Case report: Successful anesthesia management of noncardiac surgery in a patient with single atrium.

Background: Single atrium is very rare congenital cardiac anomaly in adults. The prognosis of patients with single atrium is very poor, with 50% of patients dying owing to cardiopulmonary complications in childhood. Herein, we focused on anesthesia management for noncardiac surgery in patients with single atrium. Case presentation: A 58-year-old male with a history of bilateral varicocele underwent laparotomy for high-position ligation of the spermatic vein. The patient also had a history of single atrium, atrial fibrillation, chronic heart failure, pulmonary hypertension (PH), and complete right bundle branch block (CRBBB). Given the significant complications associated with general anesthesia in patients with PH, we preferred to use low-dose epidural anesthesia for this patient. Transthoracic echocardiography was used to assess cardiac function before and during surgery and guide perioperative fluid therapy. To limit the stress response, we used a regional nerve block for reducing postoperative pain. Furthermore, we used norepinephrine to appropriately increase the systemic vascular resistance in response to the reduction of systemic vascular resistance caused by epidural anesthesia. Conclusion: Low-dose epidural anesthesia can be safely used in patients with single atrium and PH. The use of perioperative transthoracic echocardiography is helpful in guiding fluid therapy and effectively assessing the cardiac structure and function of patients. Prophylactic administration of norepinephrine before epidural injection may make it easier to maintain the patient's BP.

Nickel doping of ferrous disulfide nanocubes exhibits enhanced oxidase-like activity for In vitro detection of total antioxidant capacity.

The development of nanomaterials that mimic oxidase-like activities has recently attracted an increasing amount of attention. Obtaining highly active and cost-effective oxidase mimics has posed a significant challenge in this area of research. In this study, we successfully synthesized nickel-doped ferrous disulfide nanocubes (Ni-FeS2) via a facile one-step method. Characterization by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed that Ni was predominantly distributed within the surface layer of the Ni-FeS2 nanocubes. The incorporation of nickel in density functional theory (DFT) calculations effectively reduced the d-band center of Fe, resulting in weakened adsorption to intermediates and thereby enhancing its catalytic efficiency. Moreover, we developed a novel approach based on Ni-FeS2 (the Ni-FeS2 method) for detecting reducing substances, which exhibited good sensitivity toward ascorbic acid (AA), glutathione (GSH), and cysteine (Cys). Remarkably, the established Ni-FeS2 method was successfully employed for in vitro assessment of total antioxidant capacity (TAC) in cellular and organ samples, thereby enabling discrimination between normal, senescent, and malignant cells as well as distinguishing among healthy liver tissue, cancerous liver tissue, and metastatic organs.

Clinical significance of massive proteinuria in primary IgA nephropathy with and without nephrotic syndrome: a single center cohort study.

BACKGROUND: Both primary IgA nephropathy (IgAN) with and without nephrotic syndrome (NS) can present massive proteinuria (24-h urinary protein ≥3.5 g/d). The clinical significance of massive proteinuria may be different in the two entities and needs further research. METHODS: Data of 1870 patients with biopsy-proven IgAN in our hospital from January 2011 to December 2022 was retrospectively reviewed. A total of 242 IgAN patients with massive proteinuria were enrolled. Patients who presented with nephrotic syndrome at renal biopsy were included in the IgAN with NS cohort (IgAN-NS). The IgAN with nephrotic-range proteinuria cohort (IgAN-NR) consisted of 1:1 matched cases from the remaining according to age, gender, estimated glomerular filtration rate (eGFR) at baseline, and follow-up time. The clinical and pathological characteristics between the two cohorts were analyzed. RESULTS: The IgAN-NS had a significantly higher proteinuria level than the IgAN-NR (p < .001). Cluster analysis revealed that proteinuria was associated with lipids in IgAN-NS, while it was associated with inflammatory indicators in IgAN-NR. When the complete remission of proteinuria (CR) was not achieved, the Kaplan-Meier analysis showed the prognosis of IgAN-NS was significantly worse than that of IgAN-NR (p = .04). Then, our GLMM model and line chart showed that the serum albumin level of the IgAN-NR was always evidently higher than that of the IgAN-NS while the significant difference in urinary albumin/creatinine ratio between the two cohorts gradually disappeared during the short-term follow-up (1 year). Moreover, the Cox regression analysis showed that the increased serum albumin was an independent protective factor for the poor outcomes (eGFR decreased from the baseline ≥ 30% continuously or reached end-stage renal disease [ESRD]). CONCLUSION: The IgAN-NS had poorer clinicopathologic manifestation than IgAN-NR, including severer massive proteinuria. When the CR was not achieved, the prognosis of IgAN-NS was inferior to that of the IgAN-NR.

Inhibition of abnormal C/EBPß/α-Syn signaling pathway through activation of Nrf2 ameliorates Parkinson's disease-like pathology.

Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs) in the brain. These LBs are primarily composed of α-Synuclein (α-Syn), which has aggregated. A recent report proposes that CCAAT/enhancer-binding proteins ß (C/EBPß) may act as an age-dependent transcription factor for α-Syn, thereby initiating PD pathologies by regulating its transcription. Potential therapeutic approaches to address PD could involve targeting the regulation of α-Syn by C/EBPß. This study has revealed that Nrf2, also known as nuclear factor (erythroid-derived 2)-like 2 (NFE2L2), suppresses the transcription of C/EBPß in SH-SY5Y cells when treated with MPP+ . To activate Nrf2, sulforaphane, an Nrf2 activator, was administered. Additionally, C/EBPß was silenced using C/EBPß-DNA/RNA heteroduplex oligonucleotide (HDO). Both approaches successfully reduced abnormal α-Syn expression in primary neurons treated with MPP+ . Furthermore, sustained activation of Nrf2 via its activator or inhibition of C/EBPß using C/EBPß-HDO resulted in a reduction of aberrant α-Syn expression, thus leading to an improvement in the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) in mouse models induced by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) and those treated with preformed fibrils (PFFs). The data presented in this study illustrate that the activation of Nrf2 may provide a potential therapeutic strategy for PD by inhibiting the abnormal C/EBPß/α-Syn signaling pathway.

An Exciting Performance of Established and Novel Biomarkers in Diagnosing Periprosthetic Joint Infections: A Single-center Retrospective Cohort Study.

OBJECTIVE: Significant progress has been made in recent years in the diagnosis of periprosthetic joint infections (PJI). However, the lack of a gold standard test for the diagnosis of PJI remains a challenge.The aim of this study was to evaluate the diagnostic values of the albumin/fibrinogen ratio (AFR), the C-reactive protein/albumin ratio (CAR), and the levels of fibrinogen (FIB) and albumin (ALB) in the diagnosis of PJI. METHODS: The medical records of 158 patients who had undergone hip or knee revisions from January 2018 to May 2022 were retrospectively analyzed. Of these patients, 79 were diagnosed with PJI, while 79 were diagnosed with aseptic loosening (AL). PJI was defined using the Musculoskeletal Infection Society criteria. The plasma levels of C-reactive protein (CRP), ALB, and FIB; the erythrocyte sedimentation rate (ESR); and the AFR and CAR in the two groups were recorded and analyzed. The receiver operating characteristic curve was used to calculate the sensitivity and specificity of each indicator; the diagnostic value for each indicator was calculated as the area under the curve (AUC). RESULTS: The ESR, CRP, FIB, and CAR values in the PJI group were significantly higher than those in the AL group, and the ALB and AFR values were significantly lower than those in the AL group (p < 0.001). The AUC values of AFR and fibrinogen were 0.851 and 0.848, respectively, which were slightly higher than those of CRP (0.826) and ESR (0.846). The AUC of CAR was 0.831 which was slightly lower than that of CRP (0.846). ALB had an AUC of 0.727. The optimal threshold, sensitivity, and specificity, respectively, were 10.05, 84.81%, and 82.28% for AFR; 4.03 µg/mL, 77.22%, and 86.08% for FIB; 0.23, 72.15%, and 82.28% for CAR; and 37.30 g/L, 65.82%, and 73.42% for ALB. CONCLUSIONS: AFR, CAR, and FIB are good new auxiliary diagnostic indicators of PJI, while ALB is of fair value for the diagnosis of PJI.

Evolution of antimicrobial cysteine-rich peptides in plants.

KEY MESSAGE: We analyzed the evolutionary pattern of cysteine-rich peptides (CRPs) to infer the relationship between CRP copy number and plant ecotype, and the origin of bi-domains CRPs. Plants produce cysteine-rich peptides (CRPs) that have long-lasting broad-spectrum antimicrobial activity to protect themselves from various groups of pathogens. We analyzed 240 plant genomes, ranging from algae to eudicots, and discovered that CRPs are widely distributed in plants. Our comparative genomics results revealed that CRP genes have been amplified through both whole genome and local tandem duplication. The copy number of these genes varied significantly across lineages and was associated with the plant ecotype. This may be due to their resistance to changing pathogenic environments. The conserved and lineage-specific CRP families contribute to diverse antimicrobial activities. Furthermore, we investigated the unique bi-domain CRPs that result from unequal crossover events. Our findings provide a unique evolutionary perspective on CRPs and insights into their antimicrobial and symbiosis characteristics.

Non-coding RNA-related antitumor mechanisms of marine-derived agents.

In the last two decades, natural active substances have attracted great attention in developing new antitumor drugs, especially in the marine environment. A series of marine-derived compounds or derivatives with potential antitumor effects have been discovered and developed, but their mechanisms of action are not well understood. Emerging studies have found that several tumor-related signaling pathways and molecules are involved in the antitumor mechanisms of marine-derived agents, including noncoding RNAs (ncRNAs). In this review, we provide an update on the regulation of marine-derived agents associated with ncRNAs on tumor cell proliferation, apoptosis, cell cycle, invasion, migration, drug sensitivity and resistance. Herein, we also describe recent advances in marine food-derived ncRNAs as antitumor agents that modulate cross-species gene expression. A better understanding of the antitumor mechanisms of marine-derived agents mediated, regulated, or sourced by ncRNAs will provide new biomarkers or targets for potential antitumor drugs from preclinical discovery and development to clinical application.

Effects of propofol on macrophage activation and function in diseases.

Macrophages work with monocytes and dendritic cells to form a monocyte immune system, which constitutes a powerful cornerstone of the immune system with their powerful antigen presentation and phagocytosis. Macrophages play an essential role in infection, inflammation, tumors and other pathological conditions, but these cells also have non-immune functions, such as regulating lipid metabolism and maintaining homeostasis. Propofol is a commonly used intravenous anesthetic in the clinic. Propofol has sedative, hypnotic, anti-inflammatory and anti-oxidation effects, and it participates in the body's immunity. The regulation of propofol on immune cells, especially macrophages, has a profound effect on the occurrence and development of human diseases. We summarized the effects of propofol on macrophage migration, recruitment, differentiation, polarization, and pyroptosis, and the regulation of these propofol-regulated macrophage functions in inflammation, infection, tumor, and organ reperfusion injury. The influence of propofol on pathology and prognosis via macrophage regulation is also discussed. A better understanding of the effects of propofol on macrophage activation and function in human diseases will provide a new strategy for the application of clinical narcotic drugs and the treatment of diseases.

Gas5 inhibition promotes the axon regeneration in the adult mammalian nervous system.

Neurons in the peripheral nervous system (PNS) have robust regenerative capacity after axon injury, but the regenerative capacity is generally absent in the neurons of the central nervous system (CNS) in mammals. Increasing evidence highlighted the pivotal roles of long-noncoding RNAs (lncRNAs) in development and disease, but the role of LncRNA in triggering the regenerative capacity in CNS and PNS is not well studied. Here, we reported that lncRNA Gas5 is a suppressor for axon regeneration. Bioinformatics analysis shows that Gas5 is age-dependent up-regulated during DRG neurons development and down-regulated after sciatic nerve injury. In vitro, inhibiting the expression of Gas5 promotes the neurite growth of DRG neurons both in mice and rats. Consistently, Gas5 overexpression inhibits axon growth of mice DRG neurons. In vivo, Gas5 knockout(Gas5-/-) mice display enhanced nerve regeneration ability after sciatic nerve injury. RNA pull-down analysis indicates that Gas5 can interacts with soluble Vimentin, which is essential for peripheral nerve development and regeneration. Vimentin knockdown reverses the Gas5 silence-regulated axon pro-regeneration demonstrating that the function of Gas5 depending on Vimentin. Besides, inhibition of Gas5 expression can also enhance optic nerve regeneration indicating a potential pro-regenerative ability of Gas5 silence in CNS. Our study for the first time provides direct evidence in vivo that lncRNA plays a role in regulating central axon regrowth and Gas5 might be a novel therapeutic target for axon regeneration in both PNS and CNS.

Exploring the Biological Mechanism of Huang Yam in Treating Tumors and Preventing Antitumor Drug-Induced Cardiotoxicity Using Network Pharmacology and Molecular Docking Technology.

Drugs for the treatment of tumors could result in cardiotoxicity and cardiovascular diseases. We aimed to explore the anticancer properties of Huang yam as well as its cardioprotective properties using network pharmacology and molecular docking technology. The cardiovascular targets of the major chemical components of Huang yam were obtained from the following databases: TCMSP, ETCM, and BATMAN-TCM. The active ingredients of Huang yam were obtained from SwissADME. The cardiovascular targets of antitumor drugs were obtained using GeneCards, OMIM, DrugBank, DisGeNET, and SwissTargetPrediction databases. The drug-disease intersection genes were used to construct a drug-compound-target network using Cytoscape 3.7.1. A protein-protein interaction network was constructed using Cytoscape's BisoGenet, and the core targets of Huang yam were screened to determine their antitumor properties and identify the cardiovascular targets based on topological parameters. Potential targets were imported into the Metascape platform for GO and KEGG analysis. The results were saved and visualized using R software. The components with higher median values in the network were molecularly docked with the core targets. The network contained 10 compounds, including daucosterol, delusive, dioxin, panthogenin-B, and 124 targets, such as TP53, RPS27A, and UBC. The GO function enrichment analysis showed that there were 478 items in total. KEGG enrichment analysis showed a total of 140 main pathways associated with abnormal transcription of cancer, PI3K-Akt signaling pathway, cell cycle, cancer pathway, ubiquitination-mediated proteolysis, and other pathways. Molecular docking results showed that daucosterol, delusive, dioxin, and panthogenin-B had the highest affinity for TP53, RPS27A, and UBC. The treatment of diseases using traditional Chinese medicine encompasses multiple active ingredients, targets, and pathways. Huang yam has the potential to treat cardiotoxicity caused by antitumor drugs.

Microarray analysis of miRNA based on the regional lymph node metastasis status of esophageal squamous cell carcinoma.

BACKGROUND: Tendency toward extensive regional lymph node metastasis (LNM) is an important clinical characteristic of esophageal squamous cell carcinoma (ESCC) and differs greatly between patients. MicroRNAs (miRNAs) are involved in the invasion and metastasis of ESCC. We performed a microarray analysis of miRNAs based on LNM status to identify tumor-specific miRNAs for the prediction of LNM in ESCC. METHODS: Four pairs of ESCC tumor tissues with or without LNM were selected for microarray analysis to identify differentially expressed miRNAs, then 50 tumor tissue samples were selected to verify the differences of the screened miRNAs with quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The relations between candidate miRNAs and clinicopathologic features were analyzed to confirm tumor specificity in the prediction of LNM in ESCC. Target gene prediction using miRWalk2.0 was used to analyze the potential mechanisms of the tumor-specific miRNAs. RESULTS: The present microarray analysis identified significant differential expression in 62 miRNAs in the ESCC samples with LNM, compared to those without LNM. Of these, 19 miRNAs were selected for qRT-PCR verification, and three miRNAs were significantly upregulated in ESCC samples with LNM compared to those without LNM. The three miRNAs were not significantly associated with any other clinicopathologic features except for the TNM stage and could be regarded as tumor-specific miRNAs capable of predicting LNM in ESCC. Finally, 858 mRNAs were significantly associated with tumor-specific miRNAs and possibly involved in the regulation of LNM in ESCC. CONCLUSIONS: The present microarray analysis based on LNM status identified three tumor-specific miRNAs for predicting regional LNM in ESCC, which provides valuable clues for potential mechanism research and guarantees further investigation.

Overexpression of microRNA-19a-3p promotes lymph node metastasis of esophageal squamous cell carcinoma via the RAC1/CDC42-PAK1 pathway.

BACKGROUND: A tendency towards extensive regional lymph node metastasis (LNM) is a typical clinical characteristic of esophageal squamous cell carcinoma (ESCC). Up-regulated microRNA (miR)-19a-3p was verified as a predictor of LNM in ESCC in previous microarray analyses, but the underlying mechanisms remain unclear. Here, in vitro experiments were performed to confirm the effect of miR-19a-3p on promoting LNM and to explore the underlying mechanisms. METHODS: KYSE-150 and TE-1 cell lines were transfected with lentiviral vectors to inhibit miR-19a-3p (LV-miR-19a-3p-inhibition), and cell proliferation, invasion, and migration were assessed. Target genes of miR-19a-3p were identified by sequencing analysis and quantitative reverse transcription PCR (qRT-PCR); Western blotting was performed to confirm targets and explore the potential mechanisms underlying the effect of miR-19a-3p on LNM. RESULTS: miR-19a-3p had no effect on ESCC cell proliferation, whereas miR-19a-3p overexpression promoted the invasion and migration of ESCC cells. qRT-PCR verification and western blot analysis showed that LV-miR-19a-3p-inhibition downregulated cell division cycle 42 (CDC42), Rac family small GTPase 1 (RAC1), and p21 activated kinase 1 (PAK1). CONCLUSIONS: Overexpression of miR-19a-3p increased the invasion and migration of ESCC cells via the RAC1/CDC42-PAK1 pathway, suggesting that this pathway mediates the effect of miR-19a-3p on promoting LNM in ESCC.

Synthesis, structural characterization and antitumor activity of six rare earth metal complexes with 8-hydroxyquinoline derivatives.

The rare earth metal Gd(III), Yb(III), Lu(III), Eu(III), Tb(III) and Ho(III) complexes 1-6 with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol (H-L) as ligands were synthesized. The in vitro cytotoxicity assay indicated that the cytotoxicity of 1 was equivalent to cisplatin and higher than that of H-L and other complexes towards T24 tumor cells. The mechanism study indicated that 1 caused significant up-regulation of the proteins p27, p21 and p53 in T24 cells and cell cycle arrest in G2 phase. In addition, 1 induced effective T24 cells apoptosis via mitochondrial dysfunction pathway, which was indicated by changes in mitochondrial membrane potential (Δψ), reactive oxygen species (ROS), intracellular Ca2+ and the mitochondria-related proteins (including cytochrome C (Cyt C), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated x (Bax) and apoptotic protease activating factor-1 (Apaf-1)). Moreover, 1 could activate caspase-3/8/9 in T24 cells. Therefore, complex 1 is a promising and potent anticancer drug candidate.

PAQR9 Modulates BAG6-mediated protein quality control of mislocalized membrane proteins.

Protein quality control is crucial for maintaining cellular homeostasis and its dysfunction is closely linked to human diseases. The post-translational protein quality control machinery mainly composed of BCL-2-associated athanogene 6 (BAG6) is responsible for triage of mislocalized membrane proteins (MLPs). However, it is unknown how the BAG6-mediated degradation of MLPs is regulated. We report here that PAQR9, a member of the Progesterone and AdipoQ receptor (PAQR) family, is able to modulate BAG6-mediated triage of MLPs. Analysis with mass spectrometry identified that BAG6 is one of the major proteins interacting with PAQR9 and such interaction is confirmed by co-immunoprecipitation and co-localization assays. The protein degradation rate of representative MLPs is accelerated by PAQR9 knockdown. Consistently, the polyubiquitination of MLPs is enhanced by PAQR9 knockdown. PAQR9 binds to the DUF3538 domain within the proline-rich stretch of BAG6. PAQR9 reduces the binding of MLPs to BAG6 in a DUF3538 domain-dependent manner. Taken together, our results indicate that PAQR9 plays a role in the regulation of protein quality control of MLPs via affecting the interaction of BAG6 with membrane proteins.

Polyamine synthesis enzyme AMD1 is closely associated with tumorigenesis and prognosis of human gastric cancers.

Adenosylmethionine decarboxylase 1 (AMD1) is a key enzyme involved in biosynthesis of polyamines including spermidine and spermine. The potential function of AMD1 in human gastric cancers is unknown. We analyzed AMD1 expression level in 319 human gastric cancer samples together with the adjacent normal tissues. The protein expression level of AMD1 was significantly increased in human gastric cancer samples compared with their corresponding para-cancerous histological normal tissues (P < 0.0001). The expression level of AMD1 was positively associated with Helicobactor pylori 16sRNA (P < 0.0001), tumor size (P < 0.0001), tumor differentiation (P < 0.05), tumor venous invasion (P < 0.0001), tumor lymphatic invasion (P < 0.0001), blood vessel invasion (P < 0.0001), and tumor lymph node metastasis (TNM) stage (P < 0.0001). Patients with high expression of AMD1 had a much shorter overall survival than those with normal/low expression of AMD1. Knockdown of AMD1 in human gastric cancer cells suppressed cell proliferation, colony formation and cell migration. In a tumor xenograft model, knockdown of AMD1 suppressed the tumor growth in vivo. Inhibition of AMD1 by an inhibitor SAM486A in human gastric cancer cells arrested cell cycle progression during G1-to-S transition. Collectively, our studies at the cellular, animal and human levels indicate that AMD1 has a tumorigenic effect on human gastric cancers and affect the prognosis of the patients.

PAQR3 suppresses the growth of non-small cell lung cancer cells via modulation of EGFR-mediated autophagy.

Macroautophagy/autophagy is an evolutionarily conserved intracellular process that recycles and degrades intracellular components to sustain homeostasis in response to deficiency of nutrients or growth factors. PAQR3 is a newly discovered tumor suppressor that also regulates autophagy induced by nutrient starvation via AMPK and MTORC1 signaling pathways. In this study, we investigated whether PAQR3 modulates EGFR-mediated autophagy and whether such regulation is associated with the tumor suppressive activity of PAQR3. PAQR3 is able to inhibit the in vitro and in vivo growth of non-small cell lung cancer (NSCLC) cells. PAQR3 potentiates autophagy induced by EGFR inhibitor erlotinib. Knockdown of PAQR3 abrogates erlotinib-mediated reduction of BECN1 interaction with autophagy inhibitory proteins RUBCN/Rubicon and BCL2. PAQR3 blocks the interaction of BECN1 with the activated form of EGFR and inhibits tyrosine phosphorylation of BECN1. Furthermore, inhibition of autophagy by knocking down ATG7 abrogates the tumor suppressive activity of PAQR3 in NSCLC cells. Collectively, these data indicate that PAQR3 suppresses tumor progression of NSCLC cells through modulating EGFR-regulated autophagy. ABBREVIATIONS: AKT: thymoma viral proto-oncogene; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1; CCK-8: cell counting kit-8; CQ: chloroquine diphosphate; DMEM: Dulbecco's modified Eagle's medium; EdU: 5-ethynyl-2'-deoxyuridine; EGFR: epidermal growth factor receptor; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IgG: Immunoglobulin G; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTT: thiazolyl blue tetrazolium bromide; NSCLC: Non-small cell lung cancer; MAP2K/MEK: mitogen-activated protein kinase kinase; MAPK/ERK: mitogen-activated protein kinase; PAQR3: progestin and adipoQ receptor family member 3; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PRKAA/AMPK: protein kinase, AMP-activated alpha catalytic; RUBCN: rubicon autophagy regulator; RPS6: ribosomal protein S6; RAS: Ras proto-oncogene; RAF: Raf proto-oncogene; TKI: tyrosine kinase inhibitor; TUBA4A: tubulin alpha 4a; UVRAG: UV radiation resistance associated.

Synthesis and in vitro antitumor activity evaluation of copper(II) complexes with 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline derivatives.

Seven Cu(II) complexes with 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline derivatives as ligands: [Cu2(L1)2Cl4] (1), [Cu(L2)Cl2] (2), [Cu(L1)(NO3)2] (3), [Cu(L2)(NO3)2] (4), [Cu(L3)Cl2] (5), [Cu(L3)Br2] (6) and [Cu(L3)(NO3)2] (7){L1=9-nitro-5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline, L2=4-nitro-5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline, L3=9-bromo-5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline}, were synthesized and characterized. Their in vitro anticancer activities against T-24, MGC-80-3, HeLa, Hep-G2, A549 and SK-OV-3 were evaluated. Compared with their corresponding ligands, most of these complexes exhibited enhanced anticancer activities in contrast to their corresponding ligands and copper salt. Among them, complexes 1 and 3 displayed selective cytotoxicity to HeLa cells comparing with normal liver cell HL-7702, with IC50 values of 5.03 ±â€¯1.20 µM and 10.05 ±â€¯0.52 µM, respectively. Complexes 1 and 3 inhibited telomerase activity by interacting with c-myc promoter elements, and therefore exerted their antitumor activity. Furthermore, complexes 1 and 3 could trigger cell apoptosis via disruption of mitochondrial pathway through notably increased reactive oxygen species (ROS) levels, loss of mitochondrial membrane potential (Δψm), increase of the cytochrome c and apaf-1, decrease of bcl-2, and activation of caspases 3/9. Complexes 1 and 3 exhibited enhanced cytotoxicity, presenting synergetic effect after the ligands coordinated to copper(II) center.

PAQR3 modulates blood cholesterol level by facilitating interaction between LDLR and PCSK9.

OBJECTIVE: Low-density lipoprotein cholesterol (LDL-C) is the hallmark of atherosclerotic cardiovascular diseases. The hepatic LDL receptor (LDLR) plays an important role in clearance of circulating LDL-C. PCSK9 facilitates degradation of LDLR in the lysosome and antagonizing PCSK9 has been successfully used in the clinic to reduce blood LDL-C level. Here we identify a new player that modulates LDLR interaction with PCSK9, thus controlling LDLR degradation and cholesterol homeostasis. METHODS: The blood LDL-C and cholesterol levels were analyzed in mice with hepatic deletion of Paqr3 gene. The half-life of LDLR was analyzed in HepG2 cells. The interaction of PAQR3 with LDLR and PCSK9 was analyzed by co-immunoprecipitation and immunofluorescent staining. RESULTS: The blood LDL-C and total cholesterol levels in the mice with hepatic deletion of Paqr3 gene were significantly lower than the control mice after feeding with high-fat diet (p < 0.001 and p < 0.05 respectively). The steady-state level of LDLR protein is elevated by Paqr3 knockdown/deletion and reduced by PAQR3 overexpression. The half-life of LDLR protein is increased by Paqr3 knockdown and accelerated by PAQR3 overexpression. PAQR3 interacts with the ß-sheet domain of LDLR and the P-domain of PCSK9 respectively. In addition, PAQR3 can be localized in early endosomes and colocalized with LDLR, PCSK9 and LDL. Mechanistically, PAQR3 enhances the interaction between LDLR and PCSK9. CONCLUSION: Our study reveals that PAQR3 plays a pivotal role in controlling hepatic LDLR degradation and blood LDL-C level via modulating LDLR-PCSK9 interaction.

Alteration of Androgen Receptor Protein Stability by Triptolide in LNCaP Cells.

Background and Objective: Although triptolide was effective for prostate cancer (PCa), the mechanism is still unclear. Androgen receptor (AR) plays a large role in the development and progression of PCa, even after castration. The present study aimed at investigating the effects of triptolide on AR protein stability and the possible mechanism. Materials and Methods: By blocking protein synthesis with cycloheximide (CHX), the effect of triptolide on AR protein stability was investigated with western blot assay. The potential role of calpains in triptolide reduced AR protein stability was investigated with calpain inhibitor and Ca2+ chelator. Results: Triptolide down-regulated AR protein level when protein synthesis was blocked by CHX, demonstrating the decrease of AR protein stability. The AR protein level was restored when the cells were co-treated with triptolide and calpain inhibitor or Ca2+ chelator, indicating the important role of calpains. Conclusions: The results indicate that triptolide can activate calpain via promoting intracellular Ca2+ accumulation, and thus decrease the stability of AR protein, subsequently resulting in the breakdown of the AR protein in LNCaP cells. This work provides an experimental basis and evidence to elucidate the anti-PCa mechanisms of triptolide.

Improving dispersive property, biocompatibility and targeting gene transfection of graphene oxide by covalent attachment of polyamidoamine dendrimer and glycyrrhetinic acid.

The surface functional groups of GO have significant effects on the performances of GO-based gene delivery vector. In this work, the polyamidoamine (PAMAM) dendrimer and glycyrrhetinic acid (GA) were tethered onto the GO surface by one-step covalently cross-linking method. The micro-morphology, surface functional groups, and zeta potential of the obtained GO-PAMAM-GA hybrid were characterized and verified. The effects of GA amount in the hybrid on the dispersive property in cell culture medium, in vitro cytotoxicity to human hepatocarcinoma (SMMC-7721) and human embryonic kidney (HEK-293) cells, and gene (plasmid DNA of enhanced green fluorescent protein) transfection capacity were investigated in detail. Under optimal conditions, the obtained hybrid shows small average size (about 160 nm) and has very good dispersive stability (in 30 days) in cellular culture medium. Compared with the GO-PAMAM without GA modification, the GO-PAMAM-GA hybrid exhibits greatly enhanced biocompatibility to the two cell lines. The cellular viability of SMMC-7721 cells still retains about 98% even the concentration of the hybrid up to 200 µg mL-1. The gene transfection capacity of the GO-PAMAM has been improved about 50% through the GA functionalization. Moreover, the GO-PAMAM-GA hybrid possesses targeting gene transfection to SMMC-7721 cells.