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1.
Nat Microbiol ; 2024 May 28.
Article in English | MEDLINE | ID: mdl-38806671

ABSTRACT

Adaptation to hypoxia is a major challenge for the survival of Mycobacterium tuberculosis (Mtb) in vivo. Interferon (IFN)-γ-producing CD8+ T cells contribute to control of Mtb infection, in part by promoting antimicrobial activities of macrophages. Whether Mtb counters these responses, particularly during hypoxic conditions, remains unknown. Using metabolomic, proteomic and genetic approaches, here we show that Mtb induced Rv0884c (SerC), an Mtb phosphoserine aminotransferase, to produce D-serine. This activity increased Mtb pathogenesis in mice but did not directly affect intramacrophage Mtb survival. Instead, D-serine inhibited IFN-γ production by CD8+ T cells, which indirectly reduced the ability of macrophages to restrict Mtb upon co-culture. Mechanistically, D-serine interacted with WDR24 and inhibited mTORC1 activation in CD8+ T cells. This decreased T-bet expression and reduced IFN-γ production by CD8+ T cells. Our findings suggest an Mtb evasion mechanism where pathogen metabolic adaptation to hypoxia leads to amino acid-dependent suppression of adaptive anti-TB immunity.

2.
Nat Commun ; 15(1): 4216, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38760394

ABSTRACT

Antimicrobial peptides (AMPs), ancient scavengers of bacteria, are very poorly induced in macrophages infected by Mycobacterium tuberculosis (M. tuberculosis), but the underlying mechanism remains unknown. Here, we report that L-alanine interacts with PRSS1 and unfreezes the inhibitory effect of PRSS1 on the activation of NF-κB pathway to induce the expression of AMPs, but mycobacterial alanine dehydrogenase (Ald) Rv2780 hydrolyzes L-alanine and reduces the level of L-alanine in macrophages, thereby suppressing the expression of AMPs to facilitate survival of mycobacteria. Mechanistically, PRSS1 associates with TAK1 and disruptes the formation of TAK1/TAB1 complex to inhibit TAK1-mediated activation of NF-κB pathway, but interaction of L-alanine with PRSS1, disables PRSS1-mediated impairment on TAK1/TAB1 complex formation, thereby triggering the activation of NF-κB pathway to induce expression of AMPs. Moreover, deletion of antimicrobial peptide gene ß-defensin 4 (Defb4) impairs the virulence by Rv2780 during infection in mice. Both L-alanine and the Rv2780 inhibitor, GWP-042, exhibits excellent inhibitory activity against M. tuberculosis infection in vivo. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses its own alanine dehydrogenase to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.


Subject(s)
Alanine , Antimicrobial Peptides , Macrophages , Mycobacterium tuberculosis , NF-kappa B , Tuberculosis , Mycobacterium tuberculosis/pathogenicity , Mycobacterium tuberculosis/metabolism , Animals , Mice , NF-kappa B/metabolism , Humans , Macrophages/microbiology , Macrophages/metabolism , Macrophages/immunology , Alanine/metabolism , Antimicrobial Peptides/metabolism , Antimicrobial Peptides/genetics , Tuberculosis/microbiology , Tuberculosis/immunology , Alanine Dehydrogenase/metabolism , Alanine Dehydrogenase/genetics , MAP Kinase Kinase Kinases/metabolism , MAP Kinase Kinase Kinases/genetics , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Signal Transduction , Mice, Inbred C57BL , RAW 264.7 Cells , Female
3.
Cell Discov ; 10(1): 36, 2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38548762

ABSTRACT

Internal N6-methyladenosine (m6A) modifications are among the most abundant modifications of messenger RNA, playing a critical role in diverse biological and pathological processes. However, the functional role and regulatory mechanism of m6A modifications in the immune response to Mycobacterium tuberculosis infection remains unknown. Here, we report that methyltransferase-like 14 (METTL14)-dependent m6A methylation of NAPDH oxidase 2 (Nox2) mRNA was crucial for the host immune defense against M. tuberculosis infection and that M. tuberculosis-secreted antigen EsxB (Rv3874) inhibited METTL14-dependent m6A methylation of Nox2 mRNA. Mechanistically, EsxB interacted with p38 MAP kinase and disrupted the association of TAB1 with p38, thus inhibiting the TAB1-mediated autophosphorylation of p38. Interaction of EsxB with p38 also impeded the binding of p38 with METTL14, thereby inhibiting the p38-mediated phosphorylation of METTL14 at Thr72. Inhibition of p38 by EsxB restrained liquid-liquid phase separation (LLPS) of METTL14 and its subsequent interaction with METTL3, preventing the m6A modification of Nox2 mRNA and its association with the m6A-binding protein IGF2BP1 to destabilize Nox2 mRNA, reduce ROS levels, and increase intracellular survival of M. tuberculosis. Moreover, deletion or mutation of the phosphorylation site on METTL14 impaired the inhibition of ROS level by EsxB and increased bacterial burden or histological damage in the lungs during infection in mice. These findings identify a previously unknown mechanism that M. tuberculosis employs to suppress host immunity, providing insights that may empower the development of effective immunomodulators that target M. tuberculosis.

4.
Cell Host Microbe ; 31(11): 1820-1836.e10, 2023 11 08.
Article in English | MEDLINE | ID: mdl-37848028

ABSTRACT

Mycobacterium tuberculosis (Mtb) triggers distinct changes in macrophages, resulting in the formation of lipid droplets that serve as a nutrient source. We discover that Mtb promotes lipid droplets by inhibiting DNA repair responses, resulting in the activation of the type-I IFN pathway and scavenger receptor-A1 (SR-A1)-mediated lipid droplet formation. Bacterial urease C (UreC, Rv1850) inhibits host DNA repair by interacting with RuvB-like protein 2 (RUVBL2) and impeding the formation of the RUVBL1-RUVBL2-RAD51 DNA repair complex. The suppression of this repair pathway increases the abundance of micronuclei that trigger the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and subsequent interferon-ß (IFN-ß) production. UreC-mediated activation of the IFN-ß pathway upregulates the expression of SR-A1 to form lipid droplets that facilitate Mtb replication. UreC inhibition via a urease inhibitor impaired Mtb growth within macrophages and in vivo. Thus, our findings identify mechanisms by which Mtb triggers a cascade of cellular events that establish a nutrient-rich replicative niche.


Subject(s)
Interferon Type I , Mycobacterium tuberculosis , Mycobacterium tuberculosis/genetics , Urease/metabolism , Interferon-beta/metabolism , Interferon Type I/metabolism , Macrophages/metabolism , Nucleotidyltransferases/genetics
5.
Int Immunopharmacol ; 124(Pt B): 111058, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37844466

ABSTRACT

Mycobacterium tuberculosis (M.tb), the most successful pathogen responsible for approximately 1.6 million deaths in 2021, employs various strategies to evade host antibacterial defenses, including mechanisms to counteract nitric oxide (NO) and certain cytokines. While Amyloid ß (A4) precursor-like protein 2 (Aplp2) has been implicated in various physiological and pathological processes, its role in tuberculosis (TB) pathogenesis remains largely uncharted. This study unveils a significant reduction in Aplp2 levels in TB patients, M.tb-infected macrophages, and mice. Intriguingly, Aplp2 mutation or knockdown results in diminished macrophage-mediated killing of M.tb, accompanied by decreased inducible nitric oxide synthase (iNOS) expression and reduced cytokine production, notably interleukin-1ß (Il-1ß). Notably, Aplp2 mutant mice exhibit heightened susceptibility to mycobacterial infection, evident through aggravated histopathological damage and increased lung bacterial loads, in contrast to Mycobacterium bovis BCG-infected wild-type (WT) mice. Mechanistically, the cleaved product of APLP2, AICD2, generated by γ-secretase, translocates to the nucleus, where it interacts with p65, culminating in enhanced the nuclear factor κB (NF-κB) transcriptional activity. This interaction triggers the upregulation of Il-1ß and iNOS expression. Collectively, our findings illuminate Aplp2's pivotal role in safeguarding against mycobacterial infections by promoting M.tb clearance through NO- or IL-1ß-mediated bactericidal effects. Therefore, we unveil a novel immune evasion strategy employed by M.tb, which could potentially serve as a target for innovative TB interventions.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Humans , Animals , Mice , Amyloid beta-Peptides/metabolism , Macrophages , NF-kappa B/metabolism , Nerve Tissue Proteins/metabolism , Amyloid beta-Protein Precursor/metabolism
6.
Front Med (Lausanne) ; 10: 1141949, 2023.
Article in English | MEDLINE | ID: mdl-37351072

ABSTRACT

Background: Anemia leads to a lower cure rate and poor prognosis in tuberculosis patients. Effective predictors for the prognosis of tuberculosis with anemia (A-TB) are urgently needed. Monocyte has been proven to be a prognostic biomarker of many lung diseases. Whether monocyte that the predominant innate immune cell as early defense against tuberculosis can predict A-TB is not known. Methods: Data for A-TB patients with initial treatment in Shanghai Pulmonary Hospital were retrospectively collected and analyzed. Logistics regression analysis was used to study the correlation between peripheral blood cells and treatment outcomes. The receiver operating characteristic (ROC) curve was used to determine the cut-off value. We estimated a 12-month prognosis using Kaplan-Meier techniques. The Cox proportional hazards model was used for the univariate and multivariate analyses to analyze the predictors of poor prognosis of A-TB. Results: Of 181 patients analyzed, 94 were cured and 87 non-cured. Logistic regression analysis identified monocyte as an independent immune-related risk factor for the prognosis of A-TB (OR: 7.881, 95% CI: 1.675-37.075, P = 0.009). The ROC curve analysis proved that the most discriminative cut-off value of monocyte was 0.535 × 10^9/L. K-M analysis demonstrated that the cumulative cure rates of A-TB were significantly higher in A-TB with monocyte < 0.535 × 10^9/L (69.62%) than that in those with monocyte ≥ 0.535 × 10^9/L (38.24%) (Log-rank, χ2 = 16.530, P < 0.0001). On univariate and multivariable analysis, monocyte was an independent predictor of poor prognosis in A-TB. Similarly, monocyte was also an independent predictor of poor pulmonary cavity closure in A-TB (HR: 3.614, 95% CI: 1.335-9.787, P = 0.011). Conclusion: In A-TB patients, elevated monocyte was associated with poor prognosis and poor cavity pulmonary closure. Monocyte may provide a simple and inexpensive prognostic biomarker in A-TB.

7.
Pharmacogenet Genomics ; 33(5): 101-110, 2023 07 01.
Article in English | MEDLINE | ID: mdl-37261937

ABSTRACT

BACKGROUND: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by deficits in social communication and restrictive behaviors. Mouse nerve growth factor (mNGF), a neurotrophic factor, is critical for neuronal growth and survival, and the mNGF treatment is considered a promising therapy for neurodegeneration. In light of this, we aimed to evaluate the effect of mNGF on neurological function in ASD. METHODS: An ASD rat model was established by intraperitoneal injection of valproic acid (VPA). Social behavior, learning, and memory of the rats were measured. TdT-mediated dUTP Nick-end labeling and Nissl assays were performed to detect neuronal apoptosis and survival in the hippocampus and prefrontal cortex. Apoptosis-related proteins and oxidative stress markers were detected. RESULTS: mNGF improved locomotor activity, exploratory behavior, social interaction, and spatial learning and memory in VPA-induced ASD rats. In the hippocampus and prefrontal cortex, mNGF suppressed neuronal apoptosis, increased the number of neurons, superoxide dismutase, and glutathione levels, and decreased reactive oxygen species, nitric oxide, TNF-α, and IL-1ß levels compared with the VPA group. In addition, mNGF increased the levels of Bcl-2, p-phosphoinositide-3-kinase (PI3K), and p-serine/threonine kinase (Akt), and decreased the levels of Bax and cleaved caspase-3, while the PI3K inhibitor LY294002 reversed these effects. CONCLUSION: These data suggest that mNGF suppressed neuronal apoptosis and ameliorated the abnormal behaviors in VPA-induced ASD rats, in part, by activating the PI3K/Akt signaling pathway.


Subject(s)
Autism Spectrum Disorder , Valproic Acid , Rats , Animals , Mice , Humans , Valproic Acid/adverse effects , Autism Spectrum Disorder/chemically induced , Autism Spectrum Disorder/drug therapy , Protein Serine-Threonine Kinases/adverse effects , Protein Serine-Threonine Kinases/metabolism , Phosphatidylinositol 3-Kinase/metabolism , Phosphatidylinositol 3-Kinase/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/pharmacology , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/pharmacology , Signal Transduction , Apoptosis , Phosphatidylinositols/adverse effects , Serine/adverse effects , Disease Models, Animal
8.
J Mol Neurosci ; 73(4-5): 287-296, 2023 May.
Article in English | MEDLINE | ID: mdl-37084025

ABSTRACT

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that cannot be cured. The ASD rat model was developed in this study to demonstrate the role and mechanism of ganglioside GM1 (GM1). Rats were given valproic acid (VPA) to create the ASD rat model. The rats' behaviors were assessed using the Y-maze test, open-field test, three-chamber social interaction test, and Morris water maze test. Relative levels of glutathione (GSH), malondialdehyde (MDA), catalase (CAT), reactive oxygen species (ROS), and superoxide dismutase (SOD) were quantitated using relative kits. Nissl, TUNEL, immunofluorescent, and immunohistochemistry staining techniques were used. GM1 treatment improved the ASD model rats' behavior disorders, including locomotor activity and exploratory behavior, social interaction, learning and memory capacity, and repetitive behavior. Following GM1 injection, striatal neurons grew and apoptosis decreased. GM1 reduced the excessively elevated α-Syn in ASD by encouraging autophagy. The behavior disorder of ASD model rats was exacerbated by autophagy inhibition, which also increased α-Syn levels. By increasing autophagy, GM1 reduced α-Syn levels and, ultimately, improved behavioral abnormalities in ASD model rats.


Subject(s)
Autism Spectrum Disorder , Prenatal Exposure Delayed Effects , Rats , Animals , Female , Humans , Autism Spectrum Disorder/drug therapy , G(M1) Ganglioside/pharmacology , G(M1) Ganglioside/therapeutic use , Social Behavior , Valproic Acid/pharmacology , Maze Learning , Autophagy , Disease Models, Animal
9.
Front Immunol ; 14: 1081483, 2023.
Article in English | MEDLINE | ID: mdl-36817473

ABSTRACT

Background: Tuberculosis (TB) is a serious public health problem to human health, but the pathogenesis of TB remains elusive. Methods: To identify novel candidate genes associated with TB susceptibility, we performed a population-based case control study to genotype 41SNPs spanning 21 genes in 435 pulmonary TB patients and 375 health donors from China. Results: We found Notch4 gene rs206018 and rs422951 polymorphisms were associated with susceptibility to pulmonary tuberculosis. The association was validated in another independent cohort including 790 TB patients and 1,190 healthy controls. Moreover, we identified that the rs206018 C allele was associated with higher level of Notch4 in PBMCs from pulmonary TB patients. Furthermore, Notch4 expression increased in TB patients and higher Notch4 expression correlated with the severer pulmonary TB. Finally, we explored the origin and signaling pathways involved in the regulation of Notch4 expression in response to Mycobacterium tuberculosis (Mtb) infection. We determine that Mtb induced Notch4 and its ligand Jagged1expression in macrophages, and Notch4 through TLR2/P38 signaling pathway and Jagged1 through TLR2/ERK signaling pathway. Conclusion: Our work further strengthens that Notch4 underlay an increased risk of TB in humans and is involved in the occurrence and development of TB, which could serve as a novel target for the host-targeted therapy of TB.


Subject(s)
Tuberculosis, Pulmonary , Tuberculosis , Humans , Toll-Like Receptor 2/genetics , Case-Control Studies , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Tuberculosis, Pulmonary/microbiology , Tuberculosis/genetics , Gene Expression , Receptor, Notch4/genetics
10.
Ann Pharmacother ; 57(7): 813-821, 2023 Jul.
Article in English | MEDLINE | ID: mdl-36254661

ABSTRACT

OBJECTIVE: To investigate the impact of prenatal and early childhood antimicrobial use on autism spectrum disorders (ASD). DATA SOURCES: We searched PubMed and Embase databases for relevant studies from inception to August 2022. STUDY SELECTION AND DATA EXTRACTION: Peer-reviewed, observational studies were all acceptable. Raw data were extracted into a predefined worksheet and quality analysis was performed using the Newcastle-Ottawa Scale. DATA SYNTHESIS: Nineteen studies were identified in the meta-analysis. Prenatal antimicrobial exposure was not associated with ASD (P = 0.06 > 0.05), whereas early childhood antimicrobial exposure was associated with an increased odds ratio of ASD (OR = 1.17, 95% CI = [1.08-1.27], P value < 0.001). The sibling-matched analysis, with a very limited sample size, suggested that neither prenatal (P = 0.47 > 0.05) nor early childhood (P = 0.13 > 0.05) antimicrobial exposure was associated with ASD. Medical professionals may need to take the possible association into consideration when prescribing an antimicrobial in children. CONCLUSIONS: Early childhood antimicrobial exposure could increase the incidence of ASD. In future studies, it would be necessary to control for confounding factors, such as genetic factors, parenteral age at birth, or low birthweight, to further validate the association.


Subject(s)
Anti-Infective Agents , Autism Spectrum Disorder , Prenatal Exposure Delayed Effects , Child , Pregnancy , Female , Infant, Newborn , Humans , Child, Preschool , Autism Spectrum Disorder/epidemiology , Prenatal Exposure Delayed Effects/chemically induced , Prenatal Exposure Delayed Effects/epidemiology , Anti-Infective Agents/adverse effects , Odds Ratio , Vitamins
11.
Anal Chim Acta ; 1227: 340269, 2022 Sep 22.
Article in English | MEDLINE | ID: mdl-36089308

ABSTRACT

A composite matrix of sodium alginate (SA) and COF (Tp-DHBD) was designed and prepared for the detection of quaternary ammonium salts (QAs) containing heteroatoms. SA@Tp-DHBD self-assembled by the hydrogen bonding interaction between SA and COF has abundant hydroxyl and carboxylate anion sites, which makes for the excellent enrichment of the QAs through multiple interactions. Besides, the abundant hydroxyl groups can enhance laser absorption and energy transfer to achieve sensitive detection. The introduction of hydrophilic SA greatly promotes the dispersion of COFs to obtain good detection repeatability. Under the optimized experimental conditions, SA@Tp-DHBD was added to the solution of analytes and vortexed evenly, then directly analyzed by MALDI-TOF-MS. The detection limit of choline chloride, chlormequat chloride, and mepiquat chloride is 0.001 mg L-1; the detection limit of acetylcholine is 0.005 mg L-1. The relative standard deviations of target-target and sample-sample are below 6.0% and 7.0%, respectively. Moreover, the satisfactory recoveries in complex lake water and fruits meet the needs of practical applications. Comparative experiments were performed with the reported representative matrices, including ZIF-8 (MOF), TpBD (COF), UiO@TapbTp (MOF@COF), and α-cyano-4-hydroxycinnamic acid (organic matrix, CHCA). SA@Tp-DHBD exhibits the best matrix performance for QAs.


Subject(s)
Metal-Organic Frameworks , Fruit , Quaternary Ammonium Compounds , Salts , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Water
12.
Microbiol Spectr ; 10(4): e0260221, 2022 08 31.
Article in English | MEDLINE | ID: mdl-35699468

ABSTRACT

Sputum smear microscopy for tuberculosis diagnosis has stood the test of time. However, due to its low sensitivity, the positive detection rate for tuberculosis in clinical specimens is not high. To improve the sensitivity of microscopic observation in Mycobacterium tuberculosis (MTB) detection, we developed the MTB-specific aptamer MA1. To further improve the binding reactivity of MA1 with MTB, we constructed a new derivative aptamer with a pocket-stem-loop-structure, MA1-39, and identified it to have high binding reactivity with the MTB reference strain. We developed an aptamer fluorescence microscopy test for MTB based on MA1-39 and evaluated its feasibility for diagnosing pulmonary tuberculosis. Among 56 tested strains, MA1-39 was proven to effectively discriminate MTB from the control strains, including 12 non-tuberculosis mycobacterial (NTM) reference strains, 6 NTM isolates, and 7 other bacteria. Next, this approach was applied to 169 clinical sputum samples from suspected tuberculosis patients and non-tuberculosis controls. Molecular tests together with both clinical and bacteriological identification were used as a protocol to evaluate the efficacy of aptamer detection. Compared with the traditional acid-fast staining light microscope, the aptamer fluorescence microscope showed a higher detection rate for MTB in clinical specimens (48.8% versus 32.6%), and the specificities of the two techniques had almost no significant difference (90.4% versus 94%). In addition, aptamer fluorescence microscopy showed the same positive predictive value (PPV) as staining (84% versus 84.9%), but a higher negative predictive value (NPV; 63% versus 57.3%). In conclusion, the newly established aptamer fluorescence microscopy approach is likely to be a feasible method for microbiological diagnosis of tuberculosis. IMPORTANCE We established an aptamer fluorescence microscopy approach for rapid detection of MTB in clinical sputum samples. The use of aptamer probes was proven to significantly increase the sensitivity of sputum smear microscopy. In resource-limited countries, microscopy is currently a fast, simple, and very common test method in many laboratories, and it will remain the primary means of microbiological diagnosis of tuberculosis in the foreseeable future. Improving detection techniques can further enhance the clinical application value of this ancient diagnostic method. Since aptamer fluorescence microscopy can provide rapid and sensitive results, it may be a feasible and useful method in resource-limited settings.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis, Pulmonary , Tuberculosis , Humans , Microscopy, Fluorescence , Nontuberculous Mycobacteria , Sensitivity and Specificity , Sputum , Tuberculosis/diagnosis , Tuberculosis, Pulmonary/diagnosis , Tuberculosis, Pulmonary/microbiology
13.
Physiol Genomics ; 54(9): 325-336, 2022 09 01.
Article in English | MEDLINE | ID: mdl-35723222

ABSTRACT

Troxerutin is known for its anti-inflammatory and antioxidative effects in nerve impairment. The purpose of this study is to investigate the effect of troxerutin and cerebroprotein hydrolysate injections (TCHis) on prenatal valproic acid (VPA)-exposed rats. The VPA was administered to pregnant rats on gestational day 12.5 to induce a model of autism. The offspring were given the treatment of TCHis on postnatal day (PND) 21-50. On PND 43-50, the behavioral analysis of offspring was performed after the treatment of TCHis for 1 h. On PND 50, the offspring were harvested and the brains were collected. The hippocampus and prefrontal cortex were isolated for relevant biochemical detections. The administration of TCHis increased pain sensitivity and improved abnormal social behaviors in prenatal VPA-exposed rats. Prenatal exposure of VPA induced neuronal loss and apoptosis, enhanced reactive oxygen species (ROS) production, and promoted oxidative stress in hippocampus and prefrontal cortex, whereas these effects were reversed by the postnatal treatment of TCHis. In addition, postnatal administration of TCHis ameliorated mitochondrial function in hippocampus and prefrontal cortex of prenatal VPA-exposed rats. This study concluded that postnatal treatment of TCHis reduced oxidative stress and ameliorated abnormal behavior in a prenatal VPA-induced rat model of autism.


Subject(s)
Autistic Disorder , Prenatal Exposure Delayed Effects , Animals , Autistic Disorder/chemically induced , Autistic Disorder/drug therapy , Behavior, Animal , Disease Models, Animal , Female , Humans , Hydroxyethylrutoside/analogs & derivatives , Oxidative Stress , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Rats , Rats, Wistar , Social Behavior , Valproic Acid/pharmacology
14.
Gene ; 828: 146440, 2022 Jun 20.
Article in English | MEDLINE | ID: mdl-35339642

ABSTRACT

OBJECTIVE: Emerging evidence suggests that acupuncture plays a neuroprotective role in autism. This study aimed to explore the effect of electroacupuncture at Zusanli (ST36) on autistic-like behaviors and the underlying mechanism. METHOD: Pregnant rats were administered with valproic acid (VPA) on gestational day 12.5 to induce an autism spectrum disorder (ASD) model. The pups were given electroacupuncture at ST36 daily from postnatal day (PND) 28-48. On PND28, the adenoviral vector containing small interfering RNA Nrf2 (Ad-siRNA-Nrf2) was injected into the prefrontal cortex of rats. The behavioral analysis was performed on PND 44-48. On PND48, the animals were euthanized and the brains were collected for further detection. Nissl staining was performed to detect neuronal viability. The biochemical markers of oxidative stress were subsequently measured. RESULT: Electroacupuncture at ST36 ameliorated the locomotor activity, social behavior, spatial learning and memory and repetitive behavior compared with ASD rats. It was notable that the electroacupuncture decreased oxidative stress markers in the tissues of prefrontal cortex, enhanced translocation of nuclear factor erythroid2-related factor2 (Nrf2) from cytoplasm to nucleus, and up-regulated the levels of NADP(H) quinone oxidoreductase (NQO1) and heme oxygenase (HO-1). However, these effects induced by electroacupuncture at ST36 were abolished after injection of Ad-siRNA-Nrf2. CONCLUSION: These data suggested that electroacupuncture at ST36 protected nerve function in ASD rats through Nrf2 activation and the antioxidant response.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Electroacupuncture , NF-E2-Related Factor 2 , Animals , Female , Pregnancy , Rats , Antioxidants , Autism Spectrum Disorder/therapy , Autistic Disorder/therapy , NF-E2-Related Factor 2/genetics , Rats, Sprague-Dawley , RNA, Small Interfering
15.
Mikrochim Acta ; 189(2): 51, 2022 01 07.
Article in English | MEDLINE | ID: mdl-34994863

ABSTRACT

Efficient determination of aldehydes by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is hampered mainly by the low mass and unstable nature of analytes. In the present work, we propose a combined strategy of a reactive metal-organic framework (MOF) matrix for the derivatization and detection of aldehydes. A novel reactive MOF matrix (NH2NH-MOF) was synthesized in two steps. First, NR3+-MOF was synthesized via Cu2+ and the quaternary amine ligand 4,4'-bipyridinium, 1,1″-(1,2-ethanediyl)bis-, dibromide (PyEtBr). Then, -NHNH2 was introduced to NR3+-MOF through electrostatic adsorption between the -NR3+ and -HSO3- of 4-hydrazinylbenzenesulfonic acid to synthesize NH2NH-MOF. The acid-base chemistry of NH2NH-MOF led to uniform cocrystallization of the aldehyde-matrix mixtures and helped to achieve the detection of low-weight aldehydes with good relative standard deviations (RSDs = 0.07-12.35%). It was confirmed that this strategy can accurately quantify formaldehyde, valeraldehyde, and benzaldehyde with good linearity (r > 0.97). Furthermore, this strategy was applied to quantitatively detect benzaldehyde in wastewater, thus showing potential applications in environmental pollutant detection.


Subject(s)
Aldehydes/chemistry , Hydrazines/chemistry , Metal-Organic Frameworks/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods
16.
J Neuropathol Exp Neurol ; 81(2): 127-134, 2022 01 29.
Article in English | MEDLINE | ID: mdl-35015875

ABSTRACT

Autism is a common neurodevelopmental disorder that severely affects patients' quality of life. We aimed to investigate whether acupuncture at Zusanli (ST36) could alleviate the behavior disorder of autistic rats by inhibiting thioredoxin-interacting protein (TXNIP)-mediated activation of NLRP3. An autism model was induced by intraperitoneal injection of pregnant rats with valproic acid (VPA). The pups' behaviors were analyzed using hot plate, open field, Morris water maze, and 3-chamber social interaction tests. Nissl staining was used to visualize neurons in prefrontal cortex. Levels of TXNIP, NLRP3, interleukin (IL)-1ß, and caspase were determined by Western blot or quantitative real-time PCR. After ST36 acupuncture, pain sensitivity, autonomous activity, sociability index, sociability preference index, and learning and memory were improved in the autism model rats. Levels of TXNIP, NLRP3, IL-1ß, and caspase 1 were decreased after acupuncture. Interference with TXNIP alleviated the behavior disorders and inhibited NLRP3, caspase 1, and IL-1ß levels. In summary, ST36 acupuncture reduced TXNIP expression, inhibited the activation of the NLRP3 inflammasome, and alleviated the behavior disorder related to the prefrontal cortex of the autistic rats. These results point to a potential mechanism for acupuncture-induced improvement of autistic behavioral disorders.


Subject(s)
Acupuncture Therapy/methods , Autistic Disorder/metabolism , Cell Cycle Proteins/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Prefrontal Cortex/metabolism , Acupuncture Points , Animals , Behavior, Animal/physiology , Disease Models, Animal , Rats , Rats, Sprague-Dawley
17.
Cell Discov ; 7(1): 90, 2021 Oct 05.
Article in English | MEDLINE | ID: mdl-34608123

ABSTRACT

Pathogenic mycobacteria induce the formation of hypoxic granulomas during latent tuberculosis (TB) infection, in which the immune system contains, but fails to eliminate the mycobacteria. Fatty acid metabolism-related genes are relatively overrepresented in the mycobacterial genome and mycobacteria favor host-derived fatty acids as nutrient sources. However, whether and how mycobacteria modulate host fatty acid metabolism to drive granuloma progression remains unknown. Here, we report that mycobacteria under hypoxia markedly secrete the protein Rv0859/MMAR_4677 (Fatty-acid degradation A, FadA), which is also enriched in tuberculous granulomas. FadA acts as an acetyltransferase that converts host acetyl-CoA to acetoacetyl-CoA. The reduced acetyl-CoA level suppresses H3K9Ac-mediated expression of the host proinflammatory cytokine Il6, thus promoting granuloma progression. Moreover, supplementation of acetate increases the level of acetyl-CoA and inhibits the formation of granulomas. Our findings suggest an unexpected mechanism of a hypoxia-induced mycobacterial protein suppressing host immunity via modulation of host fatty acid metabolism and raise the possibility of a novel therapeutic strategy for TB infection.

18.
Front Microbiol ; 12: 650567, 2021.
Article in English | MEDLINE | ID: mdl-34194403

ABSTRACT

Tuberculosis (TB) remains a highly contagious public health threat. Precise and prompt diagnosis and monitoring of treatment responses are urgently needed for clinics. To pursue novel and satisfied host blood-derived biomarkers, we streamlined a bioinformatic pipeline by integrating differentially expressed genes, a gene co-expression network, and short time-series analysis to mine the published transcriptomes derived from whole blood of TB patients in the GEO database, followed by validating the diagnostic performance of biomarkers in both independent datasets and blood samples of Chinese patients using quantitative real-time PCR (qRT-PCR). We found that four genes, namely UBE2L6 (Ubiquitin/ISG15-conjugating enzyme E2 L6), BATF2 (Basic leucine zipper transcriptional factor ATF-like), SERPING1 (Plasma protease C1 inhibitor), and VAMP5 (Vesicle-associated membrane protein 5), had high diagnostic value for active TB. The transcription levels of these four gene combinations can reach up to 88% sensitivity and 78% specificity (average) for the diagnosis of active TB; the highest sensitivity can achieve 100% by parallel of BATF2 and VAMP5, and the highest specificity can reach 89.5% through a combination of SERPIG1, UBE2L6, and VAMP5, which were significantly higher than 75.3% sensitivity and 69.1% specificity by T-SPOT.TB in the same patients. Quite unexpectedly, the gene set can assess the efficacy of anti-TB response and differentiate active TB from Latent TB infection. The data demonstrated these four biomarkers might have great potency and advantage over IGRAs in the diagnosis of TB.

19.
EMBO Rep ; 22(7): e51678, 2021 07 05.
Article in English | MEDLINE | ID: mdl-33987949

ABSTRACT

Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increases survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associates with transforming growth factor ß-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocks AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravates the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators.


Subject(s)
Mycobacterium tuberculosis , Zebrafish , Animals , Galactans , Galectins/genetics , Mice
20.
Sensors (Basel) ; 21(7)2021 Mar 28.
Article in English | MEDLINE | ID: mdl-33800530

ABSTRACT

In smart homes, the computational offloading technology of edge cloud computing (ECC) can effectively deal with the large amount of computation generated by smart devices. In this paper, we propose a computational offloading strategy for minimizing delay based on the back-pressure algorithm (BMDCO) to get the offloading decision and the number of tasks that can be offloaded. Specifically, we first construct a system with multiple local smart device task queues and multiple edge processor task queues. Then, we formulate an offloading strategy to minimize the queue length of tasks in each time slot by minimizing the Lyapunov drift optimization problem, so as to realize the stability of queues and improve the offloading performance. In addition, we give a theoretical analysis on the stability of the BMDCO algorithm by deducing the upper bound of all queues in this system. The simulation results show the stability of the proposed algorithm, and demonstrate that the BMDCO algorithm is superior to other alternatives. Compared with other algorithms, this algorithm can effectively reduce the computation delay.

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