Discovery of orally bioavailable ALK PROTACs based ceritinib against ALK positive cancers.

Anaplastic lymphoma kinase (ALK) fusion genes promote a variety of human malignancies. Although several ALK inhibitors have significantly improved disease prognosis in patients with ALK positive cancers, the persistent emergence of acquired drug-resistant mutations remain the major problem in clinic treatment. Adoption of new therapeutic strategies such as proteolysis targeting chimera (PROTAC) to overcome drug resistance in BTK/AR-related cancers have shown promising prospect. Herein, we reported the integrate ALK PROTACs through overall optimization of linker, revealed that subtle structural differences can lead to significant activity difference, indicating the key role of conformation of PROTACs in inducing the formation of E3-PROTAC-target protein ternary complexes. A series of rigid ALK PROTACs were developed through conjugation of Ceritinib and thalidomide, orally bioavailable PROTAC 4B (F = 14.22 %) was obtained by overall optimization of molecular properties. 4B effectively induced long lasting degradation of ALK fusion proteins and strong repression of downstream pathway in Karpas 299 cells (DC50 = 119.33 nM, Dmax = 97.1 %) and showed comparable anti-proliferative activity to Ceritinib (IC50 = 3.11 ± 0.08 nM vs IC50 = 1.31 ± 0.43 nM). Furthermore, 4B significantly inhibited the growth of Karpas 299 xenografts in vivo with TGI of 49.5 % and showed superior anti-proliferative activity against G1202R mutation to Ceritinib (IC50 = 52.82 nM vs IC50 = 109.5 nM). Overall, 4B is expected to be a potential treatment for ALK-driven malignancies.

Vascular wall microenvironment: Endothelial cells original exosomes mediated melatonin-suppressed vascular calcification and vascular ageing in a m6A methylation dependent manner.

Vascular calcification and vascular ageing are "silent" diseases but are highly prevalent in patients with end stage renal failure and type 2 diabetes, as well as in the ageing population. Melatonin (MT) has been shown to induce cardiovascular protection effects. However, the role of MT on vascular calcification and ageing has not been well-identified. In this study, the aortic transcriptional landscape revealed clues for MT related cell-to-cell communication between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in vascular calcification and vascular ageing. Furthermore, we elucidated that it was exosomes that participate in the information transportation from ECs to VSMCs. The exosomes secreted from melatonin-treated ECs (MT-ECs-Exos) inhibited calcification and senescence of VSMCs. Mechanistically, miR-302d-5p was highly enriched in MT-ECs-Exos, while depletion of miR-302d-5p blocked the ability of MT-ECs-Exos to suppress VSMC calcification and senescence. Notably, Wnt3 was a bona fide target of miR-302d-5p and modulated VSMC calcification and senescence. Furthermore, we found that maturation of endothelial derived exosomal miR-302d-5p was promoted by WTAP in an N6-methyladenosine (m6A)-dependent manner. Interestingly, MT alleviated vascular calcification and ageing in 5/6-nephrectomy (5/6 NTP) mice, a chronic kidney disease (CKD) induced vascular calcification and vascular ageing mouse model. MT-ECs-Exos was absorbed by VSMCs in vivo and effectively prevented vascular calcification and ageing in 5/6 NTP mice. ECs-derived miR-302d-5p mediated MT induced anti-calcification and anti-ageing effects in 5/6 NTP mice. Our study suggests that MT-ECs-Exos alleviate vascular calcification and ageing through the miR-302d-5p/Wnt3 signaling pathway, dependent on m6A methylation.

MiRNA-132/212 encapsulated by adipose tissue-derived exosomes worsen atherosclerosis progression.

BACKGROUND: Visceral adipose tissue in individuals with obesity is an independent cardiovascular risk indicator. However, it remains unclear whether adipose tissue influences common cardiovascular diseases, such as atherosclerosis, through its secreted exosomes. METHODS: The exosomes secreted by adipose tissue from diet-induced obesity mice were isolated to examine their impact on the progression of atherosclerosis and the associated mechanism. Endothelial apoptosis and the proliferation and migration of vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque were evaluated. Statistical significance was analyzed using GraphPad Prism 9.0 with appropriate statistical tests. RESULTS: We demonstrate that adipose tissue-derived exosomes (AT-EX) exacerbate atherosclerosis progression by promoting endothelial apoptosis, proliferation, and migration of VSMCs within the plaque in vivo. MicroRNA-132/212 (miR-132/212) was detected within AT-EX cargo. Mechanistically, miR-132/212-enriched AT-EX exacerbates palmitate acid-induced endothelial apoptosis via targeting G protein subunit alpha 12 and enhances platelet-derived growth factor type BB-induced VSMC proliferation and migration by targeting phosphatase and tensin homolog in vitro. Importantly, melatonin decreases exosomal miR-132/212 levels, thereby mitigating the pro-atherosclerotic impact of AT-EX. CONCLUSION: These data uncover the pathological mechanism by which adipose tissue-derived exosomes regulate the progression of atherosclerosis and identify miR-132/212 as potential diagnostic and therapeutic targets for atherosclerosis.

In-Situ Grown Nanocrystal TiO2 on 2D Ti3C2 Nanosheets with Anti-Tumor Activity from Photo-Sonodynamic Treatment and Immunology.

Introduction: Traditional cancer treatment strategies often have severe toxic side effects and poor therapeutic efficacy. To address the long-standing problems related to overcoming the complexity of tumors, we develop a novel nanozyme based on the in situ oxidation of 2D Ti3C2 structure to perform simultaneous phototherapy and sonodynamic therapy on tumors. Ti3C2 nanozymes exhibit multi-enzyme activity, including intrinsic peroxidase (POD) activities, which can react with H2O2 in the tumor microenvironment. This new material can construct Ti3C2/TiO2 heterostructures in vivo. Methods: Photothermal (PTT), sonodynamic (SDT) effects, and photoacoustic (PA) image-guided synergy therapy can be achieved. Finally, anticancer immune responses occur with this nanozyme. In vivo experiments revealed that the Ti3C2/TiO2 heterostructure inhibited tumor growth. Results: Complementarily, our results showed that the Ti3C2/TiO2 heterostructure enhanced the immunogenic activity of tumors by recruiting cytotoxic T cells, thereby enhancing the tumor ablation effect. Mechanistic studies consistently indicated that Reactive Oxygen Species (ROS) regulates apoptosis of HCC cells by modulating NRF2/OSGIN1 signaling both in vitro and in vivo. As a result, Ti3C2 nanozyme effectively inhibited tumor through its synergistic ability to modulate ROS and enhance immune infiltration of cytotoxic T cells in the tumor microenvironment. Discussion: These findings open up new avenues for enhancing 2D Ti3C2 nanosheets and suggest a new way to develop more effective sonosensitizers for the treatment of cancer.

USP7 deubiquitinates epigenetic reader ZMYND8 to promote breast cancer cell migration and invasion.

The ubiquitin-proteasome system (UPS), which involves E3 ligases and deubiquitinates (DUBs), is critical for protein homeostasis. The epigenetic reader ZMYND8 (zinc finger MYND-type containing 8) has emerged as an oncoprotein, and its protein levels are elevated in various types of cancer, including breast cancer. However, the mechanism by which ZMYND8 protein levels are increased in cancer remains elusive. Although ZMYND8 has been reported to be regulated by the E3 ligase FBXW7, it is still unknown whether ZMYND8 could be modulated by DUBs. Here, we identified USP7 (ubiquitin carboxyl-terminal hydrolase 7) as a bona fide DUB for ZMYND8. Mechanically, USP7 directly binds to the PBP (PHD-BRD-PWWP) domain of ZMYND8 via its TRAF (tumor necrosis factor receptor-associated factor) domain and UBL (ubiquitin-like) domain and removes F-box and WD repeat domain containing 7 (FBXW7)-catalyzed poly-ubiquitin chains on lysine residue 1034 (K1034) within ZMYND8, thereby stabilizing ZMYND8 and stimulating the transcription of ZMYND8 target genes ZEB1 (zinc finger E-box binding homeobox 1) and VEGFA (Vascular Endothelial Growth Factor A). Consequently, USP7 enhances the capacity of breast cancer cells for migration and invasion through antagonizing FBXW7-mediated ZMYND8 degradation. Importantly, the protein levels of USP7 positively correlates with those of ZMYND8 in breast cancer tissues. These findings delineate an important layer of migration and invasion regulation by the USP7-ZMYND8 axis in breast cancer cells.

Multidimensional impact of sport types on the psychological well-being of student athletes: A multivariate investigation.

The correlation between sports participation and psychological well-being is well-documented, revealing a complex interplay influenced by competition level and cultural context. This is particularly relevant in Korea, where the university sports culture significantly impacts student life. This study evaluates how competitive versus non-competitive sports affect Korean university students' psychological well-being using a quantitative approach with SmartPLS 4 for multi-group analysis. Findings reveal that competitive sports significantly enhance mental toughness and stress management through structured coping mechanisms and robust social support, improving coping strategy effectiveness by 34 % compared to non-competitive sports. Conversely, participants in non-competitive sports experience greater general well-being with a 40 % higher use of informal support. These insights suggest that university sports programs could benefit from targeted interventions incorporating specific coping strategies and social support frameworks tailored to the competitive context. This research underscores the need for precise stress management techniques and resilience-building exercises in sports curricula to optimize psychological well-being across different sports environments in Korean universities.

Eco-friendly, highly interpenetrated and slightly swollen pHEMA hydrogel foam for durable underwater superoleophobicity and emulsion separation.

Despite the emergence of hydrogels as ideal candidates for preparing the superhydrophilic materials for emulsion separation, their structural stability and swelling still hinder their long-term use, mainly due to structure defects after swelling. Herein, differing from the common modification, the eco-friendly poly 2-hydroxyethyl methacrylate (pHEMA) hydrogel foam was designed and synthesized via a one-step strategy by using the high internal phase emulsion (HIPE) template method, which endowed it with a highly interpenetrated porous structure. Unlike the normal swellable hydrogels such as poly(N-isoproplyacrylamide) (PNIPAM) hydrogel, or modified hydrogel coatings, the pHEMA hydrogel foam displayed stable structure and underwater superoleophobicity after 20 d of immersion in water. The pHEMA hydrogel foam could separate different kinds of highly surfactant-stabilized oil-in-water (O/W) emulsions with a high separation efficiency of 99.3% for liquid paraffin emulsion obtained solely under gravity-driven. Additionally, it exhibited excellent antifouling performance and long-term acid/alkali tolerance over 100 h without decrease in emulsion separation efficiency (98.0%, oil/water ratio of 99:1) and permeation flux (over 2000 L·m-2·h-1) attributed to its stable bulky structure. Moreover, the pHEMA hydrogel foam demonstrated high cell viability of 96.87% and 95.96% after culturing the 3T3 clone A31 cells in the pHEMA hydrogel foam for 24 h and 48 h, respectively, indicating good biocompatibility. Hence, our work provides a new design to develop an eco-friendly bulk hydrogel foam that achieves stable structure and performance for emulsion separation.

Cold exposure-induced plasma exosomes impair bone mass by inhibiting autophagy.

Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our present study, we observed that exposure to cold temperature (CT) decreased bone mass and quality in mice. Furthermore, a transplant of exosomes derived from the plasma of mice exposed to cold temperature (CT-EXO) can also impair the osteogenic differentiation of BMSCs and decrease bone mass by inhibiting autophagic activity. Rapamycin, a potent inducer of autophagy, can reverse cold exposure or CT-EXO-induced bone loss. Microarray sequencing revealed that cold exposure increases the miR-25-3p level in CT-EXO. Mechanistic studies showed that miR-25-3p can inhibit the osteogenic differentiation and autophagic activity of BMSCs. It is shown that inhibition of exosomes release or downregulation of miR-25-3p level can suppress CT-induced bone loss. This study identifies that CT-EXO mediates CT-induced osteoporotic effects through miR-25-3p by inhibiting autophagy via targeting SATB2, presenting a novel mechanism underlying the effect of cold temperature on bone mass.

Photothermal therapy of xenografted tumor by carbon nanoparticles-Fe(II) complex.

Due to the unique structure, carbon nanomaterials could convert near-infrared (NIR) light into heat efficiently in tumor ablation using photothermal therapy (PTT). However, none of them has been applied in clinical treatment, because they have not been approved for clinical evaluations and the precise temperature control facility is scarce. In this study, we designed a temperature-responsive controller for PTT and used carbon nanoparticles-Fe(II) complex (CNSI-Fe) as photothermal conversion agent (PTA) for PTT of tumor in vitro and in vivo. CNSI-Fe was an innovative drug under the evaluations in clinical trials. CNSI-Fe showed excellent photothermal conversion ability in water to increase the water temperature by 40 °C within 5 min under irradiation of 808 nm laser at 0.5 W/cm2. The temperature was precisely controlled at 52 °C for both in vitro and in vivo tumor inhibition. CNSI-Fe with NIR irradiation showed higher tumor cell inhibition than CNSI. In tumor bearing mice, CNSI-Fe with NIR irradiation achieved an inhibition rate of 84.7 % and 71.4 % of them were completely cured. Mechanistically, CNSI-Fe under NIR irradiation induced the radical generation, oxidative damage and ferroptosis to kill tumor. In addition, CNSI-Fe showed good biosafety during PTT according to hematological, serum biological and histopathological examinations. These results indicated that the combination of chemotherapy and PTT provided higher antitumor efficiency using CNSI-Fe as PTA.