, and chemotherapeutics for simultaneous TNBCSCs and TNBC treatment, is reported. In this nano-prodrug, the disulfide bond not only induces self-assembly behavior of different small molecular drug but also serves as a glutathione (GSH)-responsive trigger in controlled drug release. More importantly, the differentiation-inducing agent can transform TNBCSCs into normal TNBC cells, and this differentiation with chemotherapeutics provides an effective approach to indirectly eradicate TNBCSCs. In addition, ferroptosis therapy is essentially different from the apoptosis-induced cell death of differentiation or chemotherapeutic, which causes cell death to both TNBCSCs and normal TNBC cells. In different TNBC mouse models, this nano-prodrug significantly improves anti-tumor efficacy and effectively inhibits the tumor metastasis. This all-in-one strategy enables controlled drug release and reduces stemness-related drug resistance, enhancing the chemotherapeutic sensitivity in TNBC treatment.

Circ_0020256 induces fibroblast activation to drive cholangiocarcinoma development via recruitment of EIF4A3 protein to stabilize KLF4 mRNA.

Cancer-associated fibroblasts (CAFs) are a kind of stromal cells in the cholangiocarcinoma (CCA) microenvironment, playing crucial roles in cancer development. However, the potential mechanisms of the interaction between CCA cells and CAFs remain obscure. This work investigated the role of circ_0020256 in CAFs activation. We proved circ_0020256 was up-regulated in CCA. High circ_0020256 expression facilitated TGF-ß1 secretion from CCA cells, which activated CAFs via the phosphorylation of Smad2/3. Mechanistically, circ_0020256 recruited EIF4A3 protein to stabilize KLF4 mRNA and upregulate its expression, then KLF4 bound to TGF-ß1 promoter and induced its transcription in CCA cells. KLF4 overexpression abrogated the inhibition of circ_0020256 silencing in TGF-ß1/Smad2/3-induced CAFs activation. Furthermore, CCA cell growth, migration, and epithelial-mesenchymal transition were favored by CAFs-secreted IL-6 via autophagy inhibition. We also found circ_0020256 accelerated CCA tumor growth in vivo. In conclusion, circ_0020256 promoted fibroblast activation to facilitate CCA progression via EIF4A3/KLF4 pathway, providing a potential intervention for CCA progression.

FLI1 Regulates Histamine Decarboxylase Expression to Control Inflammation Signaling and Leukemia Progression.

Aim: Histamine decarboxylase (HDC) catalyzes decarboxylation of histidine to generate histamine. This enzyme affects several biological processes including inflammation, allergy, asthma, and cancer, although the underlying mechanism is not fully understood. The present study provides a novel insight into the relationship between the transcription factor FLI1 and its downstream target HDC, and their effects on inflammation and leukemia progression. Methods: Promoter analysis combined with chromatin immunoprecipitation (ChIp) was used to demonstrate binding of FLI1 to the promoter of HDC in leukemic cells. Western blotting and RT-qPCR were used to determine expression of HDC and allergy response genes, and lentivirus shRNA was used to knock-down target genes. Proliferation, cell cycle, apoptosis assays and molecular docking were used to determine the effect of HDC inhibitors in culture. An animal model of leukemia was employed to test the effect of HDC inhibitory compounds in vivo. Results: Results presented herein demonstrate that FLI1 transcriptionally regulates HDC by direct binding to its promoter. Using genetic and pharmacological inhibition of HDC, or the addition of histamine, the enzymatic product of HDC, we show neither have a discernable effect on leukemic cell proliferation in culture. However, HDC controls several inflammatory genes including IL1B and CXCR2 that may influence leukemia progression in vivo through the tumor microenvironment. Indeed, diacerein, an IL1B inhibitor, strongly blocked Fli-1-induced leukemia in mice. In addition to allergy, FLI1 is shown to regulate genes associated with asthma such as IL1B, CPA3 and CXCR2. Toward treatment of these inflammatory conditions, epigallocatechin (EGC), a tea polyphenolic compound, is found strongly inhibit HDC independently of FLI1 and its downstream effector GATA2. Moreover, the HDC inhibitor, tetrandrine, suppressed HDC transcription by directly binding to and inhibiting the FLI1 DNA binding domain, and like other FLI1 inhibitors, tetrandrine strongly suppressed cell proliferation in culture and leukemia progression in vivo. Conclusion: These results suggest a role for the transcription factor FLI1 in inflammation signaling and leukemia progression through HDC and point to the HDC pathway as potential therapeutics for FLI1-driven leukemia.