Retinol binding protein 4 and type 2 diabetes: from insulin resistance to pancreatic ß-cell function.

BACKGROUND AND AIM: Retinol binding protein 4 (RBP4) is an adipokine that has been explored as a key biomarker of type 2 diabetes mellitus (T2DM) in recent years. Researchers have conducted a series of experiments to understand the interplay between RBP4 and T2DM, including its role in insulin resistance and pancreatic ß-cell function. The results of these studies indicate that RBP4 has a significant influence on T2DM and is considered a potential biomarker of T2DM. However, there have also been some controversies about the relationship between RBP4 levels and T2DM. In this review, we update and summarize recent studies focused on the relationship between RBP4 and T2DM and its role in insulin resistance and pancreatic ß-cell function to clarify the existing controversy and provide evidence for future studies. We also assessed the potential therapeutic applications of RBP4 in treating T2DM. METHODS: A narrative review. RESULTS: Overall, there were significant associations between RBP4 levels, insulin resistance, pancreatic ß-cell function, and T2DM. CONCLUSIONS: More mechanistic studies are needed to determine the role of RBP4 in the onset of T2DM, especially in terms of pancreatic ß-cell function. In addition, further studies are required to evaluate the effects of drug intervention, lifestyle intervention, and bariatric surgery on RBP4 levels to control T2DM and the role of reducing RBP4 levels in improving insulin sensitivity and pancreatic ß-cell function.

Differences in pulmonary nodular consolidation and pulmonary cavity among drug-sensitive, rifampicin-resistant and multi-drug resistant tuberculosis patients: the Guangzhou computerized tomography study.

Background: Pulmonary nodular consolidation (PN) and pulmonary cavity (PC) may represent the two most promising imaging signs in differentiating multidrug-resistant (MDR)-pulmonary tuberculosis (PTB) from drug-sensitive (DS)-PTB. However, there have been concerns that literature described radiological feature differences between DS-PTB and MDR-PTB were confounded by that MDR-PTB cases tend to have a longer history. This study seeks to further clarify this point. Methods: All cases were from the Guangzhou Chest Hospital, Guangzhou, China. We retrieved data of consecutive new MDR cases [n=46, inclusive of rifampicin-resistant (RR) cases] treated during the period of July 2020 and December 2021, and according to the electronic case archiving system records, the main PTB-related symptoms/signs history was ≤3 months till the first computed tomography (CT) scan in Guangzhou Chest Hospital was taken. To pair the MDR-PTB cases with assumed equal disease history length, we additionally retrieved data of 46 cases of DS-PTB patients. Twenty-two of the DS patients and 30 of the MDR patients were from rural communities. The first CT in Guangzhou Chest Hospital was analysed in this study. When the CT was taken, most cases had anti-TB drug treatment for less than 2 weeks, and none had been treated for more than 3 weeks. Results: Apparent CT signs associated with chronicity were noted in 10 cases in the DS group (10/46) and 9 cases in the MDR group (10/46). Thus, the overall disease history would have been longer than the assumed <3 months. Still, the history length difference between DS patients and MDR patients in the current study might not be substantial. The lung volume involvement was 11.3%±8.3% for DS cases and 8.4%±6.6% for MDR cases (P=0.022). There was no statistical difference between DS cases and MDR cases both in PN prevalence and in PC prevalence. For positive cases, MDR cases had more PN number (mean of positive cases: 2.63 vs. 2.28, P=0.38) and PC number (mean of positive cases: 2.14 vs. 1.38, P=0.001) than DS cases. Receiver operating characteristic curve analysis shows, PN ≥4 and PC ≥3 had a specificity of 86% (sensitivity 25%) and 93% (sensitivity 36%), respectively, in suggesting the patient being a MDR cases. Conclusions: A combination of PN and PC features allows statistical separation of DS and MDR cases.

Pulmonary blastoma treatment response to anti-PD-1 therapy: a rare case report and literature review.

Pulmonary blastoma (PB) is a rare and invasive malignancy of the lungs with a poor prognosis. Although the mainstay treatment of PB is surgery, and radiotherapy and chemotherapy have been reported, no standard therapy exists for patients inoperable in advanced stages. Moreover, little is known about driver mutation status and immunotherapy efficacy. This paper presents a male patient diagnosed with classic biphasic PB using CT-guided lung biopsy pathology and immunohistochemistry. The patient's symptoms included cough, chest pain, shortness of breath, hemoptysis, and hypodynamia. The primary focus of this paper is to discuss the impact of anti-PD-1 immunotherapy on PB. The patient experienced progression-free survival (PFS) of over 27 months following sintilimab second-line anti-PD-1 therapy. The patient has currently survived for nearly 40 months with a satisfactory quality of life.

Recent advances in the development of dual ALK/ROS1 inhibitors for non-small cell lung cancer therapy.

As a member of the insulin-receptor superfamily, ALK plays an important role in regulating the growth, proliferation, and survival of cells. ROS1 is highly homologous with ALK, and can also regulate normal physiological activities of cells. The overexpression of both is closely related to the development and metastasis of tumors. Therefore, ALK and ROS1 may serve as important therapeutic targets in non-small cell lung cancer (NSCLC). Clinically, many ALK inhibitors have shown powerful therapeutic efficacy in ALK and ROS1-positive NSCLC patients. However, after some time, patients inevitably develop drug resistance, leading to treatment failure. There are no significant drug breakthroughs in solving the problem of drug-resistant mutations. In this review, we summarize the chemical structural features of several novel dual ALK/ROS1 inhibitors, their inhibitory effect on ALK and ROS1 kinases, and future treatment strategies for patients with ALK and ROS1 inhibitor-resistant mutations.

Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives as novel EGFRL858R/T790M inhibitors.

EGFR mutations have been identified in 20,000 reported NSCLC (non-small cell lung cancer) samples, and exon 19 deletions and L858R mutations at position 21, known as "classical" mutations, account for 85-90% of the total EGFR (epidermal growth factor receptor) mutations. In this paper, two series of EGFR kinase inhibitors were designed and synthesised. Among them, compound B1 showed an IC50 value of 13 nM for kinase inhibitory activity against EGFRL858R/T790M and more than 76-fold selectivity for EGFRWT. Furthermore, in an in vitro anti-tumour activity test, compound B1 showed an effective anti-proliferation activity against H1975 cells with an IC50 value of 0.087 µΜ. We also verified the mechanism of action of compound B1 as a selective inhibitor of EGFRL858R/T790M by cell migration assay and apoptosis assay.

High prevalence of vitamin D deficiency in Asia: A systematic review and meta-analysis.

Vitamin D deficiency is a worldwide health problem. However, the prevalence of vitamin D deficiency in Asian populations is unclear. The aims of our study were to investigate the prevalence of vitamin D deficiency and its association with different health outcomes in Asia. Searches for studies published from January 2009 to January 2021 were performed in the MEDLINE (via PubMed), EMBASE, and Web of Science databases. This study was registered in the PROSPERO database (CRD42021229841). In total, 472 studies with 746,564 subjects were included in the meta-analysis. The mean serum 25-hydroxyvitamin D (25[OH]D) concentration was 49.39 nmol/L; 20.93% of the participants had 25(OH)D levels <25 nmol/L, 22.82% had levels <30 nmol/L, 57.69% had levels <50 nmol/L, and 76.85% had levels <75 nmol/L. This review found that the prevalence of vitamin D deficiency in Asia is high. The factors significantly related to vitamin D deficiency were gender, age, altitude, region, and specific diseases (diabetes, cancer, fracture, systemic lupus erythematosus [SLE], fatty liver disease, osteopenia, thyroiditis, anemia, hepatitis, metabolic diseases, and dermatitis). These findings may serve as the foundation for more detailed public health strategies and policies on this issue.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.1990850.

LncRNA LINC00961 regulates endothelial­mesenchymal transition via the PTEN­PI3K­AKT pathway.

The long noncoding RNA LINC00961 plays a crucial role in cancer and cardiovascular diseases. In the present study, the role and underlying mechanism of LINC00961 in endothelial­mesenchymal transition (EndMT) induced by transforming growth factor beta (TGF­ß), was investigated. Human cardiac microvascular endothelial cells were transfected with LV­LINC00961 or short hairpin LINC00961 plasmids to overexpress or knock down LINC00961 in the cells, respectively. The cells were then exposed to TGF­ß in serum­free medium for 48 h to induce EndMT. Flow cytometric analysis, Cell Counting Kit­8 assay and immunofluorescence staining were performed to examine the cell apoptosis rate, assess cell viability, and identify CD31+/α­SMA+ double­positive cells, respectively. Western blotting and reverse transcription­ quantitative polymerase chain reaction were used to evaluate protein and mRNA expression, respectively. Injury to endothelial cells and EndMT was induced by TGF­ß in a time­dependent manner. LINC00961 overexpression promoted injury and EndMT, whereas LINC00961 knockdown had the opposite effects. Knockdown of LINC00961 attenuated EndMT and injury to endothelial cells induced by TGF­ß via the PTEN­PI3K­AKT pathway. Inhibition of LINC00961 expression may prevent the occurrence of EndMT­related cardiovascular diseases, such as myocardial fibrosis and heart failure. Therefore, LINC00961 shows potential as a therapeutic target for cardiovascular diseases.

Systematic review and meta-analysis: association between obesity/overweight and surgical complications in IBD.

PURPOSE: While the prevalence of obesity in inflammatory bowel disease (IBD) patients is rapidly increasing, it is unclear whether obesity affects surgical outcomes in this population. This meta-analysis aims to assess the impact of obesity/overweight on patients undergoing surgery for IBD. METHODS: Databases (PubMed, Web of Science, Cochrane Library, and Springer) were searched through September 2021. The meta-analysis included patients with surgically treated IBD to investigate the impact of obesity/overweight on this population. Primary outcomes included overall complications, infectious complications, noninfectious complications, and conversion to laparotomy. RESULTS: Fifteen studies totaling 12,622 IBD patients were enrolled. Compared with nonobese (including overweight) patients, obese IBD patients have increased the risk in terms of overall complications (OR = 1.45, p < 0.001), infectious complications (OR = 1.48, p = 0.003) (especially wound complications), as well as conversion to laparotomy (OR = 1.90, p < 0.001). Among the noninfectious complications, only the incidence of visceral injury (OR = 2.36, p = 0.05) had significantly increased. Compared with non-overweight patients, the risk of developing wound complications (OR = 1.65, p = 0.01) and sepsis (OR = 1.73, p = 0.007) were increased in overweight patients, but the rates of overall complications (OR = 1.04, p = 0.81), infectious complications (OR = 1.31, p = 0.07), and conversion to laparotomy (OR = 1.33, p = 0.08) associated with body mass index (BMI) were not significantly different. CONCLUSION: Obesity is a risk factor for surgical complications in IBD patients, mainly reflected in infectious complications. Moreover, obese patients seem to have a more common chance of developing surgical complications than overweight patients.

Prevalence of and factors associated with maxillary sinus cyst in a Chinese population.

PURPOSE: This study used cone-beam computed tomography (CBCT) to assess the prevalence of and factors associated with maxillary sinus cysts (MSCs) in a Chinese population. METHODS: A total of 2,571 CBCT scans of 5,000 sinuses were analyzed. MSCs were diagnosed on the basis of imaging features within the maxillary sinus. Sex, age, dental condition, and anatomic condition were assessed. Associations with these factors were evaluated with logistic regression and a generalized estimating equations model. RESULTS: The prevalence of MSCs was 15.46% at the sinus level and 23.44% at the patient level. The prevalence of MSCs was higher for men (OR = 1.864, P < 0.001) and for patients with apical lesions (OR = 1.76, P < 0.001), severe bone loss (OR = 1.363, P < 0.05), tooth roots in contact with the sinus floor (OR = 1.68, P < 0.001), and pits or septa on the floor of the maxillary sinus (OR = 1.539, P < 0.001). CONCLUSION: This large sample had a high prevalence of MSCs. MSC prevalence was associated with multiple factors, including sex, dental condition, and anatomic condition. Maintenance of healthy dental and periodontal status might help prevent MSCs.

Effect of mesenchymal-epithelial transition amplification on immune microenvironment and efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have brought clinical benefits to patients with various histological types of lung cancer. Previous studies have shown an association between mesenchymal-epithelial transition (MET) and the immunotherapy response in non-small cell lung cancer (NSCLC) but there is a lack of clinical data on the correlation of MET amplification with the ICI response in NSCLC. METHODS: Copy number alteration (CNA), somatic mutation, and clinical data from two immunotherapy cohorts (Rizvi et al. cohort and our local cohort) were collected and pooled to further investigate the key role of MET amplification in patients with NSCLC receiving ICIs. The correlations between MET amplification and tumor immunogenicity and antitumor immunity were further investigated in The Cancer Genome Atlas (TCGA)-NSCLC [lung adenocarcinoma (LUAD)/lung squamous cell carcinoma (LUSC)] data-set. RESULTS: In the immunotherapy cohorts, MET amplification was associated with longer progression-free survival (PFS) times in patients receiving ICI treatment (P=0.039; HR =0.37; 95% CI: 0.18-0.73). In the TCGA-NSCLC data-set, MET amplification was associated with high MET mRNA and protein levels, tumor mutation burden (TMB), neoantigen load (NAL), immune-activated cell patterns, immune-related gene expression levels, and the number of gene alterations in the DNA damage response and repair (DDR) pathway. Gene set enrichment analysis (GSEA) results indicated significant up-regulation of the immune response-related pathways in the MET-amplification group. CONCLUSIONS: Our results suggest that MET amplification may be a novel predictive marker for immunotherapy efficacy in NSCLC.

GSK-3ß Inhibitors Attenuate the PM2.5-Induced Inflammatory Response in Bronchial Epithelial Cells.

BACKGROUND AND PURPOSE: PM2.5-associated airway inflammation has recently been recognized as pivotal to the development of COPD. Aberrant glycogen synthase kinase (GSK)-3ß signaling is linked to the inflammatory response. Therefore, we investigated the effects of GSK-3ß inhibitors on the PM2.5-induced inflammatory response in bronchial epithelial cells. METHODS: The production of phosphorylated GSK-3ß (p-GSK-3ß) was analyzed by immunohistochemistry with PM2.5-induced mice. HBECs were treated with various inhibitors targeting GSK-3ß or JNK before PM2.5 stimulation. The production of GSK-3ß signaling was analyzed by Western blotting. Inflammatory cytokine production was detected by qRT-PCR and ELISA. RESULTS: PM2.5 exposure caused lung inflammation, upregulated serum concentrations of HMGB1 and IL-6, decreased IL-10 expression, and significantly attenuated p-GSK-3ß production in mice. HBECs exposed to PM2.5 showed significantly reduced p-GSK-3ß production, an increased ratio of p-JNK/JNK, increased NF-κB activation and IκB degradation, and upregulated the inflammatory cytokines HMGB1 and IL-6. Intervention with GSK-3ß inhibitors TDZD-8 and SB216763 significantly suppressed PM2.5-induced outcomes. Moreover, the JNK inhibitor SP600125 also reduced the level of NF-κB phosphorylation induced by PM2.5. The differences in the levels of inflammation-related cytokines in the TDZD-8 groups were greater than those in the SB216763 groups. CONCLUSION: Inhibition of GSK-3ß weakens the PM2.5-induced inflammatory response by regulating the JNK/NF-κB signaling pathway in bronchial epithelial cells.

Concomitant Pulmonary Tuberculosis Impair Survival in Advanced Epidermal Growth Factor Receptor (EGFR) Mutant Lung Adenocarcinoma Patients Receiving EGFR-Tyrosine Kinase Inhibitor.

OBJECTIVE: Limited studies have clearly demonstrated the effect of EGFR-TKI in the treatment of EGFR mutant NSCLC patients with underlying pulmonary disease, like pulmonary tuberculosis (PTB). Here, we conducted the study to evaluate the impact of PTB on survival of Chinese EGFR mutant lung adenocarcinoma (LUAD) patients that underwent EGFR-TKI treatment. METHODS: Clinicopathologic data of 1448 LUAD patients harboring EGFR mutations from the Guangzhou Chest Hospital between 2017 and 2019 were reviewed retrospectively. Patients receiving EGFR-TKI treatment were divided into PTB and non-PTB groups. The differences in response to EGFR-TKIs and survival between the two groups were assessed. RESULTS: After EGFR-TKIs treatment, the objective response rate (58.14% vs 47.62%) as well as disease control rate (97.67% vs 85.71%) were higher in the non-PTB group than in the PTB group, but there was no statistical difference. In the survival analysis, both the median progression-free survival (7.47 months vs 11.77 months, p = 0.038) and the overall survival (13.00 months vs 20.00 months, p = 0.001) were significantly shorter in the PTB group than in the non-PTB group. Furthermore, for patients with 19Del mutation, or metastases sites less than 3, or using first-line EGFR-TKI, EGFR-TKIs treatment significantly prolonged the median PFS and OS in patients without PTB. CONCLUSION: LUAD patients with concomitant PTB have a poor response to EGFR-TKI treatment, especially in terms of survival outcome.

Design, synthesis and biological evaluation of aminopyrimidine derivatives bearing a 4,5,6,7-tetrahydrothieno [3,2-c]pyridine as potent EGFR inhibitors.

To resolve the problem of drug resistance caused by epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer, we used the principle of collocation to design and synthesize a series of aminopyrimidine derivatives with 4,5,6,7-tetrahydrothieno [3,2-c]pyridine side chains (according to the binding mode of AZD9291 to EGFRT790M) for use as EGFRL858R/T790M kinase inhibitors. The most promising compound A12, a non-covalently bound reversible inhibitor, showed excellent kinase inhibitory activity against EGFRL858R/T790M, with an IC50 value of 4.0 nM and more than 42-fold selectivity for EGFRWT (IC50 = 170.0 nM). Moreover, compound A12 showed strong anti-proliferative activity against H1975 cells, with IC50 value of 0.086 µΜ. Additionally, the effective inhibition of cell migration and the promotion of apoptosis by A12 verified its mechanism of action, as a selective inhibitor of EGFRL858R/T790M.

miR-3188 Regulates proliferation and apoptosis of granulosa cells by targeting KCNA5 in the polycystic ovary syndrome.

Abnormal proliferation of granulosa cells is implicated in ovarian dysfunction and dysregulated folliculogenesis in the polycystic ovary syndrome (PCOS). Aberrant microRNA (miRNA) expression might contribute to disordered folliculogenesis and granulosa cell proliferation in PCOS. This study aimed to investigate the roles of miR-3188 in ovarian dysfunction, as well as the mechanism involved in granulosa cell proliferation in PCOS. Firstly, peripheral blood samples were isolated from PCOS patients and healthy controls, and qRT-PCR analysis demonstrated a dramatic increase in miR-3188 in PCOS patients when compared to the healthy controls. Secondly, miR-3188 overexpression increased cell viability of the granulosa-like tumor cell line (KGN). However, cell viability of KGN was repressed by interference with miR-3188. MiR-3188 promoted cell cycle of KGN through increasing cyclinD1 and decreasing p21 levels. Moreover, cell apoptosis was suppressed by miR-3188 in KGN, indicated by enhanced Bcl-2, and reduced Bax and cleaved caspase-3 levels, whereas knockdown of miR-3188 resulted in opposite effects. Lastly, potassium voltage-gated channel subfamily A member 5 (KCNA5) was verified as a target of miR-3188. KCNA5 expression was decreased and displayed negative correlation with miR-3188 levels in PCOS patients. Overexpression of KCNA5 attenuated the promotive effects of miR-3188 on cell viability and cell cycle in KGN. In conclusion, miR-3188, a key miRNA enhanced in PCOS, promoted granulosa cell proliferation through down-regulation of KCNA5, providing a new therapeutic target for PCOS.

PM2.5 Induces the Expression of Inflammatory Cytokines via the Wnt5a/Ror2 Pathway in Human Bronchial Epithelial Cells.

Background and Purpose: Recently, fine particulate matter (PM2.5) was identified as the main exposure risk for COPD, and inflammation is central to the development of COPD. In this study, we investigated whether PM2.5 can induce the secretion of interleukin-6 (IL-6), IL-8 and IL-1ß in human bronchial epithelial cells (HBECs) in vitro via the wingless-related integration site 5A (Wnt5a)/receptor tyrosine kinase-like orphan receptor 2 (Ror2) signaling. Methods: The expression of Wnt5a and Ror2 was assessed by immunohistochemistry in motor vehicle exhaust (MVE)-induced Sprague-Dawley rats. HBECs were transfected with small interfering RNA (siRNA) targeting Wnt5a or Ror2 and subsequently stimulated with PM2.5.The secretion of IL-6, IL-8 and IL-1ß was assessed by ELISAs, and the expression of Wnt5a/Ror2 signaling were assessed by RT-PCR and Western blotting. Results: Both Wnt5a and Ror2 protein were increased in the lung of MVE-induced rats. HBECs exposed to PM2.5 for 24 h significantly upregulated Wnt5a and Ror2 expression and subsequently promoted the nuclear translocation of NF-κB, which increased the production of IL-1ß, IL-6 and IL-8. Wnt5a siRNA prevented these outcomes. Wnt5a antagonist (BOX5) also prevented inflammatory effects. Furthermore, Ror2 siRNA blocked the NF-κB activity and inhibited the release of IL-6, IL-8 and IL-1ß from PM2.5-exposed HBECs. Conclusion: PM2.5 induces the secretion of IL-6, IL-8 and IL-1ß in HBECs via the Wnt5a/Ror2 signaling, demonstrating a novel mechanism for PM2.5-associated airway inflammation.

Surfce Functionalized via AdLAMA3 Multilayer Coating for Re-epithelization Around Titanium Implants.

The peri-implant epithelium (PIE) forms a crucial seal between the oral environment and the implant surface. Compared with the junctional epithelium (JE), the biological sealing of PIE is fragile, which lacks hemidesmosomes (HDs) and internal basal lamina (extracellular matrix containing laminin332, IBL) on the upper part of the interface. In the study, we aim to prepare a coating with good biocompatibility and ability to immobilize the recombinant adenovirus vector of LAMA3 (AdLAMA3) for promoting the re-epithelization of PIE. The titanium surface functionalized with AdLAMA3 was established via layer-by-layer assembly technique and antibody-antigen specific binding. The biological evaluations including cell adhesion and the re-epithelization of PIE were investigated. The results in vitro demonstrated that the AdLAMA3 coating could improve epithelial cell attachment and cell spreading in the early stage. In vivo experiments indicated that the AdLAMA3 coating on the implant surface has the potential to accelerate the healing of the PIE, and could promote the expression of laminin α3 and the formation of hemidesmosomes. This study might provide a novel approach and experimental evidence for the precise attachment of LAMA3 to titanium surfaces. The process could improve the re-epithelization of PIE.

PM2.5 Induced the Expression of Fibrogenic Mediators via HMGB1-RAGE Signaling in Human Airway Epithelial Cells.

Background: The aim of the present study was to test whether fine particulate matter (PM2.5) induces the expression of platelet-derived growth factor-AB (PDGF-AB), PDGF-BB, and transforming growth factor-ß1 (TGF-ß1) in human bronchial epithelial cells (HBECs) in vitro via high-mobility group box 1 (HMGB1) receptor for advanced glycation end products (RAGE) signaling. Methods: Sprague-Dawley rats were exposed to motor vehicle exhaust (MVE) or clean air. HBECs were either transfected with a small interfering RNA (siRNA) targeting HMGB1 or incubated with anti-RAGE antibodies and subsequently stimulated with PM2.5. Results: The expression of HMGB1 and RAGE was elevated in MVE-treated rats compared with untreated rats, and PM2.5 increased the secretion of HMGB1 and upregulated RAGE expression and the translocation of nuclear factor κB (NF-κB) into the nucleus of HBECs. This activation was accompanied by an increase in the expression of PDGF-AB, PDGF-BB, and TGF-ß1. The HMGB1 siRNA prevented these effects. Anti-RAGE antibodies attenuated the activation of NF-κB and decreased the secretion of TGF-ß1, PDGF-AB, and PDGF-BB from HBECs. Conclusion: PM2.5 induces the expression of TGF-ß1, PDGF-AB, and PDGF-BB in vitro via HMGB1-RAGE signaling, suggesting that this pathway may contribute to the airway remodeling observed in patients with COPD.

Discovery of selective EGFR modulator to inhibit L858R/T790M double mutants bearing a N-9-Diphenyl-9H-purin-2-amine scaffold.

Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of N-9-Diphenyl-9H-purin-2-amine derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 23a showed excellent enzyme inhibitory activities and selectivity with nanomolar IC50 values for both the single T790M and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 23a displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R. And it was less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index.

Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors.

A series of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety were synthesized and evaluated for their in vitro cytotoxic activity against four cancer cell lines (HT-29, H460, A549 and MKN-45). Most of the compounds exhibited moderate-to-significant cytotoxicity. Compounds 33, 37, 39, 44, 46, 47, 53, 55, 61, 64 and 66 were further examined for their inhibitory activity against c-Met kinase. The most promising compound 47 (with c-Met IC50 value of 1.57 nM) showed remarkable cytotoxicity against HT-29, H460, A549 and MKN-45 cell lines with IC50 values of 0.08 µM, 0.14 µM, 0.11 µM and 0.031 µM, respectively, and thus it was 1.1- to 2.3- fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity.

Hepatitis C virus core protein impairs metabolic disorder of liver cell via HOTAIR-Sirt1 signalling.

It has been suggested that Hepatitis C virus (HCV) core protein is associated with metabolic disorders of liver cell. However, the precise mechanism is still unclear. The aim of the present study was to explore the impact of HCV core protein on hepatocyte metabolism by HepG2 and the possible involvement of long non-coding (lnc) RNAs in this process. The effect of HCV core protein on lncRNAs expression was examined with quantitative RT-PCR (qRT-PCR). Manipulation of HVC core protein and lncRNA HOTAIR was to evaluate the role of interaction between them on cell metabolism-related gene expression and cellular metabolism. The potential downstream Sirt1 signal was examined by western blotting and qRT-PCR. Our data suggested that suppression of HOTAIR abrogates HCV core protein-induced reduction in Sirt1 and differential expression of glucose- and lipid-metabolism-related genes. Also it benefits for metabolic homoeostasis of hepatocyte indicated by restoration of cellular reactive oxygen species (ROS) level and NAD/NADH ratio. By manipulation of HOTAIR, we concluded that HOTAIR negatively regulates Sirt1 expression through affecting its promotor methylation. Moreover, overexpression of Sirt1 reverses pcDNA-HOTAIR-induced glucose- and lipid-metabolism-related gene expression. Our study suggests that HCV core protein causes dysfunction of glucose and lipid metabolism in liver cells through HOTAIR-Sirt1 signalling pathway.