Design, synthesis and molecular docking of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazole derivatives that act as iNOS/COX-2 inhibitors with potent anti-inflammatory activity against LPS-induced RAW264.7 macrophage cells.

Inflammation, an important biological protective response to tissue damage or microbial invasion, is considered to be an alarming signal for the progress of varied biological complications. Based on the previous reports in the literature that proved the noticeable efficacy of pyrazole and thiazole scaffold as well as nitrogen heterocyclic based compounds against acute and chronic inflammatory disease, a new set of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazole derivatives were synthesized and evaluated their anti-inflammatory activities in vitro. Preliminary structure-activity relationship (SAR) analysis was conducted by their inhibitory activities against nitric oxide (NO) release in lipopolysaccharide (LPS)-induced RAW 264.7 cells, and the optimal compound 12b [3ß-hydroxy-pregn-5-en-17ß-yl-5'- (o- chlorophenyl)- 1'-(4''- phenyl -[1'', 3'']- thiazol-2''- yl) - 4',5'-dihydro - 1'H-pyrazol - 3'- yl] exhibited more potent anti-inflammatory activity than the positive control treatment methylprednisolone (MPS), with an IC50 value of 2.59 µM on NO production and low cytotoxicity against RAW 264.7 cells. In further mechanism study, our results showed that compound 12b significantly suppressed the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and inhibited the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) through blocking NF-κB p65 nuclear translocation and phosphorylation of IκBα. Compound 12b also attenuated LPS-induced activation of c-Jun amino-terminal kinase (JNK) and p38 phosphorylation in RAW 264.7 cells. Molecular docking study revealed the strong binding affinity of compound 12b to the active site of the COX-2 proteins, which confirmed that compound 12b acted as an anti-inflammatory mediator. These results indicate that steroidal derivatives bearing 4,5-dihydropyrazole thiazole structure might be considered for further research and scaffold optimization in designing anti-inflammatory drugs and compound 12b might be a promising therapeutic anti-inflammatory drug candidate.

Cost-effectiveness analysis of pembrolizumab plus chemotherapy for patients with recurrent or metastatic cervical cancer in China.

OBJECTIVE: To evaluate the cost-effectiveness of adding pembrolizumab to various therapy combinations in patients with recurrent or metastatic cervical cancer from the Chinese perspective. MATERIALS AND METHODS: The clinical data for our model was taken from the KEYNOTE-826 trial. The direct costs and utilities were collected from local price databases or previously published literature. A three-state partitioned survival model was designed to simulate the disease process of patients with recurrent or metastatic cervical cancer. All costs were estimated in US dollars, with an annual RMB exchange rate of $1 to 6.45 Yuan in 2021. The willingness to pay threshold (WTP) was set at US$37,663.26/QALY. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to evaluate the influence of variables on the model parameters. RESULTS: For patients with a programmed death-ligand 1 combined positive score greater than 1,compared to the chemotherapy group, pembrolizumab plus chemotherapy contributed an incremental 1.12 Quality-adjusted Life Years (QALYs) with an incremental cost of US$71,884.42, resulting in an incremental cost-effectiveness ratio (ICER) of US$64,338.19, which is beyond the willingness-to-pay (WTP) threshold of China. According to sensitivity analyses, the ICERs were most sensitive to the utility of progressive disease and the cost of pembrolizumab. However, those parameters had no significant impact on the model's outcomes. CONCLUSIONS: The addition of pembrolizumab to various therapy combinations chemotherapy is exorbitant and may not be cost-effective for patients with recurrent or metastatic cervical cancer in China.

LINC00152 upregulates ZEB1 expression and enhances epithelial-mesenchymal transition and oxaliplatin resistance in esophageal cancer by interacting with EZH2.

BACKGROUND: Expression of the long non-coding mRNA LINC00152 has been reported to correlate with cancer cell resistance to oxaliplatin (L-OHP). However, little is known regarding the molecular mechanism of LINC00152 in esophageal cancer (EC). Hence, we intended to characterize the role of LINC00152 in EC, with a special focus on epithelial-mesenchymal transition (EMT) and L-OHP resistance. METHODS: We collected EC tissues and identified EC cell lines with higher L-OHP resistance, and then characterized expression patterns of LINC00152, Zeste Homologue 2 (EZH2), Zinc finger e-box binding homeobox (ZEB1) and EMT-related genes using RT-qPCR and Western blot analysis. Furthermore, their functional significance was identified by gain and loss-of-function experiments. The relationship among LINC00152, EZH2 and ZEB1 was examined using RIP, RNA pull-down and ChIP assays. Additionally, resistance of EC cells to L-OHP was reflected by CCK-8 assay to detect cell viability. Animal experiments were also conducted to detect the effects of the LINC00152/EZH2/ZEB1 on EMT and L-OHP resistance. RESULTS: LINC00152, EZH2 and ZEB1 were highly expressed in EC tissues and Kyse-150/TE-1 cells. As revealed by assays in vitro and in vivo, LINC00152 positively regulated ZEB1 expression through interaction with EZH2 to enhance EMT and L-OHP resistance in EC cells. In contrast, silencing of LINC00152 contributed to attenuated EMT and drug resistance of EC cells to L-OHP. CONCLUSIONS: Our study demonstrates that LINC00152/EZH2/ZEB1 axis can regulate EMT and resistance of EC cells to L-OHP, thus presenting a potential therapeutic target for EC treatment.

The resistance of esophageal cancer cells to paclitaxel can be reduced by the knockdown of long noncoding RNA DDX11-AS1 through TAF1/TOP2A inhibition.

Esophageal cancer (EC) is one of the most common malignancies in the world. The currently used chemotherapeutic drug for the treatment of EC is paclitaxel (PTX), the efficacy of which is affected by the development of drug resistance. The present study aims to define the role of the long noncoding RNA (lncRNA) DDX11-AS1 in the progression of EC with the involvement of PTX-resistant EC cells. First, EC and adjacent normal tissue samples were collected from 82 patients with EC, after which the expression levels of DDX11-AS1, TOP2A and TAF1 were determined. The results showed that DDX11-AS1, TOP2A and TAF1 were highly expressed in EC tissues, and there was a positive correlation between the expression levels of DDX11-AS1 and TOP2A. A PTX-resistant EC cell line was constructed. Next, we evaluated the effects of DDX11-AS1 and TOP2A on the resistance of EC cells to PTX, and the regulatory relationships between DDX11-AS1, TOP2A and TAF1 were investigated. DDX11-AS1 could promote TOP2A transcription via TAF1, and the knockdown of TOP2A or DDX11-AS1 could increase the sensitivity of EC cells to PTX. The effect of DDX11-AS1 on the growth of PTX-inhibited tumors was confirmed using a tumor formation assay in nude mice. It was verified that knocking down DDX11-AS1 reduced the expression level of TOP2A and inhibited tumor growth. In conclusion, our findings suggest that DDX11-AS1 knockdown results in reduced resistance of EC cells to PTX by inhibiting TOP2A transcription via TAF1. Therefore, DDX11-AS1 knockdown could be a promising therapeutic strategy for EC.

Neuroprotection of reduced thyroid hormone with increased estrogen and progestogen in postpartum depression.

Background: Postpartum depression (PPD) is a common serious mental health problem. Recent studies have demonstrated that hormone therapy serves as a promising therapeutic approach in managing PPD. The present study aims at exploring the role of thyroid hormone (TH), estrogen and progestogen in patients with PPD.Methods: Initially, PPD patients were enrolled and a PPD mouse model was established. The serum levels of estradiol (E2), progesterone (P), triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were subsequently measured. Next, in order to identify the effects of TH, estrogen and progestogen on PPD progression, mice were administrated with E2, P, contraceptives (CA), Euthyrox and methimazole (MMI). Besides, the body weight, activities, basolateral amygdala (BLA) neuron cell structure and the related gene expression of mice were analyzed.Results: The PPD patients and the mice showed elevated serum levels of T3, T4, FT3 and FT4 along with diminished E2, P and TSH levels. In the mice administered with a combination of E2, P, and MMI, decreased TH and increased estrogen and progestogen were detected, which resulted in increased body weight, normal activities, and BLA neuron cell structure. Moreover, brain-derived neurotrophic factor (BDNF) and cAMP-responsive element-binding protein (CREB) were both up-regulated in PPD mice administrated with a combination of E2, P, and MMI, which was accompanied by decreased TH and elevated estrogen and progestogen.Conclusion: Taken together, reduced TH combined with enhanced estrogen and progestogen confers neuroprotection in PPD, highlighting a potential target in prevention and treatment of PPD.

Overexpression of long noncoding RNA LINC01419 in esophageal squamous cell carcinoma and its relation to the sensitivity to 5-fluorouracil by mediating GSTP1 methylation.

BACKGROUND: Genome-wide sequencing investigations have identified numerous long noncoding RNAs (lncRNAs) among mammals, many of which exhibit aberrant expression in cancers, including esophageal squamous cell carcinoma (ESCC). Herein, this study elucidates the role and mechanism by which LINC01419 regulates the DNA methylation of glutathione S-transferase pi 1 (GSTP1) in relation to ESCC progression and the sensitivity of ESCC cells to 5-fluorouracil (5-FU). METHODS: LINC01419 and GSTP1 levels were quantified among 38 paired ESCC and adjacent tissue samples collected from patients with ESCC. To ascertain the contributory role of LINC01419 in the progression of ESCC and identify the interaction between LINC01419 and GSTP1 promoter methylation, LINC01419 was overexpressed or silenced, and the DNA methyltransferase inhibitor 5-Aza-CdR was treated. RESULTS: Data from the GEO database (GSE21362) and the Cancer Genome Atlas displayed elevated levels of LINC01419 and downregulated levels of GSTP1 in the ESCC tissues and cells. The silencing of LINC01419 led to decreased proliferation, increased apoptosis, and enhanced sensitivity to 5-FU in ESCC cells. Notably, LINC01419 could bind to the promoter region of the GSTP1 gene, resulting in elevated GSTP1 methylation and reduced GSTP1 levels via the recruitment of DNA methyltransferase among ESCC cells, whereby ESCC progression was stimulated accompanied by reduced ESCC cell sensitivity to 5-FU. GSTP1 demethylation by 5-Aza-CdR was observed to reverse the effects of LINC01419 overexpression in ESCC cells and the response to 5-FU. CONCLUSION: Highly expressed LINC01419 in ESCC promotes GSTP1 methylation, which ultimately acts to promote the event of ESCC and diminish the sensitivity of ESCC cells to 5-FU, highlighting a novel potential strategy to improve 5-FU-based chemotherapy in ESCC.

Long noncoding RNA LINC00261 induces chemosensitization to 5-fluorouracil by mediating methylation-dependent repression of DPYD in human esophageal cancer.

Approximately 85% of a single administered dose of 5-fluorouracil (5-FU) will be degraded by dihydropyrimidine dehydrogenase (DYPD). Studies have highlighted a link between the complete or partial loss of DYPD function and clinical responses to 5-FU; however, the underlying molecular basis of DPD deficiency remains poorly understood. Hence, the aim of the present study was to evaluate the prevailing hypothesis which suggests that overexpression of LINC00261 possesses the ability to modulate the methylation-dependent repression of DPYD, ultimately resulting in an elevation of the sensitivity of human esophageal cancer cells to 5-FU. LINC00261 levels were initially quantified, followed by analysis of DYPD methylation within the cancerous tissues collected from 75 patients diagnosed with esophageal cancer undergoing 5-FU-based adjuvant chemotherapy. In an attempt to determine the levels of LINC00261 related to the esophageal cancer cell resistance to 5-FU and to identify the interaction between the levels of LINC00261 and methylation of the DYPD promoter, esophageal cancer cells TE-1 and -5 were prepared, in which LINC00261 and the 5-FU-resistant TE-1 and -5 cells were overexpressed. The levels of LINC00261 were reduced among the cancerous tissues obtained from patients exhibiting resistance to 5-FU. Overexpression of LINC00261 was determined to dramatically inhibit proliferation and resistance to apoptosis among 5-FU-resistant TE-1 and -5 cells, whereas silencing of LINC00261 was determined to enhance proliferation and resistance to apoptosis among the TE-1 and -5 cells. DPYD, a confirmed target of LINC00261, displayed a greater incidence of DNA methylation among patient's sensitive to 5-FU. A key finding revealed that overexpressed LINC00261 could increase the methylation of the DPYD promoter through the recruitment of DNA methyltransferase (DNMT), which, in turn, acts to decrease DPYD activity in 5-FU-resistant TE-1 cells, whereas a reversible change was recorded once the demethylation reagent 5-aza-2'-deoxyctidine was employed to treat the 5-FU-resistant TE-1 cells. Taken together, the results of the study provided evidence emphasizing the distinct antitumor ability of LINC00261 in cases of esophageal cancer, which was manifested by overexpression of LINC00261 detected to increase the sensitivity of human esophageal cancer cells to 5-FU by mediating methylation-dependent repression of DPYD. Our study highlighted the potential of LINC00261 as a novel target capable of improving the chemotherapeutic response and survival of patients with esophageal cancer.-Lin, K., Jiang, H., Zhuang, S.-S., Qin, Y.-S., Qiu, G.-D., She, Y.-Q., Zheng, J.-T., Chen, C., Fang, L., Zhang, S.-Y. Long noncoding RNA LINC00261 induces chemosensitization to 5-fluorouracil by mediating methylation-dependent repression of DPYD in human esophageal cancer.

Down-Regulated LncRNA-HOTAIR Suppressed Colorectal Cancer Cell Proliferation, Invasion, and Migration by Mediating p21.

BACKGROUND AND AIM: HOX transcript antisense intergenic RNA (HOTAIR) is a relatively well-understood RNA, which plays a central role in the pathogenesis of various tumors. The aim of the present study was to investigate the effect by which HOTAIR acts to influence the biological processes of colorectal cancer (CRC) through p21. METHODS: Reverse transcription quantitative polymerase chain reaction and Western blot methods were employed to provide verification regarding the changes in HOTAIR, PCNA, Ki67, p21, cyclin E, and CDK2 among the CRC tissues and cells. The correlation between the clinicopathological characteristics of patients and expression of HOTAIR and p21 was subsequently evaluated, followed by an analysis into the effects of HOTAIR on the biological processes of M5 cells. RESULTS: HOTAIR was found to be expressed at high levels, while p21 was determined to be at a low level among both the CRC tissues and the CRC cell lines. The expressions of HOTAIR and p21 were determined to be related to lymph node metastasis, tumor node metastasis, Dukes staging, distant metastases, histological types, and the degree of differentiation. Cells transfected with HOTAIR siRNA displayed inhibited rates of proliferation, invasion, and migration, as well as decreased cyclin E and CDK2, while apoptosis and p21 were increased. CONCLUSION: The principal findings demonstrated that down-regulation of HOTAIR elicits an inhibitory effect on proliferation, invasion, and migration, while promoting the apoptosis of CRC cells through the up-regulation of p21. We believe that HOTAIR could represent a novel target for the treatment of CRC.

Biomarkers for cancer-related fatigue and adverse reactions to chemotherapy in lung cancer patients.

This study was conducted to investigate the biomarkers that appear to be correlated with cancer-related fatigue (CRF) and the adverse reactions (ADRs) to chemotherapy. A total of 100 lung cancer patients were selected and CRF prior to and following chemotherapy was evaluated. The plasma levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1 and the level of 17-hydroxycorticosteroid (17-OHCS) in the urine were analyzed and correlated with CRF and the ADRs associated with chemotherapy. The incidence of CRF was found to be 88.0% and ADRs following chemotherapy occurred in 15.0% of the patients. An increase in the TNF-α and IL-1 levels was detected in patients with CRF. The level of 17-OHCS in the urine was found to be elevated in cases that experienced ADRs following chemotherapy. In conclusion, CRF is closely correlated with increased plasma levels of TNF-α and IL-1. Furthermore, an abnormally elevated 17-OHCS level in the urine may be an important indicator predicting ADR development following chemotherapy.