[Retracted] MicroRNA­584 prohibits hepatocellular carcinoma cell proliferation and invasion by directly targeting BDNF.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the Transwell invasion assay data shown in Fig. 2C and D on p. 1997 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published, or were submitted for publication at around the same time (and in some cases, have subsequently been retracted).  Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a  reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports  20: 1994-2001, 2019; DOI: 10.3892/mmr.2019.10424].

A53T α-synuclein mutation increases susceptibility to postoperative delayed neurocognitive recovery via hippocampal Ang-(1-7)/MasR axis.

Delayed neurocognitive recovery (dNCR) is a common complication in geriatric surgical patients. The impact of anesthesia and surgery on patients with neurodegenerative diseases, such as Parkinson's disease (PD) or prion disease, has not yet been reported. In this study, we aimed to determine the association between a pre-existing A53T genetic background, which involves a PD-related point mutation, and the development of postoperative dNCR. We observed that partial hepatectomy induced hippocampus-dependent cognitive deficits in 5-month-old A53T transgenic mice, a model of early-stage PD without cognitive deficits, unlike in age-matched wild-type (WT) mice. We respectively examined molecular changes at 6 h, 1 day, and 2 days after partial hepatectomy and observed that cognitive changes were accompanied by weakened angiotensin-(1-7)/Mas receptor [Ang-(1-7)/MasR] axis, increased alpha-synuclein (α-syn) expression and phosphorylation, decreased methylated protein phosphatase-2A (Me-PP2A), and prompted microglia M1 polarization and neuronal apoptosis in the hippocampus at 1 day after surgery. Nevertheless, no changes in blood-brain barrier (BBB) integrity or plasma α-syn levels in either A53T or WT mice. Furthermore, intranasal administration of selective MasR agonist AVE 0991, reversed the mentioned cognitive deficits in A53T mice, enhanced MasR expression, reduced α-syn accumulation and phosphorylation, and attenuated microglia activation and apoptotic response. Our findings suggest that individuals with the A53T genetic background may be more susceptible to developing postoperative dNCR. This susceptibility could be linked to central α-syn accumulation mediated by the weakened Ang-(1-7)/MasR/methyl-PP2A signaling pathway in the hippocampus following surgery, independent of plasma α-syn level and BBB.

Silencing HEATR1 Rescues Cisplatin Resistance of Non-Small Cell Lung Cancer by Inducing Ferroptosis via the p53/SAT1/ALOX15 Axis.

BACKGROUND: Cisplatin (DDP) is a commonly used chemotherapy agent. However, its resistance to the drug is a major challenge in its clinical application. Earlier research has suggested a connection between HEATR1 and chemoresistance in cancer. However, additional investigation is needed to better understand its involvement in resistance to DDP. In this study, we aimed to determine the regulatory effect of HEATR1 on the resistance of cisplatin in NSCLC. METHODS: We collected specimens of both DDP-resistant and non-resistant NSCLC to examine the expression of HEATR1. Additionally, we established cisplatin-resistant cells of NSCLC using the A549 cell line. Cell ability was examined by CCK-8 assay. Cell apoptosis and lipid ROS were examined by flow cytometry. The expressions of HEATR1, p53, SAT1, and ALOX15 were determined by qRT-PCR and Western blot. The tumor xenograft experiment was conducted to assess the impact of silencing HEATR1 on cisplatin resistance in vivo in NSCLC. RESULTS: The expression levels of HEATR1 were found to be significantly elevated in DDP-resistant tissues and cells of NSCLC as compared to non-resistant counterparts. Conversely, the expression levels of p53, SAT1, and ALOX15 were observed to be reduced in DDP-resistant cells. Through the inhibition of HEATR1, the proliferation of DDP-resistant cells was significantly suppressed, while the generation of lipid ROS was enhanced. This effect was achieved by activating ferroptosis and the p53/SAT1/ALOX15 pathway, as demonstrated both in vitro and in vivo. Conversely, the overexpression of HEATR1 exhibited opposite effects. Furthermore, the silencing of p53 and ALOX15 reversed the oncogenic effects of HEATR1 and inhibited ferroptosis in DDP-resistant NSCLC cells, suggesting the involvement of p53 and ALOX15 in HEATR1-mediated DDP resistance. CONCLUSION: Finally, the findings revealed that HEATR1 silencing reduced DDP resistance in NSCLC by inducing ferroptosis via the p53/SAT1/ALOX15 axis. HEATR1 might become a potential target for overcoming DDP resistance in NSCLC treatment.

Systematic characterization of CsbZIP transcription factors in Camelina sativa and functional analysis of CsbZIP-A12 mediating regulation of unsaturated fatty acid-enriched oil biosynthesis.

The basic leucine zipper (bZIP) transcription factors (TFs) function importantly in numerous life processes in plants. However, bZIP members and their biological roles remain unknown in Camelina sativa, a worldwide promising oil crop. Here, 220 CsbZIP proteins were identified in camelina and classified into thirteen groups. Two and 347 pairs of tandem and segmental duplication genes were detected to be underwent purification selection, with segmental duplication as the main driven-force of CsbZIP gene family expansion. Most CsbZIP genes displayed a tissue-specific expression pattern. Particularly, CsbZIP-A12 significantly positively correlated with many FA/oil biosynthesis-related genes, indicating CsbZIP-A12 may regulate lipid biosynthesis. Notably, yeast one-hybrid (Y1H), ß-Glucuronidase (GUS), dual-luciferase (LUC) and EMSA assays evidenced that CsbZIP-A12 located in nucleus interacted with the promoters of CsSAD2-3 and CsFAD3-3 genes responsible for unsaturated fatty acid (UFA) synthesis, thus activating their transcriptions. Overexpression of CsbZIP-A12 led to an increase of total lipid by 3.275 % compared to the control, followed with oleic and α-linolenic acid levels enhanced by 3.4 % and 5.195 %, and up-regulated the expressions of CsSAD2-3, CsFAD3-3 and CsPDAT2-3 in camelina seeds. Furthermore, heterogeneous expression of CsbZIP-A12 significantly up-regulated the expressions of NtSAD2, NtFAD3 and NtPDAT genes in tobacco plants, thereby improving the levels of total lipids and UFAs in both leaves and seeds without negative effects on other agronomic traits. Together, our findings suggest that CsbZIP-A12 upregulates FA/oil biosynthesis by activating CsSAD2-3 and CsFAD3-3 as well as possible other related genes. These data lay a foundation for further functional analyses of CsbZIPs, providing new insights into the TF-based lipid metabolic engineering to increase vegetable oil yield and health-beneficial quality in oilseeds.

Biomimetic Nano-Degrader Based CD47-SIRPα Immune Checkpoint Inhibition Promotes Macrophage Efferocytosis for Cardiac Repair.

CD47-SIRPα axis is an immunotherapeutic target in tumor therapy. However, current monoclonal antibody targeting CD47-SIRPα axis is associated with on-target off-tumor and antigen sink effects, which significantly limit its potential clinical application. Herein, a biomimetic nano-degrader is developed to inhibit CD47-SIRPα axis in a site-specific manner through SIRPα degradation, and its efficacy in acute myocardial infarction (AMI) is evaluated. The nano-degrader is constructed by hybridizing liposome with red blood cell (RBC) membrane (RLP), which mimics the CD47 density of senescent RBCs and possesses a natural high-affinity binding capability to SIRPα on macrophages without signaling capacity. RLP would bind with SIRPα and induce its lysosomal degradation through receptor-mediated endocytosis. To enhance its tissue specificity, Ly6G antibody conjugation (aRLP) is applied, enabling its attachment to neutrophils and accumulation within inflammatory sites. In the myocardial infarction model, aRLP accumulated in the infarcted myocardium blocks CD47-SIRPα axis and subsequently promoted the efferocytosis of apoptotic cardiomyocytes by macrophage, improved heart repair. This nano-degrader efficiently degraded SIRPα in lysosomes, providing a new strategy for immunotherapy with great clinical transformation potential.

Preoperative prognostic nutritional index value as a predictive factor for postoperative delirium in older adult patients with hip fractures: a secondary analysis.

BACKGROUND: Malnutrition is a common geriatric syndrome and can be targeted preoperatively to decrease the risk of postoperative delirium (POD) in older adult patients. To analyze the value of the prognostic nutritional index (PNI) to predict the incidence of POD in older adult patients with hip fractures. METHODS: This was a prospective, observational, cohort study of older adult patients with hip fractures. Preoperative PNI was calculated as 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (/µL) using preoperative laboratory results. Patients were divided into POD and non-POD groups using the Confusion Assessment Method (CAM). The risk factors associated with POD as well as the relationship between PNI values and the incidence of POD were analyzed using univariate and multivariate logistic regression analyses. The predictive value of PNI for POD was assessed using receiver operating characteristic curve analysis. RESULTS: In this cohort of 369 patients who underwent hip fracture surgery, 67 patients (18.2%) were diagnosed with POD by the CAM results. Low PNI increased the risk of POD (odds ratio (OR) = 0.928, 95% confidence interval (CI): 0.864-0.997). General anesthesia (OR = 2.307, 95% CI: 1.279-4.162) and Mini-Mental State Examination (MMSE) score (OR = 0.956, 95% CI: 0.920-0.994) were also identified as risk factors for POD. Receiver operating characteristic curve analysis suggested that PNI combined with the anesthetic method and MMSE score may be used as a potential predictive indicator of POD after hip fracture surgery. CONCLUSION: Preoperative PNI value is related to POD in older adult patients with hip fractures. TRIAL REGISTRATION: This secondary analysis study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (approval No. M2022578) and registered in the Chinese Clinical Trial Registry (ChiCTR2300070569).

Genetically Engineered Macrophages Co-Loaded with CD47 Inhibitors Synergistically Reconstruct Efferocytosis and Improve Cardiac Remodeling Post Myocardial Ischemia Reperfusion Injury.

Efferocytosis, mediated by the macrophage receptor MerTK (myeloid-epithelial-reproductive tyrosine kinase), is a significant contributor to cardiac repair after myocardial ischemia-reperfusion (MI/R) injury. However, the death of resident cardiac macrophages (main effector cells), inactivation of MerTK （main effector receptor), and overexpression of "do not eat me" signals (brake signals, such as CD47), collectively lead to the impediment of efferocytosis in the post-MI/R heart. To date, therapeutic strategies targeting individual above obstacles are relatively lacking, let alone their effectiveness being limited due to constraints from the other concurrent two. Herein, inspired by the application research of chimeric antigen receptor macrophages (CAR-Ms) in solid tumors, a genetically modified macrophage-based synergistic drug delivery strategy that effectively challenging the three major barriers in an integrated manner is developed. This strategy involves the overexpression of exogenous macrophages with CCR2 (C-C chemokine receptor type 2) and cleavage-resistant MerTK, as well as surface clicking with liposomal PEP-20 (a CD47 antagonist). In MI/R mice model, this synergistic strategy can effectively restore cardiac efferocytosis after intravenous injection, thereby alleviating the inflammatory response, ultimately preserving cardiac function. This therapy focuses on inhibiting the initiation and promoting active resolution of inflammation, providing new insights for immune-regulatory therapy.

Melatonin regulates the circadian rhythm to ameliorate postoperative sleep disorder and neurobehavioral abnormalities in aged mice.

BACKGROUND: Postoperative sleep disorder (PSD) and delirium, which may be associated with surgery and inhalational anesthetics, induce adverse effects in old adults. Emerging evidence indicates that circadian rhythm contributes to various neuropathological diseases, including Alzheimer's disease. Thus, we analyzed the potential role of circadian rhythm in PSD and delirium-like behavior in aged mice and determined whether exogenous melatonin could facilitate entrainment of the circadian rhythm after laparotomy under sevoflurane anesthesia. METHODS: We selected old C57BL/6J mice which receiving laparotomy/sevoflurane anesthesia as model animals. We employed buried food, open field, and Y maze test to assess delirium-like behavior, and electroencephalography/electromyography (EEG/EMG) were used to investigate sleep changes. We analyzed the transcription rhythm of clock genes in superchiasmatic nucleus (SCN) to explore the effects of surgery and melatonin pretreatment on the circadian rhythm. Then, we measured melatonin receptor levels in SCN and ERK/CREB pathway-related proteins in hippocampus and prefrontal cortex to assess their role in PSDs and delirium-like behavior. RESULTS: Laparotomy under sevoflurane anesthesia had a greater influence than sevoflurane alone, leading to sleep disorder, a shift in sleep-wake rhythm, and delirium-like behavior. Bmal1, Clock, and Cry1 mRNA expression showed a peak shift, MT1 melatonin receptor expression level was increased in the SCN, and p-ERK/ERK and p-CREB/CREB were decreased in hippocampus and prefrontal cortex of aged mice 1 day after laparotomy. Melatonin showed significant efficacy in ameliorating PSD and delirium-like behavior and restoring the circadian rhythm, reversing melatonin receptor and ERK/CREB pathway expression abnormalities. In addition, most of the beneficial effect of melatonin was antagonized by luzindole, a melatonin receptor antagonist. CONCLUSIONS: Melatonin receptors in SCN, circadian rhythm, and ERK/CREB signaling pathway participate in the pathophysiological processes of PSD and delirium-like behavior. Melatonin intervention could be a potential preventative approach for PSD and delirium.

Antitumor mechanism of Saikosaponin A in the Xiaoying Sanjie Decoction for treatment of anaplastic thyroid cancer by network pharmacology analysis and experiments in vitro and in vivo.

Effective therapies for anaplastic thyroid cancer (ATC) are still limited due to its dedifferentiated phenotype and high invasiveness. Xiaoying Sanjie Decoction (XYSJD), a clinically empirical Chinese medicine compound, has shown positive effects for ATC treatment and recovery. However, the pharmacological mechanisms of effective active compound in XYSJD remain unclear. In this study, we aimed at elucidating the antitumor mechanism of the active compound and identifying the kernel molecular mechanisms of XYSJD against ATC. Firstly, the main chemical constituents of XYSJD were identified by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Then we used network pharmacology and ClusterONE algorithm to analyze the possible targets and pathways of the prescription and active compound Saikosaponin A (SSA). Seven core targets, including P2RY12, PDK1, PPP1CC, PPP2CA, TBK1, ITGB1 and ITGB6, which may be involved in the anti-tumor activity of XYSJD were screened. Finally, using cell biology, molecular biology and experimental zoology techniques, we investigated the mechanism of active compound SSA in the treatment of ATC. The results of qRT-PCR indicated that these seven nuclear targets might play an important role in SSA, the active compound of XYSJD. The combined data provide preliminary study of the pharmacological mechanisms of SSA in XYSJD. SSA may be a promising potential therapeutic and chemopreventive candidate for ATC.

BOston Neonatal Brain Injury Dataset for Hypoxic Ischemic Encephalopathy (BONBID-HIE): Part I. MRI and Manual Lesion Annotation.

Hypoxic ischemic encephalopathy (HIE) is a brain injury that occurs in 1 ~ 5/1000 term neonates. Accurate identification and segmentation of HIE-related lesions in neonatal brain magnetic resonance images (MRIs) is the first step toward predicting prognosis, identifying high-risk patients, and evaluating treatment effects. It will lead to a more accurate estimation of prognosis, a better understanding of neurological symptoms, and a timely prediction of response to therapy. We release the first public dataset containing neonatal brain diffusion MRI and expert annotation of lesions from 133 patients diagnosed with HIE. HIE-related lesions in brain MRI are often diffuse (i.e., multi-focal), and small (over half the patients in our data having lesions occupying <1% of brain volume). Segmentation for HIE MRI data is remarkably different from, and arguably more challenging than, other segmentation tasks such as brain tumors with focal and relatively large lesions. We hope that this dataset can help fuel the development of MRI lesion segmentation methods for HIE and small diffuse lesions in general.

Reciprocal interaction between mitochondrial fission and mitophagy in postoperative delayed neurocognitive recovery in aged rats.

INTRODUCTION: Emerging evidence suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of postoperative delayed neurocognitive recovery (dNCR). Mitochondria exist in a dynamic equilibrium that involves fission and fusion to regulate morphology and maintains normal cell function via the removal of damaged mitochondria through mitophagy. Nonetheless, the relationship between mitochondrial morphology and mitophagy, and how they influence mitochondrial function in the development of postoperative dNCR, remains poorly understood. Here, we observed morphological alterations of mitochondria and mitophagy activity in hippocampal neurons and assessed the involvement of their interaction in dNCR following general anesthesia and surgical stress in aged rats. METHODS: Firstly, we evaluated the spatial learning and memory ability of the aged rats after anesthesia/surgery. Hippocampal mitochondrial function and mitochondrial morphology were detected. Afterwards, mitochondrial fission was inhibited by Mdivi-1 and siDrp1 in vivo and in vitro separately. We then detected mitophagy and mitochondrial function. Finally, we used rapamycin to activate mitophagy and observed mitochondrial morphology and mitochondrial function. RESULTS: Surgery impaired hippocampal-dependent spatial learning and memory ability and caused mitochondrial dysfunction. It also increased mitochondrial fission and inhibited mitophagy in hippocampal neurons. Mdivi-1 improved mitophagy and learning and memory ability of aged rats by inhibiting mitochondrial fission. Knocking down Drp1 by siDrp1 also improved mitophagy and mitochondrial function. Meanwhile, rapamycin inhibited excessive mitochondrial fission and improved mitochondrial function. CONCLUSION: Surgery simultaneously increases mitochondrial fission and inhibits mitophagy activity. Mechanistically, mitochondrial fission/fusion and mitophagy activity interact reciprocally with each other and are both involved in postoperative dNCR. These mitochondrial events after surgical stress may provide novel targets and modalities for therapeutic intervention in postoperative dNCR.

[Retracted] MicroRNA­601 serves as a potential tumor suppressor in hepatocellular carcinoma by directly targeting PIK3R3.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that one of the data panels shown for the cell invasion assays in Fig. 2D was strikingly similar to another data panel that had appeared in different form in another article by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 19: 2431­2439, 2019; DOI: 10.3892/mmr.2019.9857].

CHAC1 promotes cell ferroptosis and enhances radiation sensitivity in thyroid carcinoma.

ChaC glutathione-specific γ-glutamylcyclotransferase 1 (CHAC1) is involved in intracellular glutathione depletion, ferroptosis, and tumorigenesis. The functional role of CHAC1 expression in thyroid carcinoma has not yet been established. The present study aimed to investigate the impact and mechanisms of CHAC1 on ferroptosis and radiation sensitivity in thyroid carcinoma. CHAC1 expression was examined in tumor tissue specimens and microarrays and thyroid carcinoma cell lines. CHAC1 was silenced or overexpressed by lentivirus transfection in thyroid carcinoma cells. Cell viability and lipid ROS levels were evaluated by Cell Counting Kit-8 and flow cytometry, respectively. The effect of CHAC1 on tumor growth in vivo was also measured. Ferroptosis-related proteins were measured by western blotting. CHAC1 expression was decreased in patients with thyroid carcinoma, and overexpression of CHAC1 suppressed cell viability of BCPAP cells and tumor growth in xenografted nude mice. Exposure to Ferrostatin-1, a ferroptosis inhibitor, significantly attenuated the inhibitory effects of CHAC1 overexpression on cell viability. In CHAC1-overexpressing BCPAP cells, ferroptosis was induced as indicated by increased lipid ROS production and PTGS2 expression. Knocking down of CHAC1 in K1 cells significantly induced cell viability, reduced lipid ROS production and PTGS2 expression, and enhanced GPX4 expression. Such effects were attenuated by RSL3, a ferroptosis inducer. Furthermore, we showed that CHAC1 overexpression enhanced radiation sensitivity in BCPAP cells as indicated by decreased cell viability, while CHAC1 knockdown had reversed effects in K1 cells as indicated by increased cell viability. Taken together, CHAC1 overexpression promoted ferroptosis and enhanced radiation sensitivity in thyroid carcinoma.

Preoperative plasma visfatin may have a dual effect on the occurrence of postoperative delirium.

Background: Visfatin is considered to be a "novel pro-inflammatory cytokine." Neuroinflammatory response is one of the important mechanisms of postoperative delirium (POD). The relationship between preoperative plasma visfatin and POD is unclear. Objective: To investigate the relationship between preoperative plasma visfatin concentrations and POD (primary outcome) in older hip fracture patients and to explore whether it affects POD through inflammatory factors. Materials and methods: This prospective cohort study enrolled 176 elderly patients who were scheduled for hip fracture surgery. Preoperative plasma was collected on the morning of surgery, and visfatin levels were measured. Interleukin (IL)-1 and IL-6 were measured using patients' plasma collected on the first day after surgery. We used the 3-min diagnostic interview for Confusion Assessment Method-defined delirium (3D-CAM) twice daily within the 2 days after surgery to assess whether POD had occurred. Restricted cubic splines and piecewise regression were used to explore the relationship between preoperative plasma visfatin concentrations and POD, and further mediation analysis was used to verify whether visfatin plays a role in POD through regulating inflammatory factors. Results: The incidence of POD was 18.2%. A J-shaped association was observed between preoperative plasma visfatin levels and POD. The risk of POD decreased within the lower visfatin concentration range up to 37.87 ng/ml, with a hazard ratio of 0.59 per 5 ng/ml [odds ratio (OR) = 0.59, 95% confidence interval (CI) = 0.37-0.95], but the risk increased above this concentration (P for non-linearity < 0.001, with a hazard ratio of 1.116 per 10 ng/ml; OR = 1.10, 95% CI = 1.02-1.23). Mediation effect analysis showed that when the plasma visfatin concentration was higher than 37.87 ng/ml, the effect of visfatin on POD was mediated by IL-6 (p < 0.01). A significant indirect association with postoperative plasma IL-6 was observed between preoperative plasma visfatin and POD (adjusted ß = 0.1%; 95% CI = 4.8∼38.9%; p < 0.01). Conclusion: Visfatin is the protective factor in POD when the preoperative plasma visfatin concentration is below 37.87 ng/ml, but when it exceeds 37.87 ng/ml, the visfatin concentration is a risk factor for POD, which is mediated by postoperative plasma IL-6. The results suggest that preoperative visfatin may have a dual effect on the POD occurrence. Clinical trial registration: [www.ClinicalTrials.gov], identifier [ChiCTR21 00052674].

Targeting UBR5 in hepatocellular carcinoma cells and precise treatment via echinacoside nanodelivery.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the most common and malignant cancers with no effective therapeutic approaches. Echinacoside (ECH), a phenylethanoid glycoside isolated from Chinese herbal medicine, Cistanche salsa, can inhibit HCC progression; however, poor absorption and low bioavailability limit its biological applications. METHODS: To improve ECH sensitivity to HepG2 cells, we developed a mesoporous silica nanoparticle (MSN)-based drug delivery system to deliver ECH to HepG2 cells via galactose (GAL) and poly(ethylene glycol) diglycidyl ether (PEGDE) conjugation (ECH@Au@MSN-PEGDE-GAL, or ECH@AMPG). Gain- and loss-of-function assays were conducted to assess the effects of UBR5 on HCC cell apoptosis and glycolysis. Moreover, the interactions among intermediate products were also investigated to elucidate the mechanisms by which UBR5 functions. RESULTS: The present study showed that ubiquitin protein ligase E3 component N-recognin 5 (UBR5) acted as an oncogene in HCC tissues and that its expression was inhibited by ECH. AMPG showed a high drug loading property and a slow and sustained release pattern over time. Moreover, owing to the valid drug accumulation, ECH@AMPG promoted apoptosis and inhibited glycolysis of HepG2 cells in vitro. In vivo experiments demonstrated that AMPG also enhanced the antitumor effects of ECH in HepG2 cell-bearing mice. CONCLUSIONS: Our results indicated the clinical significance of UBR5 as a therapeutic target. On the basis of the nontoxic and high drug-loading capabilities of AMPG, ECH@AMPG presented better effects on HCC cells compared with free ECH, indicating its potential for the chemotherapy of HCC.

The role of PYCR1 in inhibiting 5-fluorouracil-induced ferroptosis and apoptosis through SLC25A10 in colorectal cancer.

Although PYCR1 is a well-recognized oncogenic gene for malignant tumors, the causal relationship of its expression with malignant growth and cytotoxic chemotherapeutics remains unclear. Therefore, this study aimed to clarify the role of PYCR1 and its interaction with SLC25A10 in a chemotherapeutic agent 5-fluorouracil (5-FU)'s toxicity to colorectal cancer cells. PYCR1 and SLC25A10 expressions were detected in The Cancer Genome Atlas database and colon adenocarcinoma (COAD) clinical samples. PYCR1 upregulation was associated with SLC25A10 expression and poor prognosis, and its high expression indicated decreased survival rates in patients with COAD. PYCR1 overexpression inhibited lipid reactive oxygen species production and promoted SLC25A10 expression in colorectal cancer cells. PYCR1 silencing enhanced the antitumor effects of 5-FU. Ferroptosis inhibitor deferoxamine suppressed the antitumor effects of PYCR1 silencing, whereas ferroptosis inducer erastin inhibited the protumor effects of PYCR1 overexpression. SLC25A10 overexpression reversed the antitumor effects of PYCR1 silencing in vitro and inhibited the antitumor effects of erastin in vivo. Therefore, PYCR1 is an oncogenic gene that promotes colorectal tumor growth and desensitizes colorectal cancer cells to 5-FU cytotoxicity by preventing apoptosis and ferroptosis.

Icariin Regulates the hsa_circ_0003159/eIF4A3/bcl-2 Axis to Promote Gastric Cancer Cell Apoptosis.

Objective: To clarify the mechanism of icariin (ICA) promoting gastric cancer (GC) cell apoptosis by regulating circ_0003159/eIF4A3/bcl-2 axis. Methods: The mRNA or protein levels were detected by qRT-PCR or the western blot. The interaction between eIF4A3 protein and circ_0003159 or eIF4A3 protein and bcl-2 mRNA were validated by RNA pull down assays and the RNA immunoprecipitation (RIP) assay. The cell viability was measured by the cell counting kit (CCK)-8 kit. The cell apoptosis was measured by flow cytometry. Results: Compared with the group Vector, the ratio of cytoplasmic eIF4A3/nuclear eIF4A3 in the cell with circ_0003159 overexpression was significantly higher. RIP and RNA pull down results proved the interaction between eIF4A3 and circ_0003159. The RIP assay further validated the interaction between eIF4A3 and bcl-2. By gain or loss of the functional experiment, hsa_circ_0003159 was proved to recruit eIF4A3 to inhibit bcl-2 expression. Hsa_circ_0003159 regulates eIF4A3/bcl-2 to reduce GC cell viability and increase apoptosis Furthermore, ICA regulates hsa_circ_0003159/eIF4A3/bcl-2 axis to inhibit GC cell activity and induce GC cell apoptosis in vitro. Conclusion: These data showed that ICA could effectively reduce the GC cell activity and induce GC cell apoptosis via hsa_circ_0003159/eIF4A3/bcl-2 axis, which provides new theoretical evidence for the treatment of GC by ICA.

Nobiletin Attenuates Anesthesia/Surgery-Induced Neurocognitive Decline by Preserving the Expression of Clock Genes in Mice.

Postoperative cognitive dysfunction (POCD) is commonly observed during the postoperative period and significantly affects the prognosis of patients. Neuroinflammation plays a vital role in the pathogenesis of POCD. Despite laboratory and clinical research over the past decades, practical pharmacological strategies for the treatment and prevention of POCD are not yet available currently. Nobiletin (NOB) is a natural polymethoxylated flavone. As an enhancer of the clock protein retinoic acid receptor-related orphan receptors (RORs), NOB has been shown to attenuate inflammation and improve cognitive decline. We speculate that NOB is a candidate for the treatment and prevention of POCD. In this study, we investigated whether and how NOB affected surgery-induced neuroinflammation and POCD in adult CD1 mice. NOB pretreatment suppressed exploratory laparotomy-induced systemic inflammation and neuroinflammation in a dose-dependent manner (< 50 mg/kg), and attenuated POCD. Moreover, NOB dose-dependently reversed the decrease of brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1, also known as Arntl) and Rors expression induced by exploratory laparotomy. The expression of Bmal was negatively correlated with tumor necrosis factor-α (TNF-α). Our results suggest that NOB attenuated POCD, possibly via preserving the expression of Bmal and Rors and inhibiting inflammation.

Type 2 Diabetes Mellitus with Tight Glucose Control and Poor Pre-Injury Stair Climbing Capacity May Predict Postoperative Delirium: A Secondary Analysis.

(1) Background: Previous evidence demonstrates that tight glycemic control and good physical function could reduce the risk of delirium. This study aimed to investigate whether the occurrence of postoperative delirium (POD) in older hip fracture surgery patients is associated with preoperative glycemic control factors or pre-injury physical performance. (2) Methods: Three-hundred and nine individuals aged over 65 years and scheduled for hip fracture surgery were included at a single center. Glycemic control factors and pre-injury physical performance were assessed preoperatively. The presence of delirium was assessed using the Confusion Assessment Method on postoperative hospitalization days. Univariate and multivariable logistic regression models and a risk prediction model of POD were established. (3) Results: Among the 309 patients, 52 (16.83%) experienced POD during the hospital stay. The numbers of pre-injury physical performance and type 2 diabetes mellitus (T2DM) patients were significantly different in the POD and non-POD groups. The multivariable model showed that development of delirium was significantly explained by preoperative fasting blood glucose (FBG) (OR 0.804, p = 0.004), stair climbing (OR 0.709, p = 0.003), T2DM (odds ratio (OR) 3.654, p = 0.001), and age-adjusted Charlson comorbidity index (ACCI) (OR 1.270, p = 0.038). The area under the receiver operating characteristic curve (AUROC) of the risk prediction model including those covariates was 0.770. (4) Conclusions: More older T2DM patients develop POD after hip fracture surgery than patients without T2DM. A simple assessment of preoperative FBG and pre-injury stair climbing capacity may identify those at high risk for the development of POD. Higher preoperative FBG and good pre-injury stair climbing capacity are protective factors for POD.