Glutarylation of Histone H4 Lysine 91 Regulates Chromatin Dynamics.

Histone posttranslational modifications (PTMs) regulate chromatin structure and dynamics during various DNA-associated processes. Here, we report that lysine glutarylation (Kglu) occurs at 27 lysine residues on human core histones. Using semi-synthetic glutarylated histones, we show that an evolutionarily conserved Kglu at histone H4K91 destabilizes nucleosome in vitro. In Saccharomyces cerevisiae, the replacement of H4K91 by glutamate that mimics Kglu influences chromatin structure and thereby results in a global upregulation of transcription and defects in cell-cycle progression, DNA damage repair, and telomere silencing. In mammalian cells, H4K91glu is mainly enriched at promoter regions of highly expressed genes. A downregulation of H4K91glu is tightly associated with chromatin condensation during mitosis and in response to DNA damage. The cellular dynamics of H4K91glu is controlled by Sirt7 as a deglutarylase and KAT2A as a glutaryltransferase. This study designates a new histone mark (Kglu) as a new regulatory mechanism for chromatin dynamics.

Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers.

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.

Comprehensive Glycomic and Glycoproteomic Analyses of Human Programmed Cell Death Protein 1 Extracellular Domain.

Human programmed cell death protein 1 (hPD-1) is an essential receptor in the immune checkpoint pathway. It has played an important role in cancer therapy. However, not all patients respond positively to the PD-1 antibody treatment, and the underlying mechanism remains unknown. PD-1 is a transmembrane glycoprotein, and its extracellular domain (ECD) is reported to be responsible for interactions and signal transduction. This domain contains 4 N-glycosylation sites and 25 potential O-glycosylation sites, which implicates the importance of glycosylation. The structure of hPD-1 has been intensively studied, but the glycosylation of this protein, especially the glycan on each glycosylation site, has not been comprehensively illustrated. In this study, hPD-1 ECD expressed by human embryonic kidney 293 (HEK 293) and Chinese hamster ovary (CHO) cells was analyzed; not only N- and O-glycosylation sites but also the glycans on these sites were comprehensively analyzed using mass spectrometry. In addition, hPD-1 ECD binding to different anti-hPD-1 antibodies was tested, and N-glycans were found functioned differently. All of this glycan information will be beneficial for future PD-1 studies.

Identification of metabolic components of carotid plaque in high-risk patients utilizing liquid chromatography-tandem mass spectrometry.

OBJECTIVE: Carotid atherosclerosis is a chronic progressive vascular disease that can be complicated by stroke in severe cases. Prompt diagnosis and treatment of high-risk patients are quite difficult due to the lack of reliable clinical biomarkers. This study aimed to explore potential plaque metabolic markers of stroke-prone risk and relevant targets for pharmacological intervention. METHOD: Carotid intima and plaque sample tissues were obtained from 20 patients with cerebrovascular symptoms of carotid origin. An untargeted metabolomics approach based on liquid chromatography-tandem mass spectrometry was utilized to characterize the metabolic profiles of the tissues. Multivariate and univariate analysis tools were used. RESULTS: A total of 154 metabolites were significantly altered in carotid plaque when compared with thickened intima. Of these, 62 metabolites were upregulated, whereas 92 metabolites were downregulated. Support vector machines identified the 15 most important metabolites, such as N-(cyclopropylmethyl)-N'-phenylurea, 9(S)-HOTrE, ACar 12:2, quinoxaline-2,3-dithiol, and l-thyroxine, as biomarkers for high-risk plaques. Metabolic pathway analysis showed that abnormal purine and nucleotide metabolism, amino acid metabolism, glutathione metabolism, and vitamin metabolism may contribute to the occurrence and progression of carotid atherosclerotic plaque. CONCLUSIONS: Our study identifies the biomarkers and related metabolic mechanisms of carotid plaque, which is stroke-prone, and provides insights and ideas for the precise prevention and targeted intervention of the disease.

Quality Improvement Initiative: Identifying Barriers to Reducing Time to First Feed With Human Milk in Low Birth Weight Infants.

Early exposure to human milk and time to first trophic feed in low birth weight (LBW) infants (<2 kg) is associated with a decreased risk of mortality, sepsis, and length of hospital stay. This project, focused on infants born at less than 2 kg, aimed to identify the mean time to first feed after birth, identify barriers to initiation of the first feed, and meet the target of having 90% of infants receive their first feed within the first 6 hours of life. This quality improvement (QI) project occurred in a thirty-bed level III NICU over 29 months using two Plan-Do-Study-Act (PDSA) cycles. A first-feed audit tool and a multifaceted educational plan were at the forefront of this initiative. Interventions were multidisciplinary, targeted, and extended to all healthcare team members caring for LBW infants, including staff of Labor and Delivery, the NICU, and the Child Health Transport Team. At the end of the QI project, 91.3% of inborn infants and 27.5% of outborn infants were being fed by 6 hours of age, compared with 78.8% and 12.5%, respectively, prior to the project. The mean time to first feed for inborn infants after the PDSA cycles was reduced to 4.4 hours, having a decrease of 80 minutes. A multidisciplinary approach was a key factor in the success of this QI initiative. Increasing staff education and improving clinical practice guidelines regarding the importance of early exposure to human milk are associated with reducing first feed times after birth.

[Two cases of cytopenia associated with multiple malformations]. / 血细胞减少伴多发畸形2例.

The first patient, a 10-year-old girl, presented with pancytopenia and recurrent epistaxis, along with a history of repeated upper respiratory infections, café-au-lait spots, and microcephaly. Genetic testing revealed compound heterozygous mutations in the DNA ligase IV (LIG4) gene, leading to a diagnosis of LIG4 syndrome. The second patient, a 6-year-old girl, was seen for persistent thrombocytopenia lasting over two years and was noted to have short stature, hyperpigmented skin, and hand malformations. She had a positive result from chromosome breakage test. She was diagnosed with Fanconi anemia complementation group A. Despite similar clinical presentations, the two children were diagnosed with different disorders, suggesting that children with hemocytopenia and malformations should not only be evaluated for hematological diseases but also be screened for other potential underlying conditions such as immune system disorders.

Portable Mass Spectrometry Approach Combined with Machine Learning for Onsite Field Detection of Huanglongbing Disease.

Huanglongbing (HLB) is one of the most serious citrus diseases in the world. Rapid, onsite, and accurate field detection of HLB is a challenging task in analytical science for a long time. Herein, we have developed a novel HLB detection method that combines headspace solid phase microextraction with portable gas chromatography-mass spectrometry (PGC-MS) approach for onsite field detection of volatile metabolites of citrus leaves. Detectability and characteristics of HLB-affected metabolites from leaves were validated, and the important biomarkers were verified by authentic compounds. A machine learning approach based on random forest algorithm is established to model the volatile metabolites from healthy, symptomatic, and asymptomatic citrus leaves. In this work, a total of 147 citrus leaf samples were analyzed. Analytical performances of this newly developed method were investigated by in-field detection of various volatile metabolites. Results demonstrated limits of detection and quantification of 0.04-0.12 and 0.17-0.44 ng/mL for different metabolites, respectively. Linear calibration curves of various metabolites were established over a concentration dynamic range of at least three orders (R2 > 0.96). Good reproducibility was obtained for intraday (3.0-17.5%, n = 6) and interday precision (8.7-18.2%, n = 7). This new HLB field detection method provides a rapid detection with 6 min for each sample via a simple optimized procedure, including onsite sampling, PGC-MS analysis, and data process and provides a high accuracy (93.3%) for simultaneous identification of healthy, symptomatic, and asymptomatic trees. These data support the use of this new method for reliable field detection of HLB. Furthermore, metabolic pathways of HLB-affected metabolites were also proposed. Overall, our results not only provide a rapid and onsite field HLB detection method but also provide valuable information for understanding metabolic change of HLB infection.

Slug-Flow Microextraction Mass Spectrometry for Enhanced Detection of Analytes in Human Tear Fluids using Noninvasive Microsampling and Nanoelectrospray Ionization via a Capillary.

In vivo noninvasive sampling and sensitive analysis of human tear fluids at the microliter level is an important but challenging task in investigating eye health. In this work, capillary microsampling coupled with slug-flow microextraction mass spectrometry (SFME-MS) was developed for enhanced detection of analytes in human tear fluids. As low as 1.0 µL of human tear fluid could be directly sampled using a capillary, and extraction/spray solvent was then loaded into the capillary to perform slug-flow microextraction and direct nanoelectrospray ionization (nESI) of analytes. All analytical procedures, including tear microsampling, microextraction, and ionization of analytes, were performed using a capillary. Enhanced detection of therapeutic drugs and disease biomarkers in human tear fluids was successfully demonstrated. Acceptable analytical performances including sensitivity, reproducibility, and quantitation were obtained. It is found that the use of SFME could improve the nESI-MS detection of trace analytes over 100-fold that depends on the chemical properties of analytes. Overall, this study showed that SFME-nESI-MS is a highly effective method for enhanced detection of trace analytes in tear fluids and is expected to be a potentially powerful tool in significant biological and clinical applications.

Household food insecurity is prevalent in a cohort of postpartum women who registered in the Canada Prenatal Nutrition Program in Toronto.

OBJECTIVE: To assess the prevalence, severity and socio-demographic predictors of household food insecurity among vulnerable women accessing the Canada Prenatal Nutrition Program (CPNP) and to examine associations between household food insecurity and breastfeeding practices to 6 months. DESIGN: Cohort investigation pooling data from two studies which administered the 18-item Household Food Security Survey Module at 6 months postpartum and collected prospective infant feeding data at 2 weeks and 2, 4 and 6 months. Household food insecurity was classified as none, marginal, moderate or severe. Logistic regression analyses were performed to assess predictors of household food insecurity and associations between household food security (any and severity) and continued and exclusive breastfeeding. SETTING: Three Toronto sites of the CPNP, a federal initiative targeting socially and/or economically vulnerable women. PARTICIPANTS: 316 birth mothers registered prenatally in the CPNP from 2017 to 2020. RESULTS: Household food insecurity at 6 months postpartum was highly prevalent (44 %), including 11 % in the severe category. Risk of household food insecurity varied by CPNP site (P < 0·001) and was higher among multiparous participants (OR 2·08; 95 % CI 1·28, 3·39). There was no association between the prevalence or severity of food insecurity and continued or exclusive breastfeeding to 6 months postpartum in the adjusted analyses. CONCLUSIONS: Household food insecurity affected nearly half of this cohort of women accessing the CPNP. Further research is needed on household food insecurity across the national CPNP and other similar programmes, with consideration of the implications for programme design, service delivery and policy responses.

Cat-Ear-Line: A Sonographic Sign of Cortical Development?

OBJECTIVES: Diagonal echogenic lines outside the lateral ventricle have often been observed in the anterior coronal planes of the normal fetal brain by neurosonography. We have observed abnormal shapes of these echogenic lines in cases of malformation of cortical development (MCD). We named the ultrasound finding "cat-ear-line" (CEL). This study aimed to examine how and when CEL develops in normal cases compared with MCD cases. METHODS: We retrospectively examined the fetal brain volume dataset acquired through transvaginal 3D neurosonography of 575 control cases and 39 MCD cases from 2014 to 2020. We defined CEL as the hyperechogenic continuous lines through subplate (SP) and intermediate zone (IZ), pre-CEL as the lines that existed only within the SP, and abnormal CEL as a mass-like or mosaic shadow-like structure that existed across the SP and IZ. All fetuses in the MCD group had some neurosonographic abnormalities and were ultimately diagnosed with MCD. RESULTS: The CEL was detected in 97.9% (369/377) of the control group from 19 to 30 weeks. The CEL visualization rate of the MCD group in the same period was 40.0% (14/35) which was significantly lower than that of the control group (P < .001). CONCLUSIONS: From this study, it appears that the CEL is an ultrasound finding observed at and beyond 19 weeks in a normally developing fetus. In some MCD cases, pre-CEL at and beyond 19 weeks or abnormal CEL was observed. Maldeveloped CEL at mid-trimester may help identify cases at-risk of subsequent MCD.

An anticancer gold(III)-activated porphyrin scaffold that covalently modifies protein cysteine thiols.

Cysteine thiols of many cancer-associated proteins are attractive targets of anticancer agents. Herein, we unequivocally demonstrate a distinct thiol-targeting property of gold(III) mesoporphyrin IX dimethyl ester (AuMesoIX) and its anticancer activities. While the binding of cysteine thiols with metal complexes usually occurs via M-S bond formation, AuMesoIX is unique in that the meso-carbon atom of the porphyrin ring is activated by the gold(III) ion to undergo nucleophilic aromatic substitution with thiols. AuMesoIX was shown to modify reactive cysteine residues and inhibit the activities of anticancer protein targets including thioredoxin, peroxiredoxin, and deubiquitinases. Treatment of cancer cells with AuMesoIX resulted in the formation of gold-bound sulfur-rich protein aggregates, oxidative stress-mediated cytotoxicity, and accumulation of ubiquitinated proteins. Importantly, AuMesoIX exhibited effective antitumor activity in mice. Our study has uncovered a gold(III)-induced ligand scaffold reactivity for thiol targeting that can be exploited for anticancer applications.

Case Report: Prenatal Recurrent Microcephaly and Corpus Callosum Abnormalities in a Chinese Family with Novel Biallelic SASS6 Mutations.

INTRODUCTION: Primary microcephaly (MCPH) is not an uncommon disorder with multiple etiologies. There are a growing number of MCPH-related genes discovered due to the extensive application of whole-exome sequencing (WES) in clinical and research settings. Biallelic mutations in the SASS6 gene cause an extremely rare MCPH, type 14. To date, only two families with SASS6 gene-related microcephaly have been reported. CASE DESCRIPTION: We report a case of recurrent congenital microcephaly in a Chinese family. The two affected fetuses presented with microcephaly early in the second trimester with agenesis of the corpus callosum. In the first affected fetus, trio WES detected two compound heterozygous candidate variants c.1139T>C(p.L380P) and c.1223C>G (p.T408S) in the SASS6 gene. Another affected fetus also inherited both variants, while the normal child carried neither variant through Sanger sequencing analysis. Both variants were classified as a variant of uncertain significance according to the current American College of Medical Genetics and Genomics guidelines. CONCLUSION: We reported novel biallelic variants in the SASS6 gene, encoding the SAS6 centriolar assembly protein, associated with prenatal onset of autosomal recessive microcephaly. We postulate that the pathomechanism of the compound heterozygous variants in close proximity could potentiate the overall coiled instability leading to the phenotypic features of our case.

[Research Progress and New Immunotherapy Strategies of Tumor Microenvironment Metabolism].

The tumor microenvironment (TME), the environment of tumorigenesis and tumor progression, incorporates multiple types of cells and non-cellular components. TME plays an important role in tumorigenesis and tumor progression. Due to the abnormal proliferation of tumors, the TME has a unique chemophysiology environment and complex metabolic patterns, which subsequently affects the role of immune cells. Understanding the metabolic patterns of TME can help us develop immunotherapy regimens that target TME. Microbial metabolism and lipid metabolism, the key metabolic processes of TME, have emerged as important foci of research. The metabolites released by the microbiome and the reprogramming of cellular lipid metabolism affect the subsistence of tumor and immune cells. In this review, we summarized the composition and metabolic characteristics of TME and discussed the latest research progress in microbial metabolism and lipid metabolism in TME. We also provided an update on relevant metabolic regulatory targets and immunotherapy strategies, stressing that identifying highly effective therapeutic targets, in spite of the apparent difficulty, is what future research should be focused on.

Design, synthesis and anti-breast cancer evaluation of biaryl pyridine analogues as potent RSK inhibitors.

In order to discover and develop the new RSK kinase inhibitor, 50 pyridyl biaryl derivatives were designed and synthesized with LJH685 as the lead compound and their anti-tumor ability was tested. The results showed that the ability of 7d compound to inhibit the phosphorylation of YB-1 was comparable to that of LJH685. Among them, after preliminary screening, compound 7d showed good activity in inhibiting cell proliferation. Therefore, we took 7d as an example and performed molecular docking analysis on it. Judging from the overlapping combination diagram with LJH685, the results have verified that compound 7d has a similar skeleton to LJH685 and has a similar docking effect with RSK. Therefore, compound 7d is in line with the RSK inhibitor we designed and could be developed to a promising anti-tumor drug in the future.

Management of blunt cerebrovascular injuries at a Canadian level 1 trauma centre: Are we meeting the grade?

BACKGROUND: Untreated blunt cerebrovascular injuries (BCVIs) are associated with high rates of death and disability due to stroke. We assessed alignment of clinical practice at our centre with current recommendations for management of BCVIs and examined rates of new and recurrent in-hospital stroke. METHODS: We retrospectively reviewed the BC Trauma Registry to identify all adult (age > 18 yr) patients with trauma with BCVIs at the largest level 1 trauma centre in British Columbia, Canada, from Apr. 1, 2013, to Mar. 31, 2018. We evaluated the registry, hospital databases and patient charts to assess alignment with guidelines for early initiation of appropriate antithrombotic therapy and follow-up imaging, and to ascertain short-term outcomes. RESULTS: A total of 186 patients met the inclusion criteria. Just over half of BCVIs (97 [52.2%]) were Biffl grade 1-2. The majority of patients were treated with acetylsalicylic acid monotherapy (144/162 [88.9%]) or low-molecular-weight heparin (2/162 [1.2%]). Although guidelines recommend repeat imaging at 7-10 days to reassess the injury and guide duration of therapy, only 61/171 patients (35.7%) underwent repeat imaging within 7 days. Neuroimaging within 3 months after injury showed brain infarction in 29 patients (15.6%). CONCLUSION: Antithrombotic therapy was initiated in the majority of eligible patients with BCVIs, but completion of follow-up imaging and documentation of clear outpatient care plans were suboptimal. This finding shows the need for routine multidisciplinary management to facilitate standardization of care for this complex population.

High levels of breastmilk feeding despite a low rate of exclusive breastfeeding for 6 months in a cohort of vulnerable women in Toronto, Canada.

Exclusive breastfeeding (EBF) for 6 months is a global public health goal, but measuring its achievement as a marker of population breastmilk feeding practices is insufficient. Additional measures are needed to understand variation in non-EBF practices and inform intervention priorities. We collected infant feeding data prospectively at seven time points to 6 months post-partum from a cohort of vulnerable women (n = 151) registered at two Canada Prenatal Nutrition Program sites in Toronto, Canada. Four categories of breastmilk feeding intensity were defined. Descriptive analyses included the (i) proportion of participants in each feeding category by time point, (ii) use of formula and non-formula supplements to breastmilk, (iii) proportion of participants practising EBF continuously for at least 3 months; and (iv) frequency of transitions between feeding categories. All participants initiated breastmilk feeding with 70% continuing for 6 months. Only 18% practised EBF for 6 months, but 48% did so for at least 3 continuous months. The proportion in the EBF category was highest from 2 to 4 months post-partum. Supplemental formula use was highest in the first 3 months; early introduction of solids and non-formula fluids further compromised EBF at 5 and 6 months post-partum. Most participants (75%) transitioned between categories of breastmilk feeding intensity, with 35% making two or more transitions. Our data show high levels of breastmilk provision despite a low rate of EBF for 6 months. Inclusion of similar analyses in future prospective studies is recommended to provide more nuanced reporting of breastmilk feeding practices and guide intervention designs.

[Mental Health Status and Its Influencing Factors among College Students during the Epidemic of Coronavirus Disease 2019:A Multi-center Cross-sectional Study].

Objective To measure the prevalence of mental health symptoms and identify the associated factors among college students at the beginning of coronavirus disease 2019(COVID-19)outbreak in China. Methods We carried out a multi-center cross-sectional study via snowball sampling and convenience sampling of the college students in different areas of China.The rates of self-reported depression,anxiety,and stress and post-traumatic stress disorder(PTSD)were assessed via the 21-item Depression-Anxiety-Stress Scale(DASS-21)and the 6-item Impact of Event Scale-Revised(IES-6),respectively.Covariates included sociodemographic characteristics,health-related data,and information of the social environment.Data pertaining to mental health service seeking were also collected.Multivariate Logistic regression analyses were performed to identify the risk factors. Results A total of 3641 valid questionnaires were collected from college students.At the beginning of the COVID-19 outbreak,535(14.69%)students had negative emotions,among which 402(11.04%),381(10.49%),and 171(4.90%)students had the symptoms of depression,anxiety,and stress,respectively.Meanwhile,1245(34.19%)college students had PTSD.Among the risk factors identified,male gender was associated with a lower likelihood of reporting depression symptoms(AOR=0.755,P=0.037],and medical students were at higher risk of depression and stress symptoms than liberal arts students(AOR=1.497,P=0.003;AOR=1.494,P=0.045).Family support was associated with lower risks of negative emotions and PTSD in college students(AOR=0.918,P<0.001;AOR=0.913,P<0.001;AOR=0.899,P<0.001;AOR=0.971,P=0.021). Conclusions College students were more sensitive to public health emergencies,and the incidence of negative emotions and PTSD was significantly higher than that before the outbreak of COVID-19.More attention should be paid to female college students who were more likely to develop negative emotions.We should strengthen positive and proper propaganda via mass media and help college students understand the situation and impact of COVID-19.Furthermore,we should enhance family support for college students.The government and relevant agencies need to provide appropriate mental health services to the students under similar circumstances to avoid the deterioration of their mental well-being.

Electropolymerization of Metal Clusters Establishing a Versatile Platform for Enhanced Catalysis Performance.

Atomically precise metal clusters are attractive as highly efficient catalysts, but suffer from continuous efficiency deactivation in the catalytic process. Here, we report the development of an efficient strategy that enhances catalytic performance by electropolymerization (EP) of metal clusters into hybrid materials. Based on carbazole ligand protection, three polymerized metal-cluster hybrid materials, namely Poly-Cu14 cba, Poly-Cu6 Au6 cbz and Poly-Cu6 Ag4 cbz, were prepared. Compared with isolated metal clusters, metal clusters immobilizing on a biscarbazole network after EP significantly improved their electron-transfer ability and long-term recyclability, resulting in higher catalytic performance. As a proof-of-concept, Poly-Cu14 cba was evaluated as an electrocatalyst for reducing nitrate (NO3 - ) to ammonia (NH3 ), which exhibited ≈4-fold NH3 yield rate and ≈2-fold Faraday efficiency enhancement compared to that of Cu14 cba with good durability. Similarly, Poly-Cu6 Au6 cbz showed 10 times higher photocatalytic efficiency towards chemical warfare simulants degradation than the cluster counterpart.

Sirtuin 3 protects against anesthesia/surgery-induced cognitive decline in aged mice by suppressing hippocampal neuroinflammation.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a very common complication that might increase the morbidity and mortality of elderly patients after surgery. However, the mechanism of POCD remains largely unknown. The NAD-dependent deacetylase protein Sirtuin 3 (SIRT3) is located in the mitochondria and regulates mitochondrial function. SIRT3 is the only sirtuin that specifically plays a role in extending lifespan in humans and is associated with neurodegenerative diseases. Therefore, the aim of this study was to evaluate the effect of SIRT3 on anesthesia/surgery-induced cognitive impairment in aged mice. METHODS: SIRT3 expression levels were decreased after surgery. For the interventional study, an adeno-associated virus (AAV)-SIRT3 vector or an empty vector was microinjected into hippocampal CA1 region before anesthesia/surgery. Western blotting, immunofluorescence staining, and enzyme-linked immune-sorbent assay (ELISA) were used to measure the oxidative stress response and downstream microglial activation and proinflammatory cytokines, and Golgi staining and long-term potentiation (LTP) recording were applied to evaluate synaptic plasticity. RESULTS: Overexpression of SIRT3 in the CA1 region attenuated anesthesia/surgery-induced learning and memory dysfunction as well as synaptic plasticity dysfunction and the oxidative stress response (superoxide dismutase [SOD] and malondialdehyde [MDA]) in aged mice with POCD. In addition, microglia activation (ionized calcium binding adapter molecule 1 [Iba1]) and neuroinflammatory cytokine levels (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1ß and IL-6) were regulated after anesthesia/surgery in a SIRT3-dependent manner. CONCLUSION: The results of the current study demonstrate that SIRT3 has a critical effect in the mechanism of POCD in aged mice by suppressing hippocampal neuroinflammation and reveal that SIRT3 may be a promising therapeutic and diagnostic target for POCD.

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used new-generation drugs for depression. Depressive symptoms are thought to be closely related to neuroinflammation. In this study, we used up-to-date protocols of culture and stimulation and aimed to understand how astrocytes respond to the antidepressants. METHODS: Primary astrocytes were isolated and cultured using neurobasal-based serum-free medium. The cells were treated with a cytokine mixture comprising complement component 1q, tumor necrosis factor α, and interleukin 1α with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses, and the underlying mechanisms were analyzed. RESULTS: All the SSRIs, including paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine, show a visible cytotoxicity within the range of applied doses, and a paradoxical effect on astrocytic inflammatory responses as manifested by the promotion of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) and the inhibition of interleukin 6 (IL-6) and/or interleukin 1ß (IL-1ß). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1ß but with no impact on iNOS and NO. All the drugs had no regulation on the polarization of astrocytic A1 and A2 types. Mechanisms associated with the antidepressants in astrocytic inflammation route via inhibition of JNK1 activation and STAT3 basal activity. CONCLUSIONS: The study demonstrated that the antidepressants possess differential cytotoxicity to astrocytes and function differently, also paradoxically for the SSRIs, to astrocytic inflammation. Our results provide novel pieces into understanding the differential efficacy and tolerability of the antidepressants in treating patients in the context of astrocytes.