TBC1D15-regulated mitochondria-lysosome membrane contact exerts neuroprotective effects by alleviating mitochondrial calcium overload in seizure.

Mitochondrial calcium overload plays an important role in the neurological insults in seizure. The Rab7 GTPase-activating protein, Tre-2/Bub2/Cdc16 domain family member 15 (TBC1D15), is involved in the regulation of mitochondrial calcium dynamics by mediating mitochondria-lysosome membrane contact. However, whether TBC1D15-regulated mitochondria-lysosome membrane contact and mitochondrial calcium participate in neuronal injury in seizure is unclear. We aimed to investigate the effect of TBC1D15-regulated mitochondria-lysosome membrane contact on epileptiform discharge-induced neuronal damage and further explore the underlying mechanism. Lentiviral vectors (Lv) infection and stereotaxic adeno-associated virus (AAV) injection were used to regulate TBC1D15 expression before establishing in vitro epileptiform discharge and in vivo status epilepticus (SE) models. TBC1D15's effect on inter-organellar interactions, mitochondrial calcium levels and neuronal injury in seizure was evaluated. The results showed that abnormalities in mitochondria-lysosome membrane contact, mitochondrial calcium overload, mitochondrial dysfunction, increased levels of reactive oxygen species, and prominent neuronal damage were partly relieved by TBC1D15 overexpression, whereas TBC1D15 knockdown markedly deteriorated these phenomena. Further examination revealed that epileptiform discharge-induced mitochondrial calcium overload in primary hippocampal neurons was closely associated with abnormal mitochondria-lysosome membrane contact. This study highlights the crucial role played by TBC1D15-regulated mitochondria-lysosome membrane contact in epileptiform discharge-induced neuronal injury by alleviating mitochondrial calcium overload.

Analysis and modelling of global online public interest in multiple other infectious diseases due to the COVID-19 pandemic.

RATIONALE: Previous research has demonstrated the applicability of Google Trends in predicting infectious diseases. AIMS AND OBJECTIVES: This study aimed to analyze public interest in other infectious diseases before and after the outbreak of COVID-19 via Google Trends data and to predict these trends via time series models. METHOD: Google Trends data for 12 common infectious diseases were obtained in this study, covering the period from 1 February 2018 to 5 May 2023. The ARIMA, TimeGPT, XGBoost, and LSTM algorithms were then utilized to establish time series prediction models. RESULTS: Our study revealed a significant decrease in public interest in most infectious diseases at the beginning of the pandemic outbreak, followed by a rebound in the post-pandemic era, which is consistent with reported disease incidences. Furthermore, our prediction models demonstrated good accuracy, with TimeGPT showing unique advantages. CONCLUSIONS: Our study highlights the potential application value of Google Trends and large pre-trained models for infectious disease prediction.

TRPML1 ameliorates seizures-related neuronal injury by regulating autophagy and lysosomal biogenesis via Ca2+/TFEB signaling pathway.

Alterations in autophagy have been observed in epilepsy, although their exact etiopathogenesis remains elusive. Transient Receptor Potential Mucolipin Protein 1 (TRPML1) is an ion channel protein that regulates autophagy and lysosome biogenesis. To explore the role of TRPML1 in seizures-induced neuronal injury and the potential mechanisms involved, an hyperexcitable neuronal model induced by Mg2+-free solution was used for the study. Our results revealed that TRPML1 expression was upregulated after seizures, which was accompanied by intracellular ROS accumulation, mitochondrial damage, and neuronal apoptosis. Activation of TRPML1 by ML-SA1 diminished intracellular ROS, restored mitochondrial function, and subsequently alleviated neuronal apoptosis. Conversely, inhibition of TRPML1 had the opposite effect. Further examination revealed that the accumulation of ROS and damaged mitochondria was associated with interrupted mitophagy flux and enlarged defective lysosomes, which were attenuated by TRPML1 activation. Mechanistically, TRPML1 activation allows more Ca2+ to permeate from the lysosome into the cytoplasm, resulting in the dephosphorylation of TFEB and its nuclear translocation. This process further enhances autophagy initiation and lysosomal biogenesis. Additionally, the expression of TRPML1 is positively regulated by WTAP-mediated m6A modification. Our findings highlighted crucial roles of TRPML1 and autophagy in seizures-induced neuronal injury, which provides a new target for epilepsy treatment.

Catalytic activity of Setd2 is essential for embryonic development in mice: establishment of a mouse model harboring patient-derived Setd2 mutation.

SETD2 is the only enzyme responsible for transcription-coupled histone H3 lysine 36 trimethylation (H3K36me3). Mutations in SETD2 cause human diseases including cancer and developmental defects. In mice, Setd2 is essential for embryonic vascular remodeling. Given that many epigenetic modifiers have recently been found to possess noncatalytic functions, it is unknown whether the major function(s) of Setd2 is dependent on its catalytic activity or not. Here, we established a site-specific knockin mouse model harboring a cancer patient-derived catalytically dead Setd2 (Setd2-CD). We found that the essentiality of Setd2 in mouse development is dependent on its methyltransferase activity, as the Setd2CD/CD and Setd2-/- mice showed similar embryonic lethal phenotypes and largely comparable gene expression patterns. However, compared with Setd2-/-, the Setd2CD/CD mice showed less severe defects in allantois development, and single-cell RNA-seq analysis revealed differentially regulated allantois-specific 5' Hoxa cluster genes in these two models. Collectively, this study clarifies the importance of Setd2 catalytic activity in mouse development and provides a new model for comparative study of previously unrecognized Setd2 functions.

Serum Metabolomic and Lipidomic Profiling Reveals the Signature for Postoperative Obesity among Adult-Onset Craniopharyngioma.

Craniopharyngioma patients often suffer from a diminished quality of life after surgery, which is usually associated with metabolic disorders and hypothalamic obesity. However, the precise etiology of these conditions remains elusive. To identify the metabolic changes after surgery, we conducted a cross-sectional study using metabolomic and lipidomic analysis to profile metabolic alterations in adult-onset craniopharyngioma patients with postoperative obesity. A cohort of 120 craniopharyngioma patients who had undergone surgery were examined. Differential analyses, including clinical characteristics, serum metabolome, and lipidome, were conducted across distinct body mass index (BMI) groups. Our findings indicated no statistically significant differences in age, sex, and fasting blood glucose among postoperative craniopharyngioma patients when stratified by BMI. However, a noteworthy difference was observed in uric acid and blood lipid levels. Further investigation revealed that alterations in metabolites and lipids were evidently correlated with increased BMI, indicating that postoperative obesity of craniopharyngioma patients affected their whole-body metabolism. Additionally, the multi-omics analysis identified specific metabolites and lipids, including uric acid and DG(18:2/20:4), as contributors to the metabolic disorders associated with postoperative obesity of craniopharyngioma patients. This work provides valuable insight into the involvement of metabolites and lipids in metabolic disorders subsequent to craniopharyngioma surgery.

Family cohesion and quality of life significantly affecting personality changes in adult epilepsy patients: a case-control study.

OBJECTIVE: The goal of epilepsy treatment is not only to control convulsive seizures but also to improve the quality of life of patients. This study aimed to investigate personality changes and the risk factors for their development in adult epilepsy patients. METHODS: A case-control study in a Class III, Class A hospital. The study comprised 206 adult epilepsy patients admitted to the Neurology Department at the First Hospital of Jilin University between October 2019 and December 2021, while the control group consisted of 154 community volunteers matched with the epilepsy group based on age, sex, and education. No additional treatment interventions were determined to be relevant in the context of this study. RESULTS: There is a significantly higher incidence of personality changes in epilepsy than in the general population, and patients with epilepsy were more likely to become psychoticism, neuroticism, and lie. Epilepsy patient's employment rate and average quality of life score were significantly lower than that of the general population and had strong family intimacy but poor adaptability in this study. There are many factors affecting personality change: sleep disorders, economic status, quality of life, use of anti-seizure drugs, family cohesion and adaptability. The independent risk factors were quality of life and family cohesion.

Threonine dehydrogenase regulates neutrophil homeostasis but not H3K4me3 levels in zebrafish.

l-threonine dehydrogenase (Tdh) is an enzyme that links threonine metabolism to epigenetic modifications and mitochondria biogenesis. In vitro studies show that it is critical for the regulation of trimethylation of histone H3 lysine 4 (H3K4me3) levels and cell fate determination of mouse embryonic stem cells (mESCs). However, whether Tdh regulates a developmental process in vivo and, if it does, whether it also primarily regulates H3K4me3 levels in this process as it does in mESCs, remains elusive. Here, we revealed that, in zebrafish hematopoiesis, tdh is preferentially expressed in neutrophils. Knockout of tdh causes a decrease in neutrophil number and slightly suppresses their acute injury-induced migration, but, unlike the mESCs, the level of H3K4me3 is not evidently reduced in neutrophils sorted from the kidney marrow of adult tdh-null zebrafish. These phenotypes are dependent on the enzymatic activity of Tdh. Importantly, a soluble supplement of nutrients that are able to fuel the acetyl-CoA pool, such as pyruvate, glucose and branched-chain amino acids, is sufficient to rescue the reduction in neutrophils caused by tdh deletion. In summary, our study presents evidence for the functional requirement of Tdh-mediated threonine metabolism in a developmental process in vivo. It also provides an animal model for investigating the nutritional regulation of myelopoiesis and immune response, as well as a useful tool for high-throughput drug/nutrition screening.

Neonatal IL-4 Over-Exposure is Accompanied by Macrophage Accumulation in Dura Mater After Instant Anti-inflammatory Cytokine Response in CSF.

Multiple studies have shown that clinical events resulting into neonatal IL-4 over-exposure, such as asthma in early life and food allergy, were associated with brain damage and that the neuroinflammation induced by them might lead to cognitive impairments, anxiety-/depressive-like behaviors. IL-4 is the most major elevated cytokine in periphery when these clinical events occur and peripheral IL-4 level positively correlates with the severity of those events. Our previous studies have verified that neonatal IL-4 over-exposure induced a delayed neuroinflammatory damage in rodents, which might have adverse implications for brain development and cognition. Neuroinflammation in brain parenchyma is often accompanied by changes in CSF cytokines levels. However, whether the cytokines levels in CSF change after neonatal IL-4 over-exposure is unknown. Here, we found a delayed pro-inflammatory cytokines response (higher IL-6, IL-1ß and, TNF levels) in both hippocampus and CSF after an instant anti-inflammatory cytokine response in IL-4 over-exposed rats. Moreover, the pro-inflammatory cytokines response appeared earlier in CSF than in hippocampus. The level of each of the pro-inflammatory cytokines in CSF positively correlated with that in hippocampus at the age of postnatal day 42. More microglia numbers/activation and higher M-CSF level in the hippocampus in IL-4 over-exposed rats were also observed. Furthermore, there were more macrophages with inflammatory activation in dural mater of IL-4 over-exposed rats. In sum, neonatal IL-4 over-exposure in rats induces delayed inflammation in CSF, suggesting CSF examination may serve as a potential method in predicting delayed neuroinflammation in brain following neonatal IL-4 over-exposure.

The cerebral lymphatic drainage system and its implications in epilepsy.

The central nervous system has long been thought to lack a clearance system similar to the peripheral lymphatic system. Therefore, the clearance of metabolic waste in the central nervous system has been a subject of great interest in neuroscience. Recently, the cerebral lymphatic drainage system, including the parenchymal clearance system and the meningeal lymphatic network, has attracted considerable attention. It has been extensively studied in various neurological disorders. Solute accumulation and neuroinflammation after epilepsy impair the blood-brain barrier, affecting the exchange and clearance between cerebrospinal fluid and interstitial fluid. Restoring their normal function may improve the prognosis of epilepsy. However, few studies have focused on providing a comprehensive overview of the brain clearance system and its significance in epilepsy. Therefore, this review addressed the structural composition, functions, and methods used to assess the cerebral lymphatic system, as well as the neglected association with epilepsy, and provided a theoretical basis for therapeutic approaches in epilepsy.

ATF5-regulated Mitochondrial Unfolded Protein Response Attenuates Neuronal Damage in Epileptic Rat by Reducing Endoplasmic Reticulum Stress Through Mitochondrial ROS.

Endoplasmic reticulum (ER) dysfunction caused by excessive ER stress is a crucial mechanism underlying seizures-induced neuronal injury. Studies have shown that mitochondrial reactive oxygen species (ROS) are closely related to ER stress, and our previous study showed that activating transcription factor 5 (ATF5)-regulated mitochondrial unfolded protein response (mtUPR) modulated mitochondrial ROS generation in a hippocampal neuronal culture model of seizures. However, the effects of ATF5-regulated mtUPR on ER stress and the underlying mechanisms remain uncertain in epilepsy. In this study, ATF5 upregulation by lentivirus infection attenuated seizures-induced neuronal damage and apoptosis in a rat model of pilocarpine-induced epilepsy, whereas ATF5 downregulation by lentivirus infection had the opposite effects. ATF5 upregulation potentiated mtUPR by increasing the expression of mitochondrial chaperone heat shock protein 60 (HSP60) and caseinolytic protease proteolytic subunit (ClpP) and reducing mitochondrial ROS generation in pilocarpine-induced seizures in rats. Additionally, upregulation of ATF5 reduced the expression of glucose-regulated protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), suggesting suppression of ER stress; Moreover, ATF5 upregulation attenuated apoptosis-related proteins such as B-cell lymphoma-2 (BCL2) downregulation, BCL2-associated X (BAX) and cleaved-caspase-3 upregulation. However, ATF5 downregulation exerted the opposite effects. Furthermore, pretreatment with the mitochondria-targeted antioxidant mito-TEMPO attenuated the harmful effects of ATF5 downregulation on ER stress and neuronal apoptosis by reducing mitochondrial ROS generation. Overall, our study suggested that ATF5-regulated mtUPR exerted neuroprotective effects against pilocarpine-induced seizures in rats and the underlying mechanisms might involve mitochondrial ROS-mediated ER stress.

Cross-sectional network analysis of plasma proteins/metabolites correlated with pathogenesis and therapeutic response in acute promyelocytic leukemia.

The treatment of PML/RARA+ acute promyelocytic leukemia (APL) with all-trans-retinoic acid and arsenic trioxide (ATRA/ATO) has been recognized as a model for translational medicine research. Though an altered microenvironment is a general cancer hallmark, how APL blasts shape their plasma composition is poorly understood. Here, we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters, proteomes, and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction therapy. Our study revealed the two prominent features of the APL plasma, suggesting a possible involvement of APL blasts in modulating plasma composition. One was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts, and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/RARA. Furthermore, results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage, which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular proteins. Overall, our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment.

Mitochondrial-regulated Tregs: potential therapeutic targets for autoimmune diseases of the central nervous system.

Regulatory T cells (Tregs) can eliminate autoreactive lymphocytes, induce self-tolerance, and suppress the inflammatory response. Mitochondria, as the energy factories of cells, are essential for regulating the survival, differentiation, and function of Tregs. Studies have shown that patients with autoimmune diseases of the central nervous system, such as multiple sclerosis, neuromyelitis optica spectrum disorder, and autoimmune encephalitis, have aberrant Tregs and mitochondrial damage. However, the role of mitochondrial-regulated Tregs in autoimmune diseases of the central nervous system remains inconclusive. Therefore, this study reviews the mitochondrial regulation of Tregs in autoimmune diseases of the central nervous system and investigates the possible mitochondrial therapeutic targets.

ATF5 Attenuates Low-magnesium-induced Apoptosis by Inhibiting Endoplasmic Reticulum Stress Via the Regulation of Mitochondrial Reactive Oxygen Species.

Mitochondrial stress and endoplasmic reticulum stress (ERS) are known to be closely linked. ATF5 is a key regulator of mitochondrial stress and is involved in ERS regulation. Previously, we used a seizure model to demonstrate that ATF5 regulates mitochondrial stress. However, whether ATF5 affects ERS in epilepsy models has yet to be elucidated. In the present study, we investigated the effects of ATF5 on low-magnesium-induced ERS and the potential mechanisms that underlie these effects. We found that lentiviral overexpression of ATF5 significantly improved low-magnesium-induced ERS, as confirmed by the reduced expression levels of GRP78, PERK, ATF4, and CHOP. In addition, ATF5 overexpression reduced reactive oxygen species (ROS) production and elevated superoxide dismutase (SOD) activity, thus demonstrating that ATF5 plays a key role in maintaining redox homeostasis. Furthermore, ATF5 overexpression rescued low-magnesium-induced neuronal apoptosis, as evidenced by the reduced expression levels of Cleaved-caspase-3 and Bax, and the restored levels of Bcl2. However, these effects were significantly eliminated by lentiviral transduction with ATF5 interference. In addition, treatment of neurons with the mitochondrial antioxidant mitoquinone attenuated the onset of oxidative stress caused by ATF5 interference, partially restored the effect on ERS, and rescued cells from apoptosis. Collectively, these data show that ATF5 attenuates low-magnesium-induced neuronal apoptosis by inhibiting ERS through preventing the accumulation of mitochondrial ROS.

Nuclear mitochondria-related genes-based molecular classification and prognostic signature reveal immune landscape, somatic mutation, and prognosis for glioma.

Background: Glioma is the most frequent malignant primary brain tumor, and mitochondria may influence the progression of glioma. The aim of this study was to analyze the role of nuclear mitochondria related genes (MTRGs) in glioma, identify subtypes and construct a prognostic model based on nuclear MTRGs and machine learning algorithms. Methods: Samples containing both gene expression profiles and clinical information were retrieved from the TCGA database, CGGA database, and GEO database. We selected 16 nuclear MTRGs and identified two clusters of glioma. Prognostic features, microenvironment, mutation landscape, and drug sensitivity were compared between the clusters. A prognostic model based on multiple machine learning algorithms was then constructed and validated by multiple datasets. Results: We observed significant discrepancies between the two clusters. Cluster One had higher nuclear MTRG expression, a lower survival rate, and higher immune infiltration than Cluster Two. For the two clusters, we found distinct predictive drug sensitivities and responses to immune therapy, and the infiltration of immune cells was significantly different. Among the 22 combinations of machine learning algorithms we tested, LASSO was the most effective in constructing the prognostic model. The model's accuracy was further verified in three independent glioma datasets. We identified MGME1 as a vital gene associated with infiltrating immune cells in multiple types of tumors. Conclusion: In short, our research identified two clusters of glioma and developed a dependable prognostic model based on machine learning methods. MGME1 was identified as a potential biomarker for multiple tumors. Our results will contribute to precise medicine and glioma management.

Systemic immune profiling of Omicron-infected subjects inoculated with different doses of inactivated virus vaccine.

SARS-CoV-2 primary strain-based vaccination exerts a protective effect against Omicron variants-initiated infection, symptom occurrence, and disease severity in a booster-dependent manner. Yet, the underlying mechanisms remain unclear. During the 2022 Omicron outbreak in Shanghai, we enrolled 122 infected adults and 50 uninfected controls who had been unvaccinated or vaccinated with two or three doses of COVID-19 inactive vaccines and performed integrative analysis of 41-plex CyTOF, RNA-seq, and Olink on their peripheral blood samples. The frequencies of HLA-DRhi classical monocytes, non-classical monocytes, and Th1-like Tem tended to increase, whereas the frequency of Treg was reduced by booster vaccine, and they influenced symptom occurrence in a vaccine dose-dependent manner. Intercorrelation and mechanistic analysis suggested that the booster vaccination induced monocytic training, which would prime monocytic activation and maturation rather than differentiating into myeloid-derived suppressive cells upon Omicron infections. Overall, our study provides insights into how booster vaccination elaborates protective immunity across SARS-CoV-2 variants.

Unraveling the transcriptome-based network of tfh cells in primary sjogren syndrome: insights from a systems biology approach.

Background: Primary Sjogren Syndrome (pSS) is an autoimmune disease characterized by immune cell infiltration. While the presence of follicular T helper (Tfh) cells in the glandular microenvironment has been observed, their biological functions and clinical significance remain poorly understood. Methods: We enrolled a total of 106 patients with pSS and 46 patients without pSS for this study. Clinical data and labial salivary gland (LSG) biopsies were collected from all participants. Histological staining was performed to assess the distribution of Tfh cells and B cells. Transcriptome analysis using RNA-sequencing (RNA-seq) was conducted on 56 patients with pSS and 26 patients without pSS to uncover the underlying molecular mechanisms of Tfh cells. To categorize patients, we employed the single-sample gene set enrichment analysis (ssGSEA) algorithm, dividing them into low- and high-Tfh groups. We then utilized gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and deconvolution tools to explore functional and immune infiltration differences between the low- and high-Tfh groups. Results: Patients with pSS had a higher positive rate of the antinuclear antibody (ANA), anti-Ro52, anti-SSA, anti-SSB and hypergammaglobulinaemia and higher levels of serum IgG compared to the non-pSS. Histopathologic analyses revealed the presence of Tfh cells (CD4+CXCR5+ICOS+) in germinal centers (GC) within the labial glands of pSS patients. GSEA, WGCNA, and correlation analysis indicated that the high-Tfh group was associated with an immune response related to virus-mediated IFN response and metabolic processes, primarily characterized by hypoxia, elevated glycolysis, and oxidative phosphorylation levels. In pSS, most immune cell types exhibited significantly higher infiltration levels in the high-Tfh group compared to the low-Tfh group. Additionally, patients in the Tfh-high group demonstrated a higher positive rate of the ANA, rheumatoid factor (RF), and hypergammaglobulinaemia, as well as higher serum IgG levels. Conclusion: Our study suggests that Tfh cells may play a crucial role in the pathogenesis of pSS and could serve as potential therapeutic targets in pSS patients.

Clinical characteristics and prognostic factors for short-term outcomes of autoimmune glial fibrillary acidic protein astrocytopathy: a retrospective analysis of 33 patients.

Background: Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a recently discovered inflammatory central nervous system (CNS) disease, whose clinical characteristics and prognostic factors for short-term outcomes have not been defined yet. We aimed to assess the symptoms, laboratory tests, imaging findings, treatment, and short-term prognosis of GFAP-A. Methods: A double-center retrospective cohort study was performed between May 2018 and July 2022. The clinical characteristics and prognostic factors for short-term outcomes were determined. Results: We enrolled 33 patients with a median age of 28 years (range: 2-68 years), 15 of whom were children (<18 years). The clinical spectrum is dominated by meningoencephalomyelitis. Besides, we also found nausea, vomiting, poor appetite, and neuropathic pain in some GFAP-A patients, which were not mentioned in previous reports. And adults were more prone to limb numbness than children. Magnetic resonance imaging revealed lesions involving the brain parenchyma, meninges, and spinal cord, exhibiting patchy, linear, punctate, and strip T2 hyperintensities. First-line immunotherapy, including corticosteroid and gamma globulin, was effective in most patients in the acute phase (P = 0.02). However, patients with overlapping AQP4 antibodies did not respond well to first-line immunotherapy and coexisting neural autoantibodies were more common in women. Additionally, the short-term prognosis was significantly better in children than in adults (P = 0.04). Positive non-neural autoantibodies and proven viral infection were independent factors associated with poor outcomes (P = 0.03, 0.02, respectively). Conclusion: We expanded the spectrum of clinical symptoms of autoimmune GFAP-A. The clinical symptoms and short-term prognosis differed between children and adults. Positive non-neural autoantibodies and proven viral infection at admission suggest a poor short-term prognosis.

Alterations in histology of the aging salivary gland and correlation with the glandular inflammatory microenvironment.

Aging-related salivary dysfunction typically causes reduced saliva volumes, which leads to debilitating consequences, even affecting patient quality of life. Understanding the respective clinicopathological characteristics and molecular mechanisms underlying salivary gland functioning during aging is vital for therapeutic purposes. Here, we provide a detailed atlas of the salivary gland microenvironment during aging, and we identified several phenotypes characteristic of aging salivary glands, including acini atrophy, increased inflammatory cells, altered immune responses, and accumulation of lysosomes and autophagosomes in aging cells, which may reflect progressive degeneration of salivary gland function. Furthermore, our analyses suggested significant enrichment of metabolic pathways in aging glands. Our results revealed complex cellular cross-talk among aging acinar cells, inflammatory factors, and immune responses. A natural aging animal model was established to verify these findings. This study provides mechanistic insights into age-related clinicopathogenesis, important implications for early diagnosis, and identification of new targets for improving salivary gland dysfunction.

Blocking coprophagy increases the levels of inflammation and depression in healthy mice as well as mice receiving fecal microbiota transplantation from disease model mice donors.

Rodents have been extensively used as animal models in microbiome studies. However, all rodents have a habitual nature called coprophagy, a phenomenon that they self-reinoculate feces into their gastrointestinal tract. Recent studies have shown that blocking coprophagy can alter rodents' diversity of gut microbiota, metabolism, neurochemistry, and cognitive behavior. However, whether rodents' coprophagy behavior affects the levels of inflammation and depression is unclear. In order to address this problem, we first blocked coprophagy in healthy mice. It displayed an increase in the levels of depression, verified by depressive-like behaviors and mood-related indicators, and inflammation, verified by the increased levels of the pro-inflammatory cytokine, in coprophagy-blocked mice. Furthermore, we transplanted fecal microbiota from chronic restraint stress (CRS) depression model mice and lipopolysaccharide (LPS) inflammation model mice to healthy recipient mice, respectively. It showed that the disease-like phenotypes in the coprophagy-blocked group were worse than those in the coprophagy-unblocked group, including severer depressive symptoms and higher levels of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α and IFN-γ) in serum, prefrontal cortex (PFC), and hippocampus (HIP). These findings showed that blocking coprophagy in mice not only increased the levels of inflammation and depression in healthy mice but also aggravated inflammation and depression induced by fecal microbiota from disease donors. The discovery may provide a vital reference for future research involving FMT in rodents.