The synergism of Lactobacillaceae, inulin, polyglucose, and aerobic exercise ameliorates hyperglycemia by modulating the gut microbiota community and the metabolic profiles in db/db mice.

This study aimed to assess the impact of Lactobacillaceae (L or H represents a low or high dose), inulin (I), and polydextrose (P) combined with aerobic exercise (A) on the composition of the gut microbiota and metabolic profiles in db/db mice. After a 12-week intervention, LIP, LIPA, and HIPA groups exhibited significant improvements in hyperglycemia, glucose tolerance, insulin resistance, inflammatory response, and short-chain fatty acid (SCFA) and blood lipid levels compared to type 2 diabetes mice (MC). After treatment, the gut microbiota composition shifted favorably in the treatment groups which significantly increased the abundance of beneficial bacteria, such as Bacteroides, Blautia, Akkermansia, and Faecalibaculum, and significantly decreased the abundance of Proteus. Metabolomics analysis showed that compared to the MC group, the contents of 5-hydroxyindoleacetic acid, 3-hydroxysebacic acid, adenosine monophosphate (AMP), xanthine and hypoxanthine were significantly decreased, while 3-ketosphinganine, sphinganine, and sphingosine were significantly increased in the LIP and LIPA groups, respectively. Additionally, LIP and LIPA not only improved sphingolipid metabolism and purine metabolism pathways but also activated AMP-activated protein kinase to promote ß-oxidation by increasing the levels of SCFAs. Faecalibaculum, Blautia, Bacteroides, and Akkermansia exhibited positive correlations with sphingosine, 3-ketosphinganine, and sphinganine, and exhibited negative correlations with hypoxanthine, xanthine and AMP. Faecalibaculum, Blautia, Bacteroides, and Akkermansia may have the potential to improve sphingolipid metabolism and purine metabolism pathways. These findings suggest that the synergism of Lactobacillaceae, inulin, polydextrose, and aerobic exercise provides a promising strategy for the prevention and management of type 2 diabetes.

Exploring the Prevalence of Tinnitus and Ear-Related Symptoms in China After the COVID-19 Pandemic: Online Cross-Sectional Survey.

BACKGROUND: Tinnitus is a complex and heterogeneous disease that has been identified as a common manifestation of COVID-19. To gain a comprehensive understanding of tinnitus symptoms in individuals following COVID-19 infection, we conducted an online survey called the China Ear Nose and Throat Symptom Survey in the COVID-19 Pandemic (CENTSS) among the Chinese population. OBJECTIVE: Our objective was to investigate tinnitus and ear-related symptoms after COVID-19 infection in the Chinese population, with the aim of providing a solid empirical foundation for improved health care. The findings from CENTSS can contribute to the development of enhanced management strategies for tinnitus in the context of long COVID. By gaining a better understanding of the factors contributing to tinnitus in individuals with COVID-19, health care providers can tailor interventions to address the specific needs of affected patients. Furthermore, this study serves as a basis for research on the long-term consequences of COVID-19 infection and its associated tinnitus symptoms. METHODS: A quantitative, online, cross-sectional survey study design was used to explore the impact of the COVID-19 pandemic on experiences with tinnitus in China. Data were collected through an online questionnaire designed to identify the presence of tinnitus and its impacts. Descriptive statistics were used to analyze individuals' demographic characteristics, COVID-19 infection-related ear symptoms, and the cognitive and emotional implications of tinnitus. Univariable and multivariable logistic regression analyses were used to model the cross-sectional baseline associations between demographic characteristics, noise exposure, educational level, health and lifestyle factors, and the occurrence of tinnitus. RESULTS: Between December 19, 2022, and February 1, 2023, we obtained responses from 1262 Chinese participants representing 24 regions, with an average age of 37 years. Among them, 540 patients (42.8%) reported experiencing ear-related symptoms after COVID-19 infection. Only 114 (9%) of these patients sought medical attention specifically for their ear symptoms, while 426 (33.8%) did not seek hospital care. Tinnitus emerged as the most prevalent and impactful symptom among all ear-related symptoms experienced after COVID-19 infection. Of the respondents, female participants (688/888, 77.78%), younger individuals (<30 years), individuals with lower education levels, participants residing in western China, and those with a history of otolaryngology diseases were more likely to develop tinnitus following COVID-19 infection. CONCLUSIONS: In summary, tinnitus was identified as the most common ear-related symptom during COVID-19 infection. Individuals experiencing tinnitus after COVID-19 infection were found to have poorer cognitive and emotional well-being. Different ear-related symptoms in patients post-COVID-19 infection may suggest viral invasion of various parts of the ear. It is therefore crucial to monitor and manage hearing-related changes resulting from COVID-19 as clinical services resume.

Clinical Profile and Outcome Analysis of Ear-Nose-Throat Symptoms in SARS-CoV-2 Omicron Subvariant Infections.

Objective: This study aimed to investigate the clinical characteristics and outcomes of ear-nose-throat (ENT) symptoms in SARS-CoV-2 Omicron infected patients resulting from local transmission. Methods: A convenience sampling network survey was conducted among individuals infected with SARS-CoV-2 to examine the characteristics and progression of ENT symptoms associated with local transmission. The survey comprised 52 questions, and univariable and multivariable logistic regression analyses were employed to assess the rate, severity, and outcome of ENT symptoms across different genders and age groups. Results: Among the 1,366 individuals included in the investigation, a peak in new infections occurred on 20th December, and the majority (78.4%) were female. The most common symptoms reported were coughing (90.6%), nasal congestion (77.2%), and runny nose (74.3%). Otologic symptoms were predominantly represented by tinnitus (29.7%). Conclusion: The rate of specific symptoms showed a significant correlation with age and gender. It is crucial to provide timely medical intervention, especially for female patients. This study offers a comprehensive understanding of the symptom spectrum in individuals infected with the virus, providing valuable insights for the development of targeted symptom management strategies.

The Synergism of Human Lactobacillaceae and Inulin Decrease Hyperglycemia via Regulating the Composition of Gut Microbiota and Metabolic Profiles in db/db Mice.

This study aimed to evaluate the effects of Limosilactobacillus fermentum and Lactiplantibacillus plantarum isolated from human feces coordinating with inulin on the composition of gut microbiota and metabolic profiles in db/db mice. These supplements were administered to db/db mice for 12 weeks. The results showed that the Lactobacillaceae coordinating with inulin group (LI) exhibited lower fasting blood glucose levels than the model control group (MC). Additionally, LI was found to enhance colon tissue and increase the levels of short-chain fatty acids. 16S rRNA sequencing revealed that the abundance of Corynebacterium and Proteus, which were significantly increased in the MC group compared with NC group, were significantly decreased by the treatment of LI that also restored the key genera of the Lachnospiraceae_NK4A136_group, Lachnoclostridium, Ruminococcus_gnavus_group, Desulfovibrio, and Lachnospiraceae_UCG-006. Untargeted metabolomics analysis showed that lotaustralin, 5-hydroxyindoleacetic acid, and 13(S)-HpODE were increased while L-phenylalanine and L-tryptophan were decreased in the MC group compared with the NC group. However, the intervention of LI reversed the levels of these metabolites in the intestine. Correlation analysis revealed that Lachnoclostridium and Ruminococcus_gnavus_group were negatively correlated with 5-hydroxyindoleacetic acid and 13(S)-HpODE, but positively correlated with L-tryptophan. 13(S)-HpODE was involved in the "linoleic acid metabolism". L-tryptophan and 5-hydroxyindoleacetic acid were involved in "tryptophan metabolism" and "serotonergic synapse". These findings suggest that LI may alleviate type 2 diabetes symptoms by modulating the abundance of Ruminococcus_gnavus_group and Lachnoclostridium to regulate the pathways of "linoleic acid metabolism", "serotonergic synapse", and" tryptophan metabolism". Our results provide new insights into prevention and treatment of type 2 diabetes.

Screening of Potential Probiotic Lactobacillaceae and Their Improvement of Type 2 Diabetes Mellitus by Promoting PI3K/AKT Signaling Pathway in db/db Mice.

The study aimed to isolate Lactobacillaceae strains with in vitro hypoglycemic activity and probiotic properties and to determine their antidiabetic abilities in vivo. Lactiplantibacillus plantarum 22, L. plantarum 25, Limosilactobacillus fermentum 11, and L. fermentum 305 with high in vitro hypoglycemic activity were screened from 23 strains of Lactobacillaceae isolated from human feces and identified by 16S rDNA sequencing. The fasting blood glucose (FBG) of the mice was recorded weekly. After 12 weeks, liver, kidney, and pancreas tissues were stained with hematoxylin and eosin (H&E) to observe histomorphology; the inflammatory factors were assayed by Quantitative Real-time PCR; PI3K and AKT were measured by Western blot; the short-chain fatty acids (SCFAs) were determined by LC-MS/MS. Inhibitory activities of L. plantarum 22, L. plantarum 25, L. fermentum 11, and L. fermentum 305 against α-amylase were 62.29 ± 0.44%, 51.81 ± 3.65%, 58.40 ± 1.68%, and 57.48 ± 5.04%, respectively. Their inhibitory activities to α-glucosidase were 14.89 ± 0.38%, 15.32 ± 0.89%, 52.63 ± 3.07%, and 51.79 ± 1.13%, respectively. Their survival rate after simulated gastrointestinal test were 12.42 ± 2.84%, 9.10 ± 1.12%, 5.86 ± 0.52%, and 8.82 ± 2.50% and their adhesion rates to Caco-2 cell were 6.09 ± 0.39%, 6.37 ± 0.28%, 6.94 ± 0.27%, and 6.91 ± 0.11%, respectively. The orthogonal tests of bacterial powders of the four strains showed that the maximum inhibitory activities to α-amylase and α-glucosidase were 93.18 ± 1.19% and 75.33 ± 2.89%, respectively. The results showed that the mixture of Lactobacillaceae could lower FBG, reduce inflammation, and liver, kidney, and pancreas damage, promote PI3K/AKT signaling pathway, and increase the content of SCFAs. The combination of L. plantarum 22, L. plantarum 25, L. fermentum 11, and L. fermentum 305 can potentially improve type 2 diabetes mellitus (T2DM).

P2X7 receptor is required for the ototoxicity caused by aminoglycoside in developing cochlear hair cells.

Aminoglycoside antibiotics (AGAs) are widely used in life-threatening infections, but they accumulate in cochlear hair cells (HCs) and result in hearing loss. Increases in adenosine triphosphate (ATP) concentrations and P2X7 receptor expression were observed after neomycin treatment. Here, we demonstrated that P2X7 receptor, which is a non-selective cation channel that is activated by high ATP concentrations, may participate in the process through which AGAs enter hair cells. Using transgenic knockout mice, we found that P2X7 receptor deficiency protects HCs against neomycin-induced injury in vitro and in vivo. Subsequently, we used fluorescent gentamicin-Fluor 594 to study the uptake of AGAs and found fluorescence labeling in wild-type mice but not in P2rx7-/- mice in vitro. In addition, knocking-out P2rx7 did not significantly alter the HC count and auditory signal transduction, but it did inhibit mitochondria-dependent oxidative stress and apoptosis in the cochlea after neomycin exposure. We thus conclude that the P2X7 receptor may be linked to the entry of AGAs into HCs and is likely to be a therapeutic target for auditory HC protection.

Insomniacs show greater prefrontal activation during verbal fluency task compared to non-insomniacs: a functional near-infrared spectroscopy investigation of depression in patients.

BACKGROUND: Previous studies have shown that insomnia affects human prefrontal function and that there are specific patterns of brain activation to counteract sleep and improve cognition. However, the effects of insomnia on the prefrontal cortex of MDD (major depressive disorder) patients and the patterns of activation to counteract sleep in MDD patients remain unclear. The aim of this study is to examine this using fNIRS (functional near-infrared spectroscopy). METHODS: Eighty depressed patients and 44 healthy controls were recruited for this study. fNIRS was used to assess changes in the concentration of oxygenated hemoglobin ([oxy-Hb]) in the prefrontal cortex of all participants during the VFT (verbal fluency test) and to record the number of words created to assess cognitive ability. The Pittsburgh Sleep Quality Index was used to assess sleep quality, and the Hamilton Rating Scale for Depression (24-item) and Hamilton Rating Scale for Anxiety (14-item) were used to assess the severity of depression and anxiety. RESULTS: When comparing patients, the healthy control group had significantly higher [oxy-Hb] values in the bilateral prefrontal cortex during VFT than the MDD group. In the MDD group, the [oxy-Hb] values in all brain regions except the right DLPFC were significantly higher in the group with insomnia than in the group without insomnia, but their VFT performance was significantly lower than in the group without insomnia and the healthy group. PSQI scores were positively correlated with [oxy-Hb] values in some left-brain regions, whereas HAMD and HAMA scores were not correlated with [oxy-Hb] values. CONCLUSION: The PFC was significantly less active during VFT in those with MDD than in healthy controls. All brain regions, except the right DLPFC, were significantly more active in MDD patients with insomnia than in those without insomnia, suggesting that sleep quality needs to be an important indicator in fNIRS screening. In addition, there was a positive correlation between the severity of insomnia in the left VLPFC and the level of activation, suggesting a role for the left brain region in the neurophysiology of overcoming sleepiness in MDD patients. these findings may provide new ideas for the treatment of MDD patients in the future. TRIAL REGISTRATION: Our experiment was registered in the China Clinical Trial Registry (registration number ChiCTR2200065622) on November 10.( The first patient was recruited in 10/11/2022.).

Lactobacillaceae improve cognitive dysfunction via regulating gut microbiota and suppressing Aß deposits and neuroinflammation in APP/PS1 mice.

Alzheimer's disease (AD), the most prevalent neurodegenerative disease, has a significant relationship with alteration of the gut microbiota (GM), and the GM-gut-brain axis has been explored to find novel therapeutic approaches for AD. The present study aimed to evaluate the effect of human Lactobacillaceae (HLL) on cognitive function in APP/PS1 mice. The results showed that HLL treatment significantly improved the cognitive function of mice via MWM and NOR tests. Furthermore, the expression of Aß plaques, tau phosphorylation and neuroinflammation were markedly reduced in the hippocampus. Meanwhile, HLL treatment significantly increased the activity of GSH-PX and decreased the expression levels of IL-6 and MDA in the brain, and simultaneously increased the abundance of beneficial bacteria and restrained pathogenic bacteria in the intestine. Interestingly, significant correlations were observed between significant changes in abundance of GMs and AD-related markers. Collectively, these findings reveal that HLL is a promising therapeutic agent and potential probiotics, which might improve the cognitive function and AD pathologies.

Global competence of medical students: An assessment scale and preliminary investigation in China.

INTRODUCTION: The importance of global competence has been acknowledged in medical care as well as medical education. This study aims to develop a scale assessing the global competence of medical students, determine the factor structure and internal consistency of the scale and explore the underlying factors influencing the global competence of Chinese medical students in 8-year programs. METHODS: A questionnaire (Global Competence Assessment Scale for Medical Students, MS-GCAS) was developed, and a cross-sectional multicenter survey was conducted in 1062 medical students from 10 medical schools in China. Questionnaire data were analyzed using exploratory factor analysis and multiple linear regression. RESULTS: The exploratory factor analysis revealed a three-factor scale. The MS-GCAS has good internal consistency (Cronbach's alpha = 0.79 to 0.87). In the multivariate regression analyses, medical education stage (p<0.05), the frequency of communicating with foreigners (p<0.001), multilingual ability (p<0.05) and grade level (p<0.05) are associated with the MS-GCAS scores. DISCUSSION: The MS-GCAS has the potential to serve as a tool to measure the global competence of medical students. This three-factor scale can be used by medical education researches to improve future versions. Medical schools should conduct further educational reforms to promote students' global competence.

Spatial architecture of the cochlear immune microenvironment in noise-induced and age-related sensorineural hearing loss.

The cochlea encodes sound stimuli and transmits them to the central nervous system, and damage to sensory cells and synapses in the cochlea leads to hearing loss. The inner ear was previously considered to be an immune privileged organ to protect the auditory organ from reactions with the immune system. However, recent studies have revealed the presence of resident macrophages in the cochlea, especially in the spiral ligament, spiral ganglion, and stria vascularis. The tissue-resident macrophages are responsible for the detection, phagocytosis, and clearance of cellular debris and pathogens from the tissues, and they initiate inflammation and influence tissue repair by producing inflammatory cytokines and chemokines. Insult to the cochlea can activate the cochlear macrophages to initiate immune responses. In this review, we describe the distribution and functions of cochlear macrophages in noise-induced hearing impairment and age-related hearing disabilities. We also focus on potential therapeutic interventions concerning hearing loss by modulating local immune responses.

Efficacy of hearing aid treatment on sound perception and residual hearing preservation in patients with tinnitus and coexisting hearing loss: study protocol for a randomized controlled trial.

BACKGROUND: Chronic subjective tinnitus poses significant challenges in clinical practice, and it is usually associated with hearing impairment, particularly with high-frequency sensorineural hearing loss (SNHL). Patients suffering from tinnitus with SNHL experience one of the most severe sensory disabilities, and this has devastating effects on their quality of life. Nowadays, mild to moderate SNHL can be managed with a properly fitted hearing aid (HA) that provides sound amplification, and several studies suggest that HAs may also benefit those with tinnitus. However, inadequate attention has been paid by medical personnel to the impact of HA use in residual hearing protection for patients with tinnitus and coexisting SNHL, and existing evidence is still at a preliminary stage. This study aims to identify and evaluate the efficacy of the use of HAs in both sound perception and residual hearing preservation among patients with tinnitus and coexisting SNHL. METHODS AND DESIGN: The present study is a prospective, single-center, outcome assessor and data analyst-blinded, randomized, controlled trial. Eligible participants will be recruited and randomly allocated into the HA intervention group and the waiting list control group at a ratio of 1:1. The primary outcome is to evaluate the severity of tinnitus using the Tinnitus Handicap Inventory as a continuous variable at 6 months from randomization. Secondary outcome measures include changes in hearing status and mental states. The trial will last 6 months, with follow-up visits at 3 months and 6 months. DISCUSSION: This will be the first randomized, controlled trial to identify and evaluate HAs' efficacy on residual hearing preservation among tinnitus patients with coexisting high-frequency SNHL in China. We are aiming for novelty and generalizability, and strengths of this study are that it will examine the effectiveness of HA in patients with tinnitus and hearing impairment and will further explore the residual hearing protection provided by HA treatment in the tinnitus group. TRIAL REGISTRATION: ClinicalTrials.gov NCT05343026. Registered on April 25, 2022.

IL-17 is a Potential Therapeutic Target in a Rodent Model of Otitis Media with Effusion.

BACKGROUND: Otitis media with effusion (OME) is a non-suppurative inflammation of the middle ear that is characterized by middle ear effusion and hearing loss. However, the mechanisms of OME are not fully understood. The aim of this study was to determine the function and the mechanism of the IL-17 cytokine in the pathogenesis of OME and to investigate IL-17 as a potential strategy for the treatment of OME. METHODS: In this study, the OME rat model was induced by ovalbumin (OVA) as previously described. The severity of OME was determined with an oto-endoscope, by histochemical analysis, and by acoustic immittance. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of RNA-sequencing (RNA-seq) data was carried out to analyze the signaling pathways related to the pathogenesis of OME, which indicated that IL-17 is involved in OME. The anti-IL-17A monoclonal antibody was administrated by nasal drip to block IL-17 to treat OME in the rat model. The rats were finally injected intraperitoneally with the inhibitor of Notch signaling pathway to study the mechanisms of IL-17-induced inflammation. Serum and lavage fluid were collected for the detection of related cytokines, and middle ear tissue was collected for Western blot, quantitative real-time PCR (qRT-PCR), and immunohistochemical and immunofluorescence analysis. RESULTS: KEGG analysis of RNA-seq data suggested that the IL-17 signaling pathway might be involved in the onset of OME. IL-17 expression was confirmed to be increased in both the serum and the middle ear of the rat model. The monoclonal antibody against IL-17 neutralized IL-17, inhibited the inflammation in the middle ear, and reduced the overall severity of OME in vivo. Furthermore, the Notch signaling pathway was activated upon IL-17 upregulation in OME and was suppressed by IL-17 blockage. However, there was no change in IL-17 expression after Notch inhibitor treatment, which reduced the severity of OME in the rat middle ear. CONCLUSION: IL-17 plays a key role in the pathogenesis of the OVA-induced OME rat model. IL-17 induced inflammatory responses via the Notch signaling pathway and targeting IL-17 might be an effective approach for OME therapy.

Asiatic Acid Improves Extracellular Matrix Remodeling in Vocal Fold Scarring Via SMAD7 Activation.

OBJECTIVES/HYPOTHESIS: Vocal fold (VF) fibroblasts are the central target for developing new strategies for the treatment of VF scarring and fibrosis. Asiatic acid (AA) is a triterpenoid derivate with antifibrotic properties. However, the effect of AA in VF scarring is poorly understood. The objective of this study was to investigate the potential application of AA as a therapeutic treatment in VF scarring. STUDY DESIGN: Xxxxx. METHODS: The functional expression of SMAD7 was knocked down with recombinant adenoviruses and adeno-associated viruses carrying shRNAs in the in vitro and in vivo models, which were constructed to investigate AA's antifibrotic function. The expression of collagens and SMADs in cultured human and rabbit cell lines and animal models was evaluated with quantitative reverse transcription polymerase chain reaction and immunohistochemistry labeling, respectively. Cell migration capacity and contraction in VF fibroblast cell lines were also evaluated. RESULTS: AA downregulated the downstream fibrotic activation in a dose-dependent manner. Meanwhile, AA attenuated VF scarring/fibrosis by reducing collagen deposition. Furthermore, the antifibrotic effects of AA were associated with the upregulation of SMAD7. In contrast, knockdown of SMAD7 inhibited the effect of AA on transforming growth factor-beta-1 (TGF-ß1) stimulation, which suggests a central role for SMAD7 in AA-induced antifibrotic activities during VF fibrosis. CONCLUSION: We concluded that AA, which is a novel therapeutic candidate for preventing VF scarring/fibrosis, might exert its antifibrotic effect via the TGF-ß1/SMAD signaling pathway. LEVEL OF EVIDENCE: NA Laryngoscope, 132:1237-1244, 2022.

Observing spontaneous, accelerated substrate binding in molecular dynamics simulations of glutamate transporters.

Glutamate transporters are essential for removing the neurotransmitter glutamate from the synaptic cleft. Glutamate transport across the membrane is associated with elevator-like structural changes of the transport domain. These structural changes require initial binding of the organic substrate to the transporter. Studying the binding pathway of ligands to their protein binding sites using molecular dynamics (MD) simulations requires micro-second level simulation times. Here, we used three methods to accelerate aspartate binding to the glutamate transporter homologue Gltph and to investigate the binding pathway. 1) Two methods using user-defined forces to prevent the substrate from diffusing too far from the binding site. 2) Conventional MD simulations using very high substrate concentrations in the 0.1 M range. The final, substrate bound states from these methods are comparable to the binding pose observed in crystallographic studies, although they show more flexibility in the side chain carboxylate function. We also captured an intermediate on the binding pathway, where conserved residues D390 and D394 stabilize the aspartate molecule. Finally, we investigated glutamate binding to the mammalian glutamate transporter, excitatory amino acid transporter 1 (EAAT1), for which a crystal structure is known, but not in the glutamate-bound state. Overall, the results obtained in this study reveal new insights into the pathway of substrate binding to glutamate transporters, highlighting intermediates on the binding pathway and flexible conformational states of the side chain, which most likely become locked in once the hairpin loop 2 closes to occlude the substrate.

Sirt-1 Regulates Physiological Process and Exerts Protective Effects against Oxidative Stress.

BACKGROUND: Recent studies suggest a correlation between the reduced Sirt-1 expression with Alzheimer's diseases (AD) and depression, respectively, suggesting a possible pathogenic role of the altered Sirt-1 expression in neuronal degenerative diseases, such as AD and depression. However, the molecular mechanisms underlying how Sirt-1 reduction impairs neuronal functions remain unknown. METHODS: We used the SK-N-SH neuroblastoma cells to study the role of Sirt-1 expression on physiological roles in neuronal cells. Gain of Sirt-1 was achieved by transiently transfecting Sirt-1 expression plasmid. Sirt-1-specific shRNA was used to elucidate the role of Sirt-1 loss of function. CCK-8 (Cell Counting Kit-8) assay and flow cytometry were used to evaluate cell proliferation. Semiquantitative western blotting was used to detect relative protein levels. A further luciferase reporter gene assay was employed to examine the effect of Sirt-1 expression on the transcriptional activity of p53. RT-qPCR was used to determine the mRNA levels of p21, Bax, and Bcl-2, which were the downstream target genes of p53. RESULTS: Sirt-1 suppressed the p53 downstream gene p21 transcription, while shRNA-mediated Sirt-1 knockdown resulted in a significant increase in p21 expression, implying a possibility that Sirt-1 promotes neuron proliferation through suppressing p53 transcriptional activity. The mRNA and protein levels of p53 were not affected by the altered Sirt-1 expression, suggesting that Sirt-1 regulates the transcriptional regulatory activity of p53 rather than p53 expression. Indeed, we further confirmed that Sirt-1 appeared to inhibit p53 transcriptional activity by attenuating its acetylation and resulted in a decrease of p53's binding to the p21 promoter. Overexpressed Sirt-1 scavenged reactive oxygen species (ROS) production in SK-N-SH with H2O2. Knockdown of Sirt-1 presented opposite effect; the addition of EX527 (Sirt-1 inhibitor) increased ROS accumulation. CONCLUSIONS: Oxidative stress induces Sirt-1 in neuron cells, and Sirt-1 promotes proliferation in SK-N-SH cells, which protects them from oxidative stress-induced cell death, potentially via suppressing the transcriptional activity of p53. These results provide a molecular explanation underlying how the reduced Sirt-1 potentially causes the AD and depression-related diseases, supporting the idea that Sirt-1 can possibly be used as a diagnostic biomarker and/or therapeutic drug target for the AD and depression-related diseases.

Sirt1 gene confers Adriamycin resistance in DLBCL via activating the PCG-1α mitochondrial metabolic pathway.

Sirt1 is closely related to cells aging, and Sirt1 also plays an important role in diffuse large B-cell lymphoma (DLBCL). However, its mechanism remains unclear. Therefore, we investigated the mechanism of Sirt1 mediated drug-resistance in DLBCL, while the recombinant lentivirus was used to regulate Sirt1 gene expression in DLBCL cell lines. Subsequently, the effect of Sirt1 on DLBCL resistance to Adriamycin was analyzed in vitro. The results show that Sirt1 overexpression confers Adriamycin resistance in DLBCL cell lines. However, inhibition of Sirt1 sensitized DLBCL cell lines to Adriamycin cytotoxicity. Additionally, tumor-bearing mice were used to verify that Sirt1 overexpression confers Adriamycin resistance in vivo after chemotherapy. In addition, we used second-generation sequencing technology and bioinformatics analysis to find that Sirt1 mediated drug-resistance is related to the Peroxisome proliferator-activated receptor (PPAR) signaling pathway, especially to PGC-1α. Interestingly, the mitochondrial energy inhibitor, tigecycline, combined with Adriamycin reversed the cellular resistance caused by Sirt1 overexpression in vivo. Moreover, western blotting and CO-IP assay reconfirmed that Sirt1-mediated drug-resistance is associated with the increased expression of PGC1-α, which induce mitochondrial biogenesis. In summary, this study confirms that Sirt1 is a potential target for DLBCL treatment.

Estrogen induces IDO expression via TGF­ß in chorionic villi and decidua during early stages of pregnancy.

Indoleamine 2,3­dioxygenase (IDO) is one of the most important proteins protecting the embryos from the mother's immune system during pregnancy; however, little is known about the regulation of expression of this protein at the maternal­fetal interface. In the current study, chorionic villi and decidua were collected from women at early stages of pregnancy. Samples of chorionic villi and decidua were cultured in medium containing different concentrations of 17ß­estradiol and estriol respectively, with or without fulvestrant. Western blot analysis and/or immunofluorescent staining were used to detect the expression of transforming growth factor ß (TGF­ß) and IDO in chorionic villi and decidua tissues. Both TGF­ß and IDO were expressed in chorionic villi and decidua. The expression levels of these two proteins increased the most in samples of chorionic villi and decidua cultured in medium containing 17ß­estradiol at the concentration of 10 ng/ml, or estriol at the concentration of 1 µg/ml. This increase could be reversed when fulvestrant was added in the medium at the concentration of 10 µg/ml. IDO expression increased in a dose­dependent manner in tissue samples cultured in medium containing TGF­ß. The results of the current study revealed that administration of estrogen at doses similar to those observed in healthy pregnant women may upregulate the expression of IDO by TGF­ß, suggesting that estrogen may prevent allogeneic fetal rejection and may be used as an immunomodulator.

Annular Surface Micromachining of Titanium Tubes Using a Magnetorheological Polishing Technique.

In this study, a novel magnetorheological (MR) polishing device under a compound magnetic field is designed to achieve microlevel polishing of the titanium tubes. The polishing process is realized by combining the rotation motion of the tube and the reciprocating linear motion of the polishing head. Two types of excitation equipment for generating an appropriate compound magnetic field are outlined. A series of experiments are conducted to systematically investigate the effect of compound magnetic field strength, rotation speed, and type and concentration of abrasive particles on the polishing performance delivered by the designed device. The experiments were carried out through controlling variables. Before and after the experiment, the surface roughness in the polished area of the workpiece is measured, and the influence of the independent variable on the polishing effect is judged by a changing rule of surface roughness so as to obtain a better parameter about compound magnetic field strength, concentration of abrasive particles, etc. It is shown from experimental results that diamond abrasive particles are appropriate for fine finishing the internal surface of the titanium-alloy tube. It is also identified that the polishing performance is excellent at high magnetic field strength, fast rotation speed, and high abrasive-particle concentration.

Deletion of HO-1 blocks development of B lymphocytes in mice.

B lymphocytes, a key cluster of cells composing the immune system, can protect against abnormal biological factors. Heme oxygenase-1 (HO-1) plays important roles in cell proliferation and immune regulation, but its effects on the development and growth of B lymphocytes are still unknown. Herein, the count of B lymphocytes in HO-1 gene knockout (HO-1+/-) mice was significantly lower than that of the HO-1 gene wild-type (HO-1WT) mice. Meanwhile, the cell count of HO-1+/- mice did not recover after irradiation for one week, due to the G0/G1 phase arrest of Pro-B cells and the augmented apoptosis of Pre-B cells. Up-regulation of HO-1 by lentivirus attenuated the Pro-B cell cycle arrest and Pre-B cell apoptosis. To understand the molecular mechanism by which HO-1 knockout blocked B lymphocyte development, protein-to-protein interaction network and Western blot were used. The PI3K/AKT signaling pathway mediated the regulatory effects of HO-1 on B lymphocytes. In conclusion, HO-1 is a crucial transcriptional repressor for B cell development.

Entinostat combined with Fludarabine synergistically enhances the induction of apoptosis in TP53 mutated CLL cells via the HDAC1/HO-1 pathway.

TP53 mutation is an indicator of poor prognostic in chronic lymphocytic leukemia (CLL). Worse still, CLL patients with TP53 mutation are associated with poor efficacy to current chemotherapeutic, such as Fludarabine. Here, we confirmed that high expression of HDAC1 in CLL patients with TP53 mutation, which is closely related to poor prognosis and drug-resistance. Subsequently, we demonstrated Entinostat (HDAC1 inhibitor) combination with Fludarabine significantly induced apoptosis in TP53 mutations CLL cells. Its mechanism was associated with up-regulation of the pro-apoptotic protein Bax and the down-regulation of HDAC1, HO-1 and BCL-2 proteins. More importantly, we also confirmed that upregulation of HDAC1 could resistant Entinostat-induced apoptosis in TP53 mutations CLL cells by activating the HDAC1/P38/HO-1 pathway. In vivo, we found that Entinostat combination with Fludarabine significantly induced tumor cells apoptosis and prolong survival time in xenograft mouse model. Finally, combining vitro and vivo experiments, we presented the first demonstration that Entinostat combination with Fludarabine had a synergistic effect on the induction of apoptosis in TP53 mutations CLL cells. In conclusion, we provide valuable pre-clinical experimental evidence for the treatment of CLL patients with poor prognosis, especially for TP53 mutations.