SNX16 is required for hepatocellular carcinoma survival via modulating the EGFR-AKT signaling pathway.

Sorting nexin 16 (SNX16), a pivotal sorting nexin, emerges in tumor progression complexity, fueling research interest. However, SNX16's biological impact and molecular underpinnings in hepatocellular carcinoma (HCC) remain elusive. This study probes SNX16's function, clinical relevance via mRNA, and protein expression in HCC. Overexpression/knockdown assays of SNX16 were employed to elucidate impacts on HCC cell invasion, proliferation, and EMT. Additionally, the study delved into SNX16's regulation of the EGFR-AKT signaling cascade mechanism. SNX16 overexpression in HCC correlates with poor patient survival; enhancing proliferation, migration, invasion, and tumorigenicity, while SNX16 knockdown suppresses these processes. SNX16 downregulation curbs phospho-EGFR, dampening AKT signaling. EGFR suppression counters SNX16-overexpression-induced HCC proliferation, motility, and invasiveness. Our findings delineate SNX16's regulatory role in HCC, implicating it as a prospective therapeutic target.

KLF4 Induces Colorectal Cancer by Promoting EMT via STAT3 Activation.

OBJECTIVE: Krüppel-like factor 4 (KLF4) has been demonstrated to exert a pro-carcinogenic effect in solid tissues. However, the precise biological function and underlying mechanisms in colorectal cancer (CRC) remains elucidated. AIMS: To investigate whether KLF4 participates in the proliferation and invasion of CRC. METHODS: The expression of KLF4 was investigated using immunohistochemistry and immunoblotting. The clinical significance of KLF4 was evaluated. Furthermore, the effect of inhibiting or overexpressing KLF4 on tumor was examined. Immunoblotting and qPCR were used to detect Epithelial-mesenchymal transition-related proteins levels. Additionally, the molecular function of KLF4 is related to the STAT3 signaling pathway and was determined through JASPAR, GSEA analysis, and in vitro experiments. RESULTS: KLF4 exhibits down-regulated expression in CRC and is part of the vessel invasion, TNM stage, and worse prognosis. In vitro studies have shown that KLF4 promotes cellular proliferation and invasion, as well as EMT processes. Xenograft tumor models confirmed the oncogenic role of KLF4 in nude mice. Furthermore, GSEA and JASPAR databases analysis reveal that the binding of KLF4 to the signal transducer and activator of transcription 3 (STAT3) promoter site induces activation of p-STAT3 signaling. Subsequent targeting of STAT3 confirmed its pivotal role in mediating the oncogenic effects exerted by KLF4. CONCLUSION: The study suggests that KLF4 activates STAT3 signaling, inducing epithelial-mesenchymal transition, thereby promoting CRC progression.

Synthesis and anti-tumor activity of asiatic acid derivatives targeting VEGFR.

To discovery novel VEGFR inhibitors, 12 novel asiatic acid derivatives were designed by computer-aided drug design (CADD) technology. Then, these novel asiatic acid derivatives were synthesized by introducing active groups at ring A and C-28 positions of asiatic acid. The structures of these novel analogues were confirmed by NMR and MS. Moreover, the anti-tumor activities of these novel asiatic acid derivatives on human hepatoma cells HepG2 and human gastric cancer cells SGC7901 were evaluated by MTT assay. As a result, compounds I2 and II4 showed stronger cytotoxicity on tumor cells than asiatic acid and positive control drugs such as gefitinib and paclitaxel. In conclusion, our study synthesized twelve novel asiatic acid derivatives and determined compounds I2 and II4 had better anti-tumor effect which may be potential candidate compounds for tumor therapy.

Design, synthesis and anti-tumor activity of asiatic acid derivatives as VEGF inhibitors.

The VEGF receptor is mock-coupled with a known active compound and the active groups of the inhibitor which can bind to VEGF were analyzed. Using asiatic acid as a lead compound, 10 novel skeleton candidate compounds were designed through introduction of the active groups onto the special location and synthesized simultaneously. Furthermore, the structure of these compounds was determined by 1H NMR, 13C NMR and MS and 9 compounds were identified as the new compounds. Moreover, the in vitro anti-tumor activities of these new compounds were determined by MTT assay on two cancer cell lines (HepG2 and SGC-7901). The results showed that compounds I1 and II2 have more potent anticancer activity than positive control drugs such as gefitinib and paclitaxel.

Design, synthesis and bioactivities evaluation of novel oleanolic acid derivatives as potent PI3K inhibitors.

Oleanolic acid has previously been shown to possess PI3K inhibitory activity, thus, the purpose of this work was to generate a series of derivatives that improve the potency. Twenty rationally designed oleanolic acid derivatives were synthesized and tested the cytotoxicity and PI3K inhibitory activity. The results suggested that attachment of additional structural elements such as association of thiazole group to A ring and insertion of phenylurea group was important for increasing activities. The most active derivative was compound II2, which exhibited PI3K inhibitory activity (IC50 = 58.42 nmol/l) and improved interaction with activity site of PI3K according with docking studies.

Discovery of Potent Glucokinase and PPARγ Dual-Target Agonists through an Innovative Scheme for Regioselective Modification of Silybin.

Glucokinase (GK) and PPARγ are important targets for antidiabetic use. Silybin is one of the major active ingredients of Silybum marianum. The regioselective modification of the five hydroxyl groups in the silybin structure has always been a challenge. In this study, we found that silybin was an agonist of GK and PPARγ. A novel synthesis scheme of silybin derivatives was designed, and a series of novel silybin derivatives has been synthesized. The derivative 8d showed relatively strong activation activity for GK and PPARγ in enzyme activity and transactivation assays (GK activation fold: 1.86; PPARγ transactivation activation percentage: 90.32%). This research suggests that silybin and its derivatives could be used as novel GK and PPARγ dual-target agonists.

Upregulated lncRNA DLX6-AS1 underpins hepatocellular carcinoma progression via the miR-513c/Cul4A/ANXA10 axis.

Recent studies have illustrated the role of aberrant regulatory interactions in the mediation of malignant phenotypes of cancer cells, which could potentially provide novel therapeutic targets to limit the destructive recurrence and metastasis of hepatocellular carcinoma (HCC). Herein, we clarify the oncogenic role of the long noncoding RNA (lncRNA) distal-less homeobox 6 antisense 1 (DLX6-AS1) in HCC in vivo and in vitro. To this end, we knocked down lncRNA DLX6-AS1 and manipulated the expression of miR-513c to characterize their effects in HCC cell viability, migration, invasion, and apoptosis. Furthermore, we probed the interactions with miR-513c's target gene Cullin4A (Cul4A) and the degradation of Annexin A10 (ANXA10) protein. Our data show that lncRNA DLX6-AS1 and Cul4A were highly expressed, while miR-513c and ANXA10 were poorly expressed in HCC tissues and cells. Moreover, the silencing of lncRNA DLX6-AS1 impeded the viability, invasion, and migration of HCC cells, while stimulating cell apoptosis. Further data indicated that lncRNA DLX6-AS1 targeted and repressed miR-513c expression, where the tumor-inhibiting effects of lncRNA DLX6-AS1 silencing was achieved by elevating miR-513c expression. Importantly, the lncRNA DLX6-AS1 upregulated the expression of Cul4A through sponging of miR-513c. The silencing of Cul4A restricted the malignant phenotypes of HCC cells by repressing the ubiquitination-mediated degradation of ANXA10. In vivo experiments verified that lncRNA DLX6-AS1 promoted the progression of HCC through the miR-513c/Cul4A/ANXA10 axis. Thus, the silencing of lncRNA DLX6-AS1 impaired miR-513c-dependent Cul4A inhibition and subsequently elevated ubiquitination-mediated degradation of ANXA10, thereby preventing the occurrence and development of HCC.

Design and synthesis of VEGFR-2 inhibitors based on oleanolic acid moiety.

In this study, twenty-four oleanolic acid (OA) derivatives were rationally designed based on molecule docking studies and their VEGFR-2 inhibitory activities were tested by Homogeneous time-resolved fluorescence (HTRF) method in vitro. All of the synthesized compounds were identified as new compounds, and the structures of these compounds were determined by 1H-NMR and ESI-MS. In the screening for VEGFR-2 inhibitors, compounds I6 and I7 exhibited excellent inhibitory effect. The results indicated that insertion of phenylurea group with a linker at position C-28 of OA can increase the activity against VEGFR-2 significantly. [Formula: see text].

Synthesis of oleanolic acid analogues targeting PDGF receptor inhibitors and their antitumor biological activities.

The PDGF receptor is mock-coupled with a known active compound, and 14 novel skeleton candidate compounds were designed and synthesized. The structure was confirmed by 1H NMR, 13C NMR and MS. The in vitro cytotoxicity of the two cancer cell lines (SGC-7901 and A549) was evaluated by MTT assay. PDGF receptor protein inhibition assays were performed on I6 and II4 using fluorescence polarization immunoassay (FPIA). [Formula: see text].

Synthesis and antitumor activity evaluation of ursolic acid derivatives.

Eighteen uronic acid derivatives were designed and synthesized, and the cytotoxicities in vitro of two cancer cell lines (BEL7402 and SGC7901) were evaluated by MTT assay. The results showed that the inhibitory rate of the compounds on both cell lines was significantly higher than the parent compound. The IC50 of compounds II4, II6, III4, and III6 are comparable or stronger than the positive control drug, the interactions between compounds II4, II6, III4, III6, and NF-κB were also studied by docking simulations.

Synthesis and anti-tumor activity of derivatives of ring A of asiatic acid.

Based on the simulation of the docking of survivin protein with known small molecule inhibitors, the active groups which can bind to target proteins were analyzed by the techniques of computer-aided drug design (CADD). These active groups were introduced into the A-ring of asiatic acid and their C-28 sites were reconstructed simultaneously. Ten asiatic acid derivatives were designed and synthesized, and their structures were confirmed by MS and NMR. The inhibitory activities of the asiatic acid derivatives against HepG2 and SGC7901 cell lines were evaluated and confirmed by the tetrazolium bromidesalt (MTT) assay. The results showed that compounds I6 and II4 exhibited more potent cytotoxicity than the positive control drug gefitinib, which was comparable to that of adriamycin.[Formula: see text].

The association between digit ratio (2D:4D) and blood pressure among children and adolescents.

Digit ratio (2D:4D) is a biomarker of prenatal hormone exposure levels; this biomarker is negatively related to prenatal androgen exposure and positively related to prenatal estrogen exposure. We investigated the correlation between digit ratio (2D:4D) and blood pressure. A school-based survey of 687 adolescents aged 8-15 years was conducted. The ring finger (4D) and index finger (2D), systolic blood pressure (SBP), diastolic blood pressure (DBP), testosterone, and estradiol levels were measured. Their dietary behaviors and physical and sedentary activity time were surveyed. The results showed the 2D:4D ratio was not significantly related to SBP, DBP, or testosterone in boys and girls. However, it was significantly positively correlated with serum estradiol levels in boys. The 2D, 4D, multiplied index of digit ratio and length (MIDRL) and average of the index finger and ring finger (AIR) were directly related to SBP in both sexes (ßs in boys were 4.16, 5.49, 2.95, and 5.25, respectively, P < 0.01; ßs in girls were 3.43, 2.71, 3.02, and 3.36, respectively, P < 0.01) and were also indirectly associated with SBP through testosterone (P < 0.05). The 2D, 4D and AIR were indirectly related to DBP in girls through testosterone (P < 0.05). In conclusion, there were direct and indirect associations between finger-length indicators and blood pressure, which implies that prenatal hormone levels might be correlated with blood pressure in children and adolescents.

The associations between left-hand digit ratio (2D:4D) and puberty characteristics among Chinese girls.

BACKGROUND: The aim of this study was to analyse the associations of left-hand digit ratio (2D:4D), digit length and puberty characteristics to show the role of prenatal hormones in development among Chinese girls. METHOD: A total of 318 Chinese girls aged 8-15 years were recruited using a stratified cluster sampling method. The index finger (2D), ring finger (4D) of the left hand, oestradiol and testosterone were measured, and age at menarche (AAM), breast (high and low) and pubic hair (high and low) development were recorded. RESULTS: Girls who had experienced menarche had longer left digits (2D and 4D) and higher oestradiol, testosterone than those who had not. The high breast group had longer digits (2D and 4D), and higher oestradiol than the low breast group. With regard to pubic hair development, the high group had high 2D:4D, longer 2D and higher oestradiol, testosterone than the low group. After adjusting for oestradiol and testosterone, 4D length was positively related to occurrence of menarche. In addition, 2D and 2D:4D were significantly correlated with pubic hair development after adjusting for oestradiol, respectively. CONCLUSION: Prenatal hormone level may be related to the development of puberty characteristics among Chinese girls.

Construction of TiO2 Nanotubes/C/MnO2 Composite Films as a Binder-Free Electrode for a High-Performance Supercapacitor.

Although titanium dioxide (TiO2) exhibits excellent promise in electrode materials for supercapacitors, its poor conductivity and low areal specific capacitance hamper further development. In this work, we have designed a clever way to deposit manganese dioxide (MnO2) in order to improve its electrochemical performance via a facile and typical hydrothermal method. In a hydrothermal process, carbon (C), which deposited via new gas thermal penetration, acts as a reducing agent, while a potassium permanganate (KMnO4) solution acts as an oxidant. In this way, MnO2, which has a high theoretical capacity, is generated on TiO2 nanotube arrays (denoted as TNTs) successfully. Remarkably, a TNTs/C/MnO2 film prepared at a hydrothermal temperature of 90 °C and 0.3 g of KMnO4 revealed a superior electrochemical property with 55 mF/cm2 areal capacitance at a scan rate of 5 mV/s, 23 times more enhanced than that of a TNTs/C film. Also, the energy density of a TNTs/C/MnO2 film reached 46.8 Wh/cm2 when the power density was 0.12 mW/cm2, and the energy density still remained at 22.4 Wh/cm2 at a high power density of 0.8 mW/cm2. After 1000 cycle tests, 93.2% capacitance was still retained, indicating excellent reversibility and cycle stability of TNTs/C/MnO2 electrode. This work opens up a facile path for efficient growth of electrode materials with high performance for energy storage devices.

Design, synthesis, and antitumor activity of oleanolic acid derivatives.

Using the techniques of computer-aided drug design, the docking of survivin and known active small molecules was simulated and then the key amino acid residue fragments of the target protein were analyzed. It led to the discovery of active groups capable of binding to the critical sites. Through the use of the natural product, oleanolic acid, as a lead compound, the introduction of the active groups onto the A-ring, and the modification of the carboxyl group at the C-28 position using esterification or amidation, 20 new oleanolic acid derivatives had been designed and synthesized. HepG2 and SGC-7901 cells were used to screen the antitumor activity through the standard MTT method. The compounds, II3, III5 and IV4, exhibited more potent cytotoxicity than positive drugs. Western blot experiment demonstrated that compound II3 can effectively inhibit the proliferation of HepG2 cells.

Computational investigation of TGF-ß receptor inhibitors for treatment of idiopathic pulmonary fibrosis: Field-based QSAR model and molecular dynamics simulation.

The discovery of drugs relevant to transforming growth factor ß (TGF-ß) receptor inhibitors have been considered as a considerable challenge during therapy idiopathic pulmonary fibrosis diseases. For the first time, herein we illustrate a field-based quantitative structure-activity relationship (QSAR) model and molecular dynamics (MD) simulations for novel 7-substituted-pyrazolo [4, 3-b] pyridine derivatives with biological activity for the TGF-ß receptor, with an attempt of elucidating the 3D structural features that are essential for the activity. Results demonstrate that the field-based model (Q2 = 0.548, R2training = 0.840, R2test = 0.750) are acceptable with good predictive capabilities. In addition, MD studies were also carried out on the training set with the aim of exploring their binding modes in the active pocket of TGF-ß receptor, resulting in some of the crucial structural fragments which are responsible for inhibitory activity. Therefore, we summarized the following features required for TGF-ß receptor inhibition: electronegative in region1, bulky groups in region2 and smaller groups in region3. Based on the model and related information, we hope the above information provides an important insight for understanding the interactions of the inhibitors and TGF-ß receptor, which may be useful in discovering novel potent inhibitors.

[Association of aggressive behavior with separation from parents and social anxiety in grade four to six of rural senior primary school students in Anhui Province in 2014].

OBJECTIVE: To explore the relationship between separation from parents and social anxiety with aggressive behaviors, to provide scientific basis for the prevention of aggression. METHODS: Stratified random sampling was used to collect 1126 students ofthe fourth, fifth and sixth grade from three primary schools in Dangshan County and two primary schools in Guzhen County. The incomplete or incorrect questionnaires were eliminated, and 1024 questionnaires were valid; the effective rate was 90. 9%. The questionnaire survey included the left-behind children's general situation and the separation from parents; the aggression questionnaire was used to detect the aggression of students; the social anxiety scale for children was used to detect the social anxiety of students. The multiple linear regression was used to analyze the relationship between the risk factor and the aggressive behavior. RESULTS: There were no significant difference of AQ score and other factor score among students in different grade( P > 0. 05), the AQ score and other factor score were higher in boy students( P < 0. 05). The AQ score and other factor score of the left-behind children were higher than the children who lived with their parents, the AQ score and other factor score of the children whose parents all out were highest( 71. 5 ± 20. 5, 14. 9 ± 6. 1, 12. 6 ± 3. 2, 17. 6 ± 5. 8, 11. 7 ± 4. 3 and15. 4 ± 5. 4), there were significant difference of AQ score and PHY and IND factor score between them( P < 0. 05). The children whose parents go out one year ago, whose parents don't go home in one year, and who hardly contact parents, these children' AQ score and each factor points are the highest. Multiple linear regression showed that sex, the situation of parents go out to work, the number of parents go back to home every year, the frequency of parent-child links and children's social society influenced the aggressive behavior of students( P < 0. 05). CONCLUSION: The lower the frequency of parental contact, the longer time to work and the higher the social anxiety score of children, the more serious the attack behavior of left-behind children.

The association between digit ratio (2D:4D) and the first spermatorrhea among Chinese boys.

BACKGROUND: The second-to-fourth digit ratio (2D:4D) is a marker of prenatal hormone exposure, which is negatively correlated with prenatal androgen and positively correlated with prenatal estrogen. The study was to analyze the association between 2D:4D and the first spermatorrhea to indirectly show the possible role of prenatal hormone during puberty development among boys. METHOD: The total of 367 boys aged 8-15 years were enrolled by using the stratified cluster sampling method. The variables of index finger (2D), ring finger (4D), height, weight, waist circumference (WC), skinfold thickness, testosterone and estradiol were measured, and the age at the first spermatorrhea was surveyed. RESULTS: The average age at the first spermatorrhea was 12.15 years. The 2D:4D was not related to first spermatorrhea, circulating testosterone in boys (P > 0.05), however, was positively correlated with circulating estradiol (P < 0.05). The direct association (OR value) between 4D, average of index finger and ring finger (AIR) and first spermatorrhea were 2.79 and 2.29, and the mediating effect (OR value) of which were 1.95 and 2.01 by testosterone, accounting for 41.18% and 46.73% of the total effect, respectively. The 2D, MIDRL, lean body mass (LBM) were indirectly related to first spermatorrhea by testosterone, the mediating effects (OR value) were 2.11, 1.71 and 2.41, respectively. CONCLUSION: The prenatal androgen exposure may be directly and indirectly related to first spermatorrhea. In addition, the high prenatal estrogen exposure may be indirectly associated with first spermatorrhea by testosterone.

Synthesis and antitumor activity evaluation of asiatic acid derivatives as survivin inhibitor.

A series of asiatic acid derivatives were synthesized and their cytotoxicities in vitro against two cancer cell lines (HepG2 and SGC7901) were evaluated by MTT assay. The results showed that compounds I2, I6, and II6 have more potent anticancer activity than that of the positive control drug paclitaxel. The interactions between the compounds I2, I6, and II6 and survivin were also studied by docking simulations.

Synthesis and antitumor activity evaluation of novel oleanolic acid derivatives.

Ten novel oleanolic acid (OA) derivatives were synthesized through modifications at positions of A ring and C-28. Inhibitory activities of the oleanolic acid derivatives against SGC7901 and A549 cell lines were evaluated and confirmed by the tetrazolium bromidesalt (MTT) assay. The lab results revealed that all these compounds displayed some antitumor activity against SGC-7901 and A-549 cell lines. Among them, II4 and II5 exhibited excellent antitumor activities against SGC7901 cells and A549 cells, compared with gefitinib. Molecular docking studies have shown that compounds II4 and II5 produce potent antitumor activities by interacting with C-kit receptor through hydrogen bonds and hydrophobic bonds.