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Int J Biol Sci ; 18(1): 386-408, 2022.
Article En | MEDLINE | ID: mdl-34975340

Responding to the coronavirus disease 2019 (COVID-19) pandemic has been an unexpected and unprecedented global challenge for humanity in this century. During this crisis, specialists from the laboratories and frontline clinical personnel have made great efforts to prevent and treat COVID-19 by revealing the molecular biological characteristics and epidemic characteristics of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, SARS-CoV-2 has severe consequences for public health, including human respiratory system, immune system, blood circulation system, nervous system, motor system, urinary system, reproductive system and digestive system. In the review, we summarize the physiological and pathological damage of SARS-CoV-2 to these systems and its molecular mechanisms followed by clinical manifestation. Concurrently, the prevention and treatment strategies of COVID-19 will be discussed in preclinical and clinical studies. With constantly unfolding and expanding scientific understanding about COVID-19, the updated information can help applied researchers understand the disease to build potential antiviral drugs or vaccines, and formulate creative therapeutic ideas for combating COVID-19 at speed.

COVID-19/pathology , COVID-19/therapy , Immunotherapy/methods , SARS-CoV-2 , Animals , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19 Vaccines , Cytokines/metabolism , Female , Humans , Immune System , Immunity, Innate , Immunologic Memory , Male , Mice
Invest Ophthalmol Vis Sci ; 63(1): 2, 2022 01 03.
Article En | MEDLINE | ID: mdl-34978559

Purpose: Our studies in mouse eye lenses demonstrate that ephrin-A5 and EphA2 are needed for normal epithelial cells and lens transparency. We sought to determine whether EphA2 and ephrin-A5 are important for lens morphometrics, nucleus formation, and refractive index. Methods: We performed tissue morphometric measurements, electron microscopy, Western blots, and interferometric measurements using an X-ray synchrotron beam source to measure the gradient of refractive index (GRIN) to compare mouse lenses with genetic disruption of EphA2 or ephrin-A5. Results: Morphometric analysis revealed that although there is no change in the overall lens volume, there is a change in lens shape in both EphA2-/- lenses and ephrin-A5-/- lenses. Surprisingly, EphA2-/- lenses had small and soft lens nuclei different from hard lens nuclei of control lenses. SEM images revealed changes in cell morphology of EphA2-/- fiber cells close to the center of the lens. Inner EphA2-/- lens fibers had more pronounced tongue-and-groove interdigitations and formed globular membrane morphology only in the deepest layers of the lens nucleus. We did not observe nuclear defects in ephrin-A5-/- lenses. There was an overall decrease in magnitude of refractive index across EphA2-/- lenses, which is most pronounced in the nucleus. Conclusions: This work reveals that Eph-ephrin signaling plays a role in fiber cell maturation, nuclear compaction, and lens shape. Loss of EphA2 disrupts the nuclear compaction resulting in a small lens nucleus. Our data suggest that Eph-ephrin signaling may be required for fiber cell membrane reorganization and compaction and for establishing a normal GRIN.

Lens Nucleus, Crystalline/growth & development , Receptor, EphA2/physiology , Refraction, Ocular/physiology , Animals , Cell Membrane/metabolism , Cell Membrane/ultrastructure , Ephrin-A5/physiology , Genotyping Techniques , Interferometry , Lens Nucleus, Crystalline/metabolism , Lens Nucleus, Crystalline/ultrastructure , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Electron, Scanning , Organelle Shape/physiology , Real-Time Polymerase Chain Reaction , Signal Transduction/physiology , X-Rays
Microb Cell Fact ; 21(1): 4, 2022 Jan 04.
Article En | MEDLINE | ID: mdl-34983528

Given a serious threat of multidrug-resistant bacterial pathogens to global healthcare, there is an urgent need to find effective antibacterial compounds to treat drug-resistant bacterial infections. In our previous studies, Bacillus velezensis CB6 with broad-spectrum antibacterial activity was obtained from the soil of Changbaishan, China. In this study, with methicillin-resistant Staphylococcus aureus as an indicator bacterium, an antibacterial protein was purified by ammonium sulfate precipitation, Sephadex G-75 column, QAE-Sephadex A 25 column and RP-HPLC, which demonstrated a molecular weight of 31.405 kDa by SDS-PAGE. LC-MS/MS analysis indicated that the compound was an antibacterial protein CB6-C, which had 88.5% identity with chitosanase (Csn) produced by Bacillus subtilis 168. An antibacterial protein CB6-C showed an effective antimicrobial activity against gram-positive bacteria (in particular, the MIC for MRSA was 16 µg/mL), low toxicity, thermostability, stability in different organic reagents and pH values, and an additive effect with conventionally used antibiotics. Mechanistic studies showed that an antibacterial protein CB6-C exerted anti-MRSA activity through destruction of lipoteichoic acid (LTA) on the cell wall. In addition, an antibacterial protein CB6-C was efficient in preventing MRSA infections in in vivo models. In conclusion, this protein CB6-C is a newly discovered antibacterial protein and has the potential to become an effective antibacterial agent due to its high therapeutic index, safety, nontoxicity and great stability.

Anti-Bacterial Agents/pharmacology , Bacterial Proteins/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Animals , Anti-Bacterial Agents/therapeutic use , Bacillus/chemistry , Bacillus/enzymology , Bacterial Proteins/chemistry , Bacterial Proteins/isolation & purification , China , Chromatography, Liquid , Drug Resistance, Multiple, Bacterial , Female , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Staphylococcal Infections/drug therapy , Tandem Mass Spectrometry
Signal Transduct Target Ther ; 7(1): 7, 2022 01 04.
Article En | MEDLINE | ID: mdl-34983926

Activation-induced cytidine deaminase (AID) initiates class-switch recombination and somatic hypermutation (SHM) in antibody genes. Protein expression and activity are tightly controlled by various mechanisms. However, it remains unknown whether a signal from the extracellular environment directly affects the AID activity in the nucleus where it works. Here, we demonstrated that a deubiquitinase USP10, which specifically stabilizes nuclear AID protein, can translocate into the nucleus after AKT-mediated phosphorylation at its T674 within the NLS domain. Interestingly, the signals from BCR and TLR1/2 synergistically promoted this phosphorylation. The deficiency of USP10 in B cells significantly decreased AID protein levels, subsequently reducing neutralizing antibody production after immunization with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or human immunodeficiency virus type 1 (HIV-1) nanoparticle vaccines. Collectively, we demonstrated that USP10 functions as an integrator for both BCR and TLR signals and directly regulates nuclear AID activity. Its manipulation could be used for the development of vaccines and adjuvants.

AIDS Vaccines/immunology , B-Cell Activating Factor/immunology , COVID-19 Vaccines/immunology , Cytidine Deaminase/immunology , HIV-1/immunology , Nanoparticles , SARS-CoV-2/immunology , Signal Transduction/immunology , Ubiquitin Thiolesterase/immunology , Ubiquitination/immunology , AIDS Vaccines/genetics , Animals , B-Cell Activating Factor/genetics , COVID-19 Vaccines/genetics , Cytidine Deaminase/genetics , HEK293 Cells , HIV-1/genetics , Humans , Mice , Mice, Knockout , SARS-CoV-2/genetics , Signal Transduction/genetics , Ubiquitin Thiolesterase/genetics
Invest Ophthalmol Vis Sci ; 63(1): 5, 2022 01 03.
Article En | MEDLINE | ID: mdl-34985498

Purpose: The gut microbiome has been linked to disease pathogenesis through their interaction in metabolic, endocrine, and immune functions. The goal of this study was to determine whether the gut and plasma microbiota could transfer microbes to the retina in type 1 diabetic mice with retinopathy. Methods: We analyzed the fecal, plasma, whole globe, and retina microbiome in Akita mice and compared with age-matched wild-type (WT) mice using 16S rRNA sequencing and metatranscriptomic analysis. To eliminate the contribution of the ocular surface and plasma microbiome, mice were perfused with sterile saline solution, the whole globes were extracted, and the neural retina was removed under sterile conditions for retinal microbiome. Results: Our microbiome analysis revealed that Akita mice demonstrated a distinct pattern of microbes within each source: feces, plasma, whole globes, and retina. WT mice and Akita mice experienced transient bacteremia in the plasma and retina. Bacteria were identified in the retina of the Akita mice, specifically Corynebacterium, Pseudomonas, Lactobacillus, Staphylococcus, Enterococcus, and Bacillus. Significantly increased levels of peptidoglycan (0.036 ± 0.001 vs. 0.023 ± 0.002; P < 0.002) and TLR2 (3.47 ± 0.15 vs. 1.99 ± 0.07; P < 0.0001) were observed in the retina of Akita mice compared to WT. Increased IBA+ cells in the retina, reduced a- and b-waves on electroretinography, and increased acellular capillary formation demonstrated the presence of retinopathy in the Akita cohort compared to WT mice. Conclusions: Together, our findings suggest that transient bacteremia exists in the plasma and retina of both cohorts. The bacteria found in Akita mice are distinct from WT mice and may contribute to development of retinal inflammation and barrier dysfunction in retinopathy.

Bacteremia/microbiology , Bacteria/isolation & purification , Diabetic Retinopathy/microbiology , Feces/microbiology , Retina/microbiology , Animals , Bacteria/genetics , Diabetes Mellitus, Type 1/microbiology , Disease Models, Animal , Electroretinography , Enzyme-Linked Immunosorbent Assay , Eye/microbiology , Gastrointestinal Microbiome/physiology , Male , Mice , Mice, Inbred C57BL , Microbiota/physiology , RNA, Ribosomal, 16S/genetics
Nucleic Acids Res ; 50(D1): D1-D10, 2022 01 07.
Article En | MEDLINE | ID: mdl-34986604

The 2022 Nucleic Acids Research Database Issue contains 185 papers, including 87 papers reporting on new databases and 85 updates from resources previously published in the Issue. Thirteen additional manuscripts provide updates on databases most recently published elsewhere. Seven new databases focus specifically on COVID-19 and SARS-CoV-2, including SCoV2-MD, the first of the Issue's Breakthrough Articles. Major nucleic acid databases reporting updates include MODOMICS, JASPAR and miRTarBase. The AlphaFold Protein Structure Database, described in the second Breakthrough Article, is the stand-out in the protein section, where the Human Proteoform Atlas and GproteinDb are other notable new arrivals. Updates from DisProt, FuzDB and ELM comprehensively cover disordered proteins. Under the metabolism and signalling section Reactome, ConsensusPathDB, HMDB and CAZy are major returning resources. In microbial and viral genomes taxonomy and systematics are well covered by LPSN, TYGS and GTDB. Genomics resources include Ensembl, Ensembl Genomes and UCSC Genome Browser. Major returning pharmacology resource names include the IUPHAR/BPS guide and the Therapeutic Target Database. New plant databases include PlantGSAD for gene lists and qPTMplants for post-translational modifications. The entire Database Issue is freely available online on the Nucleic Acids Research website ( Our latest update to the NAR online Molecular Biology Database Collection brings the total number of entries to 1645. Following last year's major cleanup, we have updated 317 entries, listing 89 new resources and trimming 80 discontinued URLs. The current release is available at

Databases, Factual , Molecular Biology , Animals , COVID-19 , Databases, Nucleic Acid , Databases, Protein , Genome, Microbial , Genome, Viral , Humans , Mice , Plants/genetics , Protein Processing, Post-Translational , Proteome , SARS-CoV-2/genetics , Signal Transduction
J Synchrotron Radiat ; 29(Pt 1): 239-246, 2022 Jan 01.
Article En | MEDLINE | ID: mdl-34985441

Rodents are used extensively as animal models for the preclinical investigation of microvascular-related diseases. However, motion artifacts in currently available imaging methods preclude real-time observation of microvessels in vivo. In this paper, a pixel temporal averaging (PTA) method that enables real-time imaging of microvessels in the mouse brain in vivo is described. Experiments using live mice demonstrated that PTA efficiently eliminated motion artifacts and random noise, resulting in significant improvements in contrast-to-noise ratio. The time needed for image reconstruction using PTA with a normal computer was 250 ms, highlighting the capability of the PTA method for real-time angiography. In addition, experiments with less than one-quarter of photon flux in conventional angiography verified that motion artifacts and random noise were suppressed and microvessels were successfully identified using PTA, whereas conventional temporal subtraction and averaging methods were ineffective. Experiments performed with an X-ray tube verified that the PTA method could also be successfully applied to microvessel imaging of the mouse brain using a laboratory X-ray source. In conclusion, the proposed PTA method may facilitate the real-time investigation of cerebral microvascular-related diseases using small animal models.

Artifacts , Image Processing, Computer-Assisted , Animals , Mice , Microvessels/diagnostic imaging , Radiography , X-Rays
BMC Neurol ; 22(1): 3, 2022 Jan 03.
Article En | MEDLINE | ID: mdl-34979964

BACKGROUND: A decrease in hippocampal neurogenesis is considered an important cause of cognitive impairment, while changes in mossy fiber sprouting are closely related to development of spontaneous recurrent seizures in chronic temporal lobe epilepsy (TLE). Racemic l-3-n-butylphthalide (DL-NBP) can alleviate cognitive impairment in ischemic stroke and Alzheimer's disease by promoting neurogenesis. DL-NBP treatment can also improve cognitive function and reduce seizure incidence in chronic epileptic mice. However, the mechanisms of action of DL-NBP remain unclear. The aim of the present study was to examine the effects of DL-NBP on mossy fiber sprouting, hippocampal neurogenesis, spontaneous epileptic seizures, and cognitive functioning in the chronic phase of TLE. METHODS: Nissl staining was used to evaluate hippocampal injury, while immunofluorescent staining was used to analyze hippocampal neurogenesis. The duration of spontaneous seizures was measured by electroencephalography. The Morris water maze was used to evaluate cognitive function. Timm staining was used to assess mossy fiber sprouting. RESULTS: TLE animals showed reduced proliferation of newborn neurons, cognitive dysfunction, and spontaneous seizures. Treatment with DL-NBP after TLE increased the proliferation and survival of newborn neurons in the dentate gyrus, reversed the neural loss in the hippocampus, alleviated cognitive impairments, and decreased mossy fiber sprouting and long-term spontaneous seizure activity. CONCLUSIONS: We provided pathophysiological and morphological evidence that DL-NBP might be a useful therapeutic for the treatment of TLE.

Epilepsy, Temporal Lobe , Animals , Benzofurans , Epilepsy, Temporal Lobe/drug therapy , Hippocampus , Mice , Mossy Fibers, Hippocampal , Neurogenesis , Rats
Virol J ; 19(1): 2, 2022 01 04.
Article En | MEDLINE | ID: mdl-34983583

The current COVID-19 pandemic caused by constantly emerging SARS-CoV-2 variants still poses a threat to public health worldwide. Effective next-generation vaccines and optimized booster vaccination strategies are urgently needed. Here, we sequentially immunized mice with a SARS-CoV-2 wild-type inactivated vaccine and a heterologous mutant RBD vaccine, and then evaluated their neutralizing antibody responses against variants including Beta, Delta, Alpha, Iota, Kappa, and A.23.1. These data showed that a third booster dose of heterologous RBD vaccine especially after two doses of inactivated vaccines significantly enhanced the GMTs of nAbs against all SARS-CoV-2 variants we tested. In addition, the WT and variants all displayed good cross-immunogenicity and might be applied in the design of booster vaccines to induce broadly neutralizing antibodies.

COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Mice , SARS-CoV-2/immunology
J Neuroinflammation ; 19(1): 2, 2022 Jan 04.
Article En | MEDLINE | ID: mdl-34983568

BACKGROUND: Anxiety disorders are the most prevalent mental illnesses in the U.S. and are estimated to consume one-third of the country's mental health treatment cost. Although anxiolytic therapies are available, many patients still exhibit treatment resistance, relapse, or substantial side effects. Further, due to the COVID-19 pandemic and stay-at-home order, social isolation, fear of the pandemic, and unprecedented times, the incidence of anxiety has dramatically increased. Previously, we have demonstrated dihydromyricetin (DHM), the major bioactive flavonoid extracted from Ampelopsis grossedentata, exhibits anxiolytic properties in a mouse model of social isolation-induced anxiety. Because GABAergic transmission modulates the immune system in addition to the inhibitory signal transmission, we investigated the effects of short-term social isolation on the neuroimmune system. METHODS: Eight-week-old male C57BL/6 mice were housed under absolute social isolation for 4 weeks. The anxiety-like behaviors after DHM treatment were examined using elevated plus-maze and open field behavioral tests. Gephyrin protein expression, microglial profile changes, NF-κB pathway activation, cytokine level, and serum corticosterone were measured. RESULTS: Socially isolated mice showed increased anxiety levels, reduced exploratory behaviors, and reduced gephyrin levels. Also, a dynamic alteration in hippocampal microglia were detected illustrated as a decline in microglia number and overactivation as determined by significant morphological changes including decreases in lacunarity, perimeter, and cell size and increase in cell density. Moreover, social isolation induced an increase in serum corticosterone level and activation in NF-κB pathway. Notably, DHM treatment counteracted these changes. CONCLUSION: The results suggest that social isolation contributes to neuroinflammation, while DHM has the ability to improve neuroinflammation induced by anxiety.

Flavonols/pharmacology , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Microglia/drug effects , Microglia/metabolism , Social Isolation/psychology , Animals , Anxiety/metabolism , Anxiety/prevention & control , Anxiety/psychology , Flavonols/therapeutic use , Male , Maze Learning/drug effects , Maze Learning/physiology , Mice , Mice, Inbred C57BL
Curr Protoc ; 2(1): e340, 2022 Jan.
Article En | MEDLINE | ID: mdl-35007410

Enamel is the hardest tissue in mammalian organisms and is the layer covering the tooth. It consists of hydroxyapatite (HAP) crystallites, which mineralize on a protein scaffold known as the enamel matrix. Enamel matrix assembly is a very complex process mediated by enamel matrix proteins (EMPs). Altered HAP deposition or disintegration of the protein scaffold can cause enamel defects. Various methods have been established for enamel phenotyping, including MicroCT scanning with various resolutions from 9 µm for in vivo imaging to 1.5 µm for ex vivo imaging. With increasing resolution, we can see not only the enamel layer itself but also a detailed map of mineralization. To study enamel microstructure, we combine the MicroCT analysis with scanning electron microscopy (SEM), which enables us to perform element analyses such as calcium-carbon ratio. However, the methods mentioned above only show the result-already formed enamel. Stimulated emission depletion (STED) microscopy provides extra information about protein structure in the form of EMP localization and position before enamel mineralization. A combination of all these methods allows analyzing the same sample on multiple levels-starting with the live animal being scanned harmlessly and quickly, followed by sacrifice and high-resolution MicroCT scans requiring no special sample preparation. The biggest advantage is that samples remain in perfect condition for SEM or STED microscopic analysis. © 2022 Wiley Periodicals LLC. Basic Protocol 1: In vivo MicroCT scanning of mouse Basic Protocol 2: Ex vivo HR-MicroCT of the teeth Basic Protocol 3: SEM for teeth microstructure Basic Protocol 4: Stimulated emission depletion (STED) microscopy.

Tooth Calcification , Tooth , Animals , Durapatite , Mice , Microscopy, Electron, Scanning , X-Ray Microtomography
J Headache Pain ; 23(1): 4, 2022 Jan 10.
Article En | MEDLINE | ID: mdl-35012445

BACKGROUND: Migraine is a common brain disorder that predominantly affects women. Migraine pain seems mediated by the activation of mechanosensitive channels in meningeal afferents. Given the role of transient receptor potential melastatin 3 (TRPM3) channels in mechanical activation, as well as hormonal regulation, these channels may play a role in the sex difference in migraine. Therefore, we investigated whether nociceptive firing induced by TRPM3 channel agonists in meningeal afferents was different between male and female mice. In addition, we assessed the relative contribution of mechanosensitive TRPM3 channels and that of mechanosensitive Piezo1 channels and transient receptor potential vanilloid 1 (TRPV1) channels to nociceptive firing relevant to migraine in both sexes. METHODS: Ten- to 13-week-old male and female wildtype (WT) C57BL/6 J mice were used. Nociceptive spikes were recorded directly from nerve terminals in the meninges in the hemiskull preparations. RESULTS: Selective agonists of TRPM3 channels profoundly activated peripheral trigeminal nerve fibres in mouse meninges. A sex difference was observed for nociceptive firing induced by either PregS or CIM0216, both agonists of TRPM3 channels, with the induced firing being particularly prominent for female mice. Application of Yoda1, an agonist of Piezo1 channels, or capsaicin activating TRPV1 channels, although also leading to increased nociceptive firing of meningeal fibres, did not reveal a sex difference. Cluster analyses of spike activities indicated a massive and long-lasting activation of TRPM3 channels with preferential induction of large-amplitude spikes in female mice. Additional spectral analysis revealed ​a dominant contribution of spiking activity in the α- and ß-ranges following TRPM3 agonists in female mice. CONCLUSIONS: Together, we revealed a specific mechanosensitive profile of nociceptive firing in females and suggest TRPM3 channels as a potential novel candidate for the generation of migraine pain, with particular relevance to females.

Migraine Disorders , TRPM Cation Channels , Animals , Female , Ion Channels , Male , Meninges , Mice , Mice, Inbred C57BL , TRPM Cation Channels/agonists , TRPV Cation Channels , Trigeminal Nerve
J Biomed Sci ; 29(1): 2, 2022 Jan 10.
Article En | MEDLINE | ID: mdl-35012534

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disorder for which no successful therapeutics are available. Valproic acid (VPA), a monocarboxylate derivative, is a known antiepileptic drug and a histone deacetylase inhibitor. METHODS: To investigate whether monocarboxylate transporter 1 (MCT1) and sodium-coupled MCT1 (SMCT1) are altered in ALS cell and mouse models, a cellular uptake study, quantitative real time polymerase chain reaction and western blot parameters were used. Similarly, whether VPA provides a neuroprotective effect in the wild-type (WT; hSOD1WT) and ALS mutant-type (MT; hSOD1G93A) NSC-34 motor neuron-like cell lines was determined through the cell viability assay. RESULTS: [3H]VPA uptake was dependent on time, pH, sodium and concentration, and the uptake rate was significantly lower in the MT cell line than the WT cell line. Interestingly, two VPA transport systems were expressed, and the VPA uptake was modulated by SMCT substrates/inhibitors in both cell lines. Furthermore, MCT1 and SMCT1 expression was significantly lower in motor neurons of ALS (G93A) model mice than in those of WT mice. Notably, VPA ameliorated glutamate- and hydrogen peroxide-induced neurotoxicity in both the WT and MT ALS cell lines. CONCLUSIONS: Together, the current findings demonstrate that VPA exhibits a neuroprotective effect regardless of the dysfunction of an MCT in ALS, which could help develop useful therapeutic strategies for ALS.

Amyotrophic Lateral Sclerosis , Monocarboxylic Acid Transporters/metabolism , Neuroprotective Agents , Symporters/metabolism , Valproic Acid/pharmacology , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/metabolism , Animals , Disease Models, Animal , Mice , Mice, Transgenic , Motor Neurons , Neuroprotective Agents/pharmacology , Superoxide Dismutase
World J Surg Oncol ; 20(1): 13, 2022 Jan 10.
Article En | MEDLINE | ID: mdl-35012553

BACKGROUND: Circular RNAs (circRNAs) are a novel type of endogenous RNAs and play vital roles in lung adenocarcinoma. However, the function and underlying mechanism of circ_0020850 in lung adenocarcinoma remain unknown. METHODS: The levels of circ_0020850, microRNA-326 (miR-326), and Beclin1 (BECN1) were analyzed by real-time quantitative polymerase chain reaction and western blot analyses. The migration and invasion were determined by wound healing and transwell assays, respectively. Colony formation assay was used to assess cell proliferation ability. The angiogenic ability was analyzed by Matrigel angiogenesis assay. The apoptosis rate was calculated by flow cytometry assay. Dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays were conducted to confirm the interaction relationship among circ_0020850, miR-326, and BECN1. A xenograft mice model was established to assess the role of circ_0020850 in vivo. RESULTS: We found that circ_0020850 was obviously overexpressed in lung adenocarcinoma tissues and cells. Knockdown of circ_0020850 inhibited migration, invasion, proliferation, and angiogenesis but induced apoptosis in lung adenocarcinoma cells in vitro, as well as curbed tumor growth in vivo. MiR-326 was a target of circ_0020850, and knockdown of miR-326 abolished the suppression effect of circ_0020850 on the malignant behaviors of lung adenocarcinoma cells. Additionally, miR-326 could negatively regulate BECN1 expression, thereby regulating lung adenocarcinoma cell phenotypes. Importantly, circ_0020850 could directly bind to miR-326 and thus relieve miR-326-mediated inhibition on BECN1. CONCLUSION: Circ_0020850 promoted the malignant development of lung adenocarcinoma by regulating miR-326/BECN1 axis, indicating that circ_0020850 might serve as a promising target for the diagnosis and treatment of lung adenocarcinoma patients.

Adenocarcinoma of Lung , MicroRNAs , RNA, Circular , Adenocarcinoma of Lung/pathology , Animals , Beclin-1/genetics , Cell Proliferation , Humans , Mice , MicroRNAs/genetics , Neoplasm Transplantation , RNA, Circular/genetics
J Agric Food Chem ; 70(1): 184-195, 2022 Jan 12.
Article En | MEDLINE | ID: mdl-35016506

The mechanisms of coffee against Parkinson disease (PD) remained incompletely elucidated. Numerous studies suggested that gut microbiota played a crucial role in the pathogenesis of PD. Here, we explored the further mechanisms of coffee against PD via regulating gut microbiota. C57BL/6 mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce a PD mouse model, then treated with coffee for 4 consecutive weeks. Behavioral tests consisting of the pole test and beam-walking test were conducted to evaluate the motor function of mice. The levels of tyrosine hydroxylase (TH) and α-synuclein (α-syn) were assessed for dopaminergic neuronal loss. The levels of occludin, glial fibrillary acidic protein (GFAP), Bcl-2, Bax, cleaved caspase-3, and cytochrome c (Cyt c) were detected. Moreover, microbial components were measured by 16s rRNA sequencing. Our results showed that coffee significantly improved the motor deficits and TH neuron loss, and reduced the level of α-syn in the MPTP-induced mice. Moreover, coffee increased the level of BBB tight junction protein occludin and reduced the level of astrocyte activation marker GFAP in the MPTP-induced mice. Furthermore, coffee significantly decreased the levels of proapoptotic proteins, including Bax, cleaved caspase-3, and cytochrome c, while it increased the level of antiapoptotic protein Bcl-2, consequently preventing MPTP-induced apoptotic cascade. Moreover, coffee improved MPTP-induced gut microbiota dysbiosis. These findings suggested that the neuroprotective effects of coffee on PD were involved in the regulation of gut microbiota, which might provide a novel option to elucidate the effects of coffee on PD.

Gastrointestinal Microbiome , Neuroprotective Agents , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Coffee , Disease Models, Animal , Dopaminergic Neurons , Mice , Mice, Inbred C57BL , RNA, Ribosomal, 16S
Braz J Med Biol Res ; 55: e11504, 2022.
Article En | MEDLINE | ID: mdl-35019033

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in the elderly. The aim of this study was to explore the effects of AD on cardiac function and autonomic nervous function, and the feasibility of electrocardiogram (ECG) in monitoring the development of AD. APP/PS1 double transgenic mice were used in the Morris water maze (MWM) experiment to evaluate the changes of cognitive ability of AD mice, then the non-invasive ECG acquisition system was used and the changes of ECG intervals and heart rate variability (HRV) were analyzed. AD mice already had cognitive dysfunction at the age of 5 months, reaching the level of mild dementia, and the degree of dementia increased with the course of disease. There were no significant changes in ECG intervals in the AD group at each month. The mean square of successive RR interval differences, percentage of intervals >6 ms different from preceding interval, and normalized high frequency power component in the AD group were decreased and low-to-high frequency power ratio and normalized low frequency power component were increased. Combined with the results of the MWM, it was shown that the regulation mechanism of sympathetic and parasympathetic nerves in mice was already imbalanced in early stage AD, which was manifested as the increase of excessive activity of sympathetic nerves and the inhibition of parasympathetic activities. Therefore, ECG-based analysis of HRV may become a means of daily monitoring of AD and provide an auxiliary basis for clinical diagnosis.

Alzheimer Disease , Animals , Electrocardiography , Heart , Heart Rate , Mice , Sympathetic Nervous System