Multi-omics data-based analysis characterizes molecular alterations of the vesicle genes in human colorectal cancer.

The role of vesicular genes in the development of colorectal cancer (CRC) is crucial. Analyzing alterations in these genes at multi-omics can aid in understanding the molecular pathways behind colorectal carcinogenesis and identifying potential treatment targets. However, studies on the overall alteration of vesicular genes in CRC are still lacking. In this study, we aimed to investigate the relationship between vesicle genetic alterations and CRC progression. To achieve this, we analyzed molecular alterations in CRC vesicle genes at eight levels, including mRNA, protein, and epigenetic levels. Additionally, we examined CRC overall survival-related genes that were obtained from a public database. Our analysis of chromatin structural variants, DNA methylation, chromatin accessibility, and proteins (including phosphorylation, ubiquitination, and malonylation), along with RNA-seq data from the TCGA database, revealed multiple levels of alterations in CRC vesicle genes in the collected tissue samples. We progressively examined the alterations of vesicle genes in mRNA and protein levels in CRC and discovered the hub genes. Further investigation identified the probable essential transcription factors. This study contributes to a thorough knowledge of the connection between vesicle gene alterations at multiple levels and the development of CRC and offers a theoretical framework for the identification of novel treatment targets.

Pseudomyopia treated with auricular point sticking combined with periocular needle-embedding therapy and prevention of true myopia: a multicenter randomized controlled trial. / è€³ç©´è´´åŽ‹è”åˆçœ¼å‘¨æ¿é’ˆæŠ€æœ¯é¢„é˜²å‡æ€§è¿‘è§†å‘çœŸæ€§è¿‘è§†è¿›å±•ï¼šå¤šä¸­å¿ƒéšæœºå¯¹ç §è¯•éªŒ.

OBJECTIVES: To observe the clinical effect and safety of auricular point sticking combined with periocular needle-embedding therapy for pseudomyopia and prevention of true myopia. METHODS: A total of 269 children with pseudomyopia were randomized into an observation group (134 cases, 2 cases dropped out) and a control group (135 cases, 5 cases dropped out). In the control group, the healthy education was provided. In the observation group, besides the intervention as the control group, the auricular point sticking was delivered at gan (CO12), pi (CO13), xin (CO15) and yan (LO5) on one ear in each treatment, combined with periocular needle-embedding technique at bilateral Cuanzhu (BL 2), Yuyao (EX-HN 4) and Sibai (ST 2). There were 2 weeks of interval after 4 weeks of treatment. One course of treatment was composed of 6 weeks and 2 courses were required. Separately, before treatment, after 6 and 12 weeks of treatment, and after 12 weeks (the 1st follow-up visit) and 24 weeks (the 2nd follow-up visit) of treatment completion, the spherical equivalent (SE), SE progression, axial length (AL) progression, accommodative amplitude (AMP), the score of the TCM symptom and the general symptom were observed in the two groups. The safety and compliance were evaluated in the two groups. RESULTS: After 6 and 12 weeks of treatment, and in the 1st and 2nd follow-up visits, SE increased when compared with that before treatment in the two groups (P<0.05), and AMP was larger than that before treatment in the observation group (P<0.05). After 12 weeks of treatment, and in the 1st and 2nd follow-up visits, the progression of SE was slower in the observation group compared with that in the control group (P<0.01, P<0.001). After 6 and 12 weeks of treatment, and in the 1st and 2nd follow-up visits, the progression of AL in the observation group was lower than that of the control group (P<0.05, P<0.01, P<0.001); and in the 1st and 2nd follow-up visits, AMP of the observation group was larger when compared with that in the control group (P<0.05, P<0.001). After 6 and 12 weeks of treatment, and in the 1st and 2nd follow-up visits, the total scores of TCM symptom and general symptom were reduced in comparison with those before treatment in the observation group (P<0.05); after 6 and 12 weeks of treatment, the total scores of TCM symptom and general symptom were lower than those before treatment in the control group (P<0.05). In the 1st and 2nd follow-up visits, the difference of the total score of TCM symptom and general symptom in the observation group was larger than that of the control group (P<0.05). In the observation group, compared with the control group, the scores for pale/dark complexion in the 1st and 2nd follow-up visits and that for lassitude in the 2nd follow-up visit were lower (P<0.05), the score for poor concentration after 12 weeks of treatment and that for poor sleep and memory in the 2nd follow-up visit were lower (P<0.05). There were no adverse reactions in the two groups. The compliance was 98.5% in the observation group and was 96.3% in the control group, without statistical difference (P>0.05). CONCLUSIONS: On the basis of health education, auricular point sticking combined with periocular needle-embedding therapy can effectively prevent from true myopia, control the increase of SE, delay the growth of AL and improve AMP in children with pseudomyopia. This compound therapeutic regimen can relieve the general symptom and comprehensively prevent from myopia through multiple approaches, with high safety and satisfactory compliance.

The potential roles of exosomes in pathological cardiomyocyte hypertrophy mechanisms and therapy: A review.

Pathological cardiac hypertrophy, characterized by the enlargement of cardiac muscle cells, leads to serious cardiac conditions and stands as a major global health issue. Exosomes, comprising small lipid bilayer vesicles, are produced by various cell types and found in numerous bodily fluids. They play a pivotal role in intercellular communication by transferring bioactive cargos to recipient cells or activating signaling pathways in target cells. Exosomes from cardiomyocytes, endothelial cells, fibroblasts, and stem cells are key in regulating processes like cardiac hypertrophy, cardiomyocyte survival, apoptosis, fibrosis, and angiogenesis within the context of cardiovascular diseases. This review delves into exosomes' roles in pathological cardiac hypertrophy, first elucidating their impact on cell communication and signaling pathways. It then advances to discuss how exosomes affect key hypertrophic processes, including metabolism, fibrosis, oxidative stress, and angiogenesis. The review culminates by evaluating the potential of exosomes as biomarkers and their significance in targeted therapeutic strategies, thus emphasizing their critical role in the pathophysiology and management of cardiac hypertrophy.

Alterations in serum metabolic profiles of early-stage hepatocellular carcinoma patients after radiofrequency ablation therapy.

OBJECTIVE: To investigate the alterations in serum metabolic profiles and early-stage hepatocellular carcinoma (HCC) patient characteristics after radiofrequency ablation (RFA) therapy. This evaluation aimed to assess treatment effectiveness and identify potential novel approaches and targets for HCC treatment and prognosis monitoring. METHODS: Untargeted metabolomics technology was employed to analyze serum metabolic profiles in healthy volunteer controls (NCs) and early stage HCC patients before and after RFA therapy. Additionally, Human Metabolome Database and Kyoto Encyclopedia of Genes and Genomes database were used to identify the differential metabolites (DMs) and metabolic pathways. Cystoscape was utilized to construct DM gene networks. Amino acid analyses were performed to validate our findings. RESULTS: We identified 11, 14, and six DMs between the NC and HCC groups, HCC patients before and after RFA therapy, and post-RFA HCC and NC groups, respectively. The expression levels of these DMs, particularly those of amino acids and lipids, significantly changed. Compared with the NC group, higher levels of L-tyrosine, aspartate, and 18-oxo-oleate were observed in HCC patients, which were significantly reduced in patients after RFA therapy. Meanwhile, HCC patients after RFA therapy had increased levels of L-arginine, phosphatidic acid (20:3), and lysophosphatidyl choline (LPC) (20:4) compared to those before therapy, while their levels before therapy were lower than those of NC. Moreover, most metabolites in the post-RFA and NC groups showed no significant changes in expression, except for L-tyrosine and LPC (16:0). These metabolites could potentially serve as characteristic factors of early-stage HCC patients after RFA therapy. Joint pathway analysis revealed striking changes, mainly in phenylalanine, tyrosine, and tryptophan biosynthesis; alanine, aspartate, and glutamate metabolism; and arginine and aminoacyl-tRNA biosynthesis. Bioinformatics analysis of publicly available data preliminarily identified 187 DM-related metabolic enzymes. CONCLUSION: Our study proposed novel targets for early-stage HCC treatment, laying the groundwork for improving treatment efficacy and prognosis of early-stage HCC patients.

Independent and interaction effects of prenatal exposure to high AQI and extreme Humidex on the risk of preterm birth: A large sample population study in northern China.

The combined effects of air pollution and extreme temperature on PTB remain unclear. To evaluate the independent effect and interaction effect of prenatal extreme exposure to air quality index (AQI) and Humidex, on PTB. Based on the National Health Care Data Platform of Shandong University, women who gave birth in 2019-2020 were selected for the study. First, the independent effects of AQI and Humidex on PTB were assessed by logistic regression model. Subsequently, the interaction effects of AQI and Humidex on PTB were estimated separately by calculation of the relative excess risk of interaction (RERI). A total of 34365 pregnant women were included and 1975 subjects were diagnosed with PTB. We observed a significant increase in the odds of PTB associated with maternal high AQI exposure, with an OR of 1.70 (95% CI: 1.59, 1.81). Similarly, extreme exposure to Humidex also demonstrated an elevated PTB odds, with a low Humidex OR of 2.48 (95% CI: 2.23, 2.76) and a high Humidex OR of 1.48 (95% CI: 1.31, 1.67). Finally, we observed an interaction between high AQI and extreme Humidex during the 1st trimester. Interaction effects were noted between high AQI and low Humidex throughout the entire trimester and the 2nd trimester. This study suggests that prenatal exposure to high AQI and extreme Humidex could increase the odds of PTB, with effects exhibiting the sensitivity window and a cumulative trend. Additionally, there is an interaction between AQI and Humidex.

The circUbqln1, regulated by XBP1s, interplays with 14-3-3ζ to inhibit collagen synthesis and promote osteoarthritis by controlling PRODH activity and proline metabolism.

INTRODUCTION: Osteoarthritis (OA) is a degenerative bone disease associated with ageing, characterized by joint pain, stiffness, swelling and deformation. Currently, pharmaceutical options for the clinical treatment of OA are very limited. Circular RNAs(cirRNAs) have garnered significant attention in OA and related drug development due to their unique RNA sequence characteristics.Therefore,exploring the role of cirRNAs in the occurrence and development of OA is of paramount importance for the development of effective medications for OA. OBJECTIVES: To identify a novel circRNA, circUbqln1, for treating osteoarthritis and elucidate its pathophysiological role and mechanisms in the treatment of OA. METHODS: The circUbqln1 expression and distribution were determined by qRT-PCR and FISH. XBP1 gene knockout(XBP1 cKO) spontaneous OA and DMM model and WT mouse CIOA model were used to explore the role of XBP1 and circUbqln1 in OA.Overexpression or knockdown of circUbqln1 lentivirus was used to observe the impacts of circUbqln1 on primary chondrocytes,C28/I2 and mice in vitro and in vivo.Chromatin immunoprecipitation,luciferase reporter assay,RNA pulldown,mass spectrometry,RNA immunoprecipitation,fluorescence in situ hybridization,and flow cytometry to explore the molecular mechanisms of circUbqln1. RESULTS: It was found that cartilage-specific XBP1 cKO mice exhibited a faster OA progression compared to normal's.Importantly,transcript factor XBP1s has the capacity to impede the biogenesis of circUbqln1,derived from Ubqln1. The circUbqln1 promotes cartilage catabolism and inhibits anabolism, therefore accelerates the occurrence of OA.Mechanismly,circUbqln1 can translocate to the chondrocyte nucleus with the assistance of phosphorylated 14-3-3ζ, upregulate the transcriptional activity of the proline dehydrogenase(Prodh) promoter and PRODH enzyme activity. Consequently, this leads to the promotion of proline degradation and the inhibition of collagen synthesis,ultimately culminating in the impairment of cartilage and its structural integrity. CONCLUSION: CircUbqln1 plays a crucial role in the occurrence and development of OA, indicating that the inhibition of circUbqln1 holds promise as a significant approach for treating OA in the future.

Dual-target inhibitors based on COX-2: a review from medicinal chemistry perspectives.

Inhibitors of COX-2 constitute a class of anti-inflammatory analgesics, showing potential against certain types of cancer. However, such inhibitors are associated with cardiovascular toxicity. Moreover, although single-target molecules possess specificity for particular targets, they often lead to poor safety, low efficacy and drug resistance due to compensatory mechanisms. A new generation of dual-target drugs that simultaneously inhibit COX-2 and another target is showing strong potential to treat cancer or reduce adverse cardiac effects. The present perspective focuses on the structure and functions of COX-2, and its role as a therapeutic target. It also explores the current state and future possibilities for dual-target strategies from a medicinal chemistry perspective.

IRE1α protects against osteoarthritis by regulating progranulin-dependent XBP1 splicing and collagen homeostasis.

Osteoarthritis (OA) is a full-joint, multifactorial, degenerative and inflammatory disease that seriously affects the quality of life of patients due to its disabling and pain-causing properties. ER stress has been reported to be closely related to the progression of OA. The inositol-requiring enzyme 1α/X-box-binding protein-1 spliced (IRE1α/XBP1s) pathway, which is highly expressed in the chondrocytes of OA patients, promotes the degradation and refolding of abnormal proteins during ER stress and maintains the stability of the ER environment of chondrocytes, but its function and the underlying mechanisms of how it contributes to the progression of OA remain unclear. This study investigates the role of IRE1α/ERN1 in OA. Specific deficiency of ERN1 in chondrocytes spontaneously resulted in OA-like cartilage destruction and accelerated OA progression in a surgically induced arthritis model. Local delivery of AdERN1 relieved degradation of the cartilage matrix and prevented OA development in an ACLT-mediated model. Mechanistically, progranulin (PGRN), an intracellular chaperone, binds to IRE1α, promoting its phosphorylation and splicing of XBP1u to generate XBP1s. XBP1s protects articular cartilage through TNF-α/ERK1/2 signaling and further maintains collagen homeostasis by regulating type II collagen expression. The chondroprotective effect of IRE1α/ERN1 is dependent on PGRN and XBP1s splicing. ERN1 deficiency accelerated cartilage degeneration in OA by reducing PGRN expression and XBP1s splicing, subsequently decreasing collagen II expression and triggering collagen structural abnormalities and an imbalance in collagen homeostasis. This study provides new insights into OA pathogenesis and the UPR and suggests that IRE1α/ERN1 may serve as a potential target for the treatment of joint degenerative diseases, including OA.

Zerumbone ameliorates the inflammatory response and organ damage in severe acute pancreatitis via the ROS/NF-κB pathway.

OBJECTIVE: The aim of the current study was to determine the mechanism by which Zerumbone (ZER) ameliorates inflammation and organ damage in a rat model of severe acute pancreatitis (SAP). METHODS: Different concentrations of ZER (10, 20 and 40 mg/kg) were administered by femoral vein puncture 30 min prior to establishment of the SAP model. Hematoxylin and eosin (H&E) staining was used to assess pathological changes in the pancreatic tissue of SAP-induced rats. The lung wet/dry (W/D) ratio was assessed and serum levels of amylase (AMY), alanine aminotransferase (ALT), creatinine (Cr), aspartate aminotransferase (AST) and phospholipase A2 (PLA2) were measured. Western blot analysis was used to examine changes in the expression of ROS/NF-κB pathway-associated proteins. RESULTS: SAP was confirmed by significant histopathological damage to the pancreas. ZER (10, 20 and 40 mg/kg) was found to alleviate pancreatitis and decrease ascites volume, lung W/D ratio, pancreatic pathology score, oxidative stress and inflammatory damage. High concentrations (20 and 40 mg/kg) of ZER were shown to increase levels of hepatorenal toxicity. In contrast, 10 mg/kg ZER was found to attenuate liver enzyme levels, reduce pathological damage to the liver, and protect against extrapancreatic organ damage to the liver in SAP-induced rats. Moreover, ZER showed no significant side effects in normal rats. Finally, we demonstrated that ZER mediated its anti-inflammatory effects on SAP through the ROS/NF-κB signaling pathway. CONCLUSION: ZER alleviated SAP-induced oxidative stress and inflammatory injury via the ROS/NF-κB pathway, and had a protective effect on lung injury and liver damage.

Progranulin regulation of autophagy contributes to its chondroprotective effect in osteoarthritis.

Progranulin (PGRN) is a multifunctional growth factor involved in many physiological processes and disease states. The apparent protective role of PGRN and the importance of chondrocyte autophagic function in the progression of osteoarthritis (OA) led us to investigate the role of PGRN in the regulation of chondrocyte autophagy. PGRN knockout chondrocytes exhibited a deficient autophagic response with limited induction following rapamycin, serum starvation, and IL-1ß-induced autophagy. PGRN-mediated anabolism and suppression of IL-1ß-induced catabolism were largely abrogated in the presence of the BafA1 autophagy inhibitor. Mechanistically, during the process of OA, PGRN and the ATG5-ATG12 conjugate form a protein complex; PGRN regulates autophagy in chondrocytes and OA through, at least partially, the interactions between PGRN and the ATG5-ATG12 conjugate. Furthermore, the ATG5-ATG12 conjugate is critical for cell proliferation and apoptosis. Knockdown or knockout of ATG5 reduces the expression of ATG5-ATG12 conjugate and inhibits the chondroprotective effect of PGRN on anabolism and catabolism. Overexpression of PGRN partially reversed this effect. In brief, the PGRN-mediated regulation of chondrocyte autophagy plays a key role in the chondroprotective role of PGRN in OA. Such studies provide new insights into the pathogenesis of OA and PGRN-associated autophagy in chondrocyte homeostasis.

JAG1 enhances angiogenesis in triple-negative breast cancer through promoting the secretion of exosomal lncRNA MALAT1.

Despite significant improvements in five-year survival rates due to early diagnosis and combination therapy, triple-negative breast cancer (TNBC) treatment remains a major challenge. Finding new and effective targets for diagnosis and drug therapy is urgent for TNBC patients. Jagged-1 (JAG1), one of the canonical ligands of the Notch signaling pathway, is involved in vascular budding and is a poor prognostic factor of TNBC. In this study, combined with quantitative real-time PCR, database analysis, animal experiments, and other means, JAG1 was confirmed to be related to the poor prognosis of TNBC patients. JAG1 was highly expressed in MDA-MB-231 Bone (231B) cells, with stronger invasion and metastasis ability than MDA-MB-231 (231) cells. Treatment of human vascular endothelial cells (HUVEC) with TNBC conditioned medium showed that TNBC JAG1 promoted the angiogenesis of HUVEC. Next, we detected the exosomes extracted from TNBC conditioned medium and found that JAG1 promoted the exosome secretion from 231 cells via ALIX-RAB11A/RAB35. In addition, we also found that the exosomes from JAG1 overexpressed TNBC cells contained more long non-coding RNA (lncRNA) MALAT1, and MALAT1 promoted angiogenesis of HUVEC by targeting miR-140-5p. Finally, the angiogenesis-promoting effect of JAG1 in TNBC was further investigated by matrix gel assay. In conclusion, we reveal that JAG1 has a pro-invasion effect on TNBC and is involved in microenvironment angiogenesis by promoting exosome secretion and the MALAT1-miR-140-5p-JAG1/VEGFA pathway.

Universal response method for the quantitative analysis of photodegradation impurities in lomefloxacin hydrochloride ear drops by liquid chromatography coupled with charged aerosol detector.

In terms of risk assessment especially for the impurities with different ultraviolet responses, quantitative analysis without the availability of corresponding reference substances currently poses a challenge. In this study, a universal response method was established for the quantitative analysis of photodegradable impurities in lomefloxacin hydrochloride ear drops by high performance liquid chromatography-charged aerosol detector (HPLC-CAD) for the first time. The chromatographic conditions and CAD parameters were optimized for a good separation and sensitivity. The uniform response of developed method was validated by impurity reference substances with different ultraviolet responses. In the gradient compensation HPLC-CAD method validation, good linearities were obtained with coefficient of determination (R2) all greater than 0.999 for lomefloxacin and impurity reference substances. The average recoveries of the impurities were 98.63%- 102.18% by UV and 97.92%- 102.57% by CAD, respectively. RSDs all were less than 2.5% for intra-day and inter-day precision by UV and CAD, with good precision and accuracy. The correction factor experimental results showed that the developed method provided a uniform response to the impurities with differences chromophores in lomefloxacin. The effects of packaging materials and excipients on the photodegradation were also investigated using the developed method. The results of correlation analysis showed that the packaging materials with low light transmittance and the organic excipients (glycerol and ethanol) could significantly improve the stability of lomefloxacin hydrochloride ear drops. The developed HPLC-CAD quantification method was a reliable and universal response method for quantitative analysis of impurities in the lomefloxacin. This study also revealed the key factors affecting the photodegradation of lomefloxacin hydrochloride ear drops, which guided enterprises to improve drug prescription and packaging materials and ensure the public medication safety.

Development of a MOF-based SPE method combined with GC-MS for simultaneous determination of alachlor, acetochlor and pretilachlor in field soil.

In this work, a rapid, highly selective, reusable and effective method was developed for simultaneous determination of alachlor, acetochlor and pretilachlor in field soil by GC-MS coupled with MIL-101 based SPE. Main factors affecting the SPE by using MIL-101 were optimized. Moreover, by comparing with the other commercial materials such as C18, PSA and Florisil, the MIL-101(Cr) exhibited excellent adsorption performance, which aimed at amide herbicides. On the other hand, method validation displayed excellent method performance, achieving good linearities with r2 ≥ 0.9921, limits of detection between 0.25-0.45 µg kg-1, enrichment factors ≥ 89, matrix effect in the range of ± 20%, recoveries between 86.3% and 102.4%, and RSD lower than 4.38%. The developed method was successfully applied to the determination of amide herbicides in soil taken from the wheat, corn and soybean field at different depths, where the concentration of alachlor, acetochlor and pretilachlor were in the range of 0.62-8.04 µg kg-1. It was demonstrated that the more depth of soil, the lower of three amide herbicides. This finding could be proposed a novel method to detect the amide herbicides in the agriculture and food industry.

HDAC inhibitor HPTA initiates anti-tumor response by CXCL9/10-recruited CXCR3+CD4+T cells against PAHs carcinogenicity.

Polycyclic aromatic hydrocarbons (PAHs) exposure in food is closely associated with the occurrence and development of breast cancer, which may attribute to altered immunotoxicity and immune regulation. Currently, cancer immunotherapy aims to promote tumor-specific T cell responses, especially CD4+T helper cells (Th) for anti-tumor immunity. The histone deacetylase inhibitors (HDACis) are found to exert an anti-tumor effect by reshaping the tumor immune microenvironment, but the immune regulatory mechanism of HDACis in PAHs-induced breast tumor remains elusive. Here, using established breast cancer models induced by 7,12-dimethylbenz[a]anthracene (DMBA), a potent carcinogenic agent of PAH, the novel HDACi, 2-hexyl-4-pentylene acid (HPTA) exhibited anti-tumor effect by activating T lymphocytes immune function. HPTA recruited CXCR3+CD4+T cells into chemokines CXCL9/10-enriched tumor sites, and the increased secretion of CXCL9/10 was regulated by the NF-κB-mediated pathway. Furthermore, HPTA promoted Th1 differentiation and assisted cytotoxic CD8+T cells in the elimination of breast cancer cells. These findings support the proposition of HPTA as a potential therapeutic in the treatment of PAHs-induced carcinogenicity.

Peptidomic analysis of the angiotensin-converting-enzyme inhibitory peptides in milk fermented with Lactobacillus delbrueckii QS306 after ultrahigh pressure treatment.

In this study, we assessed the effect of ultrahigh pressure (UHP) treatment on the concentration of peptides and angiotensin-converting enzyme (ACE) inhibitory activity in milk fermented with Lactobacillus delbrueckii QS306. The peptides were identified using peptidomic analysis, and 313 unique peptides were identified. These peptides were derived from 53 precursor proteins. Before and after UHP treatment, 361 (22.2%) peptide sequences exhibited difference, and 53 peptide segments were significantly different. Among them, small peptides (amino acid residues ≤6) isoelectric were point at pH 5-6, and the net charge was mainly positive or neutral. With hydrophobicity and ACE inhibitory activity as screening indicators, 214 small peptides with potential ACE inhibitory activity were identified, and 130 new peptides had potential ACE inhibitory activity. A novel ACE inhibitory peptide VAPFP was synthesized, whose in vitro inhibition rate was 10.56 µmol\/L. Therefore, using peptidomics, the changes in peptide sequences and enhancement in ACE inhibitory activity before and after UHP treatment could be effectively identified in milk fermented with Lactobacillus delbrueckii QS306. This study provided a convenient method for the discovery and identification of new ACE inhibitory peptides.

VPA mediates bidirectional regulation of cell cycle progression through the PPP2R2A-Chk1 signaling axis in response to HU.

Cell cycle checkpoint kinases play a pivotal role in protecting against replicative stress. In this study, valproic acid (VPA), a histone deacetylase inhibitor (HDACi), was found to promote breast cancer MCF-7 cells to traverse into G2/M phase for catastrophic injury by promoting PPP2R2A (the B-regulatory subunit of Phosphatase PP2A) to facilitate the dephosphorylation of Chk1 at Ser317 and Ser345. By contrast, VPA protected normal 16HBE cells from HU toxicity through decreasing PPP2R2A expression and increasing Chk1 phosphorylation. The effect of VPA on PPP2R2A was at the post-transcription level through HDAC1/2. The in vitro results were affirmed in vivo. Patients with lower PPP2R2A expression and higher pChk1 expression showed significantly worse survival. PPP2R2A D197 and N181 are essential for PPP2R2A-Chk1 signaling and VPA-mediated bidirectional effect on augmenting HU-induced tumor cell death and protecting normal cells.

Involvement of HIF1 stabilization and VEGF signaling modulated by Grx-1 in murine model of bronchopulmonary dysplasia.

Hypoxia inducible factor (HIF)-1α could be stabilized by Grx1 deletion, which is implicated critical in the pathogenesis of bronchopulmonary dysplasia (BPD). Until now, the stabilization of HIF-1α by glutathionylation to regulate the pulmonary microcirculation in BPD is not well addressed. In this study, we investigated whether the HIF-1α stabilization modulated by Grx1 ablation could ameliorate the pathological changes in the mouse model of BPD, including angiogenesis and alveolar formation. We found that depletion of Grx1 increased levels of GSH-protein adducts, which was associated with the improvement in the numbers of alveoli, the capillary density in the pulmonary microcirculation and the survival rate in the littermates with hyperoxic exposure. Grx1 ablation could promote HIF-1α glutathionylation by increasing GSH adducts to stabilize HIF-1α and to induce VEGF-A production in the lung tissue. The above phenotype of capillary density and VEGF-A production was removed by the pharmacological administration of YC-1, the HIF-1α inhibitor, suggesting the HIF-1α dependent manner for pulmonary microcirculatory perfusion. These data indicate that HIF-1α stabilization plays an critical role in modification pulmonary microcirculatory perfusion, which is associated with the pathological damage under hyperoxic conditions, suggesting that targeting with HIF-1α stabilization should be a potential clinical and therapeutic strategy for BPD treatment.

Oxidation of tetracycline hydrochloride with a photoenhanced MIL-101(Fe)/g-C3N4/PMS system: Synergetic effects and radical/nonradical pathways.

MIL-101(Fe)-based catalysts have been widely used for degradation of organic pollutants based on peroxymonosulfate (PMS) activation. Hence, a facile calcination and hydrothermal method was used in this study to prepare a MIL-101(Fe)/g-C3N4 composite catalyst with high activity and high stability for PMS activation to degrade tetracycline hydrochloride (TC) under visible-light irradiation. We clearly elucidated the mechanism involved in the MIL-101(Fe)/g-C3N4 photo Fenton-catalyzed PMS activation process by separating the PMS activation and pollutant oxidation processes. The synergetic effects of MIL-101(Fe) and g-C3N4 involved MIL-101(Fe) acting as an electron shuttle mediating electron transfer from the organic substrate to PMS, accompanied by redox cycling of the surface Fe(II)/Fe(III). Multiple experimental results indicated that PMS was bound to the surface of MIL-101(Fe)/g-C3N4 during visible irradiation and generation of sulfate radicals (SO4•-), hydroxyl radicals (•OH) and superoxide anion free radicals (•O2-) for the radical pathway and singlet oxygen (1O2) and holes (h+) for the nonradical pathway. The major degradation pathways for TC can be described as demethylation, deamination, deamidation and carbonylation. This work provides valuable information and advances the fundamental understanding needed for design and syntheses of metal-free conjugated polymers modified by metal-organic frameworks for heterogeneous photo-Fenton reactions.

Renal impairment may indicate postoperative low vision in young patients with proliferative diabetic retinopathy undergoing vitrectomy.

Objective: To innovatively evaluate the impact of renal impairment in young work age patients with proliferative diabetic retinopathy (PDR) on their visuality after vitrectomy. Methods: To find out whether it is possible to better predict the improvement of visual acuity after vitrectomy in working-age people without adding additional preoperative testing. In view of the fact that diabetic retinopathy and diabetic nephropathy are common diabetic complications of microvascular damage, it is considered whether preoperative renal function can be used as this evaluation index. This paper studies the design under this theme. This retrospective study included 306 patients (306 eyes) diagnosed with PDR and undergoing vitrectomy in our hospital from January 2016 to June 2023. Relevant baseline data were collected, including age, history of kidney disease and clinical laboratory test results. According to the International Standard Logarithmic Visual Acuity Checklist, the best corrected visual acuity was tested on the first day of admission and one month after surgery, and the difference between the two was subtracted. A difference >0 was defined as "vision improved". Patients were classified as vision-improved group (n=245) and non-improved group (n=61). The differences in baseline serum urea nitrogen, creatinine, uric acid, Cystatin C, estimated glomerular filtration rate (eGFR) and urine protein distribution between the two groups were statistically analyzed, binary regression analysis was performed for meaningful parameters, and random forest model ranked the characteristics in importance. Results: 1.A higher level of serum cystatin C [1.02(0.80,1.48) mg/L vs 0.86(0.67,1.12) mg/L, P<0.001] and a lower eGFR [82.3(50.33, 115.11) ml/(min/1.73m²) vs 107.69(73.9, 126.01) ml/(min/1.73m²), P=0.002] appeared in the non-(vision-)improved group compared with the vision-improved group. 2. The occurrence of preoperation proteinuria history of nephropathy take a larger proportion in non-improved group. 3. Univariate regression analysis showed history of nephrology (OR=1.887, P=0.028), preoperative serum urea nitrogen (OR=0.939, P=0.043), cystatin C (Cys-C) concentration (OR=0.75, P=0.024), eGFR (OR=1.011, P=0.003) and proteinuria (OR=3.128, P<0.001) were influencing factors to postoperative visual acuity loss in young working age PDR patients. Excluding other confounding factors, preoperative proteinuria is an independent risk factor for postoperative vision improvement in working-age PDR populations (OR=2.722, P=0.009). 4. The accuracy of the prediction random forst model is 0.81. The model appears to be superior in terms of positive prediction. Conclusion: In young work aged PDR patients undergoing vitrectomy, preoperative urine protein can be an independent indicator of postoperative visual loss. Aggressive correction of kidney injury before surgery may help improve postoperative vision in patients with PDR.

Botanical discrimination and classification of Mentha plants applying two-chiral column tandem GC-MS analysis of eight menthol enantiomers.

The concentration and distribution of menthol enantiomers have great significance in discriminating natural mint varieties and evaluating the origin of foodstuffs containing menthol additives. However, the chiral separation of eight chiral menthol enantiomers in Mentha plants offers an easy approach to eliminating or reducing the identification technology problem. The application of derivatized ß-cyclodextrin capillary chiral column coupled with derivatized γ-cyclodextrin capillary chiral column, and gas chromatography-mass spectrometry (GC-MS) technology, to isolate and analyze eight chiral menthol enantiomers in 23 natural Mentha plants was investigated. The results showed that the two-chiral columns tandem technology enabled the baseline separation of the eight menthol enantiomers. Four different menthol compounds were only detected in seven out of the 23 natural mint plants. (1R,3R,4S)-(-)-menthol and (1R,3S,4S)-(+)-neomenthol were detected in the seven mint plant samples, while (1S,3S,4R)-(+)-menthol and (1S,3R,4R)-(-)-neomenthol could not be detected in the seven mint plant samples. For the two enantiomer couples of (+/-)-isomenthol and (+/-)-neoisomenthol, only (+)-isomers were detected in field mint, candy mint, and peppermint. The Mentha plant samples were distinguished and identified by principal component analysis and radar chart statistical analysis based on the data of the menthol content and isomer ratio. Furthermore, the presence or absence of (1S,3S,4R)-(+)-menthol in the samples can be used as an identification factor for discriminating between synthetic menthol and natural sources of menthol.