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Ubiquitination status of proliferating cell nuclear antigen (PCNA) is crucial for regulating DNA lesion bypass. After the resolution of fork stalling, PCNA is subsequently deubiquitinated, but the underlying mechanism remains undefined. We found that the N-terminal domain of ATAD5 (ATAD5-N), the largest subunit of the PCNA-unloading complex, functions as a scaffold for Ub-PCNA deubiquitination. ATAD5 recognizes DNA-loaded Ub-PCNA through distinct DNA-binding and PCNA-binding motifs. Furthermore, ATAD5 forms a heterotrimeric complex with UAF1-USP1 deubiquitinase, facilitating the deubiquitination of DNA-loaded Ub-PCNA. ATAD5 also enhances the Ub-PCNA deubiquitination by USP7 and USP11 through specific interactions. ATAD5 promotes the distinct deubiquitination process of UAF1-USP1, USP7, and USP11 for poly-Ub-PCNA. Additionally, ATAD5 mutants deficient in UAF1-binding had increased sensitivity to DNA-damaging agents. Our results ultimately reveal that ATAD5 and USPs cooperate to efficiently deubiquitinate Ub-PCNA prior to its release from the DNA in order to safely deactivate the DNA repair process.
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ATPases Associadas a Diversas Atividades Celulares , Proteínas de Ligação a DNA , Antígeno Nuclear de Célula em Proliferação , Ubiquitina Tiolesterase , Peptidase 7 Específica de Ubiquitina , Ubiquitinação , ATPases Associadas a Diversas Atividades Celulares/metabolismo , ATPases Associadas a Diversas Atividades Celulares/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Humanos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Peptidase 7 Específica de Ubiquitina/metabolismo , Peptidase 7 Específica de Ubiquitina/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Tioléster Hidrolases/metabolismo , Tioléster Hidrolases/genética , Ubiquitina/metabolismo , Dano ao DNA , Ligação Proteica , Proteases Específicas de UbiquitinaRESUMO
CONTEXT/OBJECTIVE: To assess differences in autonomic function using heart rate variability (HRV) parameters between people with and without orthostatic hypotension (OH), and to determine symptoms of OH in people with spinal cord injury (SCI). METHODS: R-R interval and blood pressure (BP) data were recorded using Finometer PRO® in both the supine position and at a 60-degree tilt using a tilt table, each lasting for 6 minutes. R-R interval data were processed using the Kubios HRV analysis software to convert R-R interval into time and frequency domains for further analysis. RESULTS: Compared to the non-OH group, the SCI group with OH exhibited lower values for root mean square of the successive differences (RMSSD) and standard deviation of normal-to-normal interval (SDNN), along with an elevated heart rate during tilt-up. Participants with OH symptoms had a lower average heart rate in the supine and 60-degree positions compared to asymptomatic participants. Logistic regression analysis indicated that SDNN in the supine position correlated with the presence of OH, and that the mean heart rate in the 60-degree position was related to the presence of symptoms. CONCLUSIONS: Differences in HRV parameters were observed in people with SCI and OH, suggesting a reduced parasympathetic activity in the supine position, likely as a response to maintain homeostasis in BP regulation. Despite the presence or absence of OH symptoms, there was no difference in HRV parameters. This finding suggests that autonomic function may not be the primary determinant of these symptoms, with other factors likely being more influential.
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Excessive osteoclast activity can promote periodontitis-associated bone destruction. The inhibitory mechanisms of Weissella cibaria strains CMU and CMS1 against periodontitis have not yet been fully elucidated. In this study, we aimed to investigate whether heat-killed (HK) W. cibaria CMU and CMS1 or their respective cell-free supernatants (CFSs) inhibit osteoclast differentiation and bone resorption in response to receptor activator of nuclear factor kappa-B ligand (RANKL)-treated RAW 264.7 cells. TRAP (tartrate-resistant acid phosphatase) staining and bone resorption assays revealed that both HK bacteria and CFSs significantly suppressed the number of TRAP-positive cells, TRAP activity, and bone pit formation compared to the RANKL-treated control (p < 0.05). HK bacteria dose-dependently inhibited osteoclastogenesis while selectively regulating certain genes in CFSs (p < 0.05). We found that disrupting the direct interaction between HK bacteria and RAW 264.7 cells abolished the inhibitory effect of HK bacteria on the expression of osteoclastogenesis-associated proteins (c-Fos, nuclear factor of activated T cells c1 (NFATc1), and cathepsin K). These results suggest that dead bacteria suppress osteoclast differentiation more effectively than the metabolites and may serve as beneficial agents in preventing periodontitis by inhibiting osteoclast differentiation via direct interaction with cells.
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In this study, we evaluated the in vitro anti-biofilm, antibacterial, and anti-inflammatory activity of Weissella cibaria CMU (CMU), an oral probiotic, against periodontopathogens. Compared to other oral probiotics, CMU showed a superior inhibitory effect on the biofilm formation and growth of Streptococcus mutans on orthodontic wires and artificial teeth (p < 0.05). CMU exerted potent antibacterial effects against S. mutans and Porphyromonas gingivalis according to a line test. In human gingival fibroblasts (HGFs) stimulated by P. gingivalis, Fusobacterium nucleatum, or Prevotella intermedia, CMU suppressed the gene expression of pro-inflammatory cytokines [interleukin (IL)-6, IL-1ß, IL-8, and tumor necrosis factor-α] in a dose-dependent manner (p < 0.05). CMU restored the production of the tissue inhibitor of metalloproteinase-1 following its inhibition by P. gingivalis, and it suppressed the expression of matrix metalloproteinase (MMP)-1 and -3 induced by periodontopathogens (p < 0.05). Moreover, CMU needed direct contact with HGFs to exert their anti-inflammatory function, indicating that they act directly on gingival cells to modulate local inflammation. Our preclinical study provides evidence for the potential benefits of topical CMU treatments in preventing the development of caries and periodontitis caused by the dysbiosis of the dental plaque microbiome.
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Dietary restriction (DR) delays aging and the onset of age-associated diseases. However, it is yet to be determined whether and how restriction of specific nutrients promote longevity. Previous genome-wide screens isolated several Escherichia coli mutants that extended lifespan of Caenorhabditis elegans. Here, using 1H-NMR metabolite analyses and inter-species genetics, we demonstrate that E. coli mutants depleted of intracellular glucose extend C. elegans lifespans, serving as bona fide glucose-restricted (GR) diets. Unlike general DR, GR diets don't reduce the fecundity of animals, while still improving stress resistance and ameliorating neuro-degenerative pathologies of Aß42. Interestingly, AAK-2a, a new AMPK isoform, is necessary and sufficient for GR-induced longevity. AAK-2a functions exclusively in neurons to modulate GR-mediated longevity via neuropeptide signaling. Last, we find that GR/AAK-2a prolongs longevity through PAQR-2/NHR-49/Δ9 desaturases by promoting membrane fluidity in peripheral tissues. Together, our studies identify the molecular mechanisms underlying prolonged longevity by glucose specific restriction in the context of whole animals.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Longevidade/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Glucose/metabolismo , Fluidez de Membrana , Escherichia coli/metabolismo , Restrição Calórica , Proteínas de Membrana/metabolismoRESUMO
Aminoacyl-tRNA synthetases (ARSs) have evolved to acquire various additional domains. These domains allow ARSs to communicate with other cellular proteins in order to promote non-translational functions. Vertebrate cytoplasmic isoleucyl-tRNA synthetases (IARS1s) have an uncharacterized unique domain, UNE-I. Here, we present the crystal structure of the chicken IARS1 UNE-I complexed with glutamyl-tRNA synthetase 1 (EARS1). UNE-I consists of tandem ubiquitin regulatory X (UBX) domains that interact with a distinct hairpin loop on EARS1 and protect its neighboring proteins in the multi-synthetase complex from degradation. Phosphomimetic mutation of the two serine residues in the hairpin loop releases IARS1 from the complex. IARS1 interacts with BRCA1 in the nucleus, regulates its stability by inhibiting ubiquitylation via the UBX domains, and controls DNA repair function.
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Aminoacil-tRNA Sintetases , Isoleucina-tRNA Ligase , Isoleucina-tRNA Ligase/química , Aminoacil-tRNA Sintetases/metabolismo , Glutamato-tRNA Ligase/química , RNA de Transferência/metabolismoRESUMO
Background and Objectives: Diesel exhaust particulate matter (DEPM) is an air pollutant that is associated with asthma. In this study, the therapeutic efficacy of Weissella cibaria strains CMU (Chonnam Medical University) and CMS (Chonnam Medical School) 1, together with the drug Synatura, an anti-tussive expectorant, was investigated in a murine asthma model exacerbated by DEPM. Materials and Methods: BALB/c mice were sensitized with ovalbumin (OVA) before intranasal challenge with OVA and DEPM. W. cibaria CMU, CMS1, and Synatura were administered orally for 21 days. Results: Neither Synatura nor W. cibaria strains affected spleen, liver, or lung weights. W. cibaria strains CMU and CMS1 significantly reduced the levels of interleukin (IL)-4, OVA-specific immunoglobulin E (IgE), and total lung collagen in bronchoalveolar lavage fluid (BALF), similar to those with Synatura, regardless of the oral dose concentration (p < 0.05). In addition, the W. cibaria CMU strain significantly alleviated IL-1ß, IL-6, IL-12, monocyte chemotactic protein-1, and tumor necrosis factor-α in BALF, whereas the CMS1 strain significantly alleviated IL-10 and IL-12 in BALF (p < 0.05); however, Synatura did not show any statistical efficacy against them (p > 0.05). All concentrations of W. cibaria CMU and low concentrations of W. cibaria CMS1 significantly reduced lung bronchiolar changes and inflammatory cell infiltration. Conclusions: In conclusion, W. cibaria CMU in asthmatic mice showed better efficacy than W. cibaria CMS1 in improving asthma exacerbated by DEPM exposure, as well as better results than pharmaceuticals.
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Poluentes Atmosféricos , Asma , Animais , Asma/induzido quimicamente , Asma/tratamento farmacológico , Quimiocina CCL2/uso terapêutico , Citocinas , Modelos Animais de Doenças , Expectorantes/uso terapêutico , Humanos , Imunoglobulina E , Inflamação , Interleucina-10 , Interleucina-12 , Interleucina-6 , Pulmão , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Material Particulado , Fator de Necrose Tumoral alfa , Emissões de Veículos/toxicidade , WeissellaRESUMO
Weissella cibaria belongs to the Lactobacillaceae family and has been isolated from traditional fermented foods and saliva of children with good oral health. Previous investigations have shown that W. cibaria CMU (Chonnam Medical University) is expected to be safe based on results of in silico and in vitro analyses. However, there is a lack of studies assessing its safety in vivo. A toxicological safety evaluation of W. cibaria CMU was performed using an acute oral safety study in rats, a 14-day oral range finding study, a subsequent 13-week oral toxicity study in rats and a genetic toxicity battery (in vitro bacterial reverse mutation, in vitro chromosome aberration in Chinese Hamster Ovary cells and in vivo micronucleus study in mice). The results of the studies in rats showed that the acute lethal dose of W. cibaria CMU is > 5000 mg/kg body weight (bw)/day (1.8 × 109 CFU/kg bw/day) and the 14-day or 13-week no observed adverse effect level (NOAEL) is 5000 mg/kg bw/day (1.8 × 109 CFU/kg bw/day), the highest dose administered. W. cibaria CMU was non-mutagenic in the bacterial reverse mutation test and non-clastogenic or aneugenic in vitro and in vivo. In conclusion, the toxicological studies performed demonstrated W. cibaria CMU to be a safe strain to consume. This study is the first study examining the potential of a W. cibaria strain to cause genetic toxicity and subchronic toxicity in rats according to the Organization for Economic Cooperation and Development guidelines.
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Weissella cibaria CMS1 (oraCMS1) has been commercially used in Korea as an oral care probiotic for several years. Human respiratory syncytial virus (RSV) and the influenza A virus (H1N1) are representative viruses that cause infantile lower respiratory tract infections. Rotavirus A (RVA) is the most common cause of diarrhea in infants and young children. Here, we aimed to evaluate the efficacy of the cell-free supernatant (CFS) of oraCMS1 in inactivating RSV, H1N1, and RVA in suspension as per ASTM (American Society for Testing and Materials) E1052-20. The mixture of oraCMS1 and these viruses was evaluated at contact times of 1, 2, and 4 h. Virucidal activity was measured using a 50% tissue culture infective dose assay (log10TCID50) after infecting the host cells with the viruses. The CFS of oraCMS1 inactivated RSV by up to 99.0% after 1 h and 99.9% after 2 and 4 h, and H1N1 and RVA were inactivated by up to 99.9% and 99.0% at 2 h, respectively. Although these in vitro results cannot be directly interpreted as implying clinical efficacy, our findings suggest that oraCMS1 provides a protective barrier against RSV, H1N1, and RVA, and therefore, it can help decrease the risk of respiratory tract and intestinal infections.
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Vírus da Influenza A Subtipo H1N1 , Probióticos , Rotavirus , Vírus , Criança , Pré-Escolar , Humanos , Lactente , WeissellaRESUMO
Dissociative-based new psychoactive substances (NPSs) are increasingly available through the Internet, and public health problems related to the recreational use of these substances have been increasing globally. Two such NPSs are deschloroketamine and diphenidine, which are primarily used recreationally as ketamine substitutes. However, there is little scientific evidence to describe the dependence liability of NPSs. This study aimed to evaluate the dependence liability of deschloroketamine and diphenidine via animal behavioral experiments. We evaluated the rewarding and reinforcing effects of these NPSs using the conditioned place preference (CPP) and the self-administration (SA) paradigms in mice. Psychomotor effects and behavioral features of these compounds were assessed by quantifying locomotor activity, stereotypic movements, and dopaminergic neurotransmission. Both deschloroketamine (10 mg/kg) and diphenidine (10-60 mg/kg) produced increased locomotor activation and stereotypy that were similar to the effects of ketamine (10 mg/kg). Both deschloroketamine (10 mg/kg) and diphenidine (10, 20 mg/kg) increased the animals' preference for the drug-paired compartment in the CPP testing. In the SA testing, deschloroketamine (1 mg/kg/infusion) increased the number of active lever presses and the number of infusions received, whereas diphenidine administration (1, 2 mg/kg/infusion) did not alter either of these. Furthermore, both deschloroketamine and diphenidine increased dopamine levels in PC-12 cells. Collectively, the data suggest that deschloroketamine may have both rewarding and reinforcing effects, whereas diphenidine only induced rewarding effect.
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Ketamina/farmacologia , Piperidinas/farmacologia , Reforço Psicológico , Recompensa , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Dopamina/metabolismo , Ketamina/administração & dosagem , Ketamina/análogos & derivados , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células PC12 , Piperidinas/administração & dosagem , Psicotrópicos/farmacologia , Ratos , Autoadministração , Comportamento Estereotipado/efeitos dos fármacosRESUMO
Prolintane (1-Phenyl-2-pyrrolidinylpentane), a synthetic central nervous system (CNS) stimulant, is structurally similar to amphetamine but pharmacologically acts as a dopamine reuptake inhibitor like cocaine. While several case studies reported adverse effects and recreational use of prolintane, the abuse potential of the drug has not been systemically examined yet. In the present study, we evaluated the behavioral effects of prolintane regarding its abuse liability in rodents using locomotor activity, conditioned place preference (CPP), self-administration (SA), and drug discrimination paradigms, as well as in-vivo microdialysis experiment. First, acute prolintane (10 and 20 mg/kg, intraperitoneal injection) increased locomotor activity (distance traveled, cm) in mice but to a lesser degree than methamphetamine (as a positive control). We also found that a single and solitary injection of prolintane (20 mg/kg, IP) significantly increased extracellular dopamine in the striatum. The following result suggests that its stimulatory effects might be associated with the mesolimbic dopaminergic pathway. Further, prolintane produced a significant drug-paired place preference at doses of both 10 and 20 mg/kg. In the SA experiment, the mice that self-administered prolintane intravenously (4 mg/kg/inf) showed a higher infusion and active lever responses but not inactive lever responses. Additionally, cumulative doses of prolintane partially elicited cocaine-appropriate lever responses (38.57% at doses up to 10 mg/kg) in rats. These results implied that prolintane has not only rewarding and reinforcing effects but also interoceptive stimulus properties, which are similar to cocaine at a moderate level. Taken together, this study was the first to show, to our knowledge, that prolintane has a certain level of abuse potential and should be considered carefully as a valuable basis for legal restrictions on use.
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Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Locomoção/efeitos dos fármacos , Pirrolidinas/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Camundongos , Pirrolidinas/administração & dosagem , Ratos , Autoadministração , Transtornos Relacionados ao Uso de SubstânciasRESUMO
Oral probiotics are beneficial bacteria that can help prevent periodontal disease. However, little is known about the effects of oral probiotics on the formation of implant biofilms. This study aimed to evaluate the effects of oral probiotics Weissella cibaria CMU and CMS1 in an in vitro complex biofilm model on titanium implant surfaces. First, it was identified through colony biofilm assay that W. cibaria CMU and CMS1 inhibit the formation of multi-species biofilms formed by eight types of bacteria. Two types of saliva-coated titanium discs inoculated with early (Streptococcus gordonii, Streptococcus oralis, Streptococcus sanguinis, Actinomyces naeslundii, and Veillonella parvula), secondary (Fusobacterium nucleatum and Prevotella intermedia), and late (Porphyromonas gingivalis) colonizers were treated with the oral probiotics and then incubated anaerobically for three days. The effects of oral probiotics on titanium disc biofilm formation were analyzed using culture methods, quantitative polymerase chain reaction (qPCR), and microscopic analysis. Both probiotics significantly inhibited the formation of biofilm, and all eight bacterial species were significantly reduced. The effectiveness of both probiotic strains was confirmed by all the methods used. Oral probiotics may have dramatically reduced the biofilm formation of secondary colonizers that act as bridges, thus inhibiting biofilm formation on the titanium surface. Our results suggest that the probiotic W. cibaria offers new possibilities for the prevention of peri-implant mucositis.
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Reactive oxygen species (ROS) generate oxidized bases and single-strand breaks (SSBs), which are fixed by base excision repair (BER) and SSB repair (SSBR), respectively. Although excision and repair of damaged bases have been extensively studied, the function of the sliding clamp, proliferating cell nuclear antigen (PCNA), including loading/unloading, remains unclear. We report that, in addition to PCNA loading by replication factor complex C (RFC), timely PCNA unloading by the ATPase family AAA domain-containing protein 5 (ATAD5)-RFC-like complex is important for the repair of ROS-induced SSBs. We found that PCNA was loaded at hydrogen peroxide (H2O2)-generated direct SSBs after the 3'-terminus was converted to the hydroxyl moiety by end-processing enzymes. However, PCNA loading rarely occurred during BER of oxidized or alkylated bases. ATAD5-depleted cells were sensitive to acute H2O2 treatment but not methyl methanesulfonate treatment. Unexpectedly, when PCNA remained on DNA as a result of ATAD5 depletion, H2O2-induced repair DNA synthesis increased in cancerous and normal cells. Based on higher H2O2-induced DNA breakage and SSBR protein enrichment by ATAD5 depletion, we propose that extended repair DNA synthesis increases the likelihood of DNA polymerase stalling, shown by increased PCNA monoubiquitination, and consequently, harmful nick structures are more frequent.
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ATPases Associadas a Diversas Atividades Celulares/metabolismo , Reparo do DNA por Junção de Extremidades , Replicação do DNA , Proteínas de Ligação a DNA/metabolismo , ATPases Associadas a Diversas Atividades Celulares/genética , Proteínas de Ligação a DNA/genética , Células HEK293 , Células HeLa , Humanos , Peróxido de Hidrogênio/toxicidade , Estresse Oxidativo , Antígeno Nuclear de Célula em Proliferação/genéticaRESUMO
Recently discovered preventive effects of probiotics on oral health have attracted interest to their use for the prevention and treatment of various diseases. This study aimed to evaluate the antimicrobial and antibiofilm properties of Weissella cibaria against Streptococcus pyogenes, Staphylococcus aureus, S. pneumoniae, and Moraxella catarrhalis, the major pathogens of upper respiratory tract infections (URTIs). The antimicrobial activities of W. cibaria were compared with those of other oral probiotics using a competitive inhibition assay and the determination of the minimum inhibitory concentrations (MICs). In addition, a time-kill assay, spectrophotometry, and confocal laser scanning microscopy were used to confirm the antimicrobial and antibiofilm abilities of W. cibaria CMU (oraCMU) and CMS1 (oraCMS1). Both live cells and cell-free supernatants of all tested probiotics, except Streptococcus salivarius, showed excellent antimicrobial activities. All target pathogens were killed within 4 to 24 h at twice the MIC of oraCMU and oraCMS1, which showed the highest antimicrobial activities against M. catarrhalis. The antimicrobial substances that affected different target pathogens were different. Both oraCMU and oraCMS1 showed excellent abilities to inhibit biofilm formation and remove preformed biofilms. Our results suggest that the W. cibaria probiotics offer new possibilities for the prevention and treatment of bacterial URTIs.
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N-Methyl-1-(naphthalen-2-yl)propan-2-amine (methamnetamine, PAL-1046) is an amphetamine-based new psychoactive substance (NPS). Methamnetamine has been reported to cause excessive release of serotonin, and it is classified as an empathogen or entactogen. It is not regulated as a controlled substance in most countries, and there are no studies on its metabolism. In this study, in vitro phase I metabolism of methamnetamine in human liver microsomes (HLM) and flavin-containing monooxygenase (FMO) was investigated by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q-TOF/MS). Eight metabolites of methamnetamine were identified and were structurally characterized achieved by a combination of accurate mass analysis and tandem mass spectrometry. The identified metabolic processes include N-demethylation, N-hydroxylation, aromatic hydroxylation, and a combination of these processes. N-Hydroxylated metabolites were confirmed based on expressed FMOs. The major metabolite was formed from methamnetamine via hydroxylation of the naphthalene ring after the in vitro phase I process. These results could help detect methamnetamine ingestion by NPS abusers.
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Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Oxigenases/química , Oxigenases/metabolismo , Detecção do Abuso de Substâncias/métodos , Cromatografia Líquida , Desmetilação , Humanos , Hidroxilação , Técnicas In Vitro , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em TandemRESUMO
The possibility of preventing dental caries by taking probiotic bacterium Weissella cibaria (W. cibaria) CMU tablets to alter the pH of the dental plaque in the oral cavity was evaluated. A randomized, double-blind, placebo-controlled trial was performed on adults aged 20 years or older with 20 or more natural teeth. Ninety-two people underwent dental scaling before being randomly assigned to the experimental group (n = 49) or the control group (n = 43). Depending on the group they belonged to, W. cibaria CMU or the placebo was administered to them once daily for 8 weeks before bedtime. Twenty-four subjects were later excluded from the study because the week 8 dosing was not smoothly performed, for a final subject count of 68. The Cariview test was used to evaluate the amount of acid produced by the dental plaque to assess the risk of caries. The results showed that although there was no significant difference between the results of the two groups, the intake of the W. cibaria CMU tablets eliminated the risk of developing dental caries from acid production in the oral flora because the W. cibaria colonizes and lives in the dental plaque and the oral cavity and suppresses acids.
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Cárie Dentária , Probióticos , Weissella , Adulto , Biofilmes , Cárie Dentária/prevenção & controle , Método Duplo-Cego , Humanos , Comprimidos , Adulto JovemRESUMO
RATIONALE: Methamnetamine (MNA; PAL-1046) is a new psychoactive substance that acts as a full biogenic amine transporter (BAT) substrate. BAT substrates promote neurotransmitter release from the nerve terminal and can be abused as stimulants. However, scientific information on the abuse potential of methamnetamine is lacking. OBJECTIVE: We evaluated the abuse liability of methamnetamine. METHODS: The effective dose range of methamnetamine was determined using a climbing behavior test. The rewarding effect and reinforcing effect of the test compound were evaluated in mice by conditioned place preference (CPP) testing and self-administration (SA) testing at the selected doses. Dopamine level changes were analyzed using synaptosomes and in vivo microdialysis to investigate the effects of methamnetamine on the central nervous system. Drug discrimination experiments were used to examine the potential similarity of the interoceptive effects of methamnetamine and cocaine. RESULTS: A significant response was observed in the climbing behavior test with 10 and 40 mg/kg intraperitoneally administered methamnetamine. In the CPP test, mice intraperitoneally administered methamnetamine (10 and 20 mg/kg) showed a significant preference for the drug-paired compartment. In the SA test, mice that intravenously received 1 mg/kg/infusion showed significant active-lever responses. Dopamine was significantly increased in synaptosomes and in in vivo microdialysis tests. Furthermore, methamnetamine showed cross-generalization with cocaine in a dose-dependent manner. CONCLUSIONS: Methamnetamine exhibits interceptive stimulus properties similar to those of cocaine and induces rewarding and reinforcing effects, suggesting its dependence liability potential.
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Condicionamento Clássico/efeitos dos fármacos , Psicotrópicos/administração & dosagem , Reforço Psicológico , Recompensa , Transtornos Relacionados ao Uso de Substâncias/psicologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Condicionamento Clássico/fisiologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Roedores , AutoadministraçãoRESUMO
Altogether, 81% of Korean college students experience halitosis and concomitant psychosocial problems such as depression and lowered self-esteem, as well as poor oral-health-related quality of life. Although halitosis causes many social and psychological problems among college students, there have been no reports of improvement interventions. This study aimed to identify the effects of ingesting tablets of the oral probiotic Weissella cibaria CMU (Chonnam Medical University, Gwangju, Korea) on halitosis and examine its effects on psychosocial indicators. This was a randomized, double-blind, placebo-controlled trial. The participants were randomly assigned to the experimental group or the control group. They ingested W. cibaria CMU or the placebo, depending on which group they belonged to, before going to bed daily for eight weeks. The measured indicators were subjective halitosis, subjective oral-health status, depression, self-esteem, and oral-health-related quality of life. Measurements were at baseline and eight weeks later. The participants showed statistically significant differences in subjective halitosis and oral-health-related quality of life. For college students with halitosis, intake of the oral probiotic for eight weeks could be a useful nursing intervention for reducing halitosis and improving oral-health-related quality of life.
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Halitose , Probióticos , Método Duplo-Cego , Halitose/prevenção & controle , Humanos , Saúde Bucal , Probióticos/uso terapêutico , Qualidade de Vida , República da Coreia , Estudantes , WeissellaRESUMO
BACKGROUND: Randomized controlled trials (RCTs) are considered to provide high levels of evidence to optimize decision-making for patient care, although there can be a risk bias in their design, conduct, and analysis. Quality assessment of RCTs is necessary to assess whether they provide reliable results with little bias. MATERIALS AND METHODS: We assessed the reporting quality of RCTs published in the Journal of Neurosurgical Anesthesiology (JNA) between January 1, 2000 and December 31, 2017 using the Jadad scale, van Tulder scale, and Cochrane Collaboration Risk of Bias Tool (CCRBT). RESULTS: We identified 130 RCTs and 570 original articles. Among the 130 RCTs, 92 (70.8%) presented an appropriate blinding method, and 70 (53.8%) described an appropriate allocation method. For the entire period, the percentages of high-quality reporting articles were 71.5%, 73.1%, and 13.8% in the Jadad scale, van Tulder scale, and CCRBT assessments, respectively. There was an improvement in the van Tulder scale over time (coefficients [95% confidence interval {CI}]=0.08 [0.01-0.15]; P=0.02). Appropriate reporting of allocation in the Jadad scale (coefficients [95% CI]=1.68 [1.28-2.07]; P<0.001) and van Tulder scale (coefficients [95% CI]=2.34 [1.97-2.70]; P<0.001), and reporting of blinding in the Jadad (coefficients [95% CI]=1.09 [0.66-1.52]; P<0.001) and van Tulder scores (coefficients [95% CI]=1.85 [1.45-2.25]; P<0.001), were associated with high-quality reporting. CONCLUSIONS: The ratio of high-quality reporting RCTs in JNA was consistently high compared with other journals. Thorough consideration of allocation concealment during the peer review process can further improve the reporting quality of RCTs in JNA.