Celastrol elicits antitumor effects by inhibiting the STAT3 pathway through ROS accumulation in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common lung cancer with high mortality across the world, but it is challenging to develop an effective therapy for NSCLC. Celastrol is a natural bioactive compound, which has been found to possess potential antitumor activity. However, the underlying molecular mechanisms of celastrol activity in NSCLC remain elusive. METHODS: Cellular function assays were performed to study the suppressive role of celastrol in human NSCLC cells (H460, PC-9, and H520) and human bronchial epithelial cells BEAS-2B. Cell apoptosis levels were analyzed by flow cytometry, Hoechst 33342, caspase-3 activity analysis, and western blot analysis. Intracellular reactive oxygen species (ROS) were analyzed by flow cytometry and fluorescence microscope. Expression levels of endoplasmic reticulum (ER) stress-related proteins and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) were identified via western blot analysis. A heterograft model in nude mice was employed to evaluate the effect of celastrol in vivo. RESULTS: Celastrol suppressed the growth, proliferation, and metastasis of NSCLC cells. Celastrol significantly increased the level of intracellular ROS; thus, triggering the activation of the ER stress pathway and inhibition of the P-STAT3 pathway, and eventually leading to cell apoptosis, and the effects were reversed by the pre-treatment with N-Acetyl-L-cysteine (NAC). Celastrol also suppressed tumor growth in vivo. CONCLUSION: The outcomes revealed that celastrol plays a potent suppressive role in NSCLC in vitro and in vivo. Celastrol induces apoptosis via causing mitochondrial ROS accumulation to suppress the STAT3 pathway. Celastrol may have potential application prospects in the therapy of NSCLC.

The correlation between the change of Hounsfield units value and Modic changes in the lumbar vertebral endplate.

OBJECTIVES: To evaluate the changes of Hounsfield units (HU) value in different types of Modic changes (MCs) and to analyze the correlation between the change of HU value and area ratio of MCs region, bone mineral density (BMD), and degree of intervertebral disc degeneration. METHODS: One hundred fifty-eight endplates with MCs were included and analyzed. HU values of MCs regions and adjacent vertebral corresponding regions without MCs were measured. The area ratio of MCs region was defined as the area of MCs divided by the area of endplate or the vertebral sagittal plane. BMD was measured by Dual-energy x-ray absorptiometry (DXA). Degree of intervertebral disc degeneration was evaluated based on Pfirrmann classification. According to the types of variables, descriptive statistics, Kolmogorove-Smirnov test, paired t-test, Wilcoxon signed-rank test, Independent-Samples T Test, and Pearson correlation analysis were used. RESULTS: The HU values in any types of MCs are significantly higher than that of adjacent vertebral corresponding regions without MCs (P < 0.001). The HU value of the type III MCs is higher than that of the type I and type II MCs. HU value was positively correlated with BMD. In the levels with Grade V disc degeneration, the area ratio of MCs region was significant increased. CONCLUSIONS: HU values of the vertebral endplate and bone marrow were increased in most MCs regions with all types of MCs. HU value of endplates had a significantly positive correlation with BMD. Higher area ratio of MCs region is associated with more severe intervertebral disc degeneration.

Correlation between RNA N6-methyladenosine and ferroptosis in cancer: current status and prospects.

N6-methyladenosine (m6A) is the most abundant chemical modification in eukaryotic cells. It is a post-transcriptional modification of mRNA, a dynamic reversible process catalyzed by methyltransferase, demethylase, and binding proteins. Ferroptosis, a unique iron-dependent cell death, is regulated by various cell metabolic events, including many disease-related signaling pathways. And different ferroptosis inducers or inhibitors have been identified that can induce or inhibit the onset of ferroptosis through various targets and mechanisms. They have potential clinical value in the treatment of diverse diseases. Until now, it has been shown that in several cancer diseases m6A can be involved in the regulation of ferroptosis, which can impact subsequent treatment. This paper focuses on the concept, function, and biological role of m6A methylation modification and the interaction between m6A and ferroptosis, to provide new therapeutic strategies for treating malignant diseases and protecting the organism by targeting m6A to regulate ferroptosis.

Dysregulation of LINC00324 promotes poor prognosis in patients with glioma.

BACKGROUND: LINC00324 is a long-stranded non-coding RNA, which is aberrantly expressed in various cancers and is associated with poor prognosis and clinical features. It involves multiple oncogenic molecular pathways affecting cell proliferation, migration, invasion, and apoptosis. However, the expression, function, and mechanism of LINC00324 in glioma have not been reported. MATERIAL AND METHODS: We assessed the expression of LINC00324 of LINC00324 in glioma patients based on data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) to identify pathways involved in LINC00324-related glioma pathogenesis. RESULTS: Based on our findings, we observed differential expression of LINC00324 between tumor and normal tissues in glioma patients. Our analysis of overall survival (OS) and disease-specific survival (DSS) indicated that glioma patients with high LINC00324 expression had a poorer prognosis compared to those with low LINC00324 expression. By integrating clinical data and genetic signatures from TCGA patients, we developed a nomogram to predict OS and DSS in glioma patients. Gene set enrichment analysis (GSEA) revealed that several pathways, including JAK/STAT3 signaling, epithelial-mesenchymal transition, STAT5 signaling, NF-κB activation, and apoptosis, were differentially enriched in glioma samples with high LINC00324 expression. Furthermore, we observed significant correlations between LINC00324 expression, immune infiltration levels, and expression of immune checkpoint-related genes (HAVCR2: r = 0.627, P = 1.54e-77; CD40: r = 0.604, P = 1.36e-70; ITGB2: r = 0.612, P = 6.33e-7; CX3CL1: r = -0.307, P = 9.24e-17). These findings highlight the potential significance of LINC00324 in glioma progression and suggest avenues for further research and potential therapeutic targets. CONCLUSION: Indeed, our results confirm that the LINC00324 signature holds promise as a prognostic predictor in glioma patients. This finding opens up new possibilities for understanding the disease and may offer valuable insights for the development of targeted therapies.

Non-Angry Superficial Draining Veins: A New Technique in Identifying the Extent of Nidus Excision during Cerebral Arteriovenous Malformation Surgery.

BACKGROUND: As essential techniques, intraoperative indocyanine green video angiography (ICG-VA) and FLOW 800 have been widely used in microsurgery for arteriovenous malformations (AVMs). In the present report, we introduced a supplementary technical trick for judging the degree of lesion resection when there were superficial drainage veins. FLOW 800 analysis is used to verify our conjecture. METHODS: A retrospective analysis of a 33 case cohort treated surgically from June 2020 to September 2022 was conducted and their lesions were removed by superficial drainage veins as a supplementary technical trick and analyzed with FLOW800. RESULTS: In our 33 AVMs, the feeding artery was visualized earlier than the draining vein. Intraoperatively, the T1/2 peak and slope of the draining vein were significantly higher than that of the lesion. However, the maximum fluorescence intensity (MFI) of the draining vein decreased as the procedure progressed (p < 0.001). After reducing the blood flow to the nidus by progressive dissection of the feeding artery, the arteriovenous transit time (AVTT) decreased from 0.64 ± 0.47 s, was prolonged to 2.38 ± 0.52 (p < 0.001), and the MFI and slope of the nidus decreased from the pre-resection 435.42 ± 43.90 AI and 139.77 ± 27.55 AI/s, and decreased to 386.70 ± 48.17 AI and 116.12 ± 17.46 AI/s (p < 0.001). After resection of the nidus, the T1/2 peak of the draining vein increased from 21.42 ± 4.70 s, prolonged to after dissection of the blood feeding artery, 23.07 ± 5.29 s (p = 0.424), and after resection of the lesion, 25.13 ± 5.46 s (p = 0.016), with a slope from 135.79 ± 28.17 AI/s increased to 210.86 ± 59.67 AI/s (p < 0.001). CONCLUSIONS: ICG-VA integrated with FLOW 800 is an available method for determining the velocity of superficial drainage veins. Whether the color of the superficial drainage veins on the cortical surface returns to normal can determine whether the lesion is completely resected and can reduce the possibility of residual postoperative lesions.

Epithelial Membrane Protein-3 and Chitinase-3-like Protein-1 as New Prognostic Predictors of Glioma, a Two-Gene Study.

BACKGROUND: Glioblastoma multiforme is the most common primary intracranial tumor, with a high degree of malignancy, poor therapeutic effect, and poor prognosis. According to previous studies, CHI3L1 and EMP3 are two independent tumor predictors that are of great significance for the prognostic prediction of other tumors, and their expression levels may be related to the prognosis of glioma patients. METHODS: using Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), the Chinese Glioma Genome Atlas (CGGA), cBioPortal, LinkedOmics, and other databases, 693 glioma patients were screened to analyze the relationship between EMP3 and CHI3L1 expression and prognosis in glioma patients. RESULTS: low-grade glioma patients with a low expression of EMP3/CHI3L1 had a better prognosis, and the combination of EMP3/CHI3L1 is a new predictor for glioma patients. CONCLUSION: We used the TCGA and CGGA databases to analyze the effect of EMP3 and CHI3L1 expression on the prognosis of glioma patients and their correlation with gene expression using bioinformation analysis. The results showed that low-grade glioma patients with a low expression of EMP3 and CHI3L1 had a better prognosis, and EMP3 and CHI3L1 co-expression genes were correlated. The combination of these two factors could be a new prognostic index for glioma patients.

Microscopic with Endoscopic Surgery via Subtemporal Approach for Cavernous Sinus Cholesteatomas.

OBJECTIVE: The aim of this study was to retrospectively analyze the clinical data of 16 patients with cavernous sinus cholesteatomas, explore the surgical outcomes, and summarize the surgical experience. METHODS: Patients with cavernous sinus cholesteatomas underwent surgery between June 2016 and June 2022 at the Department of Neurosurgery at the First Affiliated Hospital of Soochow University. Clinical data were obtained from all patients for analysis. RESULTS: Common preoperative symptoms included headache, dizziness, diplopia, ptosis, and facial numbness. There were 7 patients with 2 or more symptoms. There were 13 patients with total resection and 3 patients with subtotal resection. There were 5 patients with improved postoperative symptoms, 10 patients with no significant change, and 1 patient with worse symptoms. New postoperative cranial nerve defects occurred in 4 patients. During the follow-up, all patients had favorable prognosis without progression. CONCLUSIONS: Using "double-scope" technique, the subtemporal approach, a surgical strategy for cavernous sinus cholesteatomas, was sufficient to completely resect the tumors.

Cinobufagin exerts an antitumor effect in non-small-cell lung cancer by blocking STAT3 signaling.

Background: Non-small-cell lung cancer (NSCLC) is the most common histological subtype of lung cancer with significant morbidity and mortality rates worldwide. Cinobufagin, the primary component of Chansu and the major active ingredient of cinobufacini, has attracted widespread attention for its excellent anticancer effects, but its activity remains poorly characterized in NSCLC. Methods: The functions of cinobufagin treatment in anti-tumor was evaluated using various in vitro and in vivo assays. The change of STAT3 signaling by cinobufagin was analyzed using molecular docking, immunofluorescence technic and western blotting. Results: In vitro, we confirmed the inhibitory effect of cinobufagin on cell viability, proliferation, migration, epithelial-mesenchymal transition (EMT), as well as an apoptosis-inducing effect. The antitumor effects of cinobufagin were confirmed in vivo by measuring tumor growth in a mouse xenograft model. Cinobufagin was found to significantly inhibit the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at tyrosine 705 (Y705) in a time- and concentration-dependent manner. Moreover, cinobufagin reversed IL-6-induced nuclear translocation of STAT3. Conclusions: Our study has demonstrated that cinobufagin exerts an antitumor effect in non-small-cell lung cancer by blocking STAT3 signaling, and cinobufagin is a promising candidate agent for NSCLC therapy.

Exponential Consensus of Coupled Inertial Agents With the Fully Heterogeneous and Fully Variable Setting of the Control Gains.

In this article, we consider the exponential consensus of coupled inertial (double-integrator) agents, particularly with the general setting of the damping and stiffness control gains. Each agent has one damping gain and one stiffness gain. Here, the damping and stiffness control gains of all agents can be both fully heterogeneous (FH) and fully variable (FV), which are called the FH-FV gains for convenience of reference. Specifically, the FH gains are defined as follows: 1) the damping gains of all agents are heterogeneous; 2) the stiffness gains of all agents are heterogeneous; and 3) the set of the damping gains and the set of the stiffness gains are distinct without dependence. Otherwise, the control gains are said partially heterogeneous (PH). The FV or partially variable (PV) aspect of control gains is defined similarly. The FH-FV gains setting is novel and generalizes the specially PH settings of constant gains in previous papers. We also consider the general FH-PV gains and the PH-PV gains. Then, we provide the series of conditions that ensure exponential convergence to consensus, for the agents with the FH-FV gains, the general FH-PV gains, and the PH-PV gains, respectively. The series of the conditions for each type of control gains has particular meaning for characterizing heterogeneity of the gains, especially, when the digraph of the agents is far-from-balanced.

Fabrication of Co3O4-Bi2O3-Ti catalytic membrane for efficient degradation of organic pollutants in water by peroxymonosulfate activation.

In this study, a functionalized Co3O4-Bi2O3-Ti catalytic membrane (CBO-Ti-M) was prepared and applied for removing organic pollutants via activating peroxymonosulfate (PMS) in the dead-end filtration mode. Characterizations including scanning electron microcopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) showed that the Co3O4-Bi2O3 catalyst was successfully supported on the Ti membrane. The CBO-Ti-M /PMS system could efficiently remove various organic pollutants such as sulfamethoxazole, methyl orange, bisphenol A and methylene blue, achieving removal efficiencies of 98.0%-99.5%. The effects of PMS concentration, flow rate and solution environment on degradation efficiency were investigated in detail. Furthermore, quenching experiments, electron spin resonance (ESR) and in-situ open circuit potential (OCP) tests collectively demonstrated that singlet oxygen as well as the non-radical electron transfer pathway mainly contributed in the reaction mechanism. The synergistic effect of Co and Bi was illustrated according to XPS results, and the possible degradation pathway of MB was proposed based on LC-MS analysis. Reusability test showed that pollutant removal efficiency with the CBO-Ti-M /PMS system remained stable in four runs and limited metal leaching was observed.

Using brefeldin A to disrupt cell wall polysaccharide components in rice and nitric oxide to modify cell wall structure to change aluminum tolerance.

The components and structure of cell wall are closely correlated with aluminum (Al) toxicity and tolerance for plants. However, the cell wall assembly and function construction in response to Al is not known. Brefeldin A (BFA), a macrolide, is used to disrupt cell wall polysaccharide components, and nitric oxide (NO), a signal molecule, is used to modify the cell wall structure. Pretreatment with BFA accelerated Al accumulation in root tips and Al-induced inhibition of root growth of two rice genotypes of Nipponbare and Zhefu 802, and significantly decreased the cell wall polysaccharide content including pectin, hemicellulose 1, and hemicellulose 2, indicating that BFA inhibits the biosynthesis of components in the cell wall and makes the root cell wall lose the ability to resist Al. The addition of NO donor (SNP) significantly alleviated the toxic effects of Al on root growth, Al accumulation, and oxidative damage, and decreased the content of pectin polysaccharide and functional groups of hydroxyl, carboxyl, and amino in the cell wall via FTIR analysis, while had no significant effect on hemicellulose 1 and hemicellulose 2 content compared with Al treatment. Furthermore, NO didn't change the inhibition effect of BFA-induced cell wall polysaccharide biosynthesis and root growth. Taken together, BFA disrupts the integrity of cell wall and NO modifies partial cell wall composition and their functional groups, which change the Al tolerance in rice.

Glaucocalyxin B Attenuates Ovarian Cancer Cell Growth and Cisplatin Resistance In Vitro via Activating Oxidative Stress.

Ovarian cancer is one of the fatal gynecological cancers around the world. Cisplatin is the first-line chemotherapy drug for the clinical treatment of ovarian cancer. However, many patients with ovarian cancer are still suffering from resistance to cisplatin. Therefore, the new drug combinations or treatment strategies for ovarian cancer are urgently needed. Glaucocalyxin B (GLB), a diterpenoid isolated from the aerial parts of Rabdosia japonica, has shown antitumor activity in some tumors. However, the mechanisms by which GLB inhibits ovarian cancer remain unclear. In the present study, we showed that GLB potently inhibits ovarian cancer cell growth in a dose-dependent manner. Furthermore, we found that GLB has a notably synergistic antitumor effect with cisplatin. Mechanistically, we found that GLB enhances the sensitivity of ovarian cancer cells to cisplatin via increasing reactive oxygen species (ROS) levels, the phosphorylation of c-Jun N-terminal kinase (JNK), and DNA damage. Interestingly, a synergistic inhibitory effect of GLB with cisplatin was also observed in the cells which were resistance to cisplatin. Together, these data suggest that GLB can sensitize ovarian cancer cells to cisplatin by increasing ROS levels.

The surgical management of pituitary apoplexy with occluded internal carotid artery and hidden intracranial aneurysm: illustrative case.

BACKGROUND: Approximately 0.6% to 12% of cases of pituitary adenoma are complicated by apoplexy, and nearly 6% of pituitary adenomas are comorbid aneurysms. Occlusion of the internal carotid artery (ICA) with hidden intracranial aneurysm due to compression by an apoplectic pituitary adenoma is extremely rare; thus, the surgical strategy is also unknown. OBSERVATIONS: The authors reported the case of a 48-year-old man with a large pituitary adenoma with coexisting ICA occlusion. After endoscopic transnasal surgery, repeated computed tomography angiography (CTA) demonstrated reperfusion of the left ICA but with a new-found aneurysm in the left posterior communicating artery; thus, interventional aneurysm embolization was performed. With stable recovery and improved neurological condition, the patient was discharged for rehabilitation training. LESSONS: For patients with pituitary apoplexy accompanied by a rapid decrease of neurological conditions, emergency decompression through endoscopic endonasal transsphenoidal resection can achieve satisfactory results. However, with occlusion of the ICA by enlarged pituitary adenoma or pituitary apoplexy, a hidden but rare intracranial aneurysm may be considered when patients are at high risk of such vascular disease as aneurysm, and gentle intraoperative manipulations are required. Performing CTA or digital subtraction angiography before and after surgery can effectively reduce the missed diagnosis of comorbidity and thus avoid life-threatening bleeding events from the accidental rupture of an aneurysm.

Curative effects of montmorillonite powder combined with dexamethasone on acute radiation enteritis.

OBJECTIVE: To investigate the curative effects of montmorillonite powder combined with dexamethasone on acute radiation enteritis. METHODS: Eighty-six patients with acute radiation enteritis were enrolled in this prospective research, and they were divided into a control group and an intervention group using a random number table, with 43 cases in each group. Patients in both groups received conventional treatment. The control group was treated with montmorillonite powder, and the intervention group was treated with retention enema with dexamethasone based on montmorillonite powder. The grades of mucosal damage, changes in cytokine levels, the efficacy of colonoscopy, and overall curative effects of the two groups before and after treatment were observed. RESULTS: After treatment, the levels of IL-2 and IFN-γ of the two groups were significantly reduced, and the level of IL-10 was significantly increased. The intervention group was significantly better than the control group (all P<0.001). The grades of mucosal damage in the intervention group showed better improvement than that in the control group (P<0.01), and the overall curative effects in the intervention group were significantly better than those in the control group (both P<0.05). CONCLUSION: Montmorillonite powder combined with dexamethasone is effective in treating patients with acute radiation enteritis, which can effectively alleviate mucosal damage, improve inflammation, and promote patient recovery. It has the value of promotion and application.

Novel Regulatory Factors and Small-Molecule Inhibitors of FGFR4 in Cancer.

Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase receptor that is a member of the fibroblast growth factor receptor family and is stimulated by highly regulated ligand binding. Excessive expression of the receptor and its ligand, especially FGF19, occurs in many types of cancer. Abnormal FGFR4 production explains these cancer formations, and therefore, this receptor has emerged as a potential target for inhibiting cancer development. This review discusses the diverse mechanisms of oncogenic activation of FGFR4 and highlights some currently available inhibitors targeting FGFR4.

Diagnosing Coronavirus Disease 2019 (COVID-19): Efficient Harris Hawks-Inspired Fuzzy K-Nearest Neighbor Prediction Methods.

This study is devoted to proposing a useful intelligent prediction model to distinguish the severity of COVID-19, to provide a more fair and reasonable reference for assisting clinical diagnostic decision-making. Based on patients' necessary information, pre-existing diseases, symptoms, immune indexes, and complications, this article proposes a prediction model using the Harris hawks optimization (HHO) to optimize the Fuzzy K-nearest neighbor (FKNN), which is called HHO-FKNN. This model is utilized to distinguish the severity of COVID-19. In HHO-FKNN, the purpose of introducing HHO is to optimize the FKNN's optimal parameters and feature subsets simultaneously. Also, based on actual COVID-19 data, we conducted a comparative experiment between HHO-FKNN and several well-known machine learning algorithms, which result shows that not only the proposed HHO-FKNN can obtain better classification performance and higher stability on the four indexes but also screen out the key features that distinguish severe COVID-19 from mild COVID-19. Therefore, we can conclude that the proposed HHO-FKNN model is expected to become a useful tool for COVID-19 prediction.

Novel SiOC nanocomposites for high-yield preparation of ultra-large-scale SiC nanowires.

Novel SiOC nanocomposites were successfully synthesized from commercial silica sol and sucrose via a simply designed route. The formation of SiOC nanocomposites was studied using thermogravimetry and differential scanning calorimetry. The synthesized nanocomposites were characterized by Fourier transform infrared spectroscopy, x-ray fluorescence spectrometer, x-ray photoelectron spectroscopy, x-ray diffraction, scanning electron microscopy, and transmission electron microscopy. The results indicate that the synthesized composites are amorphous in nature and homogeneous with the microstructure of close packed SiO(2) and carbon at nanoscale. The SiOC nanocomposites exhibit very high reactivity and can be annealed to produce SiC nanocrystals at 1200 degrees C which is about 300 degrees C lower than the value obtained by thermodynamic calculation. Ultra-large-scale beta-SiC nanowires with high quality were prepared by directly annealing the synthesized SiOC nanocomposites at 1500 degrees C under Ar atmosphere, where the yield of SiC nanowires was up to 59%. The SiC nanowires grow along the [111] direction with highly uniform diameters of about 100 nm. Experimental results indicate that the close contact between SiO(2) and carbon at nanoscale plays a vital role in the high yield of SiC nanowires. The present work provides an efficient strategy for the large scale production of high-quality SiC nanowires.

IL­37 expression is decreased in patients with hyperhomocysteinemia and protects cells from inflammatory injury by homocysteine.

As a novel anti­inflammatory cytokine of the interleukin (IL)­1 family, IL­37 protects the human body from diseases characterized by excessive inflammation. The pathologic process of hyperhomocysteinemia (hHcy) is accompanied by persistent inflammation. However, little is known regarding the role of IL­37 in hHcy. In the present study, the levels of cytokines including IL­37, IL­1ß, IL­6 and tumor necrosis factor­α in the supernatant were detected by ELISA. mRNA and protein expression were detected by Reverse transcription­quantitative PCR and western blotting, respectively. LDH level was determined by ELISA and the cell viability was detected through CCK­8 kit. In the present study, mean serum IL­37 levels of patients with hHcy were 32.3% lower than those of controls (P<0.01). In peripheral blood mononuclear cells (PBMCs) from patients with hHcy, mean IL­37 mRNA expression was 73.5% lower (P<0.01) and IL­37 protein expression was 77.7% lower compared with that of healthy controls (P<0.01). Furthermore, the results demonstrated that exogenous homocysteine (Hcy) stimulation markedly downregulated the mRNA and protein expression levels of IL­37 in PBMCs in vitro. In 293T cells, overexpression of IL­37 restored the cell viability impaired by Hcy, and reduced the release of lactate dehydrogenase and the proinflammatory cytokines IL­1ß, IL­6 and tumor necrosis factor­α. In conclusion, IL­37 was downregulated by Hcy in vivo and in vitro, and IL­37 exhibited a protective role against cell injury induced by Hcy.

Design, Synthesis, And Evaluation Of Cyanopyridines As Anti-Colorectal Cancer Agents Via Inhibiting STAT3 Pathway.

BACKGROUND: Colorectal cancer is one of the common malignant tumors. Cyanopyridine and aminocyanopyridine having a carbon-nitrogen bond have been shown to have significant anticancer effects. STAT3 is a promising therapeutic target in multiple cancers. However, there are currently no effective STAT3 inhibitors in clinical practice for the treatment of colorectal cancer. MATERIALS AND METHODS: We screened 27 cyanopyridines for their anticancer activity by cell viability. The HCT-116, RKO, and DLD-1 cell lines were used to evaluate the anti-colorectal cancer effect of 3n. Scratch experiments and colony formation assays were used for the assessment of cell migration and proliferation capacity. Phosphorylated STAT3, STAT3, MCL-1, and Survivin levels were assessed by Western blot analysis. RESULTS: In this study, we synthesized 27 cyanopyridines and screened their anticancer activities in three human tumor cells, HCT-116, Hela229, and A375. We found that 2-amino-3-cyanopyridine 3n has better anticancer activity with IC50 values in the low micromolar range. Furthermore, 3n significantly inhibited the migration and colony formation of colorectal cancer cells. Mechanistically, 3n inhibited the expression of STAT3 phosphorylation in a dose- and time-dependent manner. CONCLUSION: 3n is worth of further investigations toward the discovery of STAT3 inhibitor as a drug candidate for cancer therapy.

Rhein shows potent efficacy against non-small-cell lung cancer through inhibiting the STAT3 pathway.

BACKGROUND: Non-small-cell lung cancer (NSCLC) comprises about 85% of all lung cancers and is usually diagnosed at an advanced stage with poor prognosis. The IL-6/STAT3 signaling pathway plays a pivotal role in NSCLC biology. Rhein is a lipophilic anthraquinone extensively found in medicinal herbs. Emerging evidence suggests that Rhein has significant antitumor effects, supporting the potential uses of Rhein as an antitumor agent. METHODS: Cell viability and colony formation were performed to examine Rhein's potent anti-proliferative effect in human NSCLC cell lines PC-9, H460 and A549. Flow cytometry-based assay was employed to study whether Rhein could affect cell apoptosis and cycle. The expression level of P-STAT3, apoptosis and cycle-related proteins Bcl-2, Bax, MDM2, CDC2, P53 and CyclinB1 were detected by Western blotting. The xenograft models were used to evaluate the in vivo effect of Rhein. RESULTS: We found that Rhein could significantly reduce the viability and stimulate apoptosis in human NSCLC cells in a dose-dependent manner. Western blot analysis results suggested that the antitumor effect of Rhein might be mediated via STAT3 inhibition. Rhein upregulated the expression of the proapoptotic protein Bax and downregulated the expression of the antiapoptotic protein Bcl-2. In addition, Rhein induced the arrest of NSCLC cells in the G2/M phase of the cell cycle and dose dependently inhibited the expression of cycle-related proteins. The Rhein also inhibited tumor growth in H460 xenograft models. CONCLUSION: Rhein shows potent efficacy against NSCLC through inhibiting the STAT3 pathway. Our results also suggest that Rhein has a promising potential to be used as a novel antitumor agent for the treatment of NSCLC.