Proteolysis Targeting Chimeras (PROTACs) based on celastrol induce multiple protein degradation for triple-negative breast cancer treatment.

The pursuit of single drugs targeting multiple targets has become a prominent trend in modern cancer therapeutics. Natural products, known for their multi-targeting capabilities, accessibility, and cost-effectiveness, hold great potential for the development of multi-target drugs. However, their therapeutic efficacy is often hindered by complex structural modifications and limited anti-tumor activity. In this study, we present a novel approach using celastrol (CST)-based Proteolysis Targeting Chimeras (PROTACs) for breast cancer therapy. Through rational design, we have successfully developed compound 6a, a potent multiple protein degrader capable of selectively degrading GRP94 and CDK1/4 in tumor cells via the endogenous ubiquitin-proteasome system. Furthermore, compound 6a has demonstrated remarkable inhibitory effects on cell proliferation and migration, and induction of apoptosis in 4T1 cells through cell cycle arrest and activation of the Bcl-2/Bax/cleaved Caspase-3 apoptotic pathway. In vivo administration of compound 6a has effectively suppressed tumor growth with an acceptable safety profile. Our findings suggest that the CST-based PROTACs described herein can be readily extended to other natural products, offering a potential avenue for the development of natural product-based PROTACs for cancer treatment.

Poly (Vinylidene Fluoride-Hexafluoropropylene)-Lithium Titanium Aluminum Phosphate-Based Gel Polymer Electrolytes Synthesized by Immersion Precipitation for High-Performance Lithium Metal Batteries.

Gel polymer electrolytes (GPEs) have high safety and excellent electrochemical performance, so applying GPEs in lithium batteries has received much attention. However, their poor lithium ion transfer number, cycling stability, and low room temperature ionic conductivity seriously affect the utilization of gel polymer electrolytes. This paper successfully synthesized flexible poly (vinylidene fluoride-hexafluoropropylene)-lithium titanium aluminum phosphate (PVDF-HFP-LATP) gel polymer electrolytes using the immersion precipitation method. The resulting GPE has a porous honeycomb structure, which ensures that the GPE has sufficient space to store the liquid electrolyte. The GPE has a high ionic conductivity of 1.03 ×10-3 S cm-1 at room temperature (25 °C). The GPE was applied to LiFePO4/GPE/Li batteries with good rate performance at room temperature. The discharge specific capacity of 1C was as high as 121.5 mAh/g, and the capacity retention rate was 94.0% after 300 cycles. These results indicate that PVDF-HFP-LATP-based GPEs have the advantage of simplifying the production process and can improve the utility of gel polymer lithium metal batteries.

Cucurbit[7]uril-based host-guest complexes for improving bioavailability and reducing side effects of piroxicam.

Piroxicam (PX) is a nonsteroidal anti-inflammatory drug (NSAID) commonly associated with gastrointestinal (GI) injuries, including dyspepsia, heartburn, inflammation, bleeding, ulceration, and life-threatening perforation. The ß-cyclodextrin (ß-CD)-based PX formulation (PX@CD) has been shown to reduce gastric side effects by improving PX's solubility and dissolution rates. However, the solubility of PX can only be increased to a limited extent by ß-CD, due to the low binding constant between PX and ß-CD (∼100 M-1). As a result, adverse reactions such as epigastric pain and pyrosis are still commonly reported. Cucurbit[7]uril (CB[7]) is a synthetic macrocyclic host compound that binds strongly to various drugs. In this study, we demonstrated that CB[7] forms complexes with PX in the gastric acid environment with a binding constant approximately 70 times higher than that between ß-CD and PX. The PX@CB[7] inclusion complexes exhibited rapid dissolution rates in the gastric environment. In addition, PX@CB[7] showed significantly higher oral bioavailability and maximum concentration (Cmax) compared to PX and PX@CD (1:2.5), resulting in improved anti-inflammatory effects in both mouse and rat models. Moreover, PX@CB[7] (1:2.5) had the least adhesion to the gastric mucosa and caused the mildest gastric side effects in rat models when compared to PX, PX@CD (1:2.5), and PX@CB[7] (1:1). Lastly, CB[7] demonstrated good oral biocompatibility in a subacute toxicity evaluation study. These findings indicate that CB[7] could be used as an excipient to improve treatment effectiveness and decrease adverse reactions in orally administered formulations with a favorable safety profile.

Identification and validation of DNA methylation markers to predict axillary lymph node metastasis of breast cancer.

BACKGROUND: Axillary lymph node metastasis (ALNM) is one of the most important prognostic factors for breast cancer patients, and DNA methylation is involved in ALNM of breast cancer. However, the methylation profile of breast cancer ALNM remains unknown. METHODS: Breast cancer tissues were collected from patients with and without ALNM. We investigated the genome-wide DNA methylation profile in breast cancer with and without ALNM using reduced representation bisulfite sequencing (RRBS). Then, differentially methylated regions (DMRs) were verified by targeted bisulfite sequencing. RESULTS: A total of 21491 DMRs were identified between the lymph node positive group and negative group. Compared to the LN-negative breast cancer, LN-positive breast cancer had 10,920 hypermethylated DMRs and 10,571 hypomethylated DMRs. Then, 10 DMRs in the gene promoter region were detected by targeted bisulfite sequencing, these gene included HOXA5, PTOV1-AS1, RHOF, PAX6, GSTP1, RASGRF2, AKR1B1, BNIP3, CRMP1, ING5. Compared with negative lymph node, the promoter methylation levels of RASGRF2, AKR1B1 and CRMP1 increased in positive lymph node, while the promoter methylation level of RHOF decreased in positive lymph node. In addition, Cancer Genome Atlas (TCGA) data showed that RASGRF2, AKR1B1 and CRMP1 were low expressed in breast Cancer tissues, while RHOF was high expressed in breast Cancer tissues. Furthermore, in addition to highly methylated AKR1B1, RASGRF2 and CRMP1 gene promoters, BNIP3, GSTP1, HOXA5 and PAX6 gene promoters were also methylated in ER-positive and HER2-negative breast cancer with ALNM. CONCLUSIONS: When compared to negative lymph node breast cancer, the positive lymph node breast cancer has a differential methylation status. Promoter methylation of RASGRF2, AKR1B1, CRMP1 and RHOF in lymph node positive breast cancer tissues was significantly different from that in lymph node negative breast cancer tissues. AKR1B1, RASGRF2, CRMP1, BNIP3, GSTP1, HOXA5 and PAX6 genes were methylated in ER-positive and HER2-negative breast cancer with ALNM. The study provides an important biological base for understanding breast cancer with ALNM and developing therapeutic targets for breast cancer with ALNM.

Epigallocatechin-3-gallate induces autophagy-related apoptosis associated with LC3B II and Beclin expression of bladder cancer cells.

The incidence of bladder cancer in traditional green tea-consuming countries was dramatically lower than low green tea-consuming countries. Epigallocatechin-3-gallate (EGCG), an active ingredient extracted from green tea, showed effective inhibition of formation and progression of many tumors. However, whether autophagy involved in this tumor-suppression mechanism of EGCG on bladder cancer was still unclear. In this study, we demonstrated low concentration of EGCG-induced proliferation inhibition and increased apoptosis in bladder cancer cell lines (5,637 and T24 cells) indicated by the increased expression of apoptosis-related protein (caspase9, caspase3 and BAX). In addition, low dose of EGCG also regulated autophagy pathway associated protein (LC3B II and Beclin) expression and this autophagy pathway was blocked by PI3K/AKT inhibitor; moreover, knockdown of ATG5 reversed EGCG-induced apoptosis in 5,637 cells, indicating that EGCG might inhibit the bladder cancer through autophagy pathway. Our findings indicated that EGCG should be considered as a novel therapy for bladder cancer treatment by regulating autophagy pathway. PRACTICAL APPLICATIONS: Our research proved EGCG from green tea could be used as an effective anti-tumor ingredient by revealing another mechanism that epigallocatechin-3-Gallate inhibited bladder cancer cells via inducing autophagy-related apoptosis. And green tea could be considered as a kind of tumor-preventing beverage.

Research on the performance degradation assessment method of a mine hoist braking system based on variable step-size fruit fly optimization algorithm-complex Gaussian wavelet support vector data description.

According to the characteristics of the constant deceleration braking system of hoist, a variable step-size fruit fly optimization algorithm-complex Gaussian wavelet support vector data description method is proposed in this article to evaluate the performance of the brake system. This method takes the pressure-time curve of safety braking as the characteristic data and extracts the candidate characteristic parameters from it. After the comprehensive evaluation of the characteristic parameters based on correlation, monotonicity, and predictability, the characteristic parameters are selected to evaluate the overall performance of the brake system. The proposed variable step-size fruit fly optimization algorithm-complex Gaussian wavelet support vector data description model avoids the situation where the classical Drosophila optimization algorithm is easy to fall into the local optimum. The reliability of the proposed method is verified by the simulation data, and the practicability of the proposed method is verified by the test-bed data. The performance evaluation model of variable step-size fruit fly optimization algorithm-complex Gaussian wavelet support vector data description is constructed, which realizes the quantitative evaluation of the brake system health state and provides technical support for the condition-based maintenance and intelligent maintenance of the hoist brake system.

[Experimental study of repairing fat defect with human hair keratin material].

OBJECTIVE: To investigate the feasibility of adipogenesis from human hair keratin (HHK) material, so as to provide a new method for fat defect and depression deformity. METHODS: 3 Tibet mini-pigs were used. 8 fat defects (1.5 cm in diameter) were made bilaterally on the back. The ball-shaped HHK material was implanted to repair the defects at one side. The defects at contralateral side were as controls. The absorption of the HHK material and adipogenesis were studied histologically. RESULTS: 2 weeks after implantation, connective tissue and capillary grew into the porous HHK material. 4 weeks after implantation, HHK material was almost totally absorbed, leaving some material debris and foreign body granuloma. Around them, there were clusters of adipocyte. 6 weeks after implantation, the HHK material was totally degraded and the granuloma was disappeared, and then de novo adipose tissue was observed. Its volume was close to the volume of peripheral HHK material that was planted originally. 10 weeks later, the new-formed fat tissue had less fibres and was very similar to the normal fat. CONCLUSIONS: New adipose tissue can be formed after HKK material implantation. It can also be remodeled to be similar to normal fat.