Mitigation of Soil Erosion and Enhancement of Slope Stability through the Utilization of Lignin Biopolymer.

Human activities have had a profound impact on the environment, particularly in relation to surface erosion and landslides. These processes, which are natural phenomena, have been exacerbated by human actions, leading to detrimental consequences for ecosystems, communities, and the overall health of the planet. The use of lignin (LIG) as a biopolymer soil additive material is regarded as an eco-friendly solution against soil erosion and slope failure which holds immense promise. However, significant research gaps currently hinder a comprehensive understanding of its mechanisms and effectiveness. Experimental studies offer a robust platform to address these gaps by providing controlled conditions for assessing soil stability, exploring mechanisms, and evaluating adaptability. Bridging these research gaps will contribute to the development of innovative and sustainable strategies for mitigating soil erosion and preventing slope failure, thereby promoting environmental resilience and resource conservation. This study aimed to investigate the effect of the LIG biopolymer on mitigation of soil erosion, slope failure and the enhancement of soil strength by conducting laboratory tests (UU triaxial, unconfined compressive strength (UCS), and soaking) as well as flume experiments under uniform rainfall events. The alterations in the engineering characteristics and erosion resistance of silty soil mixed with a LIG additive at concentrations of 1% and 3.0% by weight have been examined. The results show that the LIG-treated samples demonstrated an enhanced resistance to surface erosion and an enhanced prevention of slope failure, as well as improved shear stress, cohesion, stiffness, and resistance to water infiltration.

Bactericidal Effects and Quality Impact of Peroxyacetic Acid and Sodium Hypochlorite on Chicken Carcasses.

There is an urgent need to develop efficient and environmentally friendly decontaminants for poultry products. In this study, we aimed to evaluate the practical application of peroxyacetic acid (PAA) as a replacement for sodium hypochlorite (SH) to sterilize fresh chicken carcasses, using microbial, color, and electronic-nose analyses. We evaluated the decontamination effects of different concentrations of PAA and SH on chicken carcasses. The bactericidal effects of PAA at pH 3, 7, and 9, and SH at pH 10, at concentrations ranging from 100 to 500 ppm on coliform bacteria, total bacteria, and Salmonella spp. were evaluated. PAA induced a similar bactericidal effect at lower concentrations than SH. Therefore, at the same concentration and treatment time, PAA showed better bactericidal effects than SH. Although treatment with PAA (pH 3) and SH (pH 10) resulted in considerable discoloration, the degree of discoloration decreased when the pH of PAA was increased to 7 and 9. Therefore, by increasing the pH of PAA, the discoloration effect on chicken carcasses can be reduced without altering the microbial-reduction effect. Electronic-nose analysis showed that the flavor of the chicken was almost unaffected by volatile components at a treatment time < 30 min. Therefore, this study experimentally identified the optimal PAA concentration for the decontamination of chicken carcasses. The study findings provide a theoretical basis for the replacement of traditional bactericides, such as SH, with PAA for the production of poultry products.

Age-related cholesterol and colorectal cancer progression: Validating squalene epoxidase for high-risk cases.

As people age, the risk and progression of colorectal cancer (CRC), along with cholesterol levels, tend to increase. Nevertheless, epidemiological studies on serum lipids and CRC have produced conflicting results. We previously demonstrated that the reduction of squalene epoxidase (SQLE) due to accumulated cholesterol within cells accelerates CRC progression through the activation of the ß-catenin pathway. This study aimed to investigate the mechanism by which age-related cholesterol accumulation within tissue accelerates CRC progression and to assess the clinical significance of SQLE in older individuals with elevated CRC risk. Using machine learning-based digital image analysis with fluorescence-immunohistochemistry, we assessed SQLE, GSK3ßpS9 (GSK3ß activity inhibition through serine 9 phosphorylation at GSK3ß), p53 wild-type (p53WT), and p53 mutant (p53MT) levels in CRC tissues. Our analysis revealed a significant reduction in SQLE, p53WT, and p53MT and increase in GSK3ßpS9 levels, all associated with the substantial accumulation of intra-tissue cholesterol in aged CRCs. Cox analysis underscored the significant influence of SQLE on overall survival and progression-free survival in grade 2-3 CRC patients aged over 50. SQLE and GSK3ßpS9 consistently exhibited outstanding prognostic and diagnostic performance, particularly in older individuals. Furthermore, combining SQLE with p53WT, p53MT, and GSK3ßpS9 demonstrated a robust diagnostic ability in the older population. In conclusion, we have identified that individuals aged over 50 face an increased risk of CRC progression due to aging-linked cholesterol accumulation within tissue and the subsequent reduction in SQLE levels. This study also provides valuable biomarkers, including SQLE and GSK3ßpS9, for older patients at elevated risk of CRC.

CM1, a Chrysin Derivative, Protects from Endotoxin-Induced Lethal Shock by Regulating the Excessive Activation of Inflammatory Responses.

Sepsis, a leading cause of death worldwide, is a harmful inflammatory condition that is primarily caused by an endotoxin released by Gram-negative bacteria. Effective targeted therapeutic strategies for sepsis are lacking. In this study, using an in vitro and in vivo mouse model, we demonstrated that CM1, a derivative of the natural polyphenol chrysin, exerts an anti-inflammatory effect by inducing the expression of the ubiquitin-editing protein TNFAIP3 and the NAD-dependent deacetylase sirtuin 1 (SIRT1). Interestingly, CM1 attenuated the Toll-like receptor 4 (TLR4)-induced production of inflammatory cytokines by inhibiting the extracellular-signal-regulated kinase (ERK)/MAPK and nuclear factor kappa B (NF-κB) signalling pathways. In addition, CM1 induced the expression of TNFAIP3 and SIRT1 on TLR4-stimulated primary macrophages; however, the anti-inflammatory effect of CM1 was abolished by the siRNA-mediated silencing of TNFAPI3 or by the genetic or pharmacologic inhibition of SIRT1. Importantly, intravenous administration of CM1 resulted in decreased susceptibility to endotoxin-induced sepsis, thereby attenuating the production of pro-inflammatory cytokines and neutrophil infiltration into the lung compared to control mice. Collectively, these findings demonstrate that CM1 has therapeutic potential for diverse inflammatory diseases, including sepsis.

Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses.

The role of the serine/glycine metabolic pathway (SGP) has recently been demonstrated in tumors; however, the pathological relevance of the SGP in thyroid cancer remains unexplored. Here, we perform metabolomic profiling of 17 tumor-normal pairs; bulk transcriptomics of 263 normal thyroid, 348 papillary, and 21 undifferentiated thyroid cancer samples; and single-cell transcriptomes from 15 cases, showing the impact of mitochondrial one-carbon metabolism in thyroid tumors. High expression of serine hydroxymethyltransferase-2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is associated with low thyroid differentiation scores and poor clinical features. A subpopulation of tumor cells with high mitochondrial one-carbon pathway activity is observed in the single-cell dataset. SHMT2 inhibition significantly compromises mitochondrial respiration and decreases cell proliferation and tumor size in vitro and in vivo. Collectively, our results highlight the importance of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer and suggest that SHMT2 is a potent therapeutic target.

Notch signaling regulates mineralization via microRNA modulation in dental pulp stem cells.

OBJECTIVES: This study investigated the miRNA expression profile in Notch-activated human dental stem pulp stem cells (DPSCs) and validated the functions of miRNAs in modulating the odonto/osteogenic properties of DPSCs. METHODS: DPSCs were treated with indirect immobilized Jagged1. The miRNA expression profile was examined using NanoString analysis. Bioinformatic analysis was performed, and miRNA expression was validated. Odonto/osteogenic differentiation was examined using alkaline phosphatase staining, Alizarin Red S staining, as well as odonto/osteogenic-related gene and protein expression. RESULTS: Fourteen miRNAs were differentially expressed in Jagged1-treated DPSCs. Pathway analysis revealed that altered miRNAs were associated with TGF-ß, Hippo, ErbB signalling pathways, FoxO and Ras signalling. Target prediction analysis demonstrated that 7604 genes were predicted to be targets for these altered miRNAs. Enrichment analysis revealed relationships to various DNA bindings. Among differentially expressed miRNA, miR-296-3p and miR-450b-5p were upregulated under Jagged1-treated conditions. Overexpression of miR-296-3p and miR-450b-5p enhanced mineralization and upregulation of odonto/osteogenic-related genes, whereas inhibition of these miRNAs revealed opposing results. The miR-296-3p and miR-450b-5p inhibitors attenuated the effects of Jagged1-induced mineralization in DPSCs. CONCLUSIONS: Jagged-1 promotes mineralization in DPSCs that are partially regulated by miRNA. The novel understanding of these miRNAs could lead to innovative controlled mechanisms that can be applied to modulate biology-targeted dental materials.

Targeting class A GPCRs for hard tissue regeneration.

G protein-coupled receptors (GPCRs) play important roles in various pathogeneses and physiological regulations. Owing to their functional diversity, GPCRs are considered one of the primary pharmaceutical targets. However, drugs targeting GPCRs have not been developed yet to regenerate hard tissues such as teeth and bones. Mesenchymal stromal cells (MSCs) have high proliferation and multi-lineage differentiation potential, which are essential for hard tissue regeneration. Here, we present a strategy for targeting class A GPCRs for hard tissue regeneration by promoting the differentiation of endogenous MSCs into osteogenic and odontogenic progenitor cells. Through in vitro screening targeted at class A GPCRs, we identified six target receptors (LPAR1, F2R, F2RL1, F2RL2, S1PR1, and ADORA2A) and candidate drugs with potent biomineralization effects. Through a combination of profiling whole transcriptome and accessible chromatin regions, we identified that p53 acts as a key transcriptional activator of genes that modulate the biomineralization process. Moreover, the therapeutic potential of class A GPCR-targeting drugs was demonstrated in tooth pulpotomy and calvarial defect models. The selected drugs revealed potent regenerative effects in both tooth and bone defects, represented by newly formed highly mineralized regions. Consequently, this study provides translational evidence for a new regenerative strategy for damaged hard tissue.

Occlusive membranes for guided regeneration of inflamed tissue defects.

Guided bone regeneration aided by the application of occlusive membranes is a promising therapy for diverse inflammatory periodontal diseases. Symbiosis, homeostasis between the host microbiome and cells, occurs in the oral environment under normal, but not pathologic, conditions. Here, we develop a symbiotically integrating occlusive membrane by mimicking the tooth enamel growth or multiple nucleation biomineralization processes. We perform human saliva and in vivo canine experiments to confirm that the symbiotically integrating occlusive membrane induces a symbiotic healing environment. Moreover, we show that the membrane exhibits tractability and enzymatic stability, maintaining the healing space during the entire guided bone regeneration therapy period. We apply the symbiotically integrating occlusive membrane to treat inflammatory-challenged cases in vivo, namely, the open and closed healing of canine premolars with severe periodontitis. We find that the membrane promotes symbiosis, prevents negative inflammatory responses, and improves cellular integration. Finally, we show that guided bone regeneration therapy with the symbiotically integrating occlusive membrane achieves fast healing of gingival soft tissue and alveolar bone.

Diagnosis of Crohn's disease and ulcerative colitis using the microbiome.

BACKGROUND: Inflammatory bowel disease (IBD) is a multifactorial chronic inflammatory disease resulting from dysregulation of the mucosal immune response and gut microbiota. Crohn's disease (CD) and ulcerative colitis (UC) are difficult to distinguish, and differential diagnosis is essential for establishing a long-term treatment plan for patients. Furthermore, the abundance of mucosal bacteria is associated with the severity of the disease. This study aimed to differentiate and diagnose these two diseases using the microbiome and identify specific biomarkers associated with disease activity. RESULTS: Differences in the abundance and composition of the microbiome between IBD patients and healthy controls (HC) were observed. Compared to HC, the diversity of the gut microbiome in patients with IBD decreased; the diversity of the gut microbiome in patients with CD was significantly lower. Sixty-eight microbiota members (28 for CD and 40 for UC) associated with these diseases were identified. Additionally, as the disease progressed through different stages, the diversity of the bacteria decreased. The abundances of Alistipes shahii and Pseudodesulfovibrio aespoeensis were negatively correlated with the severity of CD, whereas the abundance of Polynucleobacter wianus was positively correlated. The severity of UC was negatively correlated with the abundance of A. shahii, Porphyromonas asaccharolytica and Akkermansia muciniphilla, while it was positively correlated with the abundance of Pantoea candidatus pantoea carbekii. A regularized logistic regression model was used for the differential diagnosis of the two diseases. The area under the curve (AUC) was used to examine the performance of the model. The model discriminated UC and CD at an AUC of 0.873 (train set), 0.778 (test set), and 0.633 (validation set) and an area under the precision-recall curve (PRAUC) of 0.888 (train set), 0.806 (test set), and 0.474 (validation set). CONCLUSIONS: Based on fecal whole-metagenome shotgun (WMS) sequencing, CD and UC were diagnosed using a machine-learning predictive model. Microbiome biomarkers associated with disease activity (UC and CD) are also proposed.

Experimental Validation of the Cementation Mechanism of Wood Pellet Fly Ash Blended Binder in Weathered Granite Soil.

In response to climate change, wood pellets have been increasingly utilized as a sustainable energy source. However, their growing utilization increases the production of wood pellet fly ash (WA) by-products, necessitating alternative recycling technologies due to a shortage of discharging landfills. Thus, this research seeks to utilize WA by developing a new sustainable construction material, called wood pellet fly ash blended binder (WABB), and to validate its stabilizing performance in natural soils, namely weathered granite soil (WS). WABB is made from 50% WA, 30% ground granulated blast-furnace slag (GGBS), and 20% cement by dry mass. WS was mixed with 5%, 15%, and 25% WABB and was tested for a series of unconfined compressive strength (qu), pH, and suction tests at 3, 7, 14, and 28 days. For the microstructural analyses, XRD, SEM, and EDS were employed. As the WABB dosage rate increased, the average qu increased by 1.88 to 11.77, which was higher than that of compacted WS without any binder. Newly cementitious minerals were also confirmed. These results suggest that the effects of the combined hydration mechanism of WABB are due to cement's role in facilitating early strength development, GGBS's latent hydraulic properties, and WA's capacity to stimulate the alkaline components of WABB and soil grains. Thus, this research validates a new sustainable binder, WABB, as a potential alternative to conventional soil stabilizers.

Assessing Health and Economic Benefits of Omega-3 Fatty Acid Supplementation on Cardiovascular Disease in the Republic of Korea.

BACKGROUND: Cardiovascular disease (CVD) is the primary cause of mortality worldwide and imposes a significant social burden on many countries. METHODS: This study assessed the health and economic benefits of omega-3 associated with CVD. The meta-analysis estimated the risk ratio (RR) and absolute risk reduction (ARR), and the economic impact was calculated using direct and indirect costs related to CVD treatments in Korean adults. RESULTS: A total of 33 studies were included in the meta-analysis on CVD outcomes, with 80,426 participants in the intervention group and 80,251 participants in the control group. The meta-analysis determined a significant reduction in omega-3 in CVD (RR = 0.92, 95% CI: 0.86~0.97) and ARR (1.48%). Additionally, the subgroup analysis indicated that higher doses and the long-term consumption of omega-3 could further enhance these effects. After applying ARR from meta-analysis to the target population of about 1,167,370 in 2021, the Republic of Korea, it was estimated that omega-3 consumption could result in an economic benefit of KRW 300 billion by subtracting the purchase expenses of omega-3 supplements from the total social cost savings. CONCLUSION: Omega-3 supplements can help to reduce the risk of CVD and subsequent economic benefits in the Republic of Korea.

Crif1 deficiency in dopamine neurons triggers early-onset parkinsonism.

Mitochondrial dysfunction has been implicated in Parkinson's Disease (PD) progression; however, the mitochondrial factors underlying the development of PD symptoms remain unclear. One candidate is CR6-interacting factor1 (CRIF1), which controls translation and membrane insertion of 13 mitochondrial proteins involved in oxidative phosphorylation. Here, we found that CRIF1 mRNA and protein expression were significantly reduced in postmortem brains of elderly PD patients compared to normal controls. To evaluate the effect of Crif1 deficiency, we produced mice lacking the Crif1 gene in dopaminergic neurons (DAT-CRIF1-KO mice). From 5 weeks of age, DAT-CRIF1-KO mice began to show decreased dopamine production with progressive neuronal degeneration in the nigral area. At ~10 weeks of age, they developed PD-like behavioral deficits, including gait abnormalities, rigidity, and resting tremor. L-DOPA, a medication used to treat PD, ameliorated these defects at an early stage, although it was ineffective in older mice. Taken together, the observation that CRIF1 expression is reduced in human PD brains and deletion of CRIF1 in dopaminergic neurons leads to early-onset PD with stepwise PD progression support the conclusion that CRIF1-mediated mitochondrial function is important for the survival of dopaminergic neurons.

Effect of a multichannel oral irrigator on periodontal health and the oral microbiome.

Oral biofilms or dental plaques are one of the major etiological factors for diverse oral diseases. We aimed to evaluate the effect of a multichannel oral irrigator (MCOI) on periodontal health in 29 participants randomly divided into two groups: the MCOI group and the control group. To evaluate the effect of the MCOI on periodontal health, the modified Quigley Hein Plaque Index (PI), Mühlemann-Son Sulcus Bleeding Index (SBI), bleeding on probing (BOP), and swelling were evaluated and compared before and after MCOI use for 3 days. Although PI and SBI showed statistically significant increases in the control group, the MCOI group showed no significant changes in either parameter. Moreover, the percentage of BOP was significantly lower in the MCOI group. Saliva samples were analyzed by 16s rRNA amplicon sequencing to investigate changes in the oral microbiome. Sequencing results showed that Porphyromonas spp. were significantly increased in the control group, whereas no significant change was detected in the MCOI group. Using the MCOI, enriched populations and functional pathways were detected in pioneer species comprising non-mutans streptococci. These findings provide evidence of the effectiveness of the MCOI in maintaining periodontal health and a healthy microbial ecology in the oral cavity.

Terminal fucosylation of haptoglobin in cancer-derived exosomes during cholangiocarcinoma progression.

Background: Cholangiocarcinoma (CCA) is a silent tumor with a high mortality rate due to the difficulty of early diagnosis and prediction of recurrence even after timely surgery. Serologic cancer biomarkers have been used in clinical practice, but their low specificity and sensitivity have been problematic. In this study, we aimed to identify CCA-specific glycan epitopes that can be used for diagnosis and to elucidate the mechanisms by which glycosylation is altered with tumor progression. Methods: The serum of patients with various cancers was fractioned into membrane-bound and soluble components using serial ultracentrifugation. Lectin blotting was conducted to evaluate glycosylation. Proteins having altered glycosylation were identified using proteomic analysis and further confirmed using immunoblotting analysis. We performed HPLC, gene analysis, real-time cargo tracking, and immunohistochemistry to determine the origin of CCA glycosylation and its underlying mechanisms. Extracellular vesicles (EV) were isolated from the sera of 62 patients with CCA at different clinical stages and inflammatory conditions and used for glycan analysis to assess their clinical significance. Results: The results reveal that glycosylation patterns between soluble and membrane-bound fractions differ significantly even when obtained from the same donor. Notably, glycans with α1-3/4 fucose and ß1-6GlcNAc branched structures increase specifically in membrane-bound fractions of CCA. Mechanically, it is primarily due to ß-haptoglobin (ß-Hp) originating from CCA expressing fucosyltransferase-3/4 (FUT 3/4) and N-acetylglucosaminyltransferase-V (MGAT5). Newly synthesized ß-Hp is loaded into EVs in early endosomes via a KFERQ-like motif and then secreted from CCA cells to induce tumor progression. In contrast, ß-Hp expressed by hepatocytes is secreted in a soluble form that does not affect CCA progression. Moreover, evaluation of EV glycosylation in CCA patients shows that fucosylation level of EV-Hp gradually increases with tumor progression and decreases markedly when the tumors are eliminated by surgery. Conclusion: This study suggests that terminal fucosylation of Hp in cancer-derived exosomes can be a novel glycan marker for diagnosis and prognosis of CCA. These findings highlight the potential of glycan analysis in different fractions of serum for biomarker discover for other diseases. Further research is needed to understand the role of fucosylated EVs on CCA progression.

ATG9B Is a Poor Prognostic Marker Associated With Immune Evasion in Colon Adenocarcinoma.

BACKGROUND/AIM: Autophagy-related genes (ATGs) are involved in autophagy activation, which has a pleiotropic role in cancer development. However, the potential value of ATG expression levels in colon adenocarcinoma (COAD) is unclear. This study aimed to examine the modulation of ATG expression levels and their association with clinical and molecular aspects of COAD. MATERIALS AND METHODS: We used the clinical and molecular phenotypes and RNA sequencing datasets of the cancer genome atlas (TCGA)-COAD project using TCGAbiolinks and cBioPortal. Comparisons of ATG expression levels between tumor and normal tissues were performed using DESeq2 within R. Gene expression and immune cell infiltration levels were analyzed by TIMER. RESULTS: ATG9B had the highest expression levels among ATGs in COAD tissues compared to normal tissues and was related to advanced stage and poor prognosis in COAD. In addition, ATG9B expression was positively associated with the consensus molecular subtype 4 and chromosomal instability but negatively correlated with tumor mutation burden. Furthermore, high ATG9B expression levels were associated with low immune cell infiltration and decreased expression of natural killer cell activation genes. CONCLUSION: ATG9B is a poor prognostic biomarker driving immune evasion of COAD through negative correlation with immune cell infiltration.

Dimethyl itaconate is effective in host-directed antimicrobial responses against mycobacterial infections through multifaceted innate immune pathways.

BACKGROUND: Itaconate, a crucial immunometabolite, plays a critical role in linking immune and metabolic functions to influence host defense and inflammation. Due to its polar structure, the esterified cell-permeable derivatives of itaconate are being developed to provide therapeutic opportunities in infectious and inflammatory diseases. Yet, it remains largely uncharacterized whether itaconate derivatives have potentials in promoting host-directed therapeutics (HDT) against mycobacterial infections. Here, we report dimethyl itaconate (DMI) as the promising candidate for HDT against both Mycobacterium tuberculosis (Mtb) and nontuberculous mycobacteria by orchestrating multiple innate immune programs. RESULTS: DMI per se has low bactericidal activity against Mtb, M. bovis Bacillus Calmette-Guérin (BCG), and M. avium (Mav). However, DMI robustly activated intracellular elimination of multiple mycobacterial strains (Mtb, BCG, Mav, and even to multidrug-resistant Mtb) in macrophages and in vivo. DMI significantly suppressed the production of interleukin-6 and -10, whereas it enhanced autophagy and phagosomal maturation, during Mtb infection. DMI-mediated autophagy partly contributed to antimicrobial host defenses in macrophages. Moreover, DMI significantly downregulated the activation of signal transducer and activator of transcription 3 signaling during infection with Mtb, BCG, and Mav. CONCLUSION: Together, DMI has potent anti-mycobacterial activities in macrophages and in vivo through promoting multifaceted ways for innate host defenses. DMI may bring light to new candidate for HDT against Mtb and nontuberculous mycobacteria, both of which infections are often intractable with antibiotic resistance.

GDF15 Promotes Cell Growth, Migration, and Invasion in Gastric Cancer by Inducing STAT3 Activation.

Growth differentiation factor 15 (GDF15) has been reported to play an important role in cancer and is secreted and involved in the progression of various cancers, including ovarian cancer, prostate cancer, and thyroid cancer. Nevertheless, the functional mechanism of GDF15 in gastric cancer is still unclear. Immunohistochemical staining was performed to estimate the expression of GDF15 in 178 gastric cancer tissues. The biological role and action mechanism of GDF15 were investigated by examining the effect of GDF15 knockdown in AGS and SNU216 gastric cancer cells. Here, we report that the high expression of GDF15 was associated with invasion depth (p = 0.002), nodal involvement (p = 0.003), stage III/IV (p = 0.01), lymphatic invasion (p = 0.05), and tumor size (p = 0.049), which are related to poor survival in gastric cancer patients. GDF15 knockdown induced G0/G1 cell cycle arrest and remarkably inhibited cell proliferation and reduced cell motility, migration, and invasion compared to the control. GDF15 knockdown inhibited the epithelial-mesenchymal transition by regulating the STAT3 phosphorylation signaling pathways. Taken together, our results indicate that GDF15 expression is associated with aggressive gastric cancer by promoting STAT3 phosphorylation, suggesting that the GDF15-STAT3 signaling axis is a potential therapeutic target against gastric cancer progression.

Single Cell Analysis of Human Thyroid Reveals the Transcriptional Signatures of Aging.

The thyroid gland plays a critical role in the maintenance of whole-body metabolism. However, aging frequently impairs homeostatic maintenance by thyroid hormones due to increased prevalence of subclinical hypothyroidism associated with mitochondrial dysfunction, inflammation, and fibrosis. To understand the specific aging-related changes of endocrine function in thyroid epithelial cells, we performed single-cell RNA sequencing (RNA-seq) of 54 726 cells derived from pathologically normal thyroid tissues from 7 patients who underwent thyroidectomy. Thyroid endocrine epithelial cells were clustered into 5 distinct subpopulations, and a subset of cells was found to be particularly vulnerable with aging, showing functional deterioration associated with the expression of metallothionein (MT) and major histocompatibility complex class II genes. We further validated that increased expression of MT family genes are highly correlated with thyroid gland aging in bulk RNAseq datasets. This study provides evidence that aging induces specific transcriptomic changes across multiple cell populations in the human thyroid gland.

Chemical mimetics of the N-degron pathway alleviate systemic inflammation by activating mitophagy and immunometabolic remodeling.

The Arg/N-degron pathway, which is involved in the degradation of proteins bearing an N-terminal signal peptide, is connected to p62/SQSTM1-mediated autophagy. However, the impact of the molecular link between the N-degron and autophagy pathways is largely unknown in the context of systemic inflammation. Here, we show that chemical mimetics of the N-degron Nt-Arg pathway (p62 ligands) decreased mortality in sepsis and inhibited pathological inflammation by activating mitophagy and immunometabolic remodeling. The p62 ligands alleviated systemic inflammation in a mouse model of lipopolysaccharide (LPS)-induced septic shock and in the cecal ligation and puncture model of sepsis. In macrophages, the p62 ligand attenuated the production of proinflammatory cytokines and chemokines in response to various innate immune stimuli. Mechanistically, the p62 ligand augmented LPS-induced mitophagy and inhibited the production of mitochondrial reactive oxygen species in macrophages. The p62 ligand-mediated anti-inflammatory, antioxidative, and mitophagy-activating effects depended on p62. In parallel, the p62 ligand significantly downregulated the LPS-induced upregulation of aerobic glycolysis and lactate production. Together, our findings demonstrate that p62 ligands play a critical role in the regulation of inflammatory responses by orchestrating mitophagy and immunometabolic remodeling.