Discovery of novel thymidylate synthase (TS) inhibitors that influence cancer angiogenesis and metabolic reprogramming in NSCLC cells.

Based on previous work, further search for more effective and less damaging thymidylate synthase (TS) inhibitors was the focus of this study. After further optimization of the structure, in this study, a series of (E)-N-(2-benzyl hydrazine-1-carbonyl) phenyl-2,4-deoxy-1,2,3,4-tetrahydro pyrimidine-5-sulfonamide derivatives were synthesized and reported for the first time. All target compounds were screened by enzyme activity assay and cell viability inhibition assay. On the one hand, the hit compound DG1 could bind directly to TS proteins intracellularly and promote apoptosis in A549 and H1975 cells. Simultaneously, DG1 could inhibit cancer tissue proliferation more effectively than Pemetrexed (PTX) in the A549 xenograft mouse model. On the other hand, the inhibitory effect of DG1 on NSCLC angiogenesis was verified both in vivo and in vitro. In parallel, DG1 was further uncovered to inhibit the expression of CD26, ET-1, FGF-1, and EGF by angiogenic factor antibody microarray. Moreover, RNA-seq and PCR-array assays revealed that DG1 could inhibit NSCLC proliferation by affecting metabolic reprogramming. Collectively, these data demonstrated that DG1as a TS inhibitor could be promising in treating NSCLC angiogenesis, deserving further investigation.

Repairing Avascular Meniscal Lesions by Recruiting Endogenous Targeted Cells Through Bispecific Synovial-Meniscal Aptamers.

BACKGROUND: Tissue engineering is a promising treatment option for meniscal lesions in the avascular area, but a favorable cell source and its utilization in tissue-engineered menisci remain uncertain. Therefore, a more controllable and convenient method for cell recruitment is required. HYPOTHESIS: Circular bispecific synovial-meniscal (S-M) aptamers with a gelatin methacryloyl (GelMA) hydrogel can recruit endogenous synovial and meniscal cells to the site of the defect, thereby promoting in situ meniscal regeneration and chondroprotection. STUDY DESIGN: Controlled laboratory study. METHODS: Synovial and meniscal aptamers were filtered through systematic evolution of ligands by exponential enrichment (SELEX) and cross-linked to synthesize the S-M aptamer. A GelMA-aptamer system was constructed. An in vitro analysis of the bi-recruitment of synovial and meniscal cells was performed, and the migration and proliferation of the GelMA-aptamer hydrogel were also tested. For the in vivo assay, rabbits (n = 90) with meniscal defects in the avascular zone were divided into 3 groups: repair with the GelMA-aptamer hydrogel (GelMA-aptamer group), repair with the GelMA hydrogel (GelMA group), and no repair (blank group). Regeneration of the repaired meniscus and degeneration of the cartilage were assessed by gross and histological evaluations at 4, 8, and 12 weeks postoperatively. The mechanical properties of repaired menisci were also evaluated. RESULTS: In vitro synovial and meniscal cells were recruited simultaneously by the S-M aptamer with high affiliation and specificity. The GelMA-aptamer hydrogel promoted the migration of targeted cells. Compared with the other groups, the GelMA-aptamer group showed enhanced fibrocartilaginous regeneration, lower cartilage degeneration, and better mechanical strength at 12 weeks after meniscal repair. CONCLUSION/CLINICAL RELEVANCE: Bispecific S-M aptamers could be used for avascular meniscal repair by recruiting endogenous synovial and meniscal cells and promoting fibrocartilaginous regeneration.

Structural classification of MELK inhibitors and prospects for the treatment of tumor resistance: A review.

Maternal embryonic leucine zipper kinase (MELK), a member of the AMP-related serine-threonine kinase family, has been involved in regulating many cellular events, and aberrant MELK expression is associated with tumorigenesis and malignant progression in various cancers. More and more studies have found that MELK plays an essential regulatory role in tumor multidrug resistance or radio resistance. MELK inhibitors can also improve drug resistance caused by a gene mutation. These findings remind us that MELK could be a chemo- or radio-sensitizing target. However, it has also been found that most experiments on MELK rely on non-selective RNAi and small molecule reagents, which makes the results questionable, and thus the development of selective MELK inhibitors is still necessary. In this review, we summarized the identified regulatory pathways of MELK in tumor resistance and reclassified MELK inhibitors from a structural perspective. In addition, we discovered the glycosylation modification site of the MELK protein and discussed the possibility of continuing to develop small molecule inhibitors targeting the glycosylation modification site. These provide new strategies for developing selective MELK inhibitors and understanding the essential biological role of MELK in cancer.

Synthesis and evaluation of novel HER-2 inhibitors to exert anti-breast cancer ability through epithelial-mesenchymal transition (EMT) pathway.

Human epidermal growth factor receptor 2 (HER-2) is an essential member of the receptor tyrosine kinase (RTK) superfamily and has been reported as a critical method for treating HER-2 positive breast cancer. Here, we retained (E)-4-methyl-2-(4-(trifluoromethyl)styryl)oxazole, a fragment of HER-2 inhibitor Mubritinib, and synthesized 32 novel compounds from it. We screened out the most potential compound Q7j with HER-2 positive breast cancer cells through MTT assays, which possessed low toxicity on normal cells (MCF7-10A). Subsequently, wound healing, transwell, western blotting, and immunofluorescence experiments were performed, and it was found that compound Q7j could suppress cell migration by inhibiting the phosphorylation of HER-2 and affecting the expression of EMT-related proteins. Moreover, the SKBR3 orthotopic xenograft model confirmed that compound Q7j was more effective than Mubritinib in inhibiting the proliferation of cancer cells. In general, compound Q7j was a potential HER-2 inhibitor in treating breast cancer, which may be of great significance for developing and improving HER-2 small molecule inhibitors.

Discovery of N-(1,3,4-thiadiazol-2-yl)benzamide derivatives containing a 6,7-methoxyquinoline structure as novel EGFR/HER-2 dual-target inhibitors against cancer growth and angiogenesis.

Targeting EGFR and HER-2 is an essential direction for cancer treatment. Here, a series of N-(1,3,4-thiadiazol-2-yl)benzamide derivatives containing a 6,7-methoxyquinoline structure was designed and synthesized to serve as EGFR/HER-2 dual-target inhibitors. The kinase assays verified that target compounds could inhibit the kinase activity of EGFR and HER-2 selectively. The results of CCK-8 and 3D cell viability assays confirmed that target compounds had excellent anti-proliferation ability against breast cancer cells (MCF-7 and SK-BR-3) and lung cancer cells (A549 and H1975), particularly against SK-BR-3 cells, while the inhibitory effect on healthy breast cells (MCF-10A) and lung cells (Beas-2B) was weak. Among them, the hit compound YH-9 binded to EGFR and HER-2 stably in molecular dynamics studies. Further studies found thatYH-9could induce the release of cytochrome c and inhibit proliferation by promoting ROS expression in SK-BR-3 cells. Moreover,YH-9could diminish the secretion of VEGF and bFGF factors in SK-BR-3 cells, then inhibited tube formation and angiogenesis. Notably,YH-9could effectively inhibit breast cancer growth and angiogenesis with little toxicity in the SK-BR-3 cell xenograft model. Taken together,in vitroandin vivoresults revealed that YH-9 had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth and angiogenesis.

Effect of personality traits on rehabilitation effect after anterior cruciate ligament reconstruction: An observational study.

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction requires an extended period of postoperative rehabilitation. Psychological factors can affect recovery after surgery. Study of psychological factors is still limited to self-motivation, fear and pain. Study of personality traits associated with early rehabilitation outcome after ACL reconstruction is scarce. OBJECTIVE: We aimed to explore the effect of personality traits on early rehabilitation after ACL reconstruction and provide a reference for clinicians in designing a personalized rehabilitation plan. METHODS: This prospective analysis investigated 155 patients at 3 and 6 months after ACL reconstruction. Follow-up involved administration of a general data questionnaire, the Chinese Big Five Personality Inventory Brief Version, the Tegner activity score, the International Knee Documentation Committee Subjective Knee Score, the Knee injury and Osteoarthritis Outcome Score, the Lysholm Score and a balance test. RESULTS: Among the 155 patients included (124 males), Neuroticism was negatively correlated with subjective knee scores at 3 and 6 months after surgery (p<0.001). The odds of a poor balance test result was increased for each 1-point increase in Neuroticism score (odds ratio [OR] 1.74, 95% confidence interval [CI] 1.28-2.36, p<0.001). We found a positive correlation between Conscientiousness score and subjective knee scores at 3 and 6 months after surgery (p<0.001). For every 1-point increase in Conscientiousness score, the odds of a poor balance test result were decreased (OR 0.29, 95% CI 0.16-0.54, p<0.001). Agreeableness and Openness to experience scores were positively correlated with subjective knee scores at 3 and 6 months after surgery (p<0.001). We found no correlation between Extraversion and subjective knee scores at 3 and 6 months after surgery (p>0.05) but a positive correlation with the Tegner activity score at 3 and 6 months after surgery (p<0.05). CONCLUSION: We found a significant correlation between the Big Five personality dimensions and the early rehabilitation effect after ACL reconstruction, which can provide a reference for clinicians in designing a personalized rehabilitation plan.

Novel Allosteric Inhibitors of Deoxyhypusine Synthase against Malignant Melanoma: Design, Synthesis, and Biological Evaluation.

Based on the novel allosteric site of deoxyhypusine synthase (DHPS), two series of 30 novel 5-(2-methoxyphenoxy)-2-phenylpyrimidin-4-amine derivatives as DHPS inhibitors were designed and synthesized. Among them, compound 8m, with the best DHPS inhibitory potency (IC50 = 0.014 µM), exhibited excellent inhibition against melanoma cells, which was superior to that of GC7. Besides, molecular docking and molecular dynamics (MD) simulations further proved that compound 8m was tightly bound to the allosteric site of DHPS. Flow cytometric analysis and enzyme-linked immunosorbent assay (ELISA) showed that compound 8m could inhibit the intracellular reactive oxygen species (ROS) level. Furthermore, by western blot analysis, compound 8m effectively activated caspase 3 and decreased the expressions of GP-100, tyrosinase, eIF5A2, MMP2, and MMP9. Moreover, both Transwell analysis and wound healing analysis showed that compound 8m could inhibit the invasion and migration of melanoma cells. In the in vivo study, the tumor xenograft model showed that compound 8m effectively inhibited melanoma development with low toxicity.

Nanobubbles Water Curcumin Extract Reduces Injury Risks on Drop Jumps in Women: A Pilot Study.

PURPOSE: To verify the beneficial effects of Nanobubbles water curcumin extract (NCE) supplementation on health promotion and to demonstrate the application of NCE in reducing the risk of musculoskeletal injury. METHODS: In the current study, 12 females were randomly assigned to NCE (15g/day) and maltodextrin groups. Performance and related body composition were evaluated at 2 time points-presupplementation (pre-) and after 4 weeks of postsupplementation (post-). The posttest consists of a set of biochemical parameters for antifatigue activity and injury status evaluation. RESULTS: NCE group exhibited significantly lower levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), triglycerides (TG), and higher high-density lipoprotein (HDL) after a 4-week supplementation, compared with the placebo group. After a 15-minute session on the spinning bike, serum lactate and ammonia levels were decreased and glucose was economized in the NEC group. 4-week-NCE supplementation was also able to reduce the peak vertical ground reaction force (PVGRF) during drop jump. Therefore, the risk of musculoskeletal system in lower extremity could be reduced. CONCLUSION: We demonstrate that 4-week-NCE supplementation can also be used in explosiveness exercise for better physiological adaptation. Thus, NCE has potential for use with nutrient supplements toward a variety of benefits for athletics.

[Effect of compound nutrients on acute immobilization and cold water-immersion stress-induced changes of Th1/Th2 cytokines].

AIM: To investigate the effect of compound nutrients on Th1/Th2 imbalance caused by changes in cytokines of Th cell subsets, interleukin (IL)-2, IL-6 and TNF-α, in rats with acute immobilization and cold water-immersion stress. METHODS: Male SD rats were randomly assigned to three groups including normal control group (C), acute stress group (S) and acute stress+compound nutrients group (S+CN). Stress procedure was the acute immobilization and cold water-immersion. The stress rats were fed water (Group S) or compound nutrient liquid (Group S+CN) by a feeding needle 1 week before acute stress, and then restrained and immersed in cold water for 30 min. The control rats were given water in the same way without stress stimulation. The rats were killed and blood samples were collected 0, 30, 60 and 120 min after stress, respectively. Serum was separated by centrifugation and stored at -70 DegreesCelsius until assayed. The serum levels of IL-2, IL-6 and TNF-α were analyzed by an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: Acute immobilization and cold water-immersion stress reduced IL-2 level, and increased IL-6 and TNF-α level at different time points (0, 30, 60 and 120 min) after stress, which was most obvious at 30 min. Oral administration (gavage) of compound nutrients was found to moderate the acute immobilization and cold water-immersion stress-induced changes in serum IL-2, IL-6 and TNF-α, which was also most significant at 30 min after stress. CONCLUSION: Complex nutrients can significantly alleviate the changes of Th1/Th2 cytokines in stress rats, including IL-2, IL-6 and TNF-α, which suggests that compound nutrients can improve the immune regulation function of stress rats and restore Th1/Th2 balance. Compound nutrients might enhance the body's anti-stress ability and lighten the stress-related damage, thus being a possible candidate for the therapeutic modulation of stress.