The Natural Alkaloid Palmatine Selectively Induces Mitophagy and Restores Mitochondrial Function in an Alzheimer's Disease Mouse Model.

Palmatine, a natural alkaloid found in various plants, has been reported to have diverse pharmacological and biological effects, including anti-inflammatory, antioxidant, and cardiovascular effects. However, the role of palmatine in mitophagy, a fundamental process crucial for maintaining mitochondrial function, remains elusive. In this study, we found that palmatine efficiently induces mitophagy in various human cell lines. Palmatine specifically induces mitophagy and subsequently stimulates mitochondrial biogenesis. Palmatine did not interfere with mitochondrial function, similar to CCCP, suggesting that palmatine is not toxic to mitochondria. Importantly, palmatine treatment alleviated mitochondrial dysfunction in PINK1-knockout MEFs. Moreover, the administration of palmatine resulted in significant improvements in cognitive function and restored mitochondrial function in an Alzheimer's disease mouse model. This study identifies palmatine as a novel inducer of selective mitophagy. Our results suggest that palmatine-mediated mitophagy induction could be a potential strategy for Alzheimer's disease treatment and that natural alkaloids are potential sources of mitophagy inducers.

Berberine Induces Mitophagy through Adenosine Monophosphate-Activated Protein Kinase and Ameliorates Mitochondrial Dysfunction in PINK1 Knockout Mouse Embryonic Fibroblasts.

Mitophagy stimulation has been shown to have a therapeutic effect on various neurodegenerative diseases. However, nontoxic mitophagy inducers are still very limited. In this study, we found that the natural alkaloid berberine exhibited mitophagy stimulation activity in various human cells. Berberine did not interfere with mitochondrial function, unlike the well-known mitophagy inducer carbonyl cyanide m-chlorophenyl hydrazone (CCCP), and subsequently induced mitochondrial biogenesis. Berberine treatment induced the activation of adenosine monophosphate-activated protein kinase (AMPK), and the AMPK inhibitor compound C abolished berberine-induced mitophagy, suggesting that AMPK activation is essential for berberine-induced mitophagy. Notably, berberine treatment reversed mitochondrial dysfunction in PINK1 knockout mouse embryonic fibroblasts. Our results suggest that berberine is a mitophagy-specific inducer and can be used as a therapeutic treatment for neurodegenerative diseases, including Parkinson's disease, and that natural alkaloids are potential sources of mitophagy inducers.

p53 regulates mitochondrial dynamics by inhibiting Drp1 translocation into mitochondria during cellular senescence.

Cellular senescence acts as an important barrier to tumorigenesis by eliminating precancerous cells. Previous studies have shown an essential role of the tumor suppressor p53 in cellular senescence, but how p53 induces cellular senescence is not fully understood. We found that p53 promoted the formation of highly interconnected and elongated mitochondria prior to the onset of cellular senescence. The inhibition of mitochondrial elongation upon p53 expression suppressed cellular senescence, suggesting that mitochondrial elongation is required for the induction of p53-dependent senescence. p53-induced mitochondrial elongation resulted in mitochondrial dysfunction and subsequent increases in intracellular reactive oxygen species (ROS) levels, an important mediator of cellular senescence. Mechanistically, the inhibitory phosphorylation of Drp1 Ser637 increased upon p53 expression, suppressing the translocation of Drp1 into mitochondria. The transcriptional function of p53 was crucial for controlling the inhibitory phosphorylation of Drp1, whereas p21 was nonessential. Protein kinase A (PKA) activity was responsible for p53-mediated Drp1 Ser637 phosphorylation and mitochondrial dysfunction. Taken together, these results suggest that p53 regulates mitochondrial dynamics through the PKA-Drp1 pathway to induce cellular senescence.

Assessment of mitophagy in mt-Keima Drosophila revealed an essential role of the PINK1-Parkin pathway in mitophagy induction in vivo.

Mitophagy has been implicated in mitochondrial quality control and in various human diseases. However, the study of in vivo mitophagy remains limited. We previously explored in vivo mitophagy using a transgenic mouse expressing the mitochondria-targeted fluorescent protein Keima (mt-Keima). Here, we generated mt-Keima Drosophila to extend our efforts to study mitophagy in vivo. A series of experiments confirmed that mitophagy can be faithfully and quantitatively measured in mt-Keima Drosophila. We also showed that alterations in mitophagy upon environmental and genetic perturbation can be measured in mt-Keima Drosophila. Analysis of different tissues revealed a variation in basal mitophagy levels in Drosophila tissues. In addition, we found a significant increase in mitophagy levels during Drosophila embryogenesis. Importantly, loss-of-function genetic analysis demonstrated that the phosphatase and tensin homolog-induced putative kinase 1 (PINK1)-Parkin pathway is essential for the induction of mitophagy in vivo in response to hypoxic exposure and rotenone treatment. These studies showed that the mt-Keima Drosophila system is a useful tool for understanding the role and molecular mechanism of mitophagy in vivo. In addition, we demonstrated the essential role of the PINK1-Parkin pathway in mitophagy induction in response to mitochondrial dysfunction.-Kim, Y. Y., Um, J.-H., Yoon, J.-H., Kim, H., Lee, D.-Y., Lee, Y. J., Jee, H. J., Kim, Y. M., Jang, J. S., Jang, Y.-G., Chung, J., Park, H. T., Finkel, T., Koh, H., Yun, J. Assessment of mitophagy in mt-Keima Drosophila revealed an essential role of the PINK1-Parkin pathway in mitophagy induction in vivo.

Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models.

Rationale: Promotion of mitophagy is considered a promising strategy for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). The development of mitophagy-specific inducers with low toxicity and defined molecular mechanisms is essential for the clinical application of mitophagy-based therapy. The aim of this study was to investigate the potential of a novel small-molecule mitophagy inducer, ALT001, as a treatment for AD. Methods: ALT001 was developed through chemical optimization of an isoquinolium scaffold, which was identified from a chemical library screening using a mitophagy reporter system. In vitro and in vivo experiments were conducted to evaluate the potential of ALT001 as a mitophagy-targeting therapeutic agent and to investigate the molecular mechanisms underlying ALT001-induced mitophagy. The therapeutic effect of ALT001 was assessed in SH-SY5Y cells expressing mutant APP and mouse models of AD (5×FAD and PS2APP) by analyzing mitochondrial dysfunction and cognitive defects. Results: ALT001 specifically induces mitophagy both in vitro and in vivo but is nontoxic to mitochondria. Interestingly, we found that ALT001 induces mitophagy through the ULK1-Rab9-dependent alternative mitophagy pathway independent of canonical mitophagy pathway regulators such as ATG7 and PINK1. Importantly, ALT001 reverses mitochondrial dysfunction in SH-SY5Y cells expressing mutant APP in a mitophagy-dependent manner. ALT001 induces alternative mitophagy in mice and restores the decreased mitophagy level in a 5×FAD AD model mouse. In addition, ALT001 reverses mitochondrial dysfunction and cognitive defects in the PS2APP and 5×FAD AD mouse models. AAV-mediated silencing of Rab9 in the hippocampus further confirmed that ALT001 exerts its therapeutic effect through alternative mitophagy. Conclusion: Our results highlight the therapeutic potential of ALT001 for AD via alleviation of mitochondrial dysfunction and indicate the usefulness of the ULK1-Rab9 alternative mitophagy pathway as a therapeutic target.

The job demands-resource model and performance: the mediating role of employee engagement.

In case of a major social crisis, such as the coronavirus pandemic, the most important measure is to identify the determinants influencing employee health and well-being, which are directly linked to workplace job performance. Many studies have explored the role of employee engagement in the relationship between job resources, psychological capital, and job performance; however, only a few have investigated the relationships reflecting rapid changes in the work environment represented by digital transformation and a major social crisis. Considering this, this study examines how job autonomy and psychological well-being, which lower employee anxiety about health and welfare, influence in-role performance in the form of proactive employee characteristics as well as extra-role performance in the form of prosocial behavior, as mediated by employee engagement. The results of the data analysis of 1,092 corporate employees in Korea supported this model. Specifically, job autonomy and psychological well-being influence job performance (i.e., personal initiative and prosocial behavior) through improvements in employee engagement. Based on these findings, the study also discusses the implications of the results, future directions, and limitations.

Intramuscular administration of recombinant Newcastle disease virus expressing SARS-CoV-2 spike protein protects hACE-2 TG mice against SARS-CoV-2 infection.

Coronavirus disease 2019 (Covid-19) caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) became a pandemic, causing significant burden on public health worldwide. Although the timely development and production of mRNA and adenoviral vector vaccines against SARS-CoV-2 have been successful, issues still exist in vaccine platforms for wide use and production. With the potential for proliferative capability and heat stability, the Newcastle disease virus (NDV)-vectored vaccine is a highly economical and conceivable candidate for treating emerging diseases. In this study, a recombinant NDV-vectored vaccine expressing the spike (S) protein of SARS-CoV-2, rK148/beta-S, was developed and evaluated for its efficacy against SARS-CoV-2 in K18-hACE-2 transgenic mice. Intramuscular vaccination with low dose (106.0 EID50) conferred a survival rate of 76 % after lethal challenge of a SARS-CoV-2 beta (B.1.351) variant. When administered with a high dose (107.0 EID50), vaccinated mice exhibited 100 % survival rate and reduced lung viral load against both beta and delta variants (B.1.617.2). Together with the protective immunity, rK148/beta-S is an accessible and cost-effective SARS-CoV-2 vaccine.

Structural relationships among adolescents' peer attachment, career-related self-efficacy, parents' attitudes and health risk behaviours.

AIM: This study aimed to determine whether the peer attachment of adolescents, mediated by career-related self-efficacy and having parents with positive attitudes, influences health risk behaviours. DESIGN: A cross-sectional questionnaire survey. METHODS: This study adopted the secondary data analysis method, using the 2010 Korean Children and Youth Panel Survey (KCYPS). The 7th-wave panel data of 1,932 first graders in high schools were analysed using structural equation modelling. RESULTS: The final model provided a good fit for the data. Having a close relationship with peers had a direct effect on adolescents' health risk behaviours. High peer attachment also had an indirect effect on health risk behaviours, mediated by career-related self-efficacy and having parents with positive attitudes. Though adolescents with broad and intimate peer relationships may be exposed to more temptations towards health risk behaviours and tend to make riskier decisions, these influences are reduced by being exposed to positive parenting attitudes and having clear, conscious career goals.

Genetic Characterization and Pathogenicity Analysis of Recently Isolated Fowl Adenovirus 8b in Korea.

A Korean field strain of fowl adenovirus (FAdV) 8b was isolated from chickens showing high mortality. Isolated FAdV-8b strains with the hexon and fiber genes were genetically analyzed. The Korean FAdV-8b (K194/19) strain isolated in 2019 showed higher sequence identity with the FAdV-8b strain isolated in China but lower sequence identity with the Korean FAdV-8b (K187/08) strain isolated in 2008. The K194/19 strain formed a distinct subcluster within the FAdV-8b cluster in a phylogenetic tree based on hexon and fiber genes. FAdV can infect day-old chicks through vertical transmission, and so blood samples were obtained from 54-, 60-, and 63-wk-old parent chickens. FAdV-specific antibody levels were investigated with ELISA and virus neutralization (VN) tests with the K194/19 and K187/08 strains as antigens. In VN tests, all sera neutralized the K187/08 strain. However, the K194/19 strain was neutralized by sera collected from 60- and 63-wk-old chickens but not sera obtained from 54-wk-old chickens, indicating natural infection. Finally, to determine the pathogenicity of the K194/19 strain, 1-day-old and 4-wk-old specific-pathogen-free birds were infected with the K194/19 and K187/08 strains. No significant difference in pathogenicity was observed between the two strains. Although the K194/19 strain showed similar pathogenicity with the K187/08 strain, differences in nucleotide and amino acid sequences of the hexon and fiber genes may determine the evasion ability of the K187/08 neutralizing antibody, indicating the need for development of a novel FAdV vaccine.

Nota de investigación­Caracterización genética y análisis de patogenicidad de un adenovirus del pollo 8b aislado recientemente en Corea. Se aisló una cepa de campo coreana de adenovirus del pollo (FAdV) 8b de aves que mostraban una alta mortalidad. Se analizaron genéticamente cepas de FAdV-8b aisladas mediante los genes de hexón y de la fibra. La cepa coreana FAdV-8b (K194/19) aislada en 2019 mostró una mayor identidad de secuencia con la cepa FAdV-8b aislada en China, pero una menor identidad de secuencia con la cepa coreana FAdV-8b (K187/08) aislada en 2008. La cepa K194/19 formó un subgrupo distinto dentro del grupo de adenovirus del pollo 8b en un árbol filogenético basado en los genes de las fibras y hexones. El FAdV puede infectar a pollitos de un día a través de la transmisión vertical, por lo que se obtuvieron muestras de sangre de pollos reproductores de 54, 60 y 63 semanas de edad. Los niveles de anticuerpos específicos de FAdV se investigaron con ELISA y pruebas de neutralización de virus (VN) con las cepas K194/19 y K187/08 como antígenos. En las pruebas de neutralización, todos los sueros neutralizaron a la cepa K187/08. Sin embargo, la cepa K194/19 fue neutralizada por sueros recolectados de pollos de 60 y 63 semanas de edad, pero no por los sueros obtenidos de pollos de 54 semanas de edad, lo que indica una infección natural. Finalmente, para determinar la patogenicidad de la cepa K194/19, se infectaron aves libres de patógenos específicos de un día y cuatro semanas de edad con las cepas K194/19 y K187/08. No se observaron diferencias significativas en la patogenicidad entre las dos cepas. Aunque la cepa K194/19 mostró una patogenicidad similar con la cepa K187/08, las diferencias en las secuencias de nucleótidos y aminoácidos de los genes del hexón y de la fibra pueden determinar la capacidad para evadir los anticuerpos neutralizantes K187/08, lo que indica la necesidad de desarrollar una nueva vacuna contra adenovirus del pollo.

Efficacy of a novel avian metapneumovirus live vaccine candidate based on vaccination route and age.

This article describes a series of animal studies for the development of an avian metapneumovirus (aMPV) live vaccine. Although aMPV causes continual economic loss in the poultry industry, there are no live aMPV vaccines available in Korea. Furthermore, information is limited with respect to standard field practices for vaccinations at an early age. Here, the development of an aMPV live vaccine was attempted, and its efficacy was investigated with respect to the vaccination route and age to develop a method for controlling aMPV. Before vaccine development, an animal challenge model was established using the aMPV field isolate to identify the most effective time and site for collecting samples for evaluation. After attenuation of the virulent aMPV in Vero cells, a safety and efficacy test was conducted for the vaccine candidate. As a novel aMPV live vaccine candidate, aMPV K655/07HP displayed sufficient safety in day-old chicks with 10 vaccine doses. The efficacy test using 1-week-old chicks showed weaker humoral immune response than that in 4-week-old chicks. However, the candidate vaccine provided complete protection against infection caused by the challenge virus for all ages of vaccinated chicks. In conclusion, an effective aMPV challenge model was established for studying aMPV in chickens, which offered important, insightful information. The safety and efficacy study suggested that the new aMPV candidate vaccine could be used to effectively reduce the economic losses incurred because of aMPV infection.

The Sexual Risk Behaviors of Middle School Students According to School Nurse Placement Levels in Korea.

PURPOSE: This study aimed to provide basic data for the future development of school-based sexuality education and school nurse placement policies by examining the sexuality education experience in middle schools according to levels of school nurse placement and identifying factors influencing on adolescent sexual risk behaviors. METHODS: This study examined data from the 2018 14th Korean Youth Risk Behavior Survey. The raw data from 30,229 middle school students enrolled in 400 schools were analyzed using descriptive statistics, Chi-square test, independent t test, and complex sample logistic regression analysis. RESULTS: It is found that, in Korea, school nurse placement rates varied by region from 37.9% to 114.8%, resulting in different levels of sexuality and alcohol prevention education (p < .001). Sexuality and alcohol prevention education lowered the likelihood of sexual risk behaviors by 0.54 and 0.87 times, respectively. The experience of drinking alcohol increased a student's likelihood of committing sexual risk behaviors by 4.40 and 3.57 times, respectively, whereas the experience of using a drug increased the risk by 9.42 and 5.00 times, respectively. Personal factors (e.g., gender and academic achievement) and socioenvironmental factors (e.g., school type and perceived economic status) were also found to influence on the sexual risk behaviors of adolescents, although, not to the same degree as sexuality education or health risk behaviors. CONCLUSION: To protect students' sex-related health equity, more elaborate support policies are needed to ensure adequate placement of school nurses able to provide professional sexuality and related health education.