MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation.

CDK4/6 inhibitors (CDK4/6i) show anticancer activity in certain human malignancies, such as breast cancer. However, their application to other tumor types and intrinsic resistance mechanisms are still unclear. Here, we demonstrate that MYC amplification confers resistance to CDK4/6i in bladder, prostate and breast cancer cells. Mechanistically, MYC binds to the promoter of the E3 ubiquitin ligase KLHL42 and enhances its transcription, leading to RB1 deficiency by inducing both phosphorylated and total pRB1 ubiquitination and degradation. We identify a compound that degrades MYC, A80.2HCl, which induces MYC degradation at nanomolar concentrations, restores pRB1 protein levels and re-establish sensitivity of MYC high-expressing cancer cells to CDK4/6i. The combination of CDK4/6i and A80.2HCl result in marked regression in tumor growth in vivo. Altogether, these results reveal the molecular mechanisms underlying MYC-induced resistance to CDK4/6i and suggest the utilization of the MYC degrading molecule A80.2HCl to potentiate the therapeutic efficacy of CDK4/6i.

Quercetin and its derivatives for wound healing in rats/mice: Evidence from animal studies and insight into molecular mechanisms.

Aimed to clarify the effect of quercetin and its derivatives on wound healing in animal experiments. PubMed, Embase, Science Direct, Web of Science, SinoMed, Vip Journal Integration Platform, China National Knowledge Infrastructure and WanFang databases were searched for animal experiments investigating the effect of quercetin and its derivatives on wound healing to April 2023. The Review Manager 5.4 software was used to conduct meta-analysis. Eighteen studies were enrolled in this article. According to the SYRCLE's RoB tool assessment, these studies exposed relatively low methodological quality. It was shown that animals with cutaneous wound receiving quercetin had faster wound healing in wound closure (%) than the control group. Moreover, the difference in efficacy gradually emerged after third day (WMD = 7.13 [5.52, 8.74]), with a peak reached on the tenth day after wounding (WMD = 19.78 [17.82, 21.74]). Subgroup analysis revealed that quercetin for wound closure (%) was independent of the types of rats and mice, wound area and with or without diabetes. Clear conclusion was also shown regarding the external application of quercetin for wound healing (WMD = 17.77 [11.11, 24.43]). A significant reduction in the distribution of inflammatory cells occurred in the quercetin group. Quercetin could increase blood vessel density (WMD = 1.85 [0.68, -3.02]), fibroblast distribution and collagen fraction. Biochemical indicators, including IL-1ß, IL-10, TNF-α, TGF-ß, vascular endothelial growth factor (VEGF), hydroxyproline and alpha-smooth muscle actin (α-SMA), had the consistent results. Quercetin and its derivatives could promote the recovery of cutaneous wound in animals, through inhibiting inflammatory response and accelerating angiogenesis, proliferation of fibroblast and collagen deposition.

Network pharmacology and molecular docking reveal the mechanism of Qinghua Xiaoyong Formula in Crohn's disease.

Crohn's disease (CD) is a chronic inflammatory illness of the digestive system with unknown etiology, and its incidence is increasing worldwide. However, there are currently no effective treatments or medications available for individuals with CD. Therefore, novel therapeutic strategies are urgently needed. The bioactive compounds and targets associated with compounds of Qinghua Xiaoyong Formula (QHXYF) were examined using The Traditional Chinese Medicine Systems Pharmacology database, and 5 disease target databases were also used to identify CD-related disease targets. A total of 166 overlapping targets were identified from QHXYF-related and CD-related disease targets and they were found to be enriched in oxidative stress-related pathways and the PI3K/AKT signaling pathway. Molecular docking was then used to predict how the bioactive compounds would bind to the hub targets. It was found that quercetin could be the core bioactive compound and had good binding affinity to the top 5 hub targets. Finally, animal experiments were performed to further validate the findings, and the results revealed that QHXYF or quercetin inhibited 2,4,6-trinitrobenzenesulfonic acid-induced inflammation and oxidative stress processes by inhibiting the PI3K/AKT pathway, thereby improving CD symptoms. These findings suggest that QHXYF and quercetin may be potential novel treatments for CD.

PET117 assembly factor stabilizes translation activator TACO1 thereby upregulates mitochondria-encoded cytochrome C oxidase 1 synthesis.

Cytochrome c oxidase, also known as complex IV, facilitates the transfer of electrons from cytochrome c to molecular oxygen, resulting in the production of ATP. The assembly of complex IV is a tightly regulated and intricate process that entails the coordinated synthesis and integration of subunits encoded by the mitochondria and nucleus into a functional complex. Accurate regulation of translation is crucial for maintaining proper mitochondrial function, and defects in this process can lead to a wide range of mitochondrial disorders and diseases. However, the mechanisms governing mRNA translation by mitoribosomes in mammals remain largely unknown. In this study, we elucidate the critical role of PET117, a chaperone protein involved in complex IV assembly, in the regulation of mitochondria-encoded cytochrome c oxidase 1 (COX1) protein synthesis in human cells. Depletion of PET117 reduced mitochondrial oxygen consumption rate and impaired mitochondrial function. PET117 was found to interact with and stabilize translational activator of COX1 (TACO1) and prevent its ubiquitination. TACO1 overexpression rescued the inhibitory effects on mitochondria caused by PET117 deficiency. These findings provide evidence for a novel PET117-TACO1 axis in the regulation of mitochondrial protein expression, and revealed a previously unknown role of PET117 in human cells.

Targeted protein posttranslational modifications by chemically induced proximity for cancer therapy.

Post-translational modifications (PTMs) regulate all aspects of protein function. Therefore, upstream regulators of PTMs, such as kinases, acetyltransferases, or methyltransferases, are potential therapeutic targets for human diseases, including cancer. To date, multiple inhibitors and/or agonists of these PTM upstream regulators are in clinical use, while others are still in development. However, these upstream regulators control not only the PTMs of disease-related target proteins but also other disease-irrelevant substrate proteins. Thus, nontargeted perturbing activities may introduce unwanted off-target toxicity issues that limit the use of these drugs in successful clinical applications. Therefore, alternative drugs that solely regulate a specific PTM of the disease-relevant protein target may provide a more precise effect in treating disease with relatively low side effects. To this end, chemically induced proximity has recently emerged as a powerful research tool, and several chemical inducers of proximity (CIPs) have been used to target and regulate protein ubiquitination, phosphorylation, acetylation, and glycosylation. These CIPs have a high potential to be translated into clinical drugs and several examples such as PROTACs and MGDs are now in clinical trials. Hence, more CIPs need to be developed to cover all types of PTMs, such as methylation and palmitoylation, thus providing a full spectrum of tools to regulate protein PTM in basic research and also in clinical application for effective cancer treatment.

A Liquid Biopsy Signature for the Early Detection of Gastric Cancer in Patients.

BACKGROUND & AIMS: Diagnosing gastric cancer (GC) while the disease remains eligible for surgical resection is challenging. In view of this clinical challenge, novel and robust biomarkers for early detection thus improving prognosis of GC are necessary. The present study is to develop a blood-based long noncoding RNA (LR) signature for the early-detection of GC. METHODS: The present 3-step study incorporated data from 2141 patients, including 888 with GC, 158 with chronic atrophic gastritis, 193 with intestinal metaplasia, 501 healthy donors, and 401 with other gastrointestinal cancers. The LR profile of stage I GC tissue samples were analyzed using transcriptomic profiling in discovery phase. The extracellular vesicle (EV)-derived LR signature was identified with a training cohort (n = 554) and validated with 2 external cohorts (n = 429 and n = 504) and a supplemental cohort (n = 69). RESULTS: In discovery phase, one LR (GClnc1) was found to be up-regulated in both tissue and circulating EV samples with an area under the curve (AUC) of 0.9369 (95% confidence interval [CI], 0.9073-0.9664) for early-stage GC (stage I/II). The diagnostic performance of this biomarker was further confirmed in 2 external validation cohorts (Xi'an cohort, AUC: 0.8839; 95% CI: 0.8336-0.9342; Beijing cohort, AUC: 0.9018; 95% CI: 0.8597-0.9439). Moreover, EV-derived GClnc1 robustly distinguished early-stage GC from precancerous lesions (chronic atrophic gastritis and intestinal metaplasia) and GC with negative traditional gastrointestinal biomarkers (CEA, CA72-4, and CA19-9). The low levels of this biomarker in postsurgery and other gastrointestinal tumor plasma samples indicated its GC specificity. CONCLUSIONS: EV-derived GClnc1 serves as a circulating biomarker for the early detection of GC, thus providing opportunities for curative surgery and improved survival outcomes.

Analysis of Risk Factors for Postoperative Lower Extremity Deep Venous Thrombosis and its Treatment and Nursing.

Objective: To explore the risk factors of lower extremity deep venous thrombosis (LEDVT) after surgery and discuss the treatment and nursing countermeasures. Methods: A retrospective analysis was conducted on 268 surgical patients admitted between July to December 2021. The factors associated with LEDVT were analyzed using the Logistic regression model. Further, LEDVT patients were assigned to a research group treated with targeted nursing to prevent LEDVT and a control group that used routine care. Coagulation function and inflammatory cytokines before and after nursing intervention were compared between groups. The assessment of patients' mobility employed the lower limb motor function part of the Fugel-Meyer Assessment (FMA), Harris Hip Score (HHS), and Barthel index (BI), and their psychological status was evaluated using the Kolcaba's General Comfort Questionnaire (GCQ) and Self-rating Anxiety/Depression Scale (SAS/SDS). Finally, patient satisfaction with the treatment service was investigated. Results: Logistic regression analysis showed that hypertension, limb paralysis, central venous catheterization of lower limbs, and bedridden time affect postoperative LEDVT in an independent way (P < 0.05). After the intervention, the coagulation function and inflammatory reaction were improved in both groups, with more significant improvement in the research group (P < 0.05). The research group also showed higher FMA, Harris, GCQ, and BI scores while lower SAS and SDS scores than the control group postnursing intervention (P < 0.05). Finally, a higher satisfaction rate was identified in the research group as compared to the control group (P < 0.05). Conclusion: Hypertension, limb paralysis, CVC of lower limbs, and bedridden time are all independent risk factors for LEDVT after surgery. The implementation of targeted nursing strategies for the above factors can effectively alleviate the hypercoagulable state of patients after operation, reduce inflammatory responses, and improve patient comfort, which is of great significance for preventing the occurrence of LEDVT.

Brucea javanica Oil Emulsion Promotes Autophagy in Ovarian Cancer Cells Through the miR-8485/LAMTOR3/mTOR/ATG13 Signaling Axis.

Background: Ovarian cancer is a common malignant tumor of the female reproductive tract, with the highest mortality rate. At present, no effective approaches to improve the survival rate exist. B. javanica Oil Emulsion (BJOE), an extract from B. javanica (L.) Merr. [Simaroubaceae], exhibits antitumor effects and can increase the sensitivity of radiotherapy and chemotherapy in many types of cancers. MiR-8485, a discovered miRNA, has been shown to be involved in the occurrence and development of tumors. The purpose of this study was to investigate the effect of BJOE on the regulation of mammalian rapamycin target protein (mTOR) autophagy signal pathway and related autophagy factors on ovarian cancer cells through miR-8485. Methods: The main chemical constituents of BJOE were determined by UHPLC-MS/MS. Detection of miR-8485 expression in ovarian cancer cells treated with BJOE by quantitative reverse transcription polymerase chain reaction (qRT-PCR). CCK8 experiment and flow cytometry were used to observe the effects of BJOE and overexpression of miR-8485 on cell proliferation and apoptosis. Then, monodansylcadaverine (MDC) fluorescence staining was used to observe the changes of autophagy vesicles before and after the effect of BJOE and overexpressed miR-8485 on cancer cells. Next, the binding sites between miR8485 and mammalian rapamycin target protein activator 3 (LAMTOR3) were detected by double luciferase reporter assay. Furthermore, qRT-PCR and Western blot experiments were used to explore the changes of autophagy-related factors LAMTOR3, mTOR and autophagy-related 13 (ATG13), and microtubule associated protein 1 light chain 3 beta (LC3-Ⅱ) after BJOE and overexpression of miR-8485, in addition to autophagy inhibitor (3-MA) for rescue experiment verification. Results: The qRT-PCR results showed that the expression of miR-8485 increased after BJOE treatment in the SKOV3 cell. The CCK8 assay and flow cytometry analysis revealed that both BJOE and miR-8485 overexpression inhibited the proliferation and promoted the apoptosis of the SKOV3 cell. MDC fluorescence staining showed that BJOE and miR-8485 overexpression led to a significant increase in autophagy vesicles in the SKOV3 cell. Double luciferase reporter assay confirmed the existence of binding sites between miR8485 and LAMTOR3. The results of qRT-PCR and Western blot showed that BJOE and overexpressed miR-8485 downregulated the expression of LAMTOR3 and mTOR and up-regulated the expression of ATG13 and LC3-Ⅱ. Conclusion: 1) MiR-8485 may be the key factor of BJOE in promoting autophagy and apoptosis and inhibiting cell proliferation of ovarian cancer cells; 2) BJOE may play an antitumor role by regulating LAMTOR3/mTOR/ATG13 signaling axis through miR-8485 to promote autophagy in ovarian cancer cells.

Targeting micro-environmental pathways by PROTACs as a therapeutic strategy.

Tumor microenvironment (TME) composes of multiple cell types and non-cellular components, which supports the proliferation, metastasis and immune surveillance evasion of tumor cells, as well as accounts for the resistance to therapies. Therefore, therapeutic strategies using small molecule inhibitors (SMIs) and antibodies to block potential targets in TME are practical for cancer treatment. Targeted protein degradation using PROteolysis-TArgeting Chimera (PROTAC) technic has several advantages over traditional SMIs and antibodies, including overcoming drug resistance. Thus many PROTACs are currently under development for cancer treatment. In this review, we summarize the recent progress of PROTAC development that target TME pathways and propose the potential direction of future PROTAC technique to advance as novel cancer treatment options.

Contrasting Diversity and Composition of Human Colostrum Microbiota in a Maternal Cohort With Different Ethnic Origins but Shared Physical Geography (Island Scale).

Colostrum represents an important source for the transfer of important commensal bacteria from mother to newborn and has a strong impact on the newborn's health after birth. However, the composition of the colostrum microbiome is highly heterogeneous due to geographic factors and ethnicity (maternal, cultural, and subsistence factors). By analyzing the colostrum 16S rRNA gene full-length sequencing dataset in 97 healthy mothers (60 from Han, 37 from Li) from the Hainan island of China, we showed that the ethnic differences of the colostrum microbiome in a maternal cohort with different ethnic origins shared physical geography. Results indicated that the richness of microbial community in colostrum of Han women was higher than that of Li women, but there was no significant difference in Shannon index and invsimpson index between the two groups. Visualization analysis based on the distance showed an obvious ethnicity-associated structural segregation of colostrum microbiota. The relative abundance of Firmicutes was higher in the microbiota of the Han group than in Li's, while Proteobacteria was on the contrary. At the genus level, the most dominant members of the Han and Li ethnic groups were Acinetobacter and Cupriavidus, two common environmental bacteria, respectively, although skin-derived Staphylococcus and Streptococcus were still subdominant taxa. Cupriavidus lacunae was the most dominant species in the Li group, accounting for 26.10% of the total bacterial community, but only 3.43% for the Han group with the most dominant Staphylococcus petrasii (25.54%), indicating that human colostrum microbiome was more susceptible to local living environmental factors. Hence, the ethnic origin of individuals may be an important factor to consider in human milk microbiome research and its potential clinical significance during the perinatal period in ethnic-diverse societies, even within a small geographic scale.

Daphnetin ameliorates Aß pathogenesis via STAT3/GFAP signaling in an APP/PS1 double-transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) has become a major public health problem that affects the elderly population. Therapeutic compounds with curative effects are not available due to the complex pathogenesis of AD. Daphnetin, a natural coumarin derivative and inhibitor of various kinases, has anti-inflammatory and antioxidant activities. In this study, we found that daphnetin improved spatial learning and memory in an amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mouse model of AD. Daphnetin markedly decreased the levels of amyloid-ß peptide 1-40 (Aß40) and 1-42 (Aß42) in the cerebral cortex, downregulated the expressions of enzymes involved in APP processing, e.g., beta-site APP-cleaving enzyme (BACE), nicastrin and presenilin enhancer protein 2 (PEN2). We further found the reduced serum levels of inflammatory factors, including interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and chemokine (C-C motif) ligand 3 (CCL3), while daphnetin increased total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) levels in the serum. Interestingly, daphnetin markedly decreased the expression of glial fibrillary acidic protein (GFAP) and the upstream regulatory molecule- phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in APP/PS1 mice, and mainly inhibited the phosphorylation of STAT3 at Ser727 to decrease GFAP expression evidenced in a LPS-activated glial cell model. These results suggest that daphnetin ameliorates cognitive deficits and that Aß deposition in APP/PS1 mice is mainly correlated with astrocyte activation and APP processing.

Prostate-specific oncogene OTUD6A promotes prostatic tumorigenesis via deubiquitinating and stabilizing c-Myc.

MYC drives the tumorigenesis of human cancers, including prostate cancer (PrCa), thus deubiquitinase (DUB) that maintains high level of c-Myc oncoprotein is a rational therapeutic target. Several ubiquitin-specific protease (USP) family members of DUB have been reported to deubiquitinate c-Myc, but none of them is the physiological DUB for c-Myc in PrCa. By screening all the DUBs, here we reveal that OTUD6A is exclusively amplified and overexpressed in PrCa but not in other cancers, eliciting a prostatic-specific oncogenic role through deubiquitinating and stabilizing c-Myc oncoprotein. Moreover, genetic ablation of OTUD6A efficiently represses prostatic tumorigenesis of both human PrCa cells and the Hi-Myc transgenic PrCa mice, via reversing the metabolic remodeling caused by c-Myc overexpression in PrCa. These results indicate that OTUD6A is a physiological DUB for c-Myc in PrCa setting and specifically promotes prostatic tumorigenesis through stabilizing c-Myc oncoprotein, suggesting that OTUD6A could be a unique therapeutic target for Myc-driven PrCa.

Cell cycle on the crossroad of tumorigenesis and cancer therapy.

Aberrancy in cell cycle progression is one of the fundamental mechanisms underlying tumorigenesis, making regulators of the cell cycle machinery rational anticancer therapeutic targets. A growing body of evidence indicates that the cell cycle regulatory pathway integrates into other hallmarks of cancer, including metabolism remodeling and immune escape. Thus, therapies against cell cycle machinery components can not only repress the division of cancer cells, but also reverse cancer metabolism and restore cancer immune surveillance. Besides the ongoing effects on the development of small molecule inhibitors (SMIs) of the cell cycle machinery, proteolysis targeting chimeras (PROTACs) have recently been used to target these oncogenic proteins related to cell cycle progression. Here, we discuss the rationale of cell cycle targeting therapies, particularly PROTACs, to more efficiently retard tumorigenesis.

Post-translational modifications on mitochondrial metabolic enzymes in cancer.

Mitochondrion is the powerhouse of the cell. The research of nearly a century has expanded our understanding of mitochondrion, far beyond the view that mitochondrion is an important energy generator of cells. During the initiation, growth and survival of tumor cells, significant mitochondrial metabolic changes have taken place in the important enzymes of respiratory chain and tricarboxylic acid cycle, mitochondrial biogenesis and dynamics, oxidative stress regulation and molecular signaling. Therefore, mitochondrial metabolic proteins are the key mediators of tumorigenesis. Post-translational modification is the molecular switch that regulates protein function. Understanding how these mitochondria-related post-translational modification function during tumorigenesis will bring new ideas for the next generation of cancer treatment.

Safflower leaf ameliorates cognitive impairment through moderating excessive astrocyte activation in APP/PS1 mice.

In addition to beta-amyloid (Aß) plaques and neurofibrillary tangles, Alzheimer's disease (AD) is typically triggered or accompanied by abnormal inflammation, oxidative stress and astrocyte activation. Safflower (Carthamus tinctorius L.) leaf, featuring functional ingredients, is a commonly consumed leafy vegetable. Whether and how dietary safflower leaf powder (SLP) ameliorates cognitive function in an AD mouse model has remained minimally explored. Therefore, we orally administered SLP to APP/PS1 transgenic mice to explore the neuroprotective effects of SLP in preventing AD progression. We found that SLP markedly improved cognitive impairment in APP/PS1 mice, as indicated by the water maze test. We further demonstrated that SLP treatment ameliorated inflammation, oxidative stress and excessive astrocyte activation. Further investigation indicated that SLP decreased the Aß burden in APP/PS1 mice by mediating excessive astrocyte activation. Our study suggests that safflower leaf is possibly a promising, cognitively beneficial food for preventing and alleviating AD-related dementia.

Light-Controllable PROTACs for Temporospatial Control of Protein Degradation.

PROteolysis-TArgeting Chimeras (PROTACs) is an emerging and promising approach to target intracellular proteins for ubiquitination-mediated degradation, including those so-called undruggable protein targets, such as transcriptional factors and scaffold proteins. To date, plenty of PROTACs have been developed to degrade various disease-relevant proteins, such as estrogen receptor (ER), androgen receptor (AR), RTK, and CDKs. However, the on-target off-tissue and off-target effect is one of the major limitation that prevents the usage of PROTACs in clinic. To this end, we and several other groups have recently developed light-controllable PROTACs, as the representative for the third generation controllable PROTACs, by using either photo-caging or photo-switch approaches. In this review, we summarize the emerging light-controllable PROTACs and the prospective for other potential ways to achieve temporospatial control of PROTACs.

Level of phosphate diets effect on fibroblast growth factor-23 levels in chronic kidney disease subjects: A meta-analysis.

BACKGROUND: High fibroblast growth factor-23 levels increase cardiovascular disease risk in chronic kidney disease subjects. The effects of dietary phosphate levels on fibroblast growth factor-23 in chronic kidney disease subjects have conflicting results. This meta-analysis was performed to evaluate this relationship. METHODS: A systematic-literature search up to July 2020 was performed and 7 studies were detected with 548 chronic kidney disease subjects at the baseline of the studies; a total of 170 of them were with lower dietary phosphate levels and 175 were higher dietary phosphate levels. They reported relationships between dietary phosphate levels and fibroblast growth factor-23 level in chronic kidney disease subjects. Mean differences (MD) with 95% confidence intervals (CIs) were calculated comparing the lower versus higher phosphate levels effect on urinary phosphate levels and fibroblast growth factor-23 level in chronic kidney disease subjects using the contentious methods with a random or fixed-effect model. RESULTS: Lower dietary phosphate levels had significantly lower 24-hour urinary phosphate excretion (MD, -41.23; 95% CI, -59.95 to 22.52, P < .001), and lower intact fibroblast growth factor-23 level (MD, -25.68; 95% CI, -39.85 to -11.51, P < .001) compared with higher dietary phosphate levels in chronic kidney disease subjects. However, no significant difference was found between low and high dietary phosphate levels in C-terminal fibroblast growth factor-23 level in chronic kidney disease subjects (MD, -7.10; 95% CI, -14.29 to 0.10, P = .05). CONCLUSIONS: Lower dietary phosphate levels had significantly lower 24-hour urinary phosphate excretion, intact fibroblast growth factor-23 level compared with higher dietary phosphate levels in chronic kidney disease subjects. This relationship forces us to recommend low dietary phosphate levels in chronic kidney disease subjects to decrease fibroblast growth factor-23 level to avoid any possible cardiovascular disease risk in such a subject.

MiR-4729 regulates TIE1 mRNA m6A modification and angiogenesis in hemorrhoids by targeting METTL14.

BACKGROUND: Hemorrhoids are a frequently-occurring disease of the anorectal system that is often accompanied by vascular hyperplasia and edema. A METTL14-mediated RNA N-6 methyladenosine (m6A) modification can improve mRNA stability and increase its transcriptional and translational activities, closely related to the occurrence of many diseases. METHODS: Western blot, qPCR, and immunofluorescence staining were used to detect the levels of gene and protein expression. Haematoxylin and eosin staining was used for histopathological examination. RNA immunoprecipitation-PCR and RNA dot blotting were used to detect mRNA m6A modification. RESULTS: Obvious signs of angiogenesis (CD31+/vWF+) were identified in the hemorrhoids. High levels of METTL14 expression on vascular endothelial cells (CD31+) suggested that angiogenesis was accompanied by differential modification of m6A RNA. It was subsequently found that the level of miR-4729 expression was significantly decreased in hemorrhoid tissues. The luciferase reporter enzyme assay results suggested that miR-4729 silenced its expression by targeting the 3'UTR of METTL14 mRNA. MiR-4729 overexpression in human umbilical vein endothelial cells (HUVECs) inhibited the proliferation and migration of HUVECs in vitro and vascular structure formation in the outer matrix. MiR-4729 overexpression significantly inhibited endogenous METTL14 expression in HUVECs and reduced the entire m6A RNA modification, especially the level of m6A methylation at the specific site of the 3' UTR of TIE1 mRNA. Moreover, miR-4729 overexpression significantly inhibited the molecular loop of the TIE1/VEGFA signaling pathway in HUVECs. CONCLUSIONS: Our findings confirmed that the down-regulation of miR-4729 in hemorrhoid vascular endothelial cells was one of the main reasons for vascular proliferation. The overexpression of miR-4729 in vascular endothelial cells decreased the global mRNA methylation and TIE1 mRNA 3'UTR-specific site methylation by silencing METTL14 expression, reducing TIE1 mRNA stability, down-regulating the TIE1/VEGFA signal molecular loop expression, and weakening angiogenesis ability.

Hydroxytyrosol Acetate Improves the Cognitive Function of APP/PS1 Transgenic Mice in ERß-dependent Manner.

SCOPE: Alzheimer's disease (AD) is the most prevalent form of dementia in the aging population; however, no effective therapy has been established. It has been previously demonstrated that daily intake of hydroxytyrosol (HT), a polyphenol in olive oil, at a daily dietary level mildly improves cognition in AD mice. In the present study, HT acetate (HT-ac), which is a natural derivative of HT in olive oil that exhibits better bioactivity than HT improves cognition. METHODS AND RESULTS: HT-ac to APP/PS1 is orally administered to transgenic mice and used Aß-treated neuronal cultures to explore the neuroprotective effects of HT-ac in preventing AD progression. It is found that HT-ac remarkably improved the escape latency, escape distance, and the number of platform crossings of AD mice in the water maze test by ameliorating neuronal apoptosis and decreasing inflammatory cytokine levels. It is further demonstrated that HT-ac stimulated the transcription of ERß and enhanced neuronal viability and electrophysiological activity in primary neurons but that these beneficial effects of HT-ac are abolished upon ERß deficiency. CONCLUSIONS: This study suggests that as the bioactive component of olive oil, HT-ac is a promising neuroprotective nutrient that may be used to alleviate AD-related cognitive dysfunction.