Unveiling potential therapeutic targets for diabetes-induced frozen shoulder through Mendelian randomization analysis of the human plasma proteome.

INTRODUCTION: This study aimed to assess the causal relationship between diabetes and frozen shoulder by investigating the target proteins associated with diabetes and frozen shoulder in the human plasma proteome through Mendelian randomization (MR) and to reveal the corresponding pathological mechanisms. RESEARCH DESIGN AND METHODS: We employed the MR approach for the purposes of establishing: (1) the causal link between diabetes and frozen shoulder; (2) the plasma causal proteins associated with frozen shoulder; (3) the plasma target proteins associated with diabetes; and (4) the causal relationship between diabetes target proteins and frozen shoulder causal proteins. The MR results were validated and consolidated through colocalization analysis and protein-protein interaction network. RESULTS: Our MR analysis demonstrated a significant causal relationship between diabetes and frozen shoulder. We found that the plasma levels of four proteins were correlated with frozen shoulder at the Bonferroni significance level (p<3.03E-5). According to colocalization analysis, parathyroid hormone-related protein (PTHLH) was moderately correlated with the genetic variance of frozen shoulder (posterior probability=0.68), while secreted frizzled-related protein 4 was highly correlated with the genetic variance of frozen shoulder (posterior probability=0.97). Additionally, nine plasma proteins were activated during diabetes-associated pathologies. Subsequent MR analysis of nine diabetic target proteins with four frozen shoulder causal proteins indicated that insulin receptor subunit alpha, interleukin-6 receptor subunit alpha, interleukin-1 receptor accessory protein, glutathione peroxidase 7, and PTHLH might contribute to the onset and progression of frozen shoulder induced by diabetes. CONCLUSIONS: Our study identified a causal relationship between diabetes and frozen shoulder, highlighting the pathological pathways through which diabetes influences frozen shoulder.

NEDD4 and NEDD4L: Ubiquitin Ligases Closely Related to Digestive Diseases.

Protein ubiquitination is an enzymatic cascade reaction and serves as an important protein post-translational modification (PTM) that is involved in the vast majority of cellular life activities. The key enzyme in the ubiquitination process is E3 ubiquitin ligase (E3), which catalyzes the binding of ubiquitin (Ub) to the protein substrate and influences substrate specificity. In recent years, the relationship between the subfamily of neuron-expressed developmental downregulation 4 (NEDD4), which belongs to the E3 ligase system, and digestive diseases has drawn widespread attention. Numerous studies have shown that NEDD4 and NEDD4L of the NEDD4 family can regulate the digestive function, as well as a series of related physiological and pathological processes, by controlling the subsequent degradation of proteins such as PTEN, c-Myc, and P21, along with substrate ubiquitination. In this article, we reviewed the appropriate functions of NEDD4 and NEDD4L in digestive diseases including cell proliferation, invasion, metastasis, chemotherapeutic drug resistance, and multiple signaling pathways, based on the currently available research evidence for the purpose of providing new ideas for the prevention and treatment of digestive diseases.

Integrated Manipulation and Addressing of Spin Defect in Diamond.

Scalable and addressable integrated manipulation of qubits is crucial for practical quantum information applications. Different waveguides have been used to transport the optical and electrical driving pulses, which are usually required for qubit manipulation. However, the separated multifields may limit the compactness and efficiency of manipulation and introduce unwanted perturbation. Here, we develop a tapered fiber-nanowire-electrode hybrid structure to realize integrated optical and microwave manipulation of solid-state spins at nanoscale. Visible light and microwave driving pulses are simultaneously transported and concentrated along an Ag nanowire. Studied with spin defects in diamond, the results show that the different driving fields are aligned with high accuracy. The spatially selective spin manipulation is realized. And the frequency-scanning optically detected magnetic resonance (ODMR) of spin qubits is measured, illustrating the potential for portable quantum sensing. Our work provides a new scheme for developing compact, miniaturized quantum sensors and quantum information processing devices.

Intermittent Theta Burst Stimulation Attenuates Cognitive Deficits and Alzheimer's Disease-Type Pathologies via ISCA1-Mediated Mitochondrial Modulation in APP/PS1 Mice / 神经科学通报·英文版

Intermittent theta burst stimulation (iTBS), a time-saving and cost-effective repetitive transcranial magnetic stimulation regime, has been shown to improve cognition in patients with Alzheimer's disease (AD). However, the specific mechanism underlying iTBS-induced cognitive enhancement remains unknown. Previous studies suggested that mitochondrial functions are modulated by magnetic stimulation. Here, we showed that iTBS upregulates the expression of iron-sulfur cluster assembly 1 (ISCA1, an essential regulatory factor for mitochondrial respiration) in the brain of APP/PS1 mice. In vivo and in vitro studies revealed that iTBS modulates mitochondrial iron-sulfur cluster assembly to facilitate mitochondrial respiration and function, which is required for ISCA1. Moreover, iTBS rescues cognitive decline and attenuates AD-type pathologies in APP/PS1 mice. The present study uncovers a novel mechanism by which iTBS modulates mitochondrial respiration and function via ISCA1-mediated iron-sulfur cluster assembly to alleviate cognitive impairments and pathologies in AD. We provide the mechanistic target of iTBS that warrants its therapeutic potential for AD patients.

An unprecedented pair of Z/E isomeric pyridinium compound from the aqueous extract of Aspongopus chinensis Dallas / 药学学报

A novel pair of Z/E isomeric compounds with unprecedented carbon skeleton were isolated from an aqueous extract of Aspongopus chinensis Dallas by macroporous resin, silica gel, and semi-preparative high performance liquid chromatography (HPLC). Their structures were identified by nuclear magnetic resonance (NMR), Infrared spectroscopy (IR), Mass spectroscopy (MS) and other spectroscopic methods as (Z)-3-(but-1″-en-1″-yl)-1-(2ʹ-hydroxyethyl)-4-propylpyridin-1-ium, namely aspongopyridine A, and (E)-3-(but-1″-en-1″-yl)-1-(2ʹ-hydroxyethyl)-4-propylpyridin-1-ium, namely aspongopyridine B, respectively. Besides, the anti-inflammatory, anti-tumor, acetylcholinesterase inhibition and butyrylcholinesterase inhibition activities of the compounds 1 and 2 were evaluated. The results showed that compounds 1 and 2 have no anti-inflammatory, anti-tumor, and butyrylcholinesterase inhibition activities instead of weak acetylcholinesterase inhibition activity.

Merging Visible Light Photocatalysis and P(III)-Directed C-H Activation by a Single Catalyst: Modular Assembly of P-Alkyne Hybrid Ligands.

Metal-catalyzed C-H activation strategies provide an efficient approach for synthesis by minimizing atom, step, and redox economy. Developing milder, greener, and more effective protocols for these strategies is always highly desirable to the scientific community. In this study, the utilization of a single rhodium complex enabled the visible-light-induced late-stage C-H activation of biaryl-type phosphines with alkynyl bromides, employing inherent phosphorus atoms as directing groups. This chemistry combines P(III)-directed C-H activation with visible light photocatalysis, under exogenous photosensitizer-free conditions, offering a unique platform for ligand design and preparation. Furthermore, this study also explores the asymmetric catalysis and coordination chemistry of the resulting P-alkyne hybrid ligands with specific transition metals. Experimental results and density functional theory calculations demonstrate the mechanistic intricacies of this transformation.

Quantum imaging of the reconfigurable VO2 synaptic electronics for neuromorphic computing.

Neuromorphic computing has shown remarkable capabilities in silicon-based artificial intelligence, which can be optimized by using Mott materials for functional synaptic connections. However, the research efforts focus on two-terminal artificial synapses and envisioned the networks controlled by silicon-based circuits, which is difficult to develop and integrate. Here, we propose a dynamic network with laser-controlled conducting filaments based on electric field-induced local insulator-metal transition of vanadium dioxide. Quantum sensing is used to realize conductivity-sensitive imaging of conducting filament. We find that the location of filament formation is manipulated by focused laser, which is applicable to simulate the dynamical synaptic connections between the neurons. The ability to process signals with both long-term and short-term potentiation is further demonstrated with ~60 times on/off ratio while switching the pathways. This study opens the door to the development of dynamic network structures depending on easily controlled conduction pathways, mimicking the biological nervous systems.

Conditional knockout of ITGB4 in bronchial epithelial cells directs bronchopulmonary dysplasia.

Neonatal respiratory system disease is closely associated with embryonic lung development. Our group found that integrin ß4 (ITGB4) is downregulated in the airway epithelium of asthma patients. Asthma is the most common chronic respiratory illness in childhood. Therefore, we suspect whether the deletion of ITGB4 would affect fetal lung development. In this study, we characterized the role of ITGB4 deficiency in bronchopulmonary dysplasia (BPD). ITGB4 was conditionally knocked out in CCSP-rtTA, Tet-O-Cre and ITGB4f/f triple transgenic mice. Lung tissues at different developmental stages were collected for experimental detection and transcriptome sequencing. The effects of ITGB4 deficiency on lung branching morphogenesis were observed by fetal mouse lung explant culture. Deleting ITGB4 from the airway epithelial cells results in enlargement of alveolar airspaces, inhibition of branching, the abnormal structure of epithelium cells and the impairment of cilia growth during lung development. Scanning electron microscopy showed that the airway epithelial cilia of the ß4ccsp.cre group appear to be sparse, shortened and lodging. Lung-development-relevant factors such as SftpC and SOX2 significantly decreased both mRNA and protein levels. KEGG pathway analysis indicated that multiple ontogenesis-regulating-relevant pathways converge to FAK. Accordingly, ITGB4 deletion decreased phospho-FAK, phospho-GSK3ß and SOX2 levels, and the correspondingly contrary consequence was detected after treatment with GSK3ß agonist (wortmannin). Airway branching defect of ß4ccsp.cre mice lung explants was also partly recovered after wortmannin treatment. Airway epithelial-specific deletion of ITGB4 contributes to lung developmental defect, which could be achieved through the FAK/GSK3ß/SOX2 signal pathway.

Efficacy of catgut embedding in Baihui (GV20) and Feishu (BL13) and Pishu (BL20) on lung tissue, brain tissue and blood related indexes in rats with allergic rhinitis of lung deficiency type.

OBJECTIVE: To investigate the effects of acupoint catgut embedding for 3 weeks on lung tissue, blood immunoglobulin E (IgE) and interleutin-4 (IL-4), brain tissue microglia x-42 (OX-42) and toll-like receptor-2 (TLR-2) in rats with allergic rhinitis of lung deficiency type. METHODS: Forty-five female Sprague-Dawley rats were randomly divided for two times. The first time, they were randomly divided into model group and blank group (Group C) according to 2:1, and the second time, the model group were randomly divided into model control group (Group B) and intervention treatment group (Group A) according to 1:1. 15 in each group. For Group A and Group B, the lung deficiency model was made by "sulfur-moxa fumigation", and then the allergic rhinitis model was established by "ovalbumin (OVA) sensitization". Then catgut embedding was performed at acupoints in Group A and not in Group B. After 3 weeks, collect lung tissue samples for hematoxylin-eosin staining, then take blood to observe the concentration of IgE and IL-4, and finally take brain tissue to observe the results of OX-42 and TLR-2. RESULTS: IgE level (µg/mL) was (3.11 ± 0.20) in the Group A, (4.19 ± 0.44) in the Group B, and (2.29 ± 0.30) in the Group C (all < 0.001). IL-4 level (pg/mL) was (14.2 ± 0.7) in the Group A, (18.6 ± 2.4) in the Group B, and (11.4 ± 1.2) for the Group C (all < 0.001). The mean OD for OX-42 is (0.1728 ± 0.0016) in the Group A, (0.1810 ± 0.0046) in the Group B and (0.1674 ± 0.0025) in the Group C (all < 0.001). CONCLUSION: Although 3 weeks of acupoint catgut embedding already showed obvious efficacy on rats with allergic rhinitis, the allergic reaction in the body still continued. To achieve further treatment, prolonging the catgut embedding time is necessary.

The Long Non-Coding RNA AC006329.1 Facilitates Hepatocellular Carcinoma Progression and Metastasis by Regulating miR-127-5p/SHC3/ERK Axis.

Purpose: Hepatocellular carcinoma(HCC) is the most common type of liver cancer and the sixth largest common cancer worldwide. Although surgical resection, hepatic arterial chemoembolization, targeted drugs and immunotherapy are currently available, the mortality of advanced patients remains high. Therefore, new therapeutic targets are urgently needed. In recent years, many studies have found that The long non-coding RNA(lncRNA) has multiple functions in human tumors, including participating in epigenetic, transcriptional, post-transcriptional and translational regulation, and is closely related to the progression of HCC. The purpose of this study was to investigate the role of AC006329.1 in HCC progression and provide theoretical guidance for finding new targets. Patients and Methods: AC006329.1 was screened out by transcriptome sequencing and quantitative real-time polymerase chain reaction (qRT-PCR). Then a series of functional tests in vivo and in vitro were conducted to investigate the effects of AC006329.1 on HCC progression and metastasis. Epithelial-mesenchymal transformation (EMT) of HCC was detected by Western blot and immunofluorescence staining. The targeted miRNA and downstream gene of AC006329.1 were predicted by databases and the pathway regulation axis eventually validated by dual luciferase reporter assays, qRT-PCR and WB. Results: AC006329.1 was found high expressed in HCC tissues and cell lines by qRT-PCR. The prognosis of HCC patients with high expressed AC006329.1 was poor. In vitro and in vivo, overexpression of AC006329.1 can promote the progression, metastasis and EMT of HCC by acting as a sponge of miR-127-5p to increase the expression of SHC3. In addition, up-regulation of miR-127-5p or knockdown of SHC3 can both reverse the promoting effects of AC006329.1 on progression, metastasis and EMT of HCC. Finally, WB and qRT-PCR analysis was discovered that AC006329.1 can facilitate HCC progression, EMT and metastasis by competitively inhibiting miR-127-5p to activate SHC3/ERK signaling pathway. Conclusion: These above experimental results confirmed that AC006329.1 can facilitate HCC progression, EMT and metastasis by acting as a competing endogenous RNA (ceRNA) to inhibit miR-127-5p and activate SHC3/ERK signaling pathway.

Ubiquitin ligase enzymes and de-ubiquitinating enzymes regulate innate immunity in the TLR, NLR, RLR, and cGAS-STING pathways.

Ubiquitination (or ubiquitylation) and de-ubiquitination, which are both post-translational modifications (PTMs) of proteins, have become a research hotspot in recent years. Some ubiquitinated or de-ubiquitinated signaling proteins have been found to promote or suppress innate immunity through Toll-like receptor (TLR), RIG-like receptor (RIG-I-like receptor, RLR), NOD-like receptor (NLR), and the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-STING pathway. This article aimed to provide a review on the role of ubiquitination and de-ubiquitination, especially ubiquitin ligase enzymes and de-ubiquitinating enzymes, in the above four pathways. We hope that our work can contribute to the research and development of treatment strategies for innate immunity-related diseases such as inflammatory bowel disease.

Integerrima A-E, phenylethanoid glycosides from the stem of Callicarpa integerrima.

Five new phenylethanoid glycosides integerrima A-E (1-5) were isolated from the stem of Callicarpa integerrima for the first time. Their structures were elucidated by extensive spectroscopic analyses. In addition, cytotoxicity, anti-adipogenic and antioxidant activities were evaluated. All the phenylethanoid glycosides would be nontoxic to the normal human hepatocytes LO-2 and pre-adipocytes 3T3-L1 cell lines, significantly promote the proliferation of normal hepatocytes, thus displaying the potential for hepatoprotective. Integerrima A (1), C (3) and D (4) exhibited selectively moderate cytotoxic activity against the hepatoma cell lines Bel-7402, with the IC50 value at 72.66, 80.43 and 84.88 µmol/L, respectively. Moreover, integerrima D (4) had significant activities on reducing lipid droplet formation, with the inhibition rate of 48.02% on the concentration of 200 µg/mL. Finally, the result of FRAP assays exhibited remarkable antioxidant activity in integerrima E (5), which was close to the positive control ascorbic acid with the concentration of 100 µg/mL.

The platelet pannexin 1-IL-1ß axis orchestrates pancreatic ductal adenocarcinoma invasion and metastasis.

We aimed to investigate the protumor mechanisms of platelets in pancreatic ductal adenocarcinoma (PDAC). Serum samples were collected from 656 PDAC patients and 3105 healthy people, and a Panx1 knockout tumor model and an adoptive platelet transfusion mouse model were established. We showed that the blood platelet counts were not significantly different between stage III/IV and stage I/II patients, while the number of the CD41+/CD62P+ platelets was significantly elevated in stage III/IV patients, indicating that CD41+/CD62P+ platelets are associated with a poor prognosis. Further analysis showed that a high level of CD41+/CD62P+ platelets was significantly correlated with microvascular invasion (P = 0.002), advanced 8th edition AJCC stage (P < 0.001), and a high CA19-9 level (P = 0.027) and independently predicted a poor prognosis for resectable I/II PDAC. Furthermore, we found significantly higher Panx1 expression in CD41+/CD62P+ platelets than in CD41+/CD62P- platelets in PDAC patients. Mechanistically, Panx1 was able to enhance IL-1ß secretion in CD41+/CD62P+ platelets by phosphorylating p38 MAPK and consequently promoted the invasion and metastasis of PDAC cells. Finally, we synthesized a novel compound named PC63435 by the ligation of carbenoxolone (a Panx1 inhibitor) and PSGL-1 (a CD62P ligand). PC63435 specifically bound to CD41+/CD62P+ platelets, then blocked the Panx1/IL-1ß pathway and reduced the proportion of CD41+/CD62P+ platelets, which suppressed PDAC tumor invasion and metastasis in vivo. These results demonstrated that the Panx1/IL-1ß axis in CD41+/CD62P+ platelets enhanced PDAC cell malignancy and that this axis may be a promising target for PDAC therapy.

PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products.

Osteoblast apoptosis plays an important role in age-related bone loss and osteoporosis. Our previous study revealed that advanced oxidation protein products (AOPPs) could induce nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species (ROS) production, cause mitochondrial membrane potential (ΔΨm) depolarization, trigger the mitochondria-dependent intrinsic apoptosis pathway, and lead to osteoblast apoptosis and ultimately osteopenia and bone microstructural destruction. In this study, we found that AOPPs also induced mitochondrial ROS (mtROS) generation in osteoblastic MC3T3-E1 cells, which was closely related to NOX-derived ROS, and aggravated the oxidative stress condition, thereby further promoting apoptosis. Removing excessive ROS and damaged mitochondria is the key factor in reversing AOPP-induced apoptosis. Here, by in vitro studies, we showed that rapamycin further activated PINK1/Parkin-mediated mitophagy in AOPP-stimulated MC3T3-E1 cells and significantly alleviated AOPP-induced cell apoptosis by eliminating ROS and damaged mitochondria. Our in vivo studies revealed that PINK1/Parkin-mediated mitophagy could decrease the plasma AOPP concentration and inhibit AOPP-induced osteoblast apoptosis, thus ameliorating AOPP accumulation-related bone loss, bone microstructural destruction and bone mineral density (BMD) loss. Together, our study indicated that therapeutic strategies aimed at upregulating osteoblast mitophagy and preserving mitochondrial function might have potential for treating age-related osteoporosis.

Labelling Matrix Metalloproteinases.

Matrix metalloproteinases (MMPs) are a family of zinc-containing proteases that participate in many physiological and pathological processes in vivo. Recently, the MMP network has been established according to a deeper understanding of its functions. Some MMPs have been also regarded as biomarkers of various diseases, including inflammation, nerve diseases, and cancers. MMP labelling has been thus paid more attention in recent decades. Accordingly, both reagents and technologies for MMP labelling have been rapidly developed. Here we summarize the recent development of some MMP labelling methods. This review was identified through keyword (MMPs; labelling; etc.) searches in the ScienceDirect database, Scifinder, Web of Science, and PubMed for which typical cases were used for an inductive overview. In spite of the advances in MMP labelling, selective labelling of a specific MMP is still an open issue. We hope that this article can be helpful in developing specific MMP labelling methods in future.

Molten-salts assisted preparation of iron-nitrogen-carbon catalyst for efficient degradation of acetaminophen by periodate activation.

Highly efficient and stable heterogeneous catalysts were desired to activate periodate (PI) for sustainable pollution control. Herein, iron-nitrogen-carbon catalyst was synthesized using a facile molten-salts mediated pyrolysis strategy (denoted as FeNC-MS) and employed to activate PI for the degradation of acetaminophen (ACE). Compared with iron-nitrogen-carbon catalyst prepared by direct pyrolysis method (marked as FeNC), FeNC-MS exhibited superior catalytic activity due to its large specific surface area (1600 m2 g-1) and the abundance of FeNx sites. The batch experiments revealed that FeNC/PI process achieved 37 % ACE removal within 20 min, while ACE removal in FeNC-MS/PI process was 98 % under the identical conditions. Integrated with electron paramagnetic resonance tests, quenching experiments, chemical probe identification, and electrochemical experiments, we demonstrated that FeNC-MS-PI complexes-mediated electron transfer was the predominant mechanism for the oxidation of ACE. Further analysis disclosed that FeNx sites in FeNC-MS were the main active sites for the activation of PI. Additionally, FeNC-MS/PI process exhibited significant resistance to humic acid and background electrolyte, and avoided the secondary pollution imposed by Fe leaching. The possible degradation pathways of ACE were proposed. The germination experiments of lettuce seeds showed that the ecotoxicity of ACE solution was significantly reduced after treatment with FeNC-MS/PI process. Overall, this study provided a facile strategy for the synthesis of efficient iron-nitrogen-carbon catalysts and gained fundamental insight into the mechanism of PI activation by iron-nitrogen-carbon catalysts for pollutants degradation.

Apolipoprotein A-1 protected hepatic ischaemia-reperfusion injury through suppressing macrophage pyroptosis via TLR4-NF-κB pathway.

BACKGROUND AND AIMS: Apolipoprotein A-1 (ApoA-1), the major apolipoprotein of high-density lipoprotein, plays anti-atherogenic role in cardiovascular diseases and exerts anti-inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA-1 in hepatic ischaemia-reperfusion (I/R) injury is unknown. METHODS: In this study, we measured ApoA-1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA-1 knockout mice, ApoA-1 mimetic peptide D-4F treatment mice and corresponding control mice to examine the effect of ApoA-1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study. RESULTS: The results showed that ApoA-1 expression was down-regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA-1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA-1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA-1 deficiency. Furthermore, the up-regulated pyroptosis process was testified to be mediated by ApoA-1 through TLR4-NF-κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D-4F ameliorated hepatic I/R injury. CONCLUSIONS: Our study has identified the protective role of ApoA-1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4-NF-κB pathway. The effect of ApoA-1 may provide a novel therapeutic approach for hepatic I/R injury.

Effect of acid sphingomyelinase on nonalcoholic fatty liver disease via PPARα- PGC-1α pathway / 中国药理学通报

Aim To investigate the effects of acid sphingomyelinase(ASMase)on high-fat induced nonalcoholic fatty liver disease in mice and its regulation of PPARα- PGC-1α pathway. Methods ASMase knockout mice based on C57BL/6 background were constructed. Closed group heterozygotes were obtained through hybridized with wild-type mice(ASMase+/-),together with the littermate WT mice were prepared for NAFLD model in this study. The experiment was divided into four groups:WT+Chow:the WT mice were fed with normal diet for 12 weeks; WT+HFD:the WT mice were fed with high-fat diet for 12 weeks; ASMase+/-+Chow:the ASMase+/- mice were fed with normal diet for 12 weeks; ASMase+/- +HFD:the ASMase+/- mice were fed with high fat diet for 12 weeks. Biochemical method was used to detect serum TC,TG and liver TC,TG contents and liver function such as ALT and AST. Oil red staining,HE staining,Masson staining and Sirius red staining were performed to detect liver lipid accumulation,hepatocyte morphology and liver fibrosis. AmplexTM red sphingomyelinase kit was applied to detect ASMase activity. Western blot was performed to detect protein expressions of ASMase,PPARα,PGC-1α and CPT1. Results WT+HFD group displayed hypercholesterolemia and liver dysfunction. Levels of liver triglyceride(TG)were significantly higher than those in WT+Chow group(P<0.05 or P<0.01). Meanwhile,the hepatocytes showed marked steatosis,balloon-like changes,and fibrosis. Protein expression and activity of ASMase in liver increased significantly(P<0.01 or P<0.001),whereas CPT1,PPARα and PGC-1α expressions were not statistically significant compared with matched control group. Heterozygously ASMase-deficient mice reduced the elevated liver TG induced by HFD,as well as improving balloon-like changes and liver fibrosis. Furthermore,the expressions of PPARα,PGC-1α and CPT1 were up-regulated in ASMase+/- +HFD mice compared with WT+Chow group.Conclusions ASMase promotes hepatic steatosis and fibrosis,which may be related to its inhibition of PPARα-PGC-1α pathway.

Improving Blood Monocyte Energy Metabolism Enhances Its Ability to Phagocytose Amyloid-β and Prevents Alzheimer's Disease-Type Pathology and Cognitive Deficits / 神经科学通报·英文版

Deficiencies in the clearance of peripheral amyloid β (Aβ) play a crucial role in the progression of Alzheimer's disease (AD). Previous studies have shown that the ability of blood monocytes to phagocytose Aβ is decreased in AD. However, the exact mechanism of Aβ clearance dysfunction in AD monocytes remains unclear. In the present study, we found that blood monocytes in AD mice exhibited decreases in energy metabolism, which was accompanied by cellular senescence, a senescence-associated secretory phenotype, and dysfunctional phagocytosis of Aβ. Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβ in vivo and in vitro. Moreover, enhancing blood monocyte Aβ phagocytosis by improving energy metabolism alleviated brain Aβ deposition and neuroinflammation and eventually improved cognitive function in AD mice. This study reveals a new mechanism of impaired Aβ phagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.

Postoperative visual acuity assessment of different intraocular lens implantation regimens in patients with high myopia and cataract / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To evaluate the visual quality of patients with high myopia and cataract who received micro binocular single vision implantation of Tecnis Symfony intraocular lens(IOL), hybrid implantation of Tecnis Symfony IOL and Tecnis ZMB00 multifocal IOL, and binocular implantation of AcrySof IQ Panoptix IOL.METHODS: A prospective non-randomized controlled study was conducted to select patients with high myopia and cataract who underwent phacoemulsification combined with IOL implantation in the First Affiliated Hospital of Baotou Medical College from August 2020 to March 2022. According to the different IOL implantation schemes selected by patients, they are divided into micro single vision group, hybrid group and trifocal group. The postoperative follow-up was 3mo. The observation indexes included uncorrected far(5m), middle(80, 60cm)and near(33cm)visual acuity at 3mo after operation, contrast sensitivity(CS), uncorrected defocus curve under far vision, subjective visual quality score and light interference at 1 and 3mo after operation.RESULTS: There was no significant difference among the three groups in uncorrected far(5m)and middle(60cm)visual acuity at 3mo after operation(P<0.05); Uncorrected middle(80cm)distance visual acuity in the micro single vision group was similar to that in the hybrid group, and both were better than that in the trifocal group(P<0.05); Uncorrected near(33cm)distance vision of the hybrid group showed the best, followed by the trifocal group, and the lowest was in the micro single vision group(all P<0.05). The CS of dark light plus glare(12, 18c/d)was the best in the trifocal group, followed by the hybrid group, and the lowest was in the micro single vision group(all P<0.05). The defocus curve at 3mo after operation showed a span of +1.00～-3.00D, and the visual acuity of the three groups was better than 0.3 LogMAR; In the span of -1.00～-1.25D, the visual acuity of the hybrid group and micro single vision group was better than that of the trifocal group(all P<0.05); In the span of -3.00～-3.50D, the visual acuity of the hybrid group was the best, followed by trifocal group, and the lowest was in the micro single vision group(all P<0.05). At 3mo after operation, there was no significant difference in subjective visual quality scores among the three groups(P<0.05). Light interference in the micro single vision group was higher than that of the other two groups at 1mo after operation(P<0.05), and it decreased in the three groups at 3mo after operation, with no statistical significance(P<0.05).CONCLUSION: The three IOL implantation schemes can provide excellent visual quality for patients with high myopia and cataract. The vision of the micro single vision group and the hybrid group is better in the span of -1.00～-1.25D, and the hybrid group performs the best near vision in the span of -3.00～-3.50D. Although the design of micro single vision can make up for the weakness of Symfony IOL's lack of near vision, it is still worse than the hybrid group and the trifocal group.