Lupus flare and recurrent lupus nephritis following kidney transplantation in patients with lupus nephritis.

BACKGROUND: Clinical manifestations and risk factors associated with systemic lupus erythematosus (SLE) flares, including recurrent lupus nephritis (LN), in patients with LN who undergo kidney transplantation have been unclear. METHODS: Kidney transplant recipients with LN from January 1995 to December 2021 were included in this study. A disease flare was defined as either an increase in the non-renal SLE disease activity index score or the presence of biopsy-proven recurrent LN. RESULTS: Among a total of 93 patients with LN who underwent kidney transplantation, 11 patients (11.8%) experienced SLE flares during a median follow-up period of 76.9 months (IQR, 43.0-122.4). The most common clinical manifestations of SLE flares were recurrent LN (4/11, 36.4%) and hematologic manifestations (4/11, 36.4%). Patients who had flares had significantly higher anti-double-stranded DNA (anti-dsDNA) antibody titers both before and after transplantation. Furthermore, an increased anti-dsDNA antibody level before transplantation was associated with a high risk of an SLE flare (HR, 1.030; p = .008). Conversely, preemptive transplantation was associated with a lower risk of a flare (HR, 0.617; p = .026). The rate of patient death-censored graft survival was found to be considerably lower in patients with recurrent LN than in those without LN. CONCLUSIONS: Approximately 10% of patients with LN experienced an SLE flare after transplantation, with recurrent LN being the most frequent manifestation. Anti-dsDNA antibody titers before transplantation were significantly related to the risk of an SLE flare. Notably, preemptive transplantation was associated with a reduced risk of flares following transplantation.

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.

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.

Safety of herbal medicine in the postpartum period of a Korean Medicine hospital and postpartum care centre: protocol of a registry study (SAFEHERE-PC).

INTRODUCTION: Herbal medicines (HMs) are commonly used during the postpartum period in South Korea. However, the safety concerns associated with these medicines remain unresolved. This study aims to establish a registry of patients receiving HM treatment during the postpartum period and collect clinical data on treatments and adverse reactions to build evidence evaluating the safety of HM use. METHODS AND ANALYSIS: This study will use a prospective observational registry, including patients admitted to the obstetrics and gynaecology department of the Woosuk University Korean Medicine Hospital's postpartum care centre. A total of 1000 eligible patients visiting the Korean medicine hospital to recover from various postchildbirth symptoms and opting for HM treatment will be enrolled in the registry. For safety assessment, demographic information, medical history, adverse events (AEs) and treatment details, including HM prescription and concomitant medication usage, will be collected throughout the patient's hospitalisation period at the postpartum care centre for analysis. Adverse reactions will be monitored daily during hospitalisation, and collected AEs will be analysed for causality using the WHO Uppsala Monitoring Centre causality assessment and the Naranjo Algorithm Score. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board of Woosuk University Korean Medicine Medical Center (WSOH IRB H2311-03-01). The results will be published in peer-reviewed journals or disseminated through conference presentations. TRIAL REGISTRATION NUMBER: KCT0009060.

Variability in Paralytic Shellfish Toxin Profiles and Dinoflagellate Diversity in Mussels and Seawater Collected during Spring in Korean Coastal Seawater.

Paralytic shellfish toxins (PSTs) are potent neurotoxins produced by certain microalgae, particularly dinoflagellates, and they can accumulate in shellfish in coastal seawater and thus pose significant health risks to humans. To explore the relationship between toxicity and PST profiles in seawater and mussels, the spatiotemporal variations in PST concentrations and profiles were investigated along the southern coast of Korea under peak PST levels during spring. Seawater and mussel samples were collected biweekly from multiple stations, and the toxin concentrations in the samples were measured. Moreover, the dinoflagellate community composition was analyzed using next-generation sequencing to identify potential PST-producing species. The PST concentrations and toxin profiles showed substantial spatiotemporal variability, with GTX1 and GTX4 representing the dominant toxins in both samples, and C1/2 tending to be higher in seawater. Alexandrium species were identified as the primary sources of PSTs. Environmental factors such as water temperature and salinity influenced PST production. This study demonstrates that variability in the amount and composition of PSTs is due to intricate ecological interactions. To mitigate shellfish poisoning, continuous monitoring must be conducted to gain a deeper understanding of these interactions.

Korean National Burden of Disease: The Importance of Diabetes Management.

Diagnosing the current health status and disease burden in a population is crucial for public health interventions. The ability to compare the burden of different diseases through a single measure, such as disability-adjusted life years has become feasible and continues to be produced and updated through the Global Burden of Diseases (GBD) study. However, the disease burden values of the GBD study do not accurately reflect the unique situation in a specific country with various circumstances. In response, the Korean National Burden of Disease (KNBD) study was conducted to estimate the disease burden in Koreans by considering Korea's cultural context and utilizing the available data sources at the national level. Both studies identified non-communicable diseases, such as diabetes mellitus (DM), as the primary cause of disease burden among Koreans. However, the extent of public health interventions currently being conducted by the central and local governments does not align with the severity of the disease burden. This review suggests that despite the high burden of DM in South Korea, the current policies may not fully address its impact, underscoring the need for expanded chronic disease management programs and a shift towards prevention-focused healthcare paradigms.

Enhanced astaxanthin production in Haematococcus lacustris by electrochemical stimulation of cyst germination.

This study investigated the technical feasibility of using electrogermination to activate dormant cysts as an inoculum for subsequent 14-d photosynthetic astaxanthin production in Haematococcus lacustris. Electrotreatment affected the cell viability, surface charge, and morphology of H. lacustris cysts. At an optimal voltage of 2 V for 60 min, the cyst germination rate peaked at 44.6 % after 1 d, representing a 2.2-fold increase compared with that of the untreated control. Notably, electrogermination significantly enhanced both the astaxanthin content (44.9 mg/g cell) and productivity (13.2 mg/L/d) after 14 d of photobioreactor cultivation, corresponding to 1.7- and 1.5-fold increases compared with those in control, respectively. However, excessive electrotreatment, particularly at voltages exceeding 2 V or for durations beyond 60 min, did not enhance the astaxanthin production capability of H. lacustris. Proper optimization of renewable electrogermination can enable sustainable algal biorefinery to produce multiple bioactive products without compromising cell viability and astaxanthin productivity.

Incidence of Panic Disorder Diagnoses After Celebrity Disclosures of Panic Disorder in South Korea.

Importance: The persistent stigma associated with mental health conditions is a major challenge worldwide. Celebrities may improve this by openly discussing their own mental health issues, potentially influencing public attitudes and encouraging individuals to seek treatment for these conditions. Objective: To evaluate the impact of celebrity mental health disclosures on the incidence and prevalence of panic disorder diagnosis in South Korea. Design, Setting, and Participants: This cohort study included the entire South Korean population from January 2004 to December 2021, as reflected in the National Health Insurance Service data. Analysis was conducted from May 2022 through January 2024. Exposure: Time periods analyzed included the timeframe before (from January 2004 to December 2010) and after the public disclosures of panic disorder by 3 high-profile Korean celebrities between December 2010 and January 2012 (from January 2011 to December 2021). Main Outcomes and Measures: Monthly incidence and prevalence of panic disorder, defined by the presence of a clinical diagnosis of the condition. Trends were assessed using interrupted time series analysis with autoregressive integrated moving average models. To assess public interest in panic disorder, trends in search data were analyzed, examining the association between the timing of increased searches and changes in the incidence and prevalence of panic disorder. Data on obsessive-compulsive disorder (OCD) were included as a control. Results: The study covered the entire population of South Korea, including 48 559 946 individuals in January 2004 and 52 593 886 individuals in December 2021. Before 2011, the mean (SD) annual prevalence of panic disorder was stable at 560 (140) persons per 100 000 persons per year. The celebrity disclosure in December 2010 was associated with higher monthly incidence rates of panic disorder, as measured by insurance claims data, changes that were observed in both the level (5.8 persons; 95% CI, 2.2-9.5 persons) and slope (0.78 persons per month; 95% CI, 0.19-1.40 persons per month) per 100 000 persons. By 2021, the observed annual prevalence per 100 000 persons reached 7530 persons, an increase of 775.6% compared with the 860 persons (95% CI, 330-1400 persons) estimated if the disclosures had not occurred. Internet searches anticipated changes in monthly prevalence with a lag of 2 or 3 months (F = 4.26, P = .02 and F = 3.11, P = .03, respectively). The celebrity disclosures had no significant association with the incidence or prevalence of OCD. Conclusions and Relevance: In this observational cohort study, celebrity disclosure of mental health conditions was associated with a sustained reduction in stigma, as reflected in increased help-seeking behavior for the condition over more than a decade. This underscores the influential role celebrities can play in shaping public health perceptions and behaviors, offering valuable insights for the development of future mental health policies and public awareness campaigns.

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.

Establishment of a Dataset for the Traditional Korean Medicine Examination in Healthy Adults.

We established a protocol for the traditional Korean medicine examination (KME) and methodically gathered data following this protocol. Potential indicators for KME were extracted through a literature review; the first KME protocol was developed based on three rounds of expert opinions. The first KME protocol's feasibility was confirmed, and data were collected over four years from traditional Korean medicine (KM) hospitals, focusing on healthy adults, using the final KME protocol. A literature review identified 175 potential core indicators, condensed into 73 indicators after three rounds of expert consultation. The first KME protocol, which was categorized under questionnaires and medical examinations, was developed after the third round of expert opinions. A pilot study using the first KME protocol was conducted to ensure its validity, leading to modifications resulting in the development of the final KME protocol. Over four years, data were collected from six KM hospitals, focusing on healthy adults; we obtained a dataset comprising 11,036 healthy adults. This is the first protocol incorporating core indicators of KME in a quantitative form and systematically collecting data. Our protocol holds potential merit in evaluating predisposition to diseases or predicting diseases.

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.

The secreted protein Amuc_1409 from Akkermansia muciniphila improves gut health through intestinal stem cell regulation.

Akkermansia muciniphila has received great attention because of its beneficial roles in gut health by regulating gut immunity, promoting intestinal epithelial development, and improving barrier integrity. However, A. muciniphila-derived functional molecules regulating gut health are not well understood. Microbiome-secreted proteins act as key arbitrators of host-microbiome crosstalk through interactions with host cells in the gut and are important for understanding host-microbiome relationships. Herein, we report the biological function of Amuc_1409, a previously uncharacterised A. muciniphila-secreted protein. Amuc_1409 increased intestinal stem cell (ISC) proliferation and regeneration in ex vivo intestinal organoids and in vivo models of radiation- or chemotherapeutic drug-induced intestinal injury and natural aging with male mice. Mechanistically, Amuc_1409 promoted E-cadherin/ß-catenin complex dissociation via interaction with E-cadherin, resulting in the activation of Wnt/ß-catenin signaling. Our results demonstrate that Amuc_1409 plays a crucial role in intestinal homeostasis by regulating ISC activity in an E-cadherin-dependent manner and is a promising biomolecule for improving and maintaining gut health.

Mesenchymal Stem Cells Reduce the Extracellular Mitochondrial DNA-Mediated TLR9 Activation in Neonatal Hyperoxia-Induced Lung Injury.

Mitochondrial DNA (mtDNA) released from dead or injured cells can activate inflammation, and mesenchymal stem cell (MSC) transplantation can reduce inflammation and injury. However, it has not been tested whether the release of mtDNA can be reduced by MSC transplantation. We hypothesized that the level of extracellular mtDNA would be increased after hyperoxia-induced lung injury but reduced after lung injury attenuation by MSC therapy in our newborn rat model. In an in vitro study using a rat lung epithelial L2 cell line, we found that the level of extracellular mtDNA was significantly increased with H2O2-induced cell death but reduced after MSC co-incubation. In an in vivo study, we confirmed that the levels of cell death, extracellular mtDNA, and inflammatory cytokines were significantly increased in hyperoxic newborn rat lungs but reduced after MSC transplantation. The levels of extracellular mtDNA were significantly and positively correlated with the levels of the inflammatory cytokines. The TLR9/MyD88/NF-κB pathway, which is activated by binding to mtDNA, was also significantly upregulated but downregulated after MSC transplantation. We found a significant positive correlation between inflammatory cytokines and extracellular mtDNA in intubated neonates. The levels of inflammatory cytokines and extracellular mtDNA changed over time in a similar pattern in transtracheal aspirate samples from intubated neonates. In conclusion, increased levels of extracellular mtDNA are associated with increased inflammation in hyperoxia-induced lung injury, and attenuation of lung inflammation by MSC therapy is associated with reduced levels of extracellular mtDNA.

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.

Vaccination and the risk of post-acute sequelae after COVID-19 in the Omicron-predominant period.

OBJECTIVES: To assess the association of primary and third doses of vaccination with the risk of post-acute sequelae of COVID-19. METHODS: This retrospective cohort study utilized a combined database of nationwide health care claims data, COVID-19 patient registry, and vaccination records from South Korea. Individuals diagnosed with COVID-19 in the Omicron variant-dominant period of January-March 2022 were tracked for 30-120 days post-infection. The exposure of interest was the receipt of primary and third doses of the SARS-CoV-2 vaccine. The occurrence of 26 specific conditions in eight domains was compared using Cox regression with inverse probability of treatment weighting. RESULTS: This study included 394 773 unvaccinated individuals and 7 604 081 individuals receiving ≥2 doses of vaccine. Compared with unvaccinated individuals, vaccination with at least two doses was associated with a reduced risk (adjusted hazard ratio; 95% CI) of several conditions, including ischaemic heart disease (0.73; 0.57-0.94), heart failure (0.55; 0.48-0.63), cardiac dysrhythmia (0.72; 0.61-0.85), cardiac arrest (0.41; 0.33-0.51), pulmonary embolism (0.66; 0.52-0.84), venous thromboembolism (0.54; 0.44-0.66), acute renal failure (0.56; 0.46-0.67), new dialysis (0.45; 0.34-0.59), chronic obstructive pulmonary disease (0.74; 0.65-0.84), acute pancreatitis (0.64; 0.51-0.80), and diabetes (0.82; 0.71-0.95). The risks of heart failure, cardiac dysrhythmias, cardiac arrest, pulmonary embolism, and new dialysis were lower in those who were vaccinated with three doses compared with those who were vaccinated with two doses. DISCUSSION: Vaccination was associated with a decreased risk of post-acute sequelae of COVID-19, suggesting its potential role in mitigating the indirect impacts of COVID-19.

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.

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.

Microglial inhibition alleviates alpha-synuclein propagation and neurodegeneration in Parkinson's disease mouse model.

The accumulation of alpha-synuclein (αSyn) is widely recognized as the main pathological process in Parkinson's disease (PD). Additionally, neuroinflammation is considered to be one of the contributing mechanisms in the development of PD. In light of this, it is hypothesized that the reactive microglia exacerbate the propagation of αSyn and neurodegeneration, while the inhibition of microglial activity may mitigate these effects. To test this hypothesis, αSyn preformed fibrils (PFF)-injected PD mouse model was employed. Co-injection of lipopolysaccharide (LPS) and PFF was performed to investigate if microglial reactivity intensified αSyn propagation and neurodegeneration. Additionally, oral administration of PLX5622, a microglial inhibitor that targets the colony-stimulating factor 1 receptor, was given for two weeks before and after PFF injection each to explore if microglial inhibition could prevent or reduce αSyn pathology. Intrastriatal co-injection of LPS and PFF resulted in increased microglial reactivity, αSyn accumulation, and neurodegeneration compared to PFF injection alone. However, treatment with PLX5622 significantly suppressed microglial reactivity, reduced αSyn pathology, and alleviated dopaminergic neuron degeneration in the PD mouse model injected with PFF. Based on these findings, it is evident that microglial reactivity plays a crucial role in the progression of αSyn pathology and neurodegeneration in PD. Furthermore, the results suggest that microglial inhibition may hold promise as a therapeutic strategy to delay the progression of αSyn pathology in PD.