Factors influencing the degree of disability in patients with neuromyelitis optica spectrum disorders.

OBJECTIVE: To investigate the factors influencing the degree of disability in patients with neuromyelitis optica spectrum disorder (NMOSD) and provide evidence for disease monitoring and clinical intervention. METHODS: Eighty-four patients with NMOSD at Xuanwu Hospital Capital Medical University were enrolled in this retrospective study. Before treatment, blood was collected from all patients, and their expanded disability status scores were assessed. RESULTS: Of the 84 patients assessed, 66 (78.57%) had an expanded disability status scale score < 7, and 18 (21.43%) had scores ≥ 7. The univariate analysis showed that the total bilirubin (TBil), cerebrospinal fluid albumin (CSF ALB), cerebrospinal fluid immunoglobulin G (CSF IgG), QALB, and QIgG levels in the group with scores ≥ 7 were significantly different from those with scores < 7 (P < 0.05). In addition, Spearman's correlation analysis showed a significant correlation between ALB and expanded disability status scores in patients with NMOSD (P < 0.05), and the multivariate logistic regression analysis showed that TBil was an independent factor influencing the degree of disability in patients with NMOSD (P < 0.05). The receiver operating characteristic curve was constructed using TBil values; the area under the curve of TBil was 0.729 (P < 0.01), and the best cut-off value was 11.015 g/L. Its sensitivity in predicting the severity of disability in NMOSD patients was 51.5% while its specificity was 88.9%. CONCLUSION: TBil is an independent factor that influences the severity of disability in patients with NMOSD. In addition, ALB is closely related to NMOSD severity, and some factors associated with the BBB are significantly increased in severely disabled NMOSD patients.

Downregulation of Krüppel-like factor 14 accelerated cellular senescence and aging.

Aging has been considered as a risk factor in many diseases, thus, comprehensively understanding the cellular and molecular mechanisms of delayed aging is important. Here we investigated whether Krüppel-like factor 14 (KLF14) is a suppressor of cellular senescence and aging. In our research, KLF14 levels significantly decreased not only in the lymphocytes of healthy people but also in the cells and tissues of mice with aging. We performed in vitro and in vivo experiments on cells and mice to reveal the function of KLF14 in aging. KLF14 deficiency facilitates cellular senescence and aging-related pathologies in C57BL/6J mice, whereas KLF14 overexpression attenuates cellular senescence. Mechanistically, KLF14 delays aging by binding to the POLD1 promoter to positively regulate POLD1 expression. Remarkably, cellular senescence mediated by KLF14 downregulation could be alleviated by POLD1 expression. In addition, perhexiline, an agonist of KLF14, could delay cellular senescence and aging-related pathologies in senescence-accelerated P8 mice by inducing POLD1 expression, as perhexiline could enhance the effect of KLF14's transcription activation to POLD1 by elevating the binding level of KLF14 to the POLD1 promoter. Our data indicate that KLF14 might be a critical element in aging by upregulating POLD1 expression, indicating that the activation of KLF14 may delay aging and aging-associated diseases.

Reference intervals for thyroid hormones for the elderly population and their influence on the diagnosis of subclinical hypothyroidism.

Background: This study aims to establish reference intervals (RIs) for thyroid hormones in the elderly population and analyze their influence on the prevalence of subclinical hypothyroidism. Methods: Thyroid hormone records of subjects who underwent routine health checkup at our hospital between 2018 and 2020 were analyzed. Thyroid stimulating hormone (TSH), total triiodothyronine, total thyroxine, free triiodothyronine (FT3), and free thyroxine (FT4) levels were compared between young and elderly subjects. Thresholds of these thyroid hormones were established for elderly subjects. Results: A total of 22,207 subjects were included. Of them, 2,254 (10.15%) were aged ≥ 65 years. Elderly subjects had higher TSH, and lower FT3 and FT4 levels when compared with young subjects. In the elderly group, the RIs for TSH, FT3 and FT4 were 0.55-5.14 mIU/L, 3.68-5.47 pmol/L, and 12.00-19.87 pmol/L, respectively. The age and sex specific RIs for TSH were 0.56-5.07 mIU/L for men and 0.51-5.25 mIU/L for women. With whole-group RIs and age and sex-specific RIs for elderly people, the prevalence of subclinical hypothyroidism was 9.83% and 6.29% (p < 0.001), respectively. Conclusions: Elderly individuals had higher TSH levels than young individuals. Our study indicated that establishing specific RIs for elderly individuals is needed. This has implications for the diagnosis and management of subclinical hypothyroidism in the elderly population.

Integrated multi-omics approach revealed cellular senescence landscape.

Cellular senescence is a complex multifactorial biological phenomenon that plays essential roles in aging, and aging-related diseases. During this process, the senescent cells undergo gene expression altering and chromatin structure remodeling. However, studies on the epigenetic landscape of senescence using integrated multi-omics approaches are limited. In this research, we performed ATAC-seq, RNA-seq and ChIP-seq on different senescent types to reveal the landscape of senescence and identify the prime regulatory elements. We also obtained 34 key genes and deduced that NAT1, PBX1 and RRM2, which interacted with each other, could be the potential markers of aging and aging-related diseases. In summary, our work provides the landscape to study accessibility dynamics and transcriptional regulations in cellular senescence. The application of this technique in different types of senescence allows us to identify the regulatory elements responsible for the substantial regulation of transcription, providing the insights into molecular mechanisms of senescence.

Alleviating Neuroinflammation through Photothermal Conjugated Polymer Nanoparticles by Regulating Reactive Oxygen Species and Ca2+ Signaling.

Neuroinflammation is one of the important manifestations of the amyloid ß peptide (Aß) protein-induced neurotoxic signaling pathway in which the aggregation of Aß causes an increase in reactive oxygen species (ROS) and Ca2+ concentration. Here, near-infrared (NIR) photothermal-responsive conjugated polymer nanoparticles were designed to regulate ROS and Ca2+ signaling to alleviate neuroinflammation. Under 808 nm laser irradiation, the nanoparticles effectively penetrated the blood-brain barrier (BBB) and reduced the aggregation of Aß and partially disaggregated the aggregates outside the cell, thereby reducing ROS content which downregulated the oxidative stress damage to cells. Meanwhile, the nanoparticles reduced the concentration of Ca2+ by inhibiting the transient receptor potential melastatin-related 2 (TRPM2) ion channel inside the cell. Ultimately, the concentration of inflammatory factor tumor necrosis factor-α was decreased. This study provides an effective strategy to reduce neuroinflammation by simultaneously regulating ROS and Ca2+ signaling.

Potential biomarkers of spinal dural arteriovenous fistula: C4BPA and C1QA.

BACKGROUND AND PURPOSE: A major challenge in spinal dural arteriovenous fistula (SDAVF) is timely diagnosis, but no specific predictive biomarkers are known. METHODS: In the discovery cohort (case, n = 8 vs. control, n = 8), we used cerebrospinal fluid (CSF) and paired plasma samples to identify differentially expressed proteins by label-free quantitative proteomics. Further bioinformatics enrichment analyses were performed to screen target proteins. Finally, it was validated by ELISA in two of the new cohorts (case, n = 17 vs. control, n = 9), and univariate analysis, simple linear regression, and receiver operator characteristic (ROC) curve analysis were performed to evaluate the diagnostic potential. RESULTS: In the discovery cohort, the most overexpressed proteins were APOB and C4BPA in CSF samples of patients. The GO/KEGG enrichment analysis indicated that the upregulated proteins were mainly involved in the acute inflammatory response and complement activation. Hub-gene analysis revealed that APP might be the key protein in the molecular interaction network. In the validation cohort, C4BPA and C1QA were significantly overexpressed in the CSF of patients, averaging 3046.9 ng/ml and 2167.2 ng/ml, respectively. Simple linear regression demonstrated that levels of C1QA and C4 were positively correlated with total protein in CSF (R2 = 0.8021, p = 0.0005; R2 = 0.7447, p = 0.0013). The areas under the ROC curves of C4BPA and C1QA were 0.86 and 1.00, respectively. CONCLUSIONS: This study was the first to identify C4BPA and C1QA as potential biomarkers for the diagnosis of SDAVF and revealed that complement pathway activation might be one of the molecular mechanisms for venous hypertension myelopathy.

Polyisocyanide hydrogels with tunable nonlinear elasticity mediate liver carcinoma cell functional response.

Hepatocellular carcinoma development is closely related to the changes in tissue mechanics induced by excess collagen deposition and crosslinking, which leads to liver fibrosis and malignant progression. The role of matrix stiffness has been widely assessed using various linearly elastic materials. However, the liver, like many soft tissues, also exhibits nonlinear elasticity by strain-stiffening, allowing cells to mechanically interact with their micromilieus which has attracted much attention in cellular processes recently. Here, we use a biomimetic hydrogel grafting of GRGDS peptide with tunable nonlinear mechanical properties, polyisocyanides (PIC), to investigate the influence of strain-stiffening on HepG2 liver cancer cell behavior by tuning PIC polymer length. Compared to short PIC polymer with lower critical stress, PIC hydrogels composed of long polymer with higher critical stress promote the motility and invasiveness of HepG2 cells, and induce more actin stress fibers and higher expression level of mechanotransducer YAP and its nuclear translocation. Strikingly, the expression of calcium-activated potassium channel KCa3.1, an important biomarker in hepatocellular carcinoma, is also affected by the mechanical property of PIC hydrogels. It was also shown that downregulating the KCa3.1 channel can be achieved by inhibiting the formation of actin fibers. Our findings imply that the strain-stiffening property of PIC hydrogels affects the expression of KCa3.1 potassium channel via mediating cytoskeletal stress fiber formation, and ultimately influences the liver carcinoma cell functional response. STATEMENT OF SIGNIFICANCE: The effect of nonlinear elasticity by strain-stiffening, is assessed in HepG2 liver cancer cell behavior by using a biomimetic hydrogel with tunable mechanical properties, polyisocyanides (PIC). PIC gels with higher critical stress promote the motility and invasiveness of HepG2 cells and induce upregulated expression levels of KCa3.1 potassium channel and YAP, but which can be suppressed by inhibiting the formation of actin fibers. Our findings imply that the strain-stiffening property of PIC gels influences the expression of KCa3.1 potassium channel via mediating cytoskeletal stress fiber formation and, ultimately affects the liver carcinoma cell functional response.

Anoctamin 1 controls bone resorption by coupling Cl- channel activation with RANKL-RANK signaling transduction.

Osteoclast over-activation leads to bone loss and chloride homeostasis is fundamental importance for osteoclast function. The calcium-activated chloride channel Anoctamin 1 (also known as TMEM16A) is an important chloride channel involved in many physiological processes. However, its role in osteoclast remains unresolved. Here, we identified the existence of Anoctamin 1 in osteoclast and show that its expression positively correlates with osteoclast activity. Osteoclast-specific Anoctamin 1 knockout mice exhibit increased bone mass and decreased bone resorption. Mechanistically, Anoctamin 1 deletion increases intracellular Cl- concentration, decreases H+ secretion and reduces bone resorption. Notably, Anoctamin 1 physically interacts with RANK and this interaction is dependent upon Anoctamin 1 channel activity, jointly promoting RANKL-induced downstream signaling pathways. Anoctamin 1 protein levels are substantially increased in osteoporosis patients and this closely correlates with osteoclast activity. Finally, Anoctamin 1 deletion significantly alleviates ovariectomy induced osteoporosis. These results collectively establish Anoctamin 1 as an essential regulator in osteoclast function and suggest a potential therapeutic target for osteoporosis.

Rapamycin Activates Mitophagy and Alleviates Cognitive and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease, which is characterized by cognitive and synaptic plasticity damage. Rapamycin is an activator of autophagy/mitophagy, which plays an important role in identifying and degrading damaged mitochondria. The aim of this study was to investigate the effect of rapamycin on cognitive and synaptic plasticity defects induced by AD, and further explore if the underlying mechanism was associated with mitophagy. The results show that rapamycin increases Parkin-mediated mitophagy and promotes fusion of mitophagosome and lysosome in the APP/PS1 mouse hippocampus. Rapamycin enhances learning and memory viability, synaptic plasticity, and the expression of synapse-related proteins, impedes cytochrome C-mediated apoptosis, decreases oxidative status, and recovers mitochondrial function in APP/PS1 mice. The data suggest that rapamycin effectively alleviates AD-like behaviors and synaptic plasticity deficits in APP/PS1 mice, which is associated with enhanced mitophagy. Our findings possibly uncover an important function of mitophagy in eliminating damaged mitochondria to attenuate AD-associated pathology.

CTCF Mediates Replicative Senescence Through POLD1.

POLD1, the catalytic subunit of DNA polymerase δ, plays a critical role in DNA synthesis and DNA repair processes. Moreover, POLD1 is downregulated in replicative senescence to mediate aging. In any case, the components of age-related downregulation of POLD1 expression have not been fully explained. In this article, we elucidate the mechanism of the regulation of POLD1 at the transcription level and found that the transcription factor CCCTC-binding factor (CTCF) was bound to the POLD1 promoter area in two sites. The binding level of CTCF for the POLD1 promoter appeared to be related to aging and was confirmed to be positively controlled by the CTCF level. Additionally, cell senescence characteristics were detected within the cells transfected with short hairpin RNA (shRNA)-CTCF, pLenti-CMV-CTCF, shRNA-POLD1, and pLenti-CMV-POLD1, and the results showed that the CTCF may contribute to the altered expression of POLD1 in aging. In conclusion, the binding level of CTCF for the POLD1 promoter intervened by an age-related decrease in CTCF and downregulated the POLD1 expression in aging. Moreover, the decrease in CTCF-mediated POLD1 transcription accelerates the progression of cell aging.

Preliminary study on the function of the POLD1 (CDC2) EXON2 c.56G>A mutation.

BACKGROUND: Fanconi anemia (FA) is a rare recessive disease characterized by DNA damage repair deficiency, and DNA polymerase δ (whose catalytic subunit is encoded by POLD1, also known as CDC2) is closely related to DNA damage repair. Our previous study identified a novel POLD1 missense mutation c.56G>A (p. Arg19>His) in FA family members. However, the function of the POLD1 missense mutation is currently unknown. This study aimed to uncover the biological function of the POLD1 missense mutation. METHODS: Stable cell lines overexpressing wild-type POLD1 or mutant POLD1 (c.56G>A, p.Arg19His) were constructed by lentivirus infection. Cell growth curve analysis, cell cycle analysis, and a comet assay were used to analyze the function of the POLD1 mutation. RESULTS: The growth and proliferative ability of the cells with POLD1 mutation was decreased significantly compared with those of the wild-type cells (Student's t test, p < .05). The percentage of cells in the G0/G1 phase increased, and the percentage of cells in the S phase decreased significantly when POLD1 was mutated (Student's t test, p < .05). Moreover, the Olive tail moment value of the cells with the POLD1 mutation was significantly higher than that of the cells with wild-type POLD1 after H2 O2 treatment. CONCLUSIONS: The POLD1 mutation inhibited cell proliferation, slowed cell cycle progression, and reduced DNA damage repair.

Repetitive transcranial magnetic stimulation ameliorates recognition memory impairment induced by hindlimb unloading in mice associated with BDNF/TrkB signaling.

Repetitive transcranial magnetic stimulation (rTMS), which could improve learning and memory, is widely used in psychiatry and neurology as a therapeutic approach. There are few studies reporting effective countermeasures to cognition decline in astronauts during space flight. Accordingly, we examined whether rTMS was able to significantly alleviate the learning and memory deficits induced by hindlimb unloading (HU), a general accepted rodent model to simulate microgravity, in mice. Male C57BL/6 J mice were randomly divided into four groups: Sham, rTMS, HU, and HU + rTMS groups. The hindlimb unloading procedure continued for consecutive 14 days. Meanwhile, high frequency rTMS (15 Hz) was applied for 14 days from the 1st day of HU procedure. The novel object recognition test showed that the recognition memory was evidently impaired in the HU group compared to that in the Sham group, however, rTMS significantly attenuated the impairment of the memory. Furthermore, rTMS significantly improved the HU-induced LTP impairment and increased spine density in the hippocampal dentate gyrus region. Additionally, rTMS enhanced the expressions of postsynaptic function-associated proteins N-methyl-d-aspartic acid receptors (NR2B and NR2 A) and postsynaptic density protein (PSD95), upregulated BDNF/TrkB signaling and increased phosphorylation of protein kinase B (Akt) in the HU + rTMS group. In conclusion, the data suggest that high frequency rTMS may be an effective countermeasure against the learning and memory deficiency, induced by simulated microgravity.

Posttreatment squamous cell carcinoma antigen predicts treatment failure in patients with cervical squamous cell carcinoma treated with concurrent chemoradiotherapy.

OBJECTIVE: To analyze the association between posttreatment squamous cell carcinoma antigen (SCC Ag) and treatment failure in patients with cervical SCC treated with concurrent chemoradiotherapy (CCRT). METHODS: We reviewed patients with cervical SCC who were treated with definitive radiotherapy or CCRT between June 2012 and May 2015 at our institute. A receiver operating characteristic (ROC) curve was used to analyze the cutoff value of posttreatment SCC Ag in predicting treatment failure. Log-rank tests and Cox proportional hazards models were used to identify whether posttreatment SCC Ag was significant in predicting disease-free survival (DFS). RESULTS: A total of 559 patients were included in this study. With the ROC curve, the optimal cutoff posttreatment SCC Ag level was 1.8 ng/mL (sensitivity 27.1%, specificity 96.6%). A posttreatment SCC Ag level ≥ 1.8 ng/mL was observed in 47 patients. The multivariate analysis showed that posttreatment SCC Ag (hazard ratio 5.10; 95% confidence interval, 3.31-7.88; p < 0.001) was an independent prognostic factor of DFS. The 3-year overall survival (OS), DFS, local control, and distant control rates of patients with posttreatment SCC Ag < 1.8 ng/mL and ≥1.8 ng/mL were 90.7% and 46.4% (p < 0.001), 84.8% and 31.9% (p < 0.001), 81.4% and 69.5% (p < 0.001), and 90.4% and 54.1% (p < 0.001), respectively. CONCLUSION: Patients with posttreatment SCC Ag ≥ 1.8 ng/mL suffer due to a high rate of treatment failure and poor survival.

The role of squamous cell carcinoma antigen (SCC Ag) in outcome prediction after concurrent chemoradiotherapy and treatment decisions for patients with cervical cancer.

At present, the standard treatment approach for locally advanced cervical cancer is concurrent chemoradiotherapy (CCRT). An elevated pretreatment squamous cell carcinoma antigen (SCC Ag) level is associated with extensive tumors and poor survival for patients with cervical cancer treated with definitive CCRT. SCC Ag levels can be used to help physicians make decisions regarding surgery, avoiding the complications of double treatment modalities. Elevated SCC Ag is associated with radiotherapy resistance, and the rate of SCC Ag reduction during CCRT can predict tumor response after treatment. Moreover, the failure of SCC Ag levels to normalize posttreatment can predict tumor relapse, with a specificity higher than 70%, and adjuvant therapies should be considered for these patients. SCC Ag also plays an important role in the early detection of tumor relapse in patients with cervical cancer during follow-up after CCRT, with high sensitivity and good cost-effectiveness.

AG1031 induces apoptosis through suppressing SIRT1/p53 pathway in human neuroblastoma cells.

Neuroblastoma is the most common extra-cranial tumor in childhood. As an antineoplastic medicine, the effect of AG-1031 on the neuroblastoma is still unclear. Silent information regulator 1 (SIRT1) is a conserved NAD+-dependent deacetylase, which plays a key role in carcinogenesis through the deacetylation of important regulatory proteins, including p53. The purpose of the present study was to determine whether there was a significant anti-tumor effect of AG-1031 on the human neuroblastoma cells through suppressing SIRT1/p53 pathway. Our study showed that AG1031 treatment resulted in a dose-dependent decrease in human neuroblastoma SH-SY5Y cell viability. The data, obtained from both Western blot assay and Hoechst 33258 staining, further showed that AG1031 exhibited strong anti-tumor activity closely associated with significantly increasing apoptotic indices and enhancing oxidative stress levels. Moreover, AG1031 treatment could down-regulate SIRT1 in a dose-dependent manner and up-regulate p53 acetylation, while overexpression of SIRT1 significantly attenuated the anti-tumor effect of AG1031 in SH-SY5Y cells. AG1031 potently induced SH-SY5Y cells apoptosis through suppressing SIRT1/p53 signaling. These data suggest that AG1031 may be used for therapeutic intervention in neuroblastoma treatment.

rTMS pre-treatment effectively protects against cognitive and synaptic plasticity impairments induced by simulated microgravity in mice.

During space flight, microgravity has several negative effects on cognitive functions and learning and memory abilities. However, there are few effectively preventive methods that have been developed yet. Previous studies showed that repetitive transcranial magnetic stimulation (rTMS), as a novel non-invasive technique, alleviated cognitive dysfunctions and facilitated synaptic plasticity. In the present study, we used a hindlimb unloading (Hu) mouse model to simulate microgravity conditions. And then, we investigated whether rTMS played a neuroprotective role in a Hu mouse model. Behavioral experiments including Open field test and Novel object recognition test were performed. These results showed that spontaneous activity and recognition memory were reduced by Hu, while rTMS significantly protected against the harmful effect. Furthermore, electrophysiological recordings were performed to examine the level of synaptic plasticity including paired-pulse facilitation (PPF) and long-term potentiation (LTP). In the hippocampus DG and CA1 regions, dendritic spine density was measured using Golgi-Cox staining. Our data showed that rTMS effectively impeded the impairment of PPF and LTP, as well as the decrease of spine density induced by Hu. Subsequently, Western blot assay showed that rTMS inhibited the downregulation of CREB/BDNF signaling network associated proteins in Hu mice. It suggests that rTMS pre-treatment plays a neuroprotective role in protecting against cognitive impairments and synaptic plasticity deficits induced by microgravity stimulation.

Rapamycin relieves anxious emotion and synaptic plasticity deficits induced by hindlimb unloading in mice.

This study examined whether increasing autophagy could improve cognitive deficits in hindlimb unloaded (HU) mice, which was used as an animal model of synaptic plasticity impairment. Male C57BL/6 mice were randomly divided into three groups: control, HU and HU + rapamycin groups. Hindlimb unloading treatment was used to establish the animal model for 2 weeks. Rapamycin was intraperitoneally injected at a dose of 0.5 mg/kg/day along with hindlimb unloading procedure. The open field test and the elevated plus maze test showed that rapamycin considerably prevented the level of anxiety and increased exploratory behaviour in HU mice. Afterwards, long-term potentiation (LTP) recorded in the hippocampal dentate gyrus (DG) region was effectively reduced by rapamycin, which was significantly inhibited by HU procedure. In addition, rapamycin further increased the autophagy level, which was already elevated in HU mice. Meanwhile, the expression of NMDA receptor 2A and 2 B was modified by rapamycin in HU mice. Moreover, rapamycin noticeably increased the total superoxide dismutase (T-SOD) activity and reduced the malondialdehyde (MDA) as well as the level of carbonylated proteins in HU mice's hippocampus. The results show that increasing autophagy may pacificate the anxious emotion, and partly alleviate the hippocampal synaptic plasticity deficits.

TRAF-interacting protein with forkhead-associated domain (TIFA) transduces DNA damage-induced activation of NF-κB.

DNA damage-induced NF-κB activation and the secretion of inflammatory cytokines play crucial roles in carcinogenesis and cellular senescence. However, the underlying mechanisms, especially the initial sensors and transducers connecting the nuclear DNA damage signal with cytoplasmic NF-κB activation remain incompletely understood. Here, we report that TRAF-interacting protein with forkhead-associated domain (TIFA), an established NF-κB activator in the cytosol, unexpectedly exhibited nuclear translocation and accumulation on damaged chromatin following genotoxic stress. Accordingly, we also found that DNA damage-induced transcriptional activation and the resulting secretion of classic NF-κB targets, including interleukin (IL)-6 and IL-8, was greatly enhanced in TIFA-overexpressing cells compared with control cells. Mechanistically, DNA damage-induced TIFA phosphorylation at threonine 9 (pThr-9), and this phosphorylation event, involving the pThr-binding forkhead-associated domain, was crucial for its enrichment on damaged chromatin and subsequent NF-κB activation. Moreover, in conjunction with its partner protein, the E3 ligase TNF receptor-associated factor 2 (TRAF2), TIFA relayed the DNA damage signals by stimulating ubiquitination of NF-κB essential modulator (NEMO), whose sumoylation, phosphorylation, and ubiquitination were critical for NF-κB's response to DNA damage. Consistently, TRAF2 knockdown suppressed TIFA overexpression-enhanced NEMO ubiquitination under genotoxic stress, and a unphosphorylatable Thr-9-mutated TIFA variant had only minor effects on NEMO poly-ubiquitination. Finally, in agreement with the model of DNA damage-associated secretory senescence barrier against carcinogenesis, ectopic TIFA expression limited proliferation of multiple myeloma cancer cells. In conclusion our results indicate that TIFA functions as a key transducer in DNA damage-induced NF-κB activation.

Rapamycin Effectively Impedes Melamine-Induced Impairments of Cognition and Synaptic Plasticity in Wistar Rats.

Our previous investigation demonstrated that autophagy significantly reduced melamine-induced cell death in PC12 cells via inhibiting the excessive generation of ROS. In the present study, we further examine if rapamycin, used as an autophagy activator, can play a significant role in protecting neurons and alleviating the impairment of spatial cognition and hippocampal synaptic plasticity in melamine-treated rats. Male Wistar rats were divided into three groups: control, melamine-treated, and melamine-treated + rapamycin. The animal model was established by administering melamine at a dose of 300 mg/kg/day for 4 weeks. Rapamycin was intraperitoneally given at a dose of 1 mg/kg/day for 28 consecutive days. The Morris water maze test showed that spatial learning and reversal learning in melamine-treated rats were considerably damaged, whereas rapamycin significantly impeded the cognitive function impairment. Rapamycin efficiently alleviated the melamine-induced impairments of both long-term potentiation (LTP) and depotentiation, which were damaged in melamine rats. Rapamycin further increased the expression level of autophagy markers, which were significantly enhanced in melamine rats. Moreover, rapamycin noticeably decreased the reactive oxygen species level, while the superoxide dismutase activity was remarkably increased by rapamycin in melamine rats. Malondialdehyde assay exhibited that rapamycin prominently reduced the malondialdehyde (MDA) level of hippocampal neurons in melamine-treated rats. In addition, rapamycin significantly decreased the caspase-3 activity, which was elevated by melamine. Consequently, our results suggest that regulating autophagy may become a new targeted therapy to relieve the damage induced by melamine.

Nicotine Significantly Improves Chronic Stress-Induced Impairments of Cognition and Synaptic Plasticity in Mice.

The aim of this study was to examine if nicotine was able to improve cognition deficits in a mouse model of chronic mild stress. Twenty-four male C57BL/6 mice were divided into three groups: control, stress, and stress with nicotine treatment. The animal model was established by combining chronic unpredictable mild stress (CUMS) and isolated feeding. Mice were exposed to CUMS continued for 28 days, while nicotine (0.2 mg/kg) was also administrated for 28 days. Weight and sucrose consumption were measured during model establishing period. The anxiety and behavioral despair were analyzed using the forced swim test (FST) and open-field test (OFT). Spatial cognition was evaluated using Morris water maze (MWM) test. Following behavioral assessment, both long-term potentiation (LTP) and depotentiation (DEP) were recorded in the hippocampal dentate gyrus (DG) region. Both synaptic and Notch1 proteins were measured by Western. Nicotine increased stressed mouse's sucrose consumption. The MWM test showed that spatial learning and reversal learning in stressed animals were remarkably affected relative to controls, whereas nicotine partially rescued cognitive functions. Additionally, nicotine considerably alleviated the level of anxiety and the degree of behavioral despair in stressed mice. It effectively mitigated the depression-induced impairment of hippocampal synaptic plasticity, in which both the LTP and DEP were significantly inhibited in stressed mice. Moreover, nicotine enhanced the expression of synaptic and Notch1 proteins in stressed animals. The results suggest that nicotine ameliorates the depression-like symptoms and improves the hippocampal synaptic plasticity closely associated with activating transmembrane ion channel receptors and Notch signaling components. Graphical Abstract ᅟ.