Risk of Severe COVID-19 and Protective Effectiveness of Vaccination Among Solid Organ Transplant Recipients.

BACKGROUND: Solid organ transplant recipients (SOTRs) are at higher risk for severe infection. However, the risk for severe COVID-19 and vaccine effectiveness among SOTRs remain unclear. METHODS: This retrospective study used a nationwide health care claims database and COVID-19 registry from the Republic of Korea (2020 to 2022). Adult SOTRs diagnosed with COVID-19 were matched with up to 4 non-SOTR COVID-19 patients by propensity score. Severe COVID-19 was defined as treatment with high-flow nasal cannulae, mechanical ventilation, or extracorporeal membrane oxygenation. RESULTS: Among 6783 SOTRs with COVID-19, severe COVID-19 was reported with the highest rate in lung transplant recipients (13.16%), followed by the heart (6.30%), kidney (3.90%), and liver (2.40%). SOTRs had a higher risk of severe COVID-19 compared to non-SOTRs, and lung transplant recipients showed the highest risk (adjusted odds ratio, 18.14; 95% confidence interval [CI], 8.53-38.58). Vaccine effectiveness against severe disease among SOTRs was 47% (95% CI, 18%-65%), 64% (95% CI, 49%-75%), and 64% (95% CI, 29%-81%) for 2, 3, and 4 doses, respectively. CONCLUSIONS: SOTRs are at significantly higher risk for severe COVID-19 compared to non-SOTRs. Vaccination is effective in preventing the progression to severe COVID-19. Efforts should be made to improve vaccine uptake among SOTRs, while additional protective measures should be developed.

Progranulin haploinsufficiency mediates cytoplasmic TDP-43 aggregation with lysosomal abnormalities in human microglia.

BACKGROUND: Progranulin (PGRN) haploinsufficiency due to progranulin gene (GRN) variants can cause frontotemporal dementia (FTD) with aberrant TAR DNA-binding protein 43 (TDP-43) accumulation. Despite microglial burden with TDP-43-related pathophysiology, direct microglial TDP-43 pathology has not been clarified yet, only emphasized in neuronal pathology. Thus, the objective of this study was to investigate TDP-43 pathology in microglia of patients with PGRN haploinsufficiency. METHODS: To design a human microglial cell model with PGRN haploinsufficiency, monocyte-derived microglia (iMGs) were generated from FTD-GRN patients carrying pathogenic or likely pathogenic variants (p.M1? and p.W147*) and three healthy controls. RESULTS: iMGs from FTD-GRN patients with PGRN deficiency exhibited severe neuroinflammation phenotype and failure to maintain their homeostatic molecular signatures, along with impaired phagocytosis. In FTD-GRN patients-derived iMGs, significant cytoplasmic TDP-43 aggregation and accumulation of lipid droplets with profound lysosomal abnormalities were observed. These pathomechanisms were mediated by complement C1q activation and upregulation of pro-inflammatory cytokines. CONCLUSIONS: Our study provides considerable cellular and molecular evidence that loss-of-function variants of GRN in human microglia can cause microglial dysfunction with abnormal TDP-43 aggregation induced by inflammatory milieu as well as the impaired lysosome. Elucidating the role of microglial TDP-43 pathology in intensifying neuroinflammation in individuals with FTD due to PGRN deficiency and examining consequential effects on microglial dysfunction might yield novel insights into the mechanisms underlying FTD and neurodegenerative disorders.

Therapeutic efficacy of thrombin-preconditioned mesenchymal stromal cell-derived extracellular vesicles on Escherichia coli-induced acute lung injury in mice.

BACKGROUND: Acute lung injury (ALI) following pneumonia involves uncontrolled inflammation and tissue injury, leading to high mortality. We previously confirmed the significantly increased cargo content and extracellular vesicle (EV) production in thrombin-preconditioned human mesenchymal stromal cells (thMSCs) compared to those in naïve and other preconditioning methods. This study aimed to investigate the therapeutic efficacy of EVs derived from thMSCs in protecting against inflammation and tissue injury in an Escherichia coli (E. coli)-induced ALI mouse model. METHODS: In vitro, RAW 264.7 cells were stimulated with 0.1 µg/mL liposaccharides (LPS) for 1 h, then were treated with either PBS (LPS Ctrl) or 5 × 107 particles of thMSC-EVs (LPS + thMSC-EVs) for 24 h. Cells and media were harvested for flow cytometry and ELISA. In vivo, ICR mice were anesthetized, intubated, administered 2 × 107 CFU/100 µl of E. coli. 50 min after, mice were then either administered 50 µL saline (ECS) or 1 × 109 particles/50 µL of thMSC-EVs (EME). Three days later, the therapeutic efficacy of thMSC-EVs was assessed using extracted lung tissue, bronchoalveolar lavage fluid (BALF), and in vivo computed tomography scans. One-way analysis of variance with post-hoc TUKEY test was used to compare the experimental groups statistically. RESULTS: In vitro, IL-1ß, CCL-2, and MMP-9 levels were significantly lower in the LPS + thMSC-EVs group than in the LPS Ctrl group. The percentages of M1 macrophages in the normal control, LPS Ctrl, and LPS + thMSC-EV groups were 12.5, 98.4, and 65.9%, respectively. In vivo, the EME group exhibited significantly lower histological scores for alveolar congestion, hemorrhage, wall thickening, and leukocyte infiltration than the ECS group. The wet-dry ratio for the lungs was significantly lower in the EME group than in the ECS group. The BALF levels of CCL2, TNF-a, and IL-6 were significantly lower in the EME group than in the ECS group. In vivo CT analysis revealed a significantly lower percentage of damaged lungs in the EME group than in the ECS group. CONCLUSION: Intratracheal thMSC-EVs administration significantly reduced E. coli-induced inflammation and lung tissue damage. Overall, these results suggest therapeutically enhanced thMSC-EVs as a novel promising therapeutic option for ARDS/ALI.

Urodynamic study and its correlation with cardiac meta-iodobenzylguanidine (MIBG) in body-first and brain-first subtypes of Parkinson's disease.

BACKGROUND AND PURPOSE: Lower urinary tract symptoms (LUTS) are frequently observed in patients with Parkinson's disease (PD), but the underlying mechanism remains elusive. The concept of "body-first" and "brain-first" subtypes in PD has been proposed, but the correlation of PD subtype with LUTS remains unclear. We aimed to investigate the disparities in urological dysfunctions between body-first and brain-first subtypes of PD using urodynamic studies (UDS). METHODS: We reviewed patients with PD (disease duration <3 years) who had undergone UDS and completed urological questionnaires (Overactive Bladder Symptom Score [OABSS] and International Prostate Symptom Score [IPSS]) and a voiding diary. Patients were categorized as having body-first or brain-first PD based on cardiac sympathetic denervation (CSD) using cardiac meta-iodobenzylguanidine (MIBG) uptake and the presence of rapid eye movement sleep behavior disorder (RBD), assessed using a questionnaire (PD with CSD and RBD indicating the body-first subtype). RESULTS: A total of 55 patients with PD were categorized into body-first PD (n = 37) and brain-first PD (n = 18) groups. The body-first PD group exhibited smaller voiding volume and first desire volume (FDV) than the brain-first PD group (p < 0.05 in both). Also, the body-first PD group had higher OABSS and IPSS scores, and higher prevalence of overactive bladder diagnosed by OABSS, compared to the brain-first PD group. In multiple linear regression, cardiac MIBG uptake was positively correlated with FDV and voiding volume and negatively correlated with OABSS and IPSS (p < 0.05 in all). CONCLUSIONS: Patients with the body-first PD subtype exhibited more pronounced overactive bladder symptoms and impaired storage function in the early stage of disease. Additionally, cardiac MIBG was significantly associated with urological dysfunction.

Exploring 2-mercapto-N-arylacetamide analogs as promising anti-melanogenic agents: in vitro and in vivo evaluation.

Based on the hypothesis that the 2-mercaptoacetamide moiety chelates the copper ions of tyrosinase, 2-mercapto-N-arylacetamide (2-MAA) analogs were designed and synthesized as potential tyrosinase inhibitors. Four 2-MAA analogs showed low IC50 values ranging from 0.95 to 2.0 µM against mushroom tyrosinase, which was 12-26 times lower than that of kojic acid (IC50 value = 24.3 µM). However, according to a copper ion chelation experiment performed, the 2-MAA analogs did not participate in chelation with copper ions. To identify the mode of inhibition of the 2-MAA analogs, kinetic studies were performed, and the results were supported by docking results. In addition, docking simulation results suggested that the 2-MAA analogs strongly inhibited tyrosinase activity because of the hydrogen bonding of the amide NH group and the hydrophobic interaction of the aryl ring instead of chelation with copper ions. In experiments using B16F10 cells, 2-MAA analogs were shown to inhibit melanin production by inhibiting cellular tyrosinase activity. Western blotting showed that in addition to directly inhibiting tyrosinase activity, analog 7 also has an anti-melanogenic effect by inhibiting the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase. The 2-MAA analogs showed no appreciable cytotoxicity against HaCaT and B16F10 cells, making them suitable for dermal applications. In a depigmentation experiment using zebrafish embryos, analogs 1 and 2 showed more potent depigmentation effects than kojic acid even at 1000 times lower concentration than that of kojic acid. These results suggest that the 2-MAA analogs are promising anti-melanogenic agents that can inhibit most tyrosinases in various species.

Trends in Healthy Life Expectancy (HALE) and Disparities by Income and Region in Korea (2008-2020): Analysis of a Nationwide Claims Database.

BACKGROUND: Healthy life expectancy is a well-recognized indicator for establishing health policy goals used in Korea's Health Plan. This study aimed to explore Koreans' healthy life expectancy and its gender, income, and regional disparities from 2008 to 2020. METHODS: This study was conducted on the entire population covered by health insurance and medical aid program in Korea. The incidence-based "years lived with disability" for 260 disease groups by gender, income level, and region was calculated employing the methodology developed in the Korean National Burden of Disease Study, and it was used as the number of healthy years lost to calculate health-adjusted life expectancy (HALE). RESULTS: Koreans' HALE increased from 68.89 years in 2008 to 71.82 years in 2020. Although the gender disparity in HALE had been decreasing, it increased to 4.55 years in 2020. As of 2020, 5.90 years out of 8.67 years of the income disparity (Q5-Q1) in HALE were due to the disparity between Q1 and Q2, the low-income groups. Income and regional disparities in HALE exhibited an increasing trend, and these disparities were higher in men than in women. CONCLUSION: A subgroup with a low health level was identified through the HALE results, and it was confirmed that improving the health level of this population can reduce health inequalities and improve health at the national level. Further exploration of the HALE calculation methodology may help in the development of effective policies such as prioritizing interventions for health risk factors.

Measuring the Burden of Disease in Korea Using Disability-Adjusted Life Years (2008-2020).

BACKGROUND: The measurement of health levels and monitoring of characteristics and trends among populations and subgroups are essential for informing evidence-based policy decisions. This study aimed to examine the burden of disease in Korea for both the total population and subgroups in 2020, as well as analyze changes in disease burden from 2008 to 2020. METHODS: We employed the methodology developed in the Korean National Burden of Disease and Injuries Study to calculate disability-adjusted life years (DALYs) by sex, causes, region, and income level from 2008 to 2020. DALYs were derived by combining years of life lost and years lived with disability. RESULTS: In 2020, the burden of disease for the Korean population was estimated to be 25,439 DALYs per 100,000 population, reflecting a 13.8% increase since 2008. The leading causes of DALYs were diabetes mellitus, followed by low back pain and ischemic stroke. A sex-specific gap reversal was observed, with the disease burden for men surpassing that of women starting in 2017. Furthermore, variations in disease burden were identified across 250 regions and income quintiles. CONCLUSION: It is imperative to establish appropriate health policies that prioritize the diseases with significantly increasing burdens and subgroups experiencing high disease burdens. The findings of this study are expected to serve as a foundation for developing healthcare policies aimed at improving the health levels of Koreans and achieving health equity.

Trends of Gaps Between Health-Adjusted Life Expectancy and Life Expectancy at the Regional Level in Korea Using a Group-Based Multi-Trajectory Modeling Approach (2008-2019).

BACKGROUND: Health-adjusted life expectancy (HALE) is an indicator of the average lifespan in good health. Through this study, we aimed to identify regional disparities in the gap between HALE and life expectancy, considering the trends that have changed over time in Korea. METHODS: We employed a group-based multi-trajectory modeling approach to capture trends in the gap between HALE and life expectancy at the regional level from 2008 to 2019. HALE was calculated using incidence-based "years lived with disability." This methodology was also employed in the Korean National Burden of Disease Study. RESULTS: Based on five different information criteria, the most fitted number of trajectory groups was seven, with at least 11 regions in each group. Among the seven groups, one had an exceptionally large gap between HALE and life expectancy compared to that of the others. This group was assigned to 17 regions, of which six were metropolitan cities. CONCLUSION: Based on the results of this study, we identified regions in which health levels have deteriorated over time, particularly within specific areas of metropolitan cities. These findings can be used to design comprehensive policy interventions for community health promotion and urban regeneration projects in the future.

Investigation of the Efficacy of Benzylidene-3-methyl-2-thioxothiazolidin-4-one Analogs with Antioxidant Activities on the Inhibition of Mushroom and Mammal Tyrosinases.

Based on the fact that substances with a ß-phenyl-α,ß-unsaturated carbonyl (PUSC) motif confer strong tyrosinase inhibitory activity, benzylidene-3-methyl-2-thioxothiazolidin-4-one (BMTTZD) analogs 1-8 were prepared as potential tyrosinase inhibitors. Four analogs (1-3 and 5) inhibited mushroom tyrosinase strongly. Especially, analog 3 showed an inhibitory effect that was 220 and 22 times more powerful than kojic acid in the presence of l-tyrosine and l-dopa, respectively. A kinetic study utilizing mushroom tyrosinase showed that analogs 1 and 3 competitively inhibited tyrosinase, whereas analogs 2 and 5 inhibited tyrosinase in a mixed manner. A docking simulation study indicated that analogs 2 and 5 could bind to both the tyrosinase active and allosteric sites with high binding affinities. In cell-based experiments using B16F10 cells, analogs 1, 3, and 5 effectively inhibited melanin production; their anti-melanogenic effects were attributed to their ability to inhibit intracellular tyrosinase activity. Moreover, analogs 1, 3, and 5 inhibited in situ B16F10 cellular tyrosinase activity. In three antioxidant experiments, analogs 2 and 3 exhibited strong antioxidant efficacy, similar to that of the positive controls. These results suggest that the BMTTZD analogs are promising tyrosinase inhibitors for the treatment of hyperpigmentation-related disorders.

Herpes Zoster Reactivation After mRNA and Adenovirus-Vectored Coronavirus Disease 2019 Vaccination: Analysis of National Health Insurance Database.

BACKGROUND: Our study aimed to determine the risk of herpes zoster reactivation and coronavirus disease 2019 (COVID-19) vaccination (mRNA vaccine [BNT162b2] and adenovirus-vectored vaccine [ChAdOx1 nCoV-19]). METHODS: This retrospective study analyzed herpes zoster cases diagnosed between 26 February 2021 and 30 June 2021 and registered in the National Health Insurance Service database. A matched case-control study with a 1:3 matching ratio and a propensity score matching (PSM) study with a 1:1 ratio of vaccinated and unvaccinated individuals were performed. RESULTS: In the matched case control analysis, BNT162b2 was associated with an increased risk of herpes zoster reactivation (first dose adjusted odds ratio [aOR], 1.11; 95% confidence interval [CI], 1.06-1.15; second dose aOR, 1.17; 95% CI, 1.12-1.23). PSM analysis revealed a statistically significant increase in risk within 18 days following any vaccination (adjusted hazard ratio [aHR], 1.09; 95% CI, 1.02-1.16). BNT162b2 was associated with an increased risk at 18 days postvaccination (aHR, 1.65; 95% CI, 1.35-2.02) and second dose (aHR, 1.10; 95% CI, 1.02-1.19). However, the risk did not increase in both analyses of ChAdOx1 vaccination. CONCLUSIONS: mRNA COVID-19 vaccination possibly increases the risk of herpes zoster reactivation, and thus close follow-up for herpes zoster reactivation is required.

Incidence of and risk factors for myelodysplastic syndromes in patients with rheumatologic diseases.

OBJECTIVE: We investigated the incidence rate and risk factors of myelodysplastic syndromes (MDS) in patients with rheumatologic disease. METHODS: We conducted a retrospective cohort study of patients who were diagnosed with rheumatologic diseases at a tertiary-care hospital between May 2009 and July 2022 and identified the patients who were subsequently diagnosed with MDS. Each patient with MDS was matched with five age- and sex-matched controls chosen from the cohort of patients with each specific rheumatologic disease. RESULTS: During a total follow-up of 55 841 person-years (PY), MDS occurred in 64 patients, yielding an incidence rate of 1.15/1000 PY (median age, 57.0 [IQR, 41.0-69.0]; median duration to MDS diagnosis, 6.5 years [IQR, 3.0-9.0]). In an age-matched analysis, systemic lupus erythematosus (SLE) was a significant risk factor for MDS (adjusted hazard ratio, 2.61 [CI, 1.19-36.06], P= 0.01). Refractory cytopenia with multilineage dysplasia was the most common phenotype of MDS (35.9%), and more than half of the patients had karyotypes with favorable prognoses (54.7%). Compared with matched controls, rheumatoid arthritis, SLE, and ankylosing spondylitis patients with MDS had lower levels of haemoglobin at the time of diagnosis of rheumatologic disease. Furthermore, the MDS patients with SLE and Behcet's disease had higher levels of glucocorticoid use in terms of frequency of use or mean dose than the control patients. CONCLUSION: SLE is a significant risk factor for MDS among patients with rheumatologic diseases. A lower haemoglobin level at the time of diagnosis of rheumatologic disease was associated with the future development of MDS.

COVID-19 Vaccination Status Among Korean Pediatric Population With Comorbidities.

The pediatric population with comorbidities is a high-risk group for severe coronavirus disease 2019 (COVID-19). As of January 2023, the COVID-19 vaccination rate for at least two doses among Korean children 5-11 years is low at 1.1%. We summarized the COVID-19 vaccination status for the pediatric population (5-17 years) with comorbidities through July 2022 using the National Health Insurance Service database. Pediatric patients with comorbidities had higher vaccination rates than the general pediatric population (2.4% vs. 1.1% in 5-11-year-olds [P < 0.001], 76.5% vs. 66.1% in 12-17-year-olds [P < 0.001]). However, there were substantial differences according to comorbidity category, and the 2-dose vaccination rate was lowest among children with immunodeficiency in all age groups (1.1% in 5-11-year-olds, 51.2% in 12-17-year-olds). The COVID-19 vaccination rate among Korean children has remained stagnant at a low proportion despite ongoing outreach. Thus, more proactive strategies are needed alongside continuous surveillance.

Relevance Index Regional Variation by Each Disease and Its Essential Medical Field: A Retrospective Data Analysis From 2016-2020 in Korea.

BACKGROUND: To precisely build a healthcare delivery system at regional levels, local patients' healthcare service utilization patterns must be examined. Hence, this study utilized trend analysis of the relevance index of each disease of each essential medical service field at the municipal and provincial levels. METHODS: This study analyzed customized databases released by the National Health Insurance Service from 2016-2020. Diseases defined in the Korean National Burden of Disease (KNBD) study were categorized into the following essential medical service fields: trauma care, cardiocerebrovascular, maternal and neonatal, mental health, infection, cancer, older adults' care and rehabilitation, and others. Relevance index, the percentage of medical service utilization in a region by the residents of that region relative to their total medical service utilization, was examined by region (17 municipal and provincial regions) and disease area. The relevance index was determined based on the number of patients and the total out-of-pocket expenses. RESULT: Eight of the 17 regions showed over a 90.0% relevance index in the infection area. In the cancer area, 14 regions (not including Seoul, Daegu, and Busan) had a relevance index lower than 75.0%. Throughout the analysis period (2016-2020), there were no significant variations in the relevance index. Diseases such as bone and connective tissue cancer (39.0%), neural tube defects (16.7%), and autism (57.1%) had low relevance index in the essential medical service fields. In all 17 regions, the relevance index of inpatients was lower than that of outpatients, and that for out-of-pocket expenses was lower than that based on the number of patients. CONCLUSION: The relevance index of major diseases of each essential medical service field calculated in this study can provide good indicators for monitoring the level of an independent regional healthcare delivery system.

Nationwide Trends in Non-COVID-19 Infectious Disease Laboratory Tests in the Era of the COVID-19 Pandemic in Korea.

The coronavirus disease 2019 pandemic has brought significant changes to infectious disease management globally. This study explored changes in clinical microbiological testing trends and their implications for infectious disease incidence and medical utilization during the pandemic. We collected nationwide claims for monthly clinical microbiology tests from January 2018 to March 2022 using the National Health Insurance Service database. Seasonal autoregressive integrated moving average models were employed to make predictions for each disease based on the baseline period (January 2018 to January 2020). The results showed a significant decrease in general bacterial and fungal cultures, respiratory infectious disease-related, and inflammatory markers, while the representatives of tests for vector-borne diseases, healthcare-associated infections, and chronic viral infections remained stable. The study highlights the potential of clinical microbiological testing trends as an additional surveillance tool and offers implications for future infectious disease management and surveillance strategies in pandemic settings.

Erratum: Correction of Authors in the Article "Relevance Index Regional Variation by Each Disease and Its Essential Medical Field: A Retrospective Data Analysis From 2016-2020 in Korea".

This corrects the article on p. e130 in vol. 38, PMID: 37096313.

Comparison of Trends in the Incidence of Traumatic Spinal Cord Injury in Daily Life, Automobile Accidents, and Industrial Accidents: A National Multi-Insurance Study in Korea.

BACKGROUND: To examine the incidence of traumatic spinal cord injury (TSCI) from all etiologies, we measured and compared the incidence of TSCI from three national or quasi-national databases in South Korea, namely, the National Health Insurance Service (NHIS), automobile insurance (AUI), and Industrial Accident Compensation Insurance (IACI). METHODS: We reviewed patients with TSCI reported in the NHIS database between 2009 and 2018, and in the AUI and IACI databases between 2014 and 2018. TSCI patients were defined as those first admitted to the hospital with a diagnosis of TSCI according to the International Classification of Diseases (10th revision) criteria. Age-adjusted incidence was calculated using direct standardization using the 2005 South Korean population or the 2000 US population as the standard population. The annual percentage changes (APC) of TSCI incidence were calculated. The Cochrane-Armitage trend test was performed according to the injured body region. RESULTS: In the NHIS database, age-adjusted TSCI incidence using the Korean standard population increased significantly from 2009 to 2018 (from 33.73 per million in 2009 to 38.14 per million in 2018, APC = 1.2%, P = 0.014). Contrarily, age-adjusted incidence in the AUI database significantly decreased from 13.88 per million in 2014 to 11.57 per million in 2018 (APC = - 5.1%, P = 0.009). In the IACI database, the age-adjusted incidence showed no significant difference, while crude incidence showed a significant increase (from 22.02 per million in 2014 to 28.92 per million in 2018, APC = 6.1%, P = 0.038). According to the age group, all the three databases showed high incidences of TSCI in those in their 60s and 70s or older. Among those in their 70s or older, the incidence of TSCI increased dramatically in the NHIS and IACI databases, while no significant trend was found in AUI database. In 2018, the number of TSCI patients was the highest among those over 70 years of age in the NHIS, whereas among those in their 50s were the highest in both AUI and IACI. The proportion of patients with cervical spinal cord injury was the most common in all these databases. CONCLUSIONS: The differences in trends in the incidence of TSCI may be due to the different etiologies and different characteristics of subjects depending on insurance type. These results imply the need for tailored medical strategies for the different injury mechanisms represented by three national insurance services in South Korea.

Striatal Subregion Analysis Associated with REM Sleep Behavior Disorder in Parkinson's Disease.

BACKGROUND AND PURPOSE: REM sleep behavior disorder (RBD) in Parkinson's disease (PD) is associated with characteristic clinical subtypes and prognosis. In addition, nigrostriatal pathway, the most vulnerable anatomical area in PD, formed neuronal network interplaying with cortical and subcortical structures, and which may cause PD clinical phenotype. We evaluated the regional selectivity of presynaptic striatal dopaminergic denervation associated with RBD in PD. METHODS: We compared two groups (n = 16) of PD patients with and without RBD in terms of specific binding ratios (SBR) in subregions of the striatum, which were measured using positron emission tomography with 18F-FP-CIT. SBRs of the anterior and posterior caudate, ventral striatum, and posterior and ventral putamen regions were measured in more or less affected side, and right or left side, or bilateral sum of the striatum. RESULTS: Age, disease duration, and severity of parkinsonism were not significantly different between groups. Although group differences in all areas were not significant with multiple comparison corrections, SBR of the ventral striatum and anterior caudate in sum of both sides was significantly less in the RBD than in the non-RBD group without correction (p < 0.05). In the right anterior caudate and left ventral striatum, SBR was also lower in the RBD than in the non-RBD group without correction (p < 0.05). Attention function was impaired in the RBD group compared with the non-RBD group (p < 0.05). However, these statistical significances were not definite after correction of multiple comparisons (p > 0.05). CONCLUSIONS: There is a possibility that RBD in early PD may be associated with presynaptic dopaminergic denervation in the ventral striatum and anterior caudate, which may explain decreased attention in our RBD group. RBD in PD may imply a distinct pathological progression. However, further study using large numbers of participants or longitudinal observation is necessary for the statistical conclusion because of small sample size.

Mesenchymal Stromal Cells Primed by Toll-like Receptors 3 and 4 Enhanced Anti-Inflammatory Effects against LPS-Induced Macrophages via Extracellular Vesicles.

Although it has been suggested that toll-like receptor (TLR) 3 and TLR4 activation alters mesenchymal stromal cells (MSCs)' immunoregulatory function as anti- or pro-inflammatory phenotypes, we have previously confirmed that TLR4-primed hUCB-MSCs alleviate lung inflammation and tissue injury in an E. coli-induced acute lung injury (ALI) mouse model. Therefore, we hypothesized that strong stimulation of TLR3 or TLR4 prompts hUCB-MSCs to exhibit an anti-inflammatory phenotype mediated by extracellular vesicles (EVs). In this study, we compared the anti-inflammatory effect of TLR3-primed and TLR4-primed hUCB-MSCs against an LPS-induced ALI in vitro model by treating MSCs, MSC-derived conditioned medium (CM), and MSC-derived extracellular vesicles (EVs). LPS-induced rat primary alveolar macrophage and RAW 264.7 cells were treated with naïve, TLR3-, and TLR4-primed MSCs and their derived CM and EVs. Flow cytometry and ELISA were used to evaluate M1-M2 polarization of macrophages and pro-inflammatory cytokine levels, respectively. LPS-stimulated macrophages showed significantly increased pro-inflammatory cytokines compared to those of the normal control, and the percentage of M2 macrophage phenotype was predominantly low. In reducing the inflammatory cytokines and enhancing M2 polarization, TLR3- and TLR4-primed MSCs were significantly more effective than the naïve MSCs, and this finding was also observed with the treatment of MSC-derived CMs and EVs. No significant difference between the efficacy of TLR3- and TLR-primed MSCs was observed. Strong stimulation of TLR3- and TLR4-stimulated hUCB-MSCs significantly reduced pro-inflammatory cytokine secretion from LPS-induced macrophages and significantly enhanced the M2 polarization of macrophages. We further confirmed that TLR-primed MSC-derived EVs can exert anti-inflammatory and immunosuppressive effects alone comparable to MSC treatment. We hereby suggest that in the LPS-induced macrophage in vitro model, EVs derived from both TLR3 and TLR4-primed MSCs can be a therapeutic candidate by promoting the M2 phenotype.

Forsythiaside A Activates AMP-Activated Protein Kinase and Regulates Oxidative Stress via Nrf2 Signaling.

Forsythiaside A (FA) is an active constituent isolated from Forsythia suspensa, a beneficial herb used in traditional medicine known for its antioxidant and anti-inflammatory properties. Although various studies have suggested that FA has the protective effects, its impacts on arachidonic acid (AA) plus iron in vitro models and carbon tetrachloride (CCl4)-induced mouse liver damage in vivo have not been explored. In this study, HepG2 cells were subjected to AA + iron treatment to induce apoptosis and mitochondrial impairment and determine the molecular mechanisms. FA exhibited protective effects by inhibiting cell damage and reactive oxygen species (ROS) production induced by AA + iron, as assessed via immunoblot and flow cytometry analyses. Further molecular investigations revealed that FA resulted in the activation of extracellular-signal-related protein kinase (ERK), which subsequently triggered the activation of AMP-activated protein kinase (AMPK), a critical regulator of cellular oxidative stress. Additionally, FA modulated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which is a significant antioxidant transcription factor regulated by the AMPK pathway. For in vivo studies, mice were orally administered FA and then subjected to induction of CCl4-based hepatotoxicity. The protective effect of FA was confirmed via blood biochemistry and immunohistochemical analyses. In conclusion, our findings demonstrated the protective effects of FA against oxidative stress both in vitro and in vivo, thus indicating that FA is a potential candidate for liver protection. Our study sheds light on the mechanistic pathways involved in the antioxidant effects of FA, highlighting the hepatoprotective potential of naturally occurring compounds in traditional herbs, such as FA.

SOCS3 Protein Mediates the Therapeutic Efficacy of Mesenchymal Stem Cells against Acute Lung Injury.

Mesenchymal stem cells (MSCs) have been studied as novel therapeutic agents because of their immunomodulatory properties in inflammatory diseases. The suppressor of cytokine signaling (SOCS) proteins are key regulators of the immune response and macrophage modulation. In the present study, we hypothesized that SOCS in MCSs might mediate macrophage modulation and tested this in a bacteria-induced acute lung injury (ALI) mouse model. The macrophage phenotype was observed in RAW264.7 alveolar macrophages exposed to lipopolysaccharide (LPS) in an in vitro model, and in the ALI mouse model induced by tracheal administration of Escherichia coli (1 × 107 CFU in 0.05mL PBS). In LPS-exposed RAW264.7 cells, the levels of markers of M1 macrophages, such as CD86 and pro-inflammatory cytokines (IL-1α, IL-1ß, IL-6 and TNF-α), significantly increased, but they significantly reduced after MSC treatment. Meanwhile, the levels of markers of M2 macrophages, such as CD204 and anti-inflammatory cytokines (IL-4 and IL-10), increased after LPS exposure, and further significantly increased after MSC treatment. This regulatory effect of MSCs on M1/M2 macrophage polarization was significantly abolished by SOCS3 inhibition. In the E. coli-induced ALI model, tissue injury and inflammation in the mouse lung were significantly attenuated by the transplantation of MSCs, but not by SOCS3-inhibited MSCs. The regulatory effect of MSCs on M1/M2 macrophage polarization was observed in the lung injury model but was significantly abolished by SOCS3 inhibition. Taken together, our findings suggest that SOCS3 is an important mediator for macrophage modulation in anti-inflammatory properties of MSCs.