CircORC2 promoted proliferation and inhibited the sensitivity of osteosarcoma cell lines to cisplatin by regulating the miR-485-3p/TRIM2 axis.

Resistance to chemotherapy leads to poor prognosis for osteosarcoma (OS) patients. However, due to the high metastasis of tumor and the decrease in sensitivity of tumor cells to cisplatin (DDP), the 5-year survival rate of OS patients is still unsatisfactory. This study explored a mechanism for improving the sensitivity of OS cells to DDP. A DDP-resistant OS cell model was established, and we have found that circORC2 and TRIM2 were upregulated in DDP-resistant OS cells, but miR-485-3p was downregulated. The cell viability and proliferation of the OS cells decreased gradually with the increase of DDP dose, but a gradual increase in apoptosis was noted. CircORC2 promoted OS cell proliferation and DDP resistance and upregulated TRIM2 expression by targeting miR-485-3p. Functionally, circORC2 downregulated miR-485-3p to promote OS cell proliferation and inhibit DDP sensitivity. Additionally, it promoted cell proliferation and inhibited the sensitivity of DDP by regulating the miR-485-3p/TRIM2 axis. In conclusion, circORC2 promoted cell proliferation and inhibited the DDP sensitivity in OS cells via the miR-485-3p/TRIM2 axis. These findings indicated the role of circORC2 in regulating the sensitivity of OS cells to DDP.

LncRNA SNHG12 suppresses adipocyte inflammation and insulin resistance by regulating the HDAC9/Nrf2 axis.

Obesity is often associated with low-grade inflammation. The incidence of obesity has increased annually worldwide, which seriously affects human health. A previous study indicated that long noncoding RNA SNHG12 was downregulated in obesity. Nevertheless, the role of SNHG12 in obesity remains to be elucidated. In this study, qRT-PCR, western blot, and ELISA were utilized to examine the gene and protein expression. Flow cytometry was employed to investigate the M2 macrophage markers. RNA pull-down assay and RIP were utilized to confirm the interactions of SNHG12, hnRNPA1, and HDAC9. Eventually, a high-fat diet-fed mouse model was established for in vivo studies. SNHG12 overexpression suppressed adipocyte inflammation and insulin resistance and promoted M2 polarization of macrophages that was caused by TNF-α treatment. SNHG12 interacted with hnRNPA1 to downregulate HDAC9 expression, which activated the Nrf2 signaling pathway. HDAC9 overexpression reversed the effect of SNHG12 overexpression on inflammatory response, insulin resistance, and M2 phenotype polarization. Overexpression of SNHG12 improved high-fat diet-fed mouse tissue inflammation. This study revealed the protective effect of SNHG12 against adipocyte inflammation and insulin resistance. This result further provides a new therapeutic target for preventing inflammation and insulin resistance in obesity.

Design, synthesis and antitumor activity of a novel FGFR2-selective degrader to overcome resistance of the FGFR2V564F gatekeeper mutation based on a pan-FGFR inhibitor.

Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR inhibitors have been approved by the FDA, their long-term therapeutic efficacy is hampered by acquired resistance to gatekeeper mutations and low subtype selectivity. FGFR2 has been found to be frequently amplified or mutated in many tumors. In this study, we designed several PROTACs with different E3 ligands based on LY2874455. By screening the length of the linker and the binding site in various degraders, we obtained a novel and highly efficient FGFR2-selective degrader 28e (DC50 = 0.645 nM, DCmax = 86 %). Compound 28e selectively degraded FGFR2 and essentially avoided degradation of FGFR1,3,4 isoforms (DC50 > 300 nM). Compound 28e significantly inhibited the proliferation of FGFR2-overexpressing cell lines, including KATOIII, SNU16, and AN3CA (IC50 = 0.794 nM/0.207 nM/4.626 nM), comparable to parental inhibitors. At the same time, the preferred compound showed superiority over the parental inhibitor in kinase inhibitory activity against the gatekeeper mutant isoform FGFR2V564F (IC50 = 0.121 nM). In summary, we identified 28e as a novel selective degrader of FGFR2 with high potency and high potential to overcome resistance to gatekeeper mutation. The discovery of 28e provides new evidence for the strategy of pan-inhibitor-based development of selective degrading agents.

ANCA-associated systemic vasculitis initially mimicking peripheral neuropathy in an elderly woman.

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated systemic vasculitis (AASV) is a rare systemic immunological condition that predominantly impacts small arteries, veins, and capillaries, often leading to kidney damage and pulmonary injury. It is important to note that individuals primarily presenting with peripheral neuropathy (PN) are uncommon in AASV, which can result in significant misdiagnosis or undiagnosed cases. The severity and location of PN can vary among patients. In this article, we present a case of an AASV patient initially showing signs of PN. This case highlights the significance of considering AASV as a potential cause of unexplained neurological symptoms. Timely identification and proper treatment are essential for improving the survival rate and functional prognosis of AASV patients.

Alterations of DNA methylation profile in peripheral blood of children with simple obesity.

Purpose: To investigate the association between DNA methylation and childhood simple obesity. Methods: Genome-wide analysis of DNA methylation was conducted on peripheral blood samples from 41 children with simple obesity and 31 normal controls to identify differentially methylated sites (DMS). Subsequently, gene functional analysis of differentially methylated genes (DMGs) was carried out. After screening the characteristic DMGs based on specific conditions, the methylated levels of these DMS were evaluated and verified by pyrosequencing. Receiver operating characteristic (ROC) curve analysis assessed the predictive efficacy of corresponding DMGs. Finally, Pearson correlation analysis revealed the correlation between specific DMS and clinical data. Results: The overall DNA methylation level in the obesity group was significantly lower than in normal. A total of 241 DMS were identified. Functional pathway analysis revealed that DMGs were primarily involved in lipid metabolism, carbohydrate metabolism, amino acid metabolism, human diseases, among other pathways. The characteristic DMS within the genes Transcription factor A mitochondrial (TFAM) and Piezo type mechanosensitive ion channel component 1(PIEZO1) were recognized as CpG-cg05831083 and CpG-cg14926485, respectively. Furthermore, the methylation level of CpG-cg05831083 significantly correlated with body mass index (BMI) and vitamin D. Conclusions: Abnormal DNA methylation is closely related to childhood simple obesity. The altered methylation of CpG-cg05831083 and CpG-cg14926485 could potentially serve as biomarkers for childhood simple obesity. Supplementary Information: The online version contains supplementary material available at 10.1007/s13755-024-00275-w.

The Monocyte-to-Lymphocyte Ratio on the 6th Day Postburn Is Associated with Clinical Outcome of Severe Burns.

OBJECTIVE: As an immune/inflammatory indicator, the application of monocyte-lymphocyte ratio (MLR) in the treatment of severe burns is lacking. The aim of this study was to investigate the dynamic changes of the MLR value in the early stage of severe burns and its clinical value. METHODS: This is a 5-year retrospective cohort study involving 100 patients with severe burns (II-III degree and total body surface area (TBSA) >50%), in which the lymphocyte count, monocyte count, MLR value, C-reactive protein (CRP), creatinine (Scr), and capillary leakage index (CLI) were evaluated soon after injury, and 30-day mortality rates were investigated. RESULTS: The MLR values in non-survivors with severe burns were higher than those in survivors in the first two days after injury, while the values on the 3rd, 5th, 6th and 7th day after injury were lower than those in survivors. The differences between the 6th and 7th days after injury were statistically significant. According to the results of logistic and Cox regression analysis, the MLR values on the 6th day after injury were independent predictors of mortality, and the area under the ROC curve of the 6th day MLR for severe burn-delayed death prediction was 0.658 (95% confidence interval, 0.541-0.774), and the optimal cut-off value was 0.991. The 30-day mortality rates differed significantly between the MLR6 ≥0.991 group and the MLR6≤0.991 group (P<0.05). Within one week after injury, the MLR values were negatively correlated with Scr, CRP and CLI levels for severe burns. CONCLUSIONS: Our results revealed the dynamic characteristics of the MLR value in the early stage of severe burns, reflecting important changes in the immune/inflammatory related stress response soon after injury, low MLR level was associated with the worsening of disease condition.

A biological age model based on physical examination data to predict mortality in a Chinese population.

Biological age could be reflective of an individual's health status and aging degree. Limited estimations of biological aging based on physical examination data in the Chinese population have been developed to quantify the rate of aging. We developed and validated a novel aging measure (Balanced-AGE) based on readily available physical health examination data. In this study, a repeated sub-sampling approach was applied to address the data imbalance issue, and this approach significantly improved the performance of biological age (Balanced-AGE) in predicting all-cause mortality with a 10-year time-dependent AUC of 0.908 for all-cause mortality. This mortality prediction tool was found to be effective across different subgroups by age, sex, smoking, and alcohol consumption status. Additionally, this study revealed that individuals who were underweight, smokers, or drinkers had a higher extent of age acceleration. The Balanced-AGE may serve as an effective and generally applicable tool for health assessment and management among the elderly population.

Controllable Circularly Polarized Luminescence with High Dissymmetry Factor via Co-Assembly of Achiral Dyes in Liquid Crystal Polymer Films.

Circularly polarized luminescence (CPL) materials are highly demanded due to their great potential in optoelectronic and chiroptical elements. However, the preparation of CPL films with high luminescence dissymmetry factors (glum ) remains a formidable task, which impedes their practical application in film-based devices. Herein, a facile strategy to prepare solid CPL film with a high glum through exogenous chiral induction and amplification of liquid crystal polymers is proposed. Amplification and reversion of the CPL appear when the films are annealed at the chiral nematic liquid crystalline temperature and the maximal glum up to 0.30 due to the enhancement of selective reflection. Thermal annealing treatment at different liquid crystalline states facilitates the formation of the chiral liquid phase and adjusts the circularly polarized emission. This work not only provides a straightforward and versatile platform to construct organic films capable of exhibiting strong circularly polarized emission but also is helpful in understanding the exact mechanism for the liquid crystal enhancement of CPL performance.

Pulmonary Adenoid Cystic Carcinoma Mimicking Asthma-Like Symptoms: A Case Report and Literature Review.

Introduction: Pulmonary adenoid cystic carcinoma (PACC) is a rare, low-grade malignant salivary gland-type tumor characterized by a dormant onset and slow progression, often leading to misdiagnosis. Due to its rarity, limited cases have been reported in the literature. This report aimed to enhance clinicians' understanding of this infrequent disease. Case Presentation: We present the case of a 41-year-old female patient diagnosed with PACC. Our report provides a comprehensive analysis of the patient's imaging, pathology, and treatment, with a particular focus on immunohistochemical results. Importantly, we emphasize the significance of considering foreign bodies and tumors in the bronchus when encountering asthma-like symptoms unresponsive to conventional treatments. Due to the uncertain etiology and pathophysiology of PACC, there are currently no established guidelines for chemotherapy and radiotherapy. Conclusion: PACC predominantly manifests as bronchial lesions without significant clinical heterogeneity. Therefore, it is crucial to consider foreign bodies and tumors in the bronchus when dealing with asthma-like symptoms, especially in patients without chronic lung disease who do not respond to anti-infective, antispasmodic, and antiasthmatic treatments. Additionally, meticulous examination of lesions is essential for timely diagnosis and intervention, ultimately improving patient survival rates.

Postnatal feeding with high-fat combined with high-glucose diet induces precocious puberty in Sprague‒Dawley rat pups.

With economic development and overnutrition, including high-fat diets (HFD) and high-glucose diets (HGD), the incidence of obesity in children is increasing, and thus, the incidence of precocious puberty is increasing. Therefore, it is of great importance to construct a suitable animal model of overnutrition-induced precocious puberty for further in-depth study. Here, we fed a HFD, HGD, or HFD combined with a HGD to pups after P-21 weaning, while weaned pups fed a normal diet served as the control group. The results showed that HFD combined with a HGD increased the body weight (BW) of weaned rat pups. In addition, a HFD, HGD, and HFD combined with a HGD lowered the age at which vaginal opening occurred and accelerated the vaginal cell cycle. Furthermore, a HFD combined with a HGD increased the weight of the uterus and ovaries of weaned rat pups. Additionally, a HFD combined with a HGD promoted the development of reproductive organs in weaned female rat pups. Ultimately, a HFD combined with a HGD was found to elevate the serum levels of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH), leptin, adiponectin, and oestradiol (E2) and increase hypothalamic GnRH, Kiss-1, and GPR54 expression levels in weaned female rat pups. The current study found that overnutrition, such as that through a HFD combined with HGD, could induce precocious puberty in weaned female rat pups. In addition, a rat model of overnutrition-induced precocious puberty was established.

SMURF1 activates the cGAS/STING/IFN-1 signal axis by mediating YY1 ubiquitination to accelerate the progression of lupus nephritis.

Aggravated endoplasmic reticulum stress (ERS) and apoptosis in podocytes play an important role in lupus nephritis (LN) progression, but its mechanism is still unclear. Herein, the role of SMURF1 in regulating podocytes apoptosis and ERS during LN progression were investigated. MRL/lpr mice was used as LN model in vivo. HE staining was performed to analyze histopathological changes. Mouse podocytes (MPC5 cells) were treated with serum IgG from LN patients (LN-IgG) to construct LN model in vitro. CCK8 assay was adopted to determine the viability. Cell apoptosis was measured using flow cytometry and TUNEL staining. The interactions between SMURF1, YY1 and cGAS were analyzed using ChIP and/or dual-luciferase reporter gene and/or Co-IP assays. YY1 ubiquitination was analyzed by ubiquitination analysis. Our results found that SMURF1, cGAS and STING mRNA levels were markedly increased in serum samples of LN patients, while YY1 was downregulated. YY1 upregulation reduced LN-IgG-induced ERS and apoptosis in podocytes. Moreover, SMURF1 upregulation reduced YY1 protein stability and expression by ubiquitinating YY1 in podocytes. Rescue studies revealed that YY1 knockdown abrogated the inhibition of SMURF1 downregulation on LN-IgG-induced ERS and apoptosis in podocytes. It was also turned out that YY1 alleviated podocytes injury in LN by transcriptional inhibition cGAS/STING/IFN-1 signal axis. Finally, SMURF1 knockdown inhibited LN progression in vivo. In short, SMURF1 upregulation activated the cGAS/STING/IFN-1 signal axis by regulating YY1 ubiquitination to facilitate apoptosis in podocytes during LN progression.

Dual gene-activated dermal scaffolds regulate angiogenesis and wound healing by mediating the coexpression of VEGF and angiopoietin-1.

The vascularization of dermal substitutes is a key challenge in efforts to heal deep skin defects. In this study, dual gene-activated dermal scaffolds (DGADSs-1) were fabricated by loading nanocomposite particles of polyethylenimine (PEI)/multiple plasmid DNAs (pDNAs) encoding vascular endothelial growth factor and angiopoietin-1 at a ratio of 1:1. In a similar manner, DGADSs-2 were loaded with a chimeric plasmid encoding both VEGF and Ang-1. In vitro studies showed that both types of DGADSs released PEI/pDNA nanoparticles in a sustained manner; they demonstrated effective transfection ability, leading to upregulated expression of VEGF and Ang-1. Furthermore, both types of DGADSs promoted fibroblast proliferation and blood vessel formation, although DGADSs-1 showed a more obvious promotion effect. A rat full-thickness skin defect model showed that split-thickness skin transplanted using a one-step method could achieve full survival at the 12th day after surgery in both DGADSs-1 and DGADSs-2 groups, and the vascularization time of dermal substitutes was significantly shortened. Compared with the other three groups of scaffolds, the DGADSs-1 group had significantly greater cell infiltration, collagen deposition, neovascularization, and vascular maturation, all of which promoted wound healing. Thus, compared with single-gene-activated dermal scaffolds, DGADSs show greater potential for enhancing angiogenesis. DGADSs with different loading modes also exhibited differences in terms of angiogenesis; the effect of loading two genes (DGADSs-1) was better than the effect of loading a chimeric gene (DGADSs-2). In summary, DGADSs, which continuously upregulate VEGF and Ang-1 expression, offer a new functional tissue-engineered dermal substitute with the ability to activate vascularization.

A non-linear relationship between triglyceride glucose waist circumference and nonalcoholic fatty liver disease in a Japanese population: a secondary analysis.

Introduction: Nonalcoholic fatty liver disease (NAFLD) is a common metabolic disorder associated with insulin resistance (IR). Triglyceride glucose waist circumference (TyG-WC) is a novel index of IR that reflects both visceral fat and hepatic steatosis. However, it is not known whether TyG-WC and NAFLD exhibit a nonlinear relationship in Japanese subjects with normal plasma glucose level. Thus, we examined the relationship between TyG-WC and NAFLD, in addition to determining the threshold level of TyG-WC associated with NAFLD. Methods: A secondary analysis was performed based on a previous study that extracted medical examination records from Murakami Memorial Hospital between 2004 and 2015 in order to detect chronic diseases and their risk factors. TyG-WC was determined at baseline. NAFLD is the dependent variable. Univariate and multivariate logistic regression models were used to evaluate the risk of NAFLD incidence. Based on the smoothing plot, a two-piecewise linear regression model was used to examine the threshold effect of TyG-WC on NAFLD. A subgroup analysis was carried out in order to study other factors that may influence the association between TyG-WC and NAFLD. Results: 14,280 met the criteria for inclusion in the current secondary analysis. The adjusted OR (95% CI) for NAFLD in all subjects was 1.007 (95% CI 1.006-1.009, P < 0.001). The relationship between TyG-WC and NAFLD in Japanese subjects with normal plasma glucose level is nonlinear. TyG-WC is positively associated with NAFLD when TyG-WC is ranged between 480 and 800. In subgroup analyses, there was a significant interaction between BMI and TyG-WC associated NAFLD risk (P for interaction <0.001). Discussion: The relationship between TyG-WC and NAFLD is nonlinear. TyG-WC is positively associated with NAFLD when TyG-WC is ranged between 480 and 800. There is potential clinical significance for the TyG-WC in identifying groups at high risk for NAFLD in subjects with normal plasma glucose level.

Design, synthesis and biological evaluation of indazole derivatives as selective covalent inhibitors of FGFR4 in wild-type and gatekeeper mutants.

Fibroblast growth factor receptor 4 (FGFR4) has been proved to be an effective target for cancer therapy. Aberration in FGF19/FGFR4 signaling is oncogenic driving force in human hepatocellular carcinoma (HCC). FGFR4 gatekeeper mutations induced acquired resistance remains an unmet clinical challenge for HCC treatment. In this study, a series of 1H-indazole derivatives were designed and synthesized as new irreversible inhibitors of wild-type and gatekeeper mutant FGFR4. These new derivatives showed significant FGFR4 inhibitory and antitumor activities, among which compound 27i was demonstrated to be the most potent compound (FGFR4 IC50 = 2.4 nM). Remarkably, compound 27i exhibited no activity against a panel of 381 kinases at 1 µM. Additionally, compound 27i displayed nanomolar IC50s against huh7 (IC50 = 21 nM) and two mutant cell lines, BaF3/ETV6-FGFR4-V550L and BaF3/ETV6-FGFR4-N535K (IC50 = 2.5/171 nM). Meanwhile, compound 27i exhibited potent antitumor potency (TGI: 83.0%, 40 mg/kg, BID) in Huh7 xenograft mouse models with no obvious toxicity observed. Overall, compound 27i was identified as a promising preclinical candidate for overcoming FGFR4 gatekeeper mutations for HCC treatment.

Machine-Learning-Enabled Framework in Engineering Plastics Discovery: A Case Study of Designing Polyimides with Desired Glass-Transition Temperature.

Great and continuous efforts have been made to discover high-performance engineering plastics with specific properties to replace traditional engineering materials in many fields. The utilization of machine learning (ML) has brought more opportunities for the discovery of high-performing engineering plastics. However, hindered by either the relatively small database or a lack of accurate structure descriptors with clear physical and chemical meanings relating to polymer properties, the current ML studies show some flaws in the accuracy and efficiency in polymer development. Herein, we collected a dataset of 878 polyimides (PI), one of the best engineering plastics, with experimentally measured glass-transition temperature (Tg) values, and developed a rapid and accurate ML approach to design PI candidates with the desired Tg value. After the conversion from PI structures into "mechanically identifiable" SMILES (Simplified molecular input line entry system) language, the eight most critical descriptors were ultimately obtained by multiple analysis methods. The physiochemical meaning of the key descriptors was further analyzed carefully to translate the implicit "machine language" to chemical knowledge. The artificial neural network (ANN)-based model gave the most accurate results with a root-mean-square error of ∼11 K among the studied ML methods. More importantly, three potential PI candidates with desired Tg (DPIs) were designed according to the chemical insight of the key descriptors, which were then verified by experiments. The experimental and predicted Tg values of DPIs have an acceptable average deviation of ca. 3.66%. This accuracy has reached the level of the traditional molecular simulation, but the time consumption and hold-up computing resource are tremendously reduced. Furthermore, the current ML approach could offer a scalable and adaptable framework in future engineer plastics innovation.

Plasma amino acids by age and gender in Hangzhou, Eastern China.

BACKGROUND AND OBJECTIVES: Amino acids (AAs) are crucial nutrients and fundamental building blocks of organisms that can be utilized to assess nutritional status and detect diseases. However, insufficient information has been reported on plasma AA in the Eastern Chinese population. METHODS AND STUDY DESIGN: 1859 persons who underwent physical examination in our hospital from January to December 2020 were enrolled. Plasma AA levels were determined by ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS.), and the effects of age and sex on 19 plasma AA profiles were analyzed. The Python language was used for data analysis and graphic visualization. RESULTS: Plasma arginine, proline, threonine, as-paragine, phenylalanine, and glycine in males, and plasma lysine, leucine, proline, valine, isoleucine, alanine, tyrosine, phenylalanine, and hydroxyproline levels in females increased with age. The 2-aminobutyric acid and serine levels in both sexes, and isoleucine, valine, leucine, and histidine levels in males decreased with age. Glycine level was higher in females than in males, and other 17 AAs except arginine and aspartate were higher in males than in females. CONCLUSIONS: Our study indicated that plasma AA levels can reflect the nutritional status and dietary structure of the population, with high obesity rate and high incidence of chronic diseases in eastern China. Age has certain effects on plasma AA levels, especially compared with sex.

Gut microbiome combined with metabolomics reveals biomarkers and pathways in central precocious puberty.

BACKGROUND: Central precocious puberty (CPP) is a common disease in prepubertal children and results mainly from disorders in the endocrine system. Emerging evidence has highlighted the involvement of gut microbes in hormone secretion, but their roles and downstream metabolic pathways in CPP remain unknown. METHODS: To explore the gut microbes and metabolism alterations in CPP, we performed the 16S rRNA sequencing and untargeted metabolomics profiling for 91 CPP patients and 59 healthy controls. Bioinformatics and statistical analyses, including the comparisons of alpha and beta diversity, abundances of microbes, were undertaken on the 16S rRNA gene sequences and metabolism profiling. Classifiers were constructed based on the microorganisms and metabolites. Functional and pathway enrichment analyses were performed for identification of the altered microorganisms and metabolites in CPP. RESULTS: We integrated a multi-omics approach to investigate the alterations and functional characteristics of gut microbes and metabolites in CPP patients. The fecal microbiome profiles and fecal and blood metabolite profiles for 91 CPP patients and 59 healthy controls were generated and compared. We identified the altered microorganisms and metabolites during the development of CPP and constructed a machine learning-based classifier for distinguishing CPP. The Area Under Curves (AUCs) of the classifies were ranged from 0.832 to 1.00. In addition, functional analysis of the gut microbiota revealed that the nitric oxide synthesis was closely associated with the progression of CPP. Finally, we investigated the metabolic potential of gut microbes and discovered the genus Streptococcus could be a candidate molecular marker for CPP treatment. CONCLUSIONS: Overall, we utilized multi-omics data from microorganisms and metabolites to build a classifier for discriminating CPP patients from the common populations and recognized potential therapeutic molecular markers for CPP through comprehensive analyses.

A novel VEGFR inhibitor ZLF-095 with potent antitumor activity and low toxicity.

Angiogenesis plays a critical role in the survival, progression and metastasis of malignant tumors. Multiple factors are known to induce tumor angiogenesis, vascular endothelial growth factor (VEGF) is the most important one. Lenvatinib is an oral multi-kinase inhibitor of VEGFRs which has been approved for the treatment of various malignancies as the first-line agent by the Food and Drug Administration (FDA). It shows excellent antitumor efficacy in clinical practice. However, the adverse effects of Lenvatinib may seriously impair the therapeutic effect. Here we report the discovery and characterization of a novel VEGFR inhibitor (ZLF-095), which exhibited high activity and selectivity for VEGFR1/2/3. ZLF-095 displayed apparently antitumor effect in vitro and in vivo. We discovered that Lenvatinib could provoke fulminant ROS-caspase3-GSDME-dependent pyroptosis in GSDME-expressing cells by loss of mitochondrial membrane potential, which may be one of the reasons for Lenvatinib's toxicity. Meanwhile, ZLF-095 showed less toxicity than Lenvatinib by switching pyroptosis to apoptosis. These results suggest that ZLF-095 could become a potential angiogenesis inhibitor for cancer therapy.

EGCG Restores Keratinocyte Autophagy to Promote Diabetic Wound Healing through the AMPK/ULK1 Pathway.

BACKGROUND: Delayed wound healing, a common problem in patients with diabetes mellitus (DM), is associated with impaired keratinocyte autophagy. Epigallocatechin gallate (EGCG), a catechin, has been proven to promote diabetic wound healing. This study aims to explore the therapeutic mechanism of EGCG on diabetic wound healing. METHODS: High glucose (HG)-induced keratinocytes and streptozotocin (STZ)-induced DM rats were prepared and intervened with EGCG to examine its therapeutic effects in in vivo and in vitro settings. The AMPK inhibitor, Compound C, was utilized to determine whether EGCG exerted its therapeutic effects through the AMPK/ULK1 pathway. RESULTS: In vitro, EGCG improved HG-induced autophagy impairment in keratinocytes by increasing LC3II/LC3I, Becline1, and ATG5 levels and decreasing p62 level. Mechanically, EGCG activated the AMPK/ULK1 pathway, thereby promoting keratinocyte autophagy through the phosphorylation of AMPK and ULK1. Notably, EGCG promoted the proliferation, migration, synthesis and release of C-C motif chemokine ligand 2 (CCL2) in HG-treated keratinocytes. Furthermore, EGCG indirectly promoted the activation of fibroblasts, as evidenced by increased alpha-smooth muscle actin (α-SMA) and Collagen I levels. In vivo, EGCG promoted wound healing in DM rats, primarily by reducing inflammatory infiltration and increasing granulation tissue to promote wound epithelialization. Besides, EGCG promoted ATG5, KRT10, KRT14, TGF-ß1, Collagen I, and α-SMA expressions in the neonatal epithelial tissues of DM rats. However, the use of Compound C reversed the effects of EGCG. CONCLUSIONS: These findings indicated that EGCG restored keratinocyte autophagy to promote diabetic wound healing through the AMPK/ULK1 pathway.