Macrophage-Capturing Self-Assembly Photosensitizer Nanoparticles Induces Immune Microenvironment Re-Programming and Golgi-Responsive Immunogenic Cell Death in Head and Neck Carcinoma.

Head and neck carcinoma treatment is shifted toward the combination of therapy causing immune checkpoint blockade (ICB) and immunogenic cell death. In this study, a CSFRi-chimeric TAMCSFR+-targeting extracellular vesicle (EV@CSFRi) platform is developed and designed an intracellular protoporphyrin conjugated with RVRR peptide sequence for furin-cleavage to perform Golgi-targeting and generating ROS (GT-RG). The graphical abstract illustrates the self-assembly of GT-RG nanoparticles into nanofiber through the hydrophily of RVRR and hydrophobicity of RG, and the red line indicates the site of furin cleavage. As is shown in the Graphical abstract, the Golgi-targeting Protoporphyrin-RVRR platform is composed with CSFRi-chimeric extracellular vesicles and forms the tumor-responsive TAM-reprogramming bilayers (GT-RGEV@CSFRi). The GT-RGEV@CSFRi acted as a multifunctional theranostic platform, which can induce immunogenic cell death and further help modulate TAM, thus suppressing the HNC xenograft model by combination therapy with anti-PD-1.

Neuro death through autophagy via the acetylation of FoxO1 by SIRT2 in the hippocampus of mice in a autism spectrum disorder mice model.

Autism Spectrum Disorder (ASD) is a series of complex neurodevelopmental disorders, which can affect children's social, behavioral and communication abilities. A member of the Sirtuins family of NAD + dependent deacetylases called SIRT2 could regulate the inflammation progress during stress, but the relevant mechanism has not been clearly defined. In the present study, the ASD model of wild type and SIRT2 knock out mice was established to evaluate the impact on the homeostasis of neurons in the hippocampus using western blotting, immunofluorescence and Nissl staining. The results showed that the amplification of neuronal richness was significantly decreased and neuroinflammation increased in the hippocampus following ASD due to autophagy, caused by enhancing the acetylation of FoxO1 using SIRT2 gene deletion and indicating this should be the target for ASD or other psychological stress treatment.

[Galangin alleviates learning and memory impairments in APP/PS1 double- transgenic mice by regulating Akt/MEF2D/Beclin-1 signaling pathway].

The study aimed to investigate the effects of galangin on learning and memory impairments and Akt/MEF2 D/Beclin-1 signaling pathway in APP/PS1 double-transgenic mice. The mice in this experiment were divided into the normal group, model group, low-(25 mg·kg~(-1)), medium-(50 mg·kg~(-1)), and high-dose(100 mg·kg~(-1)) galangin groups, donepezil(3 mg·kg~(-1)) group, Akt inhibitor(25 mg·kg~(-1)) group, and autophagy inhibitor(30 mg·kg~(-1)) group, with ten in each group, and administered with the corresponding drugs for 30 successive days. On the 24 th day of medication, the water maze and dark avoidance tests were performed. The levels of p-tau, ß-amyloid peptide 1-42(Aß_(42)), acetylcholinesterase(AChE), ß-site amyloid precursor protein cleaving enzyme 1(BACE1), and amyloid precursor protein(APP) in hippocampus were detected by ELISA, the Beclin-1 mRNA expression by RT-PCR, the expression of Aß_(42) and glial fibrillary acidic protein(GFAP) by immunohistochemistry, and the expression of myocyte enhancer factor 2 D(MEF2 D) by immunofluorescence assay. The pathological changes in hippocampus were observed after HE staining, and the expression of Akt, MEF2 D, and Beclin-1 in hippocampus were assayed by Western blot. These results showed that compared with the normal group, the model group exhibited prolonged swimming time, increased number of errors and electric shocks, up-regulated p-tau, Aß_(42), APP, AChE, BACE1, GFAP, and Beclin-1, shortened incubation period, decreased p-Akt and MEF2 D, and obvious hippocampal injury. Compared with the model group, donepezil and galangin shortened the swimming time, reduced the number of errors and electric shocks, down-regulated the expression of p-tau, Aß_(42), APP, AChE, BACE1, GFAP, and Beclin-1, prolonged the incubation period, up-regulated p-Akt and MEF2 D, and improved the pathological changes in hippocampus. Compared with the autophagy inhibitor group, galangin prolonged the swimming time, elevated the number of errors and electric shocks, enhanced the expression of p-tau, Aß_(42), APP, AChE, BACE1, GFAP, and Beclin-1, shortened the incubation period, and diminished the expression of p-Akt and MEF2 D. In conclusion, galangin improves the learning and memory impairments and hippocampal neuron injury of APP/PS1 mice, which may be related to its regulation of Akt/MEF2 D/Beclin-1 signaling pathway.

Application value of computed tomography and magnetic resonance imaging three-dimensional reconstruction and digital subtraction angiography in percutaneous transhepatic cholangial drainage.

Objective: This study aims to explore the application value of computed tomography (CT) three-dimensional (3D) reconstruction, magnetic resonance imaging (MRI) 3D reconstruction, and conventional digital subtraction angiography (DSA) fluoroscopy in percutaneous transhepatic cholangial drainage (PTCD). Methods: The clinical data of 180 patients with obstructive jaundice requiring PTCD from December 2017 to December 2021 were retrospectively analyzed. Following PTCD, CT 3D reconstruction, MRI 3D reconstruction, and conventional DSA fluoroscopy were conducted, after which the surgical success rates, liver function results, and postsurgical complications were compared. Results: The puncture accuracies under CT 3D reconstruction, MRI 3D reconstruction, and conventional DSA fluoroscopy were 90.0% (54/60), 96.7% (58/60), and 80% (48/60), respectively. The degree of jaundice and epigastric discomfort was relieved in all three groups after surgery, while a significant reduction in the levels of total bilirubin and direct bilirubin was observed relative to the levels before surgery (P < 0.05). The incidences of complications in the CT 3D reconstruction, MRI 3D reconstruction, and conventional DSA fluoroscopy groups were 6.7% (4/60), 3.3% (2/60), and 13.3% (8/60), respectively, and the differences among the three groups were statistically significant (P < 0.05). Conclusion: Conducting conventional enhanced CT and MRI scans in patients before surgery might be more practical than the conventional puncture method. Among the methods under study, MRI 3D reconstruction was found to be safer and more feasible than CT 3D reconstruction and conventional DSA fluoroscopy in PTCD. MRI 3D reconstruction could reduce the degree of jaundice, improve the success rate of surgery, reduce the incidence of complications due to surgery, and improve the patients' tolerance to surgery.

Autism with dysphasia accompanied by mental retardation caused by FOXP1 exon deletion: A case report.

BACKGROUND: Forkhead box protein 1 (FOXP1) (OMIM: 605515) at chromosomal region 3p14.1 plays an important regulatory role in cell development and functions by regulating genetic expression. Earlier studies have suggested that FOXP1, an oncogene, is capable of initiating tumorigenicity depending on the cell type. FOXP1 also plays an important role in regulating the cell development and functions of the immune system, e.g., regulating B-cell maturation and mononuclear phagocyte differentiation, and in the occurrence and development of various immune diseases. The mRNA of this gene is widely expressed in humans, and its differential expression is related to numerous diseases. CASE SUMMARY: A 5-year-old boy mainly presented with attention deficit and hyperactivity disorder and developmental retardation accompanied by gait instability and abnormal facial features (low-set ears). DNA samples were extracted from the child's and his parents' peripheral blood to detect whole-exome sequences and whole-genome copy number variations. Results revealed heterozygous deletions of exon 6-21 of FOXP1 gene in the child. Physical examination upon admission showed that the child was generally in good condition, had a moderate nutritional status, a slightly slow response to external stimuli, equally large and equally round bilateral pupils, was sensitive to light reflection, and had poor eye contact and joint attention. He had no meaningful utterance and could not pronounce words properly. He was able to use gestures to simply express his thoughts, to perform simple actions, and to listen to instructions. He had no rash, cafe-au-lait macules, or depigmentation spots. He had thick black hair and low-set ears. He had highly sensitive skin, especially on his face and palms. He had no abnormal palm fingerprint. Cardiopulmonary and abdominal examinations revealed no abnormalities. He had normal limb muscle strength and tension. He showed normal tendon reflexes of both knees. His bilateral Babinski and meningeal irritation signs were negative. He had a normal male vulva. CONCLUSION: We report the characteristic features of autism with dysphasia accompanied by mental retardation caused by FOXP1 exon deletion. This study provides a molecular basis for etiological diagnosis and treatment of the child, as well as for genetic counseling for the pedigree.

Integrated Metabolomics and Proteomics Analysis Revealed Second Messenger System Disturbance in Hippocampus of Chronic Social Defeat Stress Rat.

Depression is a common and disabling mental disorder characterized by high disability and mortality, but its physiopathology remains unclear. In this study, we combined a non-targeted gas chromatography-mass spectrometry (GC-MS)-based metabolomic approach and isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis to elucidate metabolite and protein alterations in the hippocampus of rat after chronic social defeat stress (CSDS), an extensively used animal model of depression. Ingenuity pathway analysis (IPA) was conducted to integrate underlying relationships among differentially expressed metabolites and proteins. Twenty-five significantly different expressed metabolites and 234 differentially expressed proteins were identified between CSDS and control groups. IPA canonical pathways and network analyses revealed that intracellular second messenger/signal transduction cascades were most significantly altered in the hippocampus of CSDS rats, including cyclic adenosine monophosphate (cAMP), phosphoinositol, tyrosine kinase, and arachidonic acid systems. These results provide a better understanding of biological mechanisms underlying depression, and may help identify potential targets for novel antidepressants.

[Summary and prospect of medicinal plant active substances in regulation of p65 nuclear translocation].

As the most important nuclear transcription factors in the cells, NF-κB is involved in many intracellular signaling pathways and transcription and regulation of genetic information. The signal transduction pathways mainly include the activation of IκB kinase, degradation of IκB protein and the nuclear translocation of p65. p65 trans-nuclear binding with DNA is the key for NF-κB to play a role. Abnormal activation of NF-κB is a major factor in the induction of oxidative stress, inflammation, cancer and so on. Therefore, maintaining the balance of NF-κB activity and regulating the nuclear translocation of p65 have great significance for further research on related subjects. In this paper, the regulation effects of the main active substances of medicinal plants (such as polyphenols, saponins, and alkaloids) on p65 nuclear translocation and the upstream pathway of NF-κB were discussed, expecting to provide reference for the development of natural active substances for functional food.

14-3-3 Isoforms Differentially Regulate NFκB Signaling in the Brain After Ischemia-Reperfusion.

Mammalian 14-3-3 isoforms exist predominantly in the brain and are heavily involved in neurological diseases. However, the isoform-specific role of 14-3-3 proteins in the brain remains largely unclear. Here, we investigated the role of 14-3-3 isoforms in rat brains after transient middle cerebral artery occlusion and reperfusion. 14-3-3ß, η, γ and ζ but not ε or τ were selectively upregulated in cerebral cortical neurons after ischemia-reperfusion (I/R). Selectively, 14-3-3ß, γ and ζ were translocated from cytoplasm into the nuclei of neurons after I/R. 14-3-3 bound to p65 and suppressed p65 expression in N2a cells. In the brain, 14-3-3 could either colocalize with p65 in the nuclei of neurons or segregate from p65 expression in cortical neurons after I/R. All evidence together suggests that 14-3-3 isoforms are differentially induced to enter into the nuclei of neurons after I/R, which might regulate NFκB signaling directly or indirectly. Since 14-3-3 proteins are essential for cell survival and NFκB is a key transcriptional factor, our data suggest that the 14-3-3/p65 signaling pathway might be a potential therapeutic target for stroke.

Ginsenoside Rd promotes neurogenesis in rat brain after transient focal cerebral ischemia via activation of PI3K/Akt pathway.

AIM: To investigate the effects of ginsenoside Rd (Rd) on neurogenesis in rat brain after ischemia/reperfusion injury (IRI). METHODS: Male SD rats were subjected to transient middle cerebral artery occlusion (MCAO) followed by reperfusion. The rats were injected with Rd (1, 2.5, and 5 mg·kg(-1)·d(-1), ip) from d 1 to d 3 after MCAO, and with BrdU (50 mg·kg(-1)·d(-1), ip) from d 3 to d 6, then sacrificed on 7 d. The infarct size and neurological scores were assessed. Neurogenesis in the brains was detected by BrdU, DCX, Nestin, and GFAP immunohistochemistry staining. PC12 cells subjected to OGD/reperfusion were used as an in vitro model of brain ischemia. VEGF and BDNF levels were assessed with ELISA, and Akt and ERK phosphorylation was measured using Western blotting. RESULTS: Rd administration dose-dependently decreased the infarct size and neurological scores in the rats with IRI. The high dose of Rd 5 (mg·kg(-1)·d(-1)) significantly increased Akt phosphorylation in ipsilateral hemisphere, and markedly increased the number of BrdU/DCX and Nestin/GFAP double-positive cells in ischemic area, which was partially blocked by co-administration of the PI3 kinase inhibitor LY294002. Treatment with Rd (25, 50, and 100 µmol/L) during reperfusion significantly increased the expression of VEGF and BDNF in PC12 cells with IRI. Furthermore, treatment with Rd dose-dependently increased the phosphorylation of Akt and ERK, and significantly decreased PC12 cell apoptosis, which were blocked by co-application of LY294002. CONCLUSION: Rd not only attenuates ischemia/reperfusion injury in rat brain, but also promotes neurogenesis via increasing VEGF and BDNF expression and activating the PI3K/Akt and ERK1/2 pathways.

[Response of isozyme and stress indexes of Coptis chinensis to UV-B radiation].

OBJECTIVE: To study the physiological mechanism of anti-stress of Coptic chinensis and provide theoretical basis for its cultivation and promoting its quality. METHODS: Different degrees of the range of time and intensity of UV-B radiation were set in the experiment. Used the technique of polyacrylamide gelatin vertical board electrophoresis (PAGE) to analyse the isozyme and related stress index. RESULTS: The isoenzymic bands of SOD1 (Rf = 0.125), SOD2 (Rf = 0.312), CAT1 (Rf = 0.428), POD3 (Rf = 0.290), POD4 (Rf = 0.636) were induced by UV-B radiation after 3 hours, with the increase of the time of UV-B radiation, those isoenzymic bands was going to vanish or became unclear. Moreover, isoenzymic bands of CAT1 (Rf = 0.428), POD3 (Rf = 0.290) disappeared in advance under heavy intensity of UV-B radiation. Furthermore, the contents of MDA, soluble sugar, proline were higher dramatically than those of control group under UV-B radiation. However, excluding the increases of proline in UL group, the content of MDA, soluble sugar, proline of other groups commenced to decrease slowly and isoenzymic bands of soluble protein increase after 7 hours of UV-B radiation. CONCLUSION: The increase of the expression of antioxidase isozyme, accumulation of soluble sugar, soluble protein and other antioxidase matter is induced by the short-time UV-B radiation, which can protect Coptis chinensis from being harmed by UV-B radiation. However, regulation system of Coptis chinensis are broken, metabolism is disordered, the bands of antioxidase isozyme vanish or weaken, the bands of soluble protein are increased and widened, these phenomenon is caused by 7 hours of UV-B radiation.

Relationship between serum heparanase and microscopic venous invasion in patients with hepatocellular carcinoma.

The serum heparanase level of 92 patients with hepatocellular carcinoma (HCC) measured by enzyme-linked immunosorbent assay (median, 91.4 U/mL) was higher than that of 19 healthy control subjects. Serum heparanase levels were higher in patients with HCC characterized by large tumors (>5 cm), advanced pTNM stage (III and IV), tumor capsule absence, and portal vein invasion. Positive correlations between serum heparanase and tumor heparanase expression were observed in 92 patients with HCC, 53 among them treated with tumor resection. In these 53 patients, the rate of microscopic venous invasion was significantly higher in 18 cases with high serum heparanase levels (>91.4 U/mL) than in the other 35 cases with low heparanase levels (14/18 vs 10/35; P = .001). Serum heparanase and vascular endothelial growth factor were identified as independent predictive factors for HCC microscopic venous invasion. The postoperative recurrence-free time (median, 8.7 months; range, 4.1-22.9 months), recurrence rate (72% [13/18]), 1.5-year disease-free survival rate (29.7%) were significantly worse in these 18 patients.

Significance of serum connective tissue growth factor in patients with hepatocellular carcinoma and relationship with angiogenesis.

BACKGROUND: Connective tissue growth factor (CTGF) expression changes variously in different human malignancies. The role of CTGF in hepatocellular carcinoma (HCC) is still not clear. The purpose of this study was to investigate the role of serum CTGF in patients with HCC and its correlation with HCC angiogenesis. METHODS: CTGF, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) were measured by ELISA in preoperative sera of 88 patients with HCC with tumor resection and 39 healthy subjects. The relationship between CTGF and HCC clinicopathological parameters was observed. Prognostic significance of CTGF for survival of patients with HCC was assessed by Kaplan-Meier analysis. RESULTS: Preoperative serum CTGF level was significantly higher in patients with HCC than in healthy subjects (median, 63.5 vs. 11.4 ng/ml; P < 0.001). Serum CTGF correlated significantly with a series of clinicopathological parameters (big tumor size, advanced pathological tumor-node-metastasis stage, absence of tumor capsule, portal vein invasion). Serum CTGF showed a significant correlation with disease-free survival and overall survival of patients with HCC. Patients with high serum CTGF (>63.5 ng/ml) had a poorer disease-free survival time than the others (CTGF < or = 63.5 ng/ml; median disease-free survival time, 9.6 vs. 19.3 months). Patients with high serum CTGF had poorer overall survival time (median, 13.1 months) than the others (median, 21.7 months). In multivariate Cox analysis, CTGF was identified as an independent and significant prognostic factor of survival of HCC patients. CONCLUSIONS: Serum CTGF plays an important role in the progression of HCC. Serum CTGF may be a potential indicator of angiogenesis of HCC.

Silencing neuroglobin enhances neuronal vulnerability to oxidative injury by down-regulating 14-3-3gamma.

AIM: To explore the protective role and mechanism of endogenous neuroglobin (Ngb) in neuronal cells under oxidative stress. METHODS: A stable N2a neuroblastoma cell line expressing the Ngb-siRNA plasmid (N2a/Ngb-siRNA) was established by neomycin screening. Reverse transcription (RT)-PCR and Western blot analysis were used to detect Ngb gene and protein levels. Hydrogen peroxide was used to induce oxidative stress in N2a cells. Cytotoxicity and cell viability were measured by lactate dehydrogenase (LDH) and WST-8 assays. Apoptotic cells were detected by Hoechst staining. RESULTS: Cotransfection of Ngb-siRNA with Ngb-GFP plasmids suppressed the expression of Ngb-GFP in N2a cells. RT-PCR and Western blot analysis showed that the expression of endogenous Ngb was successfully knocked down to about 20% in N2a/Ngb-siRNA cells compared with control cells. A WST-8 assay demonstrated that viability was significantly decreased in N2a/Ngb-siRNA cells and N2a cells transiently transfected with Ngb-siRNA plasmids compared with controls following hydrogen peroxide treatment. An LDH assay demonstrated a time-dependent increase in the death of Ngb-siRNA-transfected N2a cells following hydrogen peroxide treatment. Hoechst staining demonstrated that the quantity of apoptotic cells among N2a/Ngb-siRNA cells following hydrogen peroxide treatment significantly increased compared with controls. In N2a/Ngb-siRNA cells, the expression level of activated caspase-3 significantly increased, whereas the expression of 14-3-3gamma decreased compared with that of N2a/vec cells. Transfection of 14-3-3gamma plasmids significantly enhanced the viability of N2a/Ngb-siRNA cells following hydrogen peroxide treatment compared with vector controls. CONCLUSION: Ngb contributes to neuronal defensive machinery against oxidative injuries by regulating 14-3-3gamma expression.Acta Pharmacologica Sinica (2009) 30: 913-918; doi: 10.1038/aps.2009.70.