Synthesis and biological evaluation of 1-phenyl-tetrahydro-ß-carboline-based first dual PRMT5/EGFR inhibitors as potential anticancer agents.

Protein arginine methyltransferase 5 (PRMT5) and epidermal growth factor receptor (EGFR) are both involved in the regulation of various cancer-related processes, and their dysregulation or overexpression has been observed in many types of tumors. In this study, we designed and synthesized a series of 1-phenyl-tetrahydro-ß-carboline (THßC) derivatives as the first class of dual PRMT5/EGFR inhibitors. Among the synthesized compounds, 10p showed the most potent dual PRMT5/EGFR inhibitory activity, with IC50 values of 15.47 ± 1.31 and 19.31 ± 2.14 µM, respectively. Compound 10p also exhibited promising antiproliferative activity against A549, MCF7, HeLa, and MDA-MB-231 cell lines, with IC50 values below 10 µM. Molecular docking studies suggested that 10p could bind to PRMT5 and EGFR through hydrophobic, π-π, and cation-π interactions. Furthermore, 10p displayed favorable pharmacokinetic properties and oral bioavailability (F = 30.6%) in rats, and administrated orally 10p could significantly inhibit the growth of MCF7 orthotopic xenograft tumors. These results indicate that compound 10p is a promising hit compound for the development of novel and effective dual PRMT5/EGFR inhibitors as potential anticancer agents.

An Updated Overview of Synthetic α-glucosidase Inhibitors: Chemistry and Bioactivities.

Diabetes mellitus (DM) is a critical global health issue, affecting nearly half a billion people worldwide, with an increasing incidence rate and mortality. Type 2 diabetes is caused by the body's inability to effectively use insulin, and approximately 95% of patients have type 2 diabetes. α-glucosidase has emerged as an important therapeutic target for the treatment of type 2 diabetes. In the past years, three α-glucosidase inhibitors have been approved for clinical use, namely acarbose, voglibose, and miglitol. However, the undesirable effects associated with these carbohydrate mimic-based α-glucosidase inhibitors have limited their clinical applications. Consequently, researchers have shifted their focus towards the development of non-carbohydrate mimic α-glucosidase inhibitors that can safely and effectively manage postprandial hyperglycemia in type 2 diabetes. Herein, this article provides an overview of the synthetic α-glucosidase inhibitors, particularly those based on heterocycles, which have been reported from 2018 to 2022. This article aims to provide useful information for medicinal chemists in further developing clinically available anti-type 2 diabetes drugs.

Discovery of marine phidianidine-based Nrf2 activators and their potential against oxLDL- and HG-induced injury in HUVECs.

One effective strategy for treating atherosclerosis is to inhibit the injury of vascular endothelial cells (VECs) induced by oxidized low-density lipoprotein (oxLDL) and high glucose (HG). This study synthesized and evaluated a series of novel Nrf2 activators derived from the marine natural product phidianidine for their ability to protect human umbilical VECs against oxLDL- and HG-induced injury. The results of in vitro bioassays demonstrated that compound D-36 was the most promising Nrf2 activator, effectively inhibiting the apoptosis of HUVECs induced by oxLDL and HG. Furthermore, Nrf2 knockdown experiments confirmed that compound D-36 protected against oxLDL- and HG-induced apoptosis in HUVECs by activating the Nrf2 pathway. These findings provide important insights into a new chemotype of marine-derived Nrf2 activators that could potentially be optimized to develop effective anti-atherosclerosis agents.

Discovery of tetrahydroisoquinolineindole derivatives as first dual PRMT5 inhibitors/hnRNP E1 upregulators: Design, synthesis and biological evaluation.

Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as an important therapeutic target for treating various types of cancer. Upregulation of tumor suppressor hnRNP E1 has also been considered as an effective antitumor therapy. In this study, a series of tetrahydroisoquinolineindole hybrids were designed and prepared, and compounds 3m and 3s4 were found to be selective inhibitors of PRMT5 and upregulators of hnRNP E1. Molecular docking studies indicated that compounds 3m occupied the substrate site of PRMT5 and formed essential interactions with amino acid residues. Furthermore, compounds 3m and 3s4 exerted antiproliferative effects against A549 cells by inducing apoptosis and inhibiting cell migration. Importantly, silencing of hnRNP E1 eliminated the antitumor effect of 3m and 3s4 on the apoptosis and migration in A549 cells, suggesting a regulatory relationship between PRMT5 and hnRNP E1. Additionally, compound 3m exhibited high metabolic stability on human liver microsomes (T1/2 = 132.4 min). In SD rats, the bioavailability of 3m was 31.4%, and its PK profiles showed satisfactory AUC and Cmax values compared to the positive control. These results suggest that compound 3m is the first class of dual PRMT5 inhibitor and hnRNP E1 upregulator that deserves further investigation as a potential anticancer agent.

Arginine Methyltransferase 5 (PRMT5) Inhibitors with 3-(1H-benzo[d]imidazol- 2-yl)anilines Core Identified by Virtual Screening and Biological Evaluation.

BACKGROUND: PRMT5 is a major enzyme responsible for the post-translational symmetric demethylation of protein arginine residues, which has been validated as an effective therapeutic target for cancer. Thus, many nucleoside-based PRMT5 inhibitors have been reported in the past year. OBJECTIVE: To discover a novel series of non-nucleoside PRMT5 inhibitors through a molecular docking-based virtual screening approach. METHODS: Our in-house compound library was virtually screened using the Glide program, identifying a new PRMT5 inhibitor 1. Based on the structural similarity of hit 1, a series of structure-oriented derivatives, including 3a-3e, 7a-7g, and 12a-12f, were synthesized and selected for the inhibitory activity evaluation against PRMT5, as well as cytotoxicity against MV4-11 cell. RESULTS: The analogs 7a-7e with benzimidazole core exhibited potent PRMT5 inhibitory activities, with 7e displaying the most potent activity with an IC50 of 6.81 ± 0.12 µM. In the anti-proliferative assay, compound 7e showed a strong inhibitory effect on MV4-11 cell growth. Finally, the binding mode of 7e with PRMT5 was predicted to provide insights for further structural optimization. CONCLUSION: The newly discovered PRMT5 inhibitors have potential antitumor activity against MV4-11 cells. This work highlighted this series of 3-(1H-benzo[d]imidazol-2-yl)aniline derivatives as novel anti-cancer lead compounds targeting PRMT5, which were worthy of further investigation.

Design, synthesis and biological evaluation of marine phidianidine-inspired derivatives against oxidized ldl-induced endothelial injury by activating Nrf2 anti-oxidation pathway.

Inhibition of oxidized low-density lipoprotein (oxLDL)-induced vascular endothelial cell (VEC) injury is one of the effective strategies for treating atherosclerosis. In the present study, a series of novel marine phidianidine-inspired indole-1,2,4-oxadiazoles was designed, synthesized, and evaluated for their effects against oxLDL-induced injury in VECs. Among them, compound D-6, displaying the most effective protective activity, was found to inhibit oxLDL-induced apoptosis and the expression of ICAM-1 and VCAM-1 in VECs. Mechanistic studies showed that D-6 could trigger Nrf2 nuclear translocation, subsequently resulting in increased expression of Nrf2 target gene HO-1. Meanwhile, D-6 suppressed the increase of ROS level and nuclear translocation of NF-κB induced by oxLDL. Importantly, Nrf2 knockdown attenuated the inhibition effects of D-6 on oxLDL-induced apoptosis, ROS production and NF-κB nuclear translocation. Collectively, our studies demonstrated that compound D-6 protected against oxLDL-induced endothelial injury by activating Nrf2/HO-1 anti-oxidation pathway.

Design, synthesis and biological evaluation of novel (E)-2-benzylidene-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)hydrazine-1-carboxamide derivatives as α-glucosidase inhibitors.

In this present study, a series of novel (E)-2-benzylidene-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)hydrazine-1-carboxamide derivatives against α-glucosidase were designed and synthesized, and their biological activities were evaluated in vitro and in vivo. Most of the designed analogues exhibited better inhibitory activity than the marketed acarbose, especially the most potent compound 7 with an IC50 value of 9.26 ± 1.84 µM. The direct binding of 7 and 8 with α-glucosidase was confirmed by fluorescence quenching experiments, and the kinetic and molecular docking studies revealed that 7 and 8 inhibited α-glucosidase in a non-competitive manner. Cytotoxicity bioassay indicated compounds 7 and 8 were non-toxic towards LO2 and HepG2 at 100 µM. Furthermore, both compounds were demonstrated to have in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-treated rats.

Discovery of new 2-phenyl-1H-benzo[d]imidazole core-based potent α-glucosidase inhibitors: Synthesis, kinetic study, molecular docking, and in vivo anti-hyperglycemic evaluation.

In the present study, a series of 2-phenyl-1H-benzo[d]imidazole-based α-glucosidase inhibitors were synthesized and evaluated for their in vitro and in vivo anti-diabetic potential. Screening of an in-house library revealed a moderated α-glucosidase inhibitor, 6a with 3-(1H-benzo[d]imidazol-2-yl)aniline core, and then the structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased activity than 6a, and the most promising inhibitors were found to be compounds 15o and 22d with IC50 values of 2.09 ± 0.04 and 0.71 ± 0.02 µM, respectively. Fluorescence quenching experiment confirmed the direct binding of compounds 15o and 22d with α-glucosidase. Kinetic study revealed that both compounds were non-competitive inhibitors, that was consistent with the result of molecular docking studies where they located at the allosteric site of the enzyme. Cell viability evaluation demonstrated the non-cytotoxicity of 15o and 22d against LO2 cells. Furthermore, the in vivo pharmacodynamic study revealed that compound 15o showed significant hypoglycemic activity and improved oral sucrose tolerance, comparable to the positive control acarbose.

Novel tetrahydrobenzo[b]thiophen-2-yl)urea derivatives as novel α-glucosidase inhibitors: Synthesis, kinetics study, molecular docking, and in vivo anti-hyperglycemic evaluation.

α-Glucosidase inhibitors, which can inhibit the digestion of carbohydrates into glucose, are one of important groups of anti-type 2 diabetic drugs. In the present study, we report our effort on the discovery and optimization of α-glucosidase inhibitors with tetrahydrobenzo[b]thiophen-2-yl)urea core. Screening of an in-house library revealed a moderated α-glucosidase inhibitors, 5a, and then the following structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased inhibitory activity against α-glucosidase than the parental compound 5a (IC50 of 26.71 ± 1.80 µM) and the positive control acarbose (IC50 of 258.53 ± 1.27 µM). Among them, compounds 8r (IC50 = 0.59 ± 0.02 µM) and 8s (IC50 = 0.65 ± 0.03 µM) were the most potent inhibitors, and showed selectivity over α-amylase. The direct binding of both compounds with α-glucosidase was confirmed by fluorescence quenching experiments. Kinetics study revealed that these compounds were non-competitive inhibitors, which was consistent with the molecular docking results that compounds 8r and 8s showed high preference to bind to the allosteric site instead of the active site of α-glucosidase. In addition, compounds 8r and 8s were not toxic (IC50 > 100 µM) towards LO2 and HepG2 cells. Finally, the in vivo anti-hyperglycaemic activity assay results indicated that compounds 8r could significantly decrease the level of plasma glucose and improve glucose tolerance in SD rats treated with sucrose. The present study provided the tetrahydrobenzo[b]thiophen-2-yl)urea chemotype for developing novel α-glucosidase inhibitors against type 2 diabetes.

Virtual Water Trade in the Service Sector: China's Inbound Tourism as a Case Study.

Research on virtual water and the water footprint is mainly focused on agriculture and industry, and less so on the service sector. The trade in products generates virtual water flow, as does the flow of people. The flow of international tourists will inevitably lead to the transfer and exchange of water resources embedded in the virtual form. This study takes China's inbound tourism flow as the research object, from the perspective of the water footprint, in order to explore virtual water "exports" to the world. Based on kernel density estimation and ArcGIS spatial analysis, spatial-temporal evolution and structural difference were investigated. Virtual water "exports" showed an increasing trend. The kernel density estimation curves basically exhibited a "single peak" feature which indicated that virtual water "exports" from tourism were not significantly polarized in China. In terms of spatial evolution, this varied greatly at the provincial and regional level and Guangdong was always in the high value area. The south displayed greater values than the north, but this difference in provinces narrowed over the years. The water footprint of food was the largest, more specifically, the green component of this water footprint. Promoting a reasonable diet, reducing food waste, improving agricultural production technology, reducing the frequency of changing hotel supplies, and encouraging the use of new energy helped to reduce the water footprint. Virtual water trade in the service sector provides a new idea for helping to mitigate the global water crisis, in addition to virtual water flow for agricultural products.

Escape or stay? Effects of haze pollution on domestic travel: Comparative analysis of different regions in China.

Haze pollution has significant impacts on tourist perception and behaviour, including a sharp increase in risk perception and a decline in tourism experience quality. However, given the intervention of multiple factors, whether these impacts necessarily have a negative effect on the overall scale of regional tourism remains unknown. Hence, this paper explored the overall effect of haze pollution on domestic travel. Using 28 major cities in China as examples, we employed a two-way fixed effect panel model to investigate this issue. Combined with the comparisons between the results of different subgroups, including high cities, medium cities, low cities, outbreak cities and non-outbreak cities, this study found that there was no significant effect of haze concentration on domestic travel, but public awareness of haze pollution had a significant positive effect on that. Meanwhile, public awareness exerted a negative moderating effect of haze concentration and domestic travel. The findings are beneficial for understanding the new situation faced by the tourism industry, and several suggestions are provided for policy makers and travel agencies.

Virtual water trade of agricultural products: A new perspective to explore the Belt and Road.

The Belt and Road is an initiative of cooperation and development that was proposed by China. Moreover, most of the spanning countries faced water shortages and agriculture consumed a lot of water. Virtual water links water, food and trade and is an effective tool to ease water shortages. Therefore, this paper aims to understand the Belt and Road from the new perspective of virtual water trade of agricultural products. We considered agricultural products trade from 2001 to 2015. On the whole, the results indicated that China was in virtual water trade surplus with the countries along the Belt and Road. However, in terms of each country, >40 spanning countries were in virtual water trade surplus with China and eased water shortages. Russia had the largest net imported virtual water from China. Furthermore, the proportion of the grey water footprint that China exported to the spanning countries was much higher than that imported, no matter from the whole or different geographical regions. Moreover, more than half of the countries' virtual water trade with China conformed to the virtual water strategy, which helped to ease water crises. Furthermore, the products that they exported to China were mainly advantageous products that each spanning countries have. Virtual water trade is a new perspective to explore the Belt and Road. Agricultural products trade with China definitely benefits both the countries along the Belt and Road and China from the perspective of virtual water. The findings are beneficial for the water management of the countries along the Belt and Road and China, alleviating water shortages, encouraging the rational allocation of water resources in the various departments. They can provide references for optimizing trade structures as well.

[Combination of transrectal 125I seeds implantation brachytherapy and intermittent hormonal therapy for locally advanced prostate cancer].

OBJECTIVE: To evaluate the clinical efficacy of transrectal 125 I seeds implantation brachytherapy (BT) combined with intermittent hormonal therapy (IHT) in the treatment of locally advanced prostate cancer. METHODS: We treated 27 patients with locally advanced prostate cancer by transrectal 125I seeds implantation BT combined with IHT, and dynamically observed the changes in the PSA level, prostate volume, maximum urinary flow rate (Qmax) and International Prostate Symptoms Score (IPSS). RESULTS: All the implantation procedures were completed smoothly, lasting 20 to 35 minutes, with 40 to 58 seeds implanted. At 6 months after implantation, the PSA level was < 0.2 microg/L in all the patients (< 0.1 microg/L in 19 cases), the prostate volume was significantly reduced (P < 0.05), and Qmax and IPSS remarkably improved (P < 0.05). At 3 years after implantation, 19 cases were in the first cycle and the other 8 in the third cycle of IHT, of which 2 progressed to androgen-independent prostate cancer, and another 2 developed early bone metastasis. The rates of 3-year biochemically and clinically progression-free survival were 70.3% and 85.2%, respectively, and the rate of therapeutic effectiveness was 92.6%. No severe complications occurred in any of the cases. CONCLUSION: Transrectal 125I seeds implantation BT combined with IHT is a safe and minimally invasive procedure for locally advanced prostate cancer, which can effectively retard its clinical progression with no such complications as severe urethral, rectal or erectile dysfunction.

[Oral lichen planus: a retrospective study of 724 Chinese patients].

OBJECTIVE: To retrospectively analyze oral lichen planus (OLP) patients and to summarize the clinical characteristic of OLP in Chinese patients. METHODS: A total of 724 patients with histologically and clinically confirmed OLP were collected from department of oral mucosa in School of Stomatology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University between 1978 and 2006. RESULTS: The OLP patients were followed up from 1 month to 259 months (mean 21 months). Of the 724 patients, 68.23% were women and 31.77% were men. The buccal mucosa was the most common site of involvement in each form, followed by the dorsal tongue, ventral tongue, lip, gingiva, palate and the floor of mouth. The reticular form of the disease was the predominant type in 53.82% of patients at initial presentation. About 48.76% of the patients had multiple oral sites of involvement. Fifteen OLP lesions developed into carcinoma, the malignant transformation rate was 2.07%. CONCLUSIONS: Because OLP has potential of malignant change, a long time and periodical follow-up is of great importance for detection of malignant lesions.

[The application of 18F-fluorodeoxyglucose positron emission tomography in the diagnosis and staging of lung cancer].

OBJECTIVE: To study the clinical value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in the diagnosis and staging of lung cancer. METHODS: Ninety-four patients with lung nodular changes were examined by CT, 18F-FDG PET and pathology, cytology. 18F-FDG PET images were analyzed by semi-quantitative standard uptake value (SUV) only and (or) SUV plus visual observation. Focuses with a SUV > 2.5 were judged as malignant changes, while SUV < or = 2.5 was judged as benign. SUV plus visual analysis, based on the focal SUV, the nodular size and shape, and clinical data, was carried out by two nuclear doctors. CT imaging was interpreted by two radiological doctors. The sensitivity, specificity, accuracy, positive predictive and negative predictive values of 18F-FDG PET and CT in the diagnosis, and in the evaluation of lymphatic metastasis and remote metastasis of lung lesions were calculated. The diagnostic efficiency of the two methods (SUV or visual plus SUV method) was compared. RESULTS: (1) 58 cases were confirmed to be malignant by surgery or pathological examination, while 36 cases were proved benign by pathology or empirical therapy. (2) The sensitivity, specificity, accuracy, positive and negative predictive values were 69%, 65%, 68%, 82% and 49% respectively for CT; and 91%, 89%, 90%, 93% and 87% respectively for SUV analysis; and 95%, 94%, 95%, 97% and 92% respectively for visual plus SUV methods. (3) Among 34 patients with mediastinal lymph node involvement confirmed by pathology, 18F-FDG PET detected 30 cases, while CT detected only 18 cases (P < 0.01). (4) 18F-FDG PET revealed 19 cases with distant metastases, while CT only discovered 8 cases with distant metastases. As a result, the therapy was modified by PET examination in 14 patients. CONCLUSION: 18F-FDG PET imaging is of important clinical value in the diagnosis of lung lesions and the staging of malignancy.