PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production.

Naive human embryonic stem cells (hESCs) that resemble the pre-implantation epiblasts are fueled by a combination of aerobic glycolysis and oxidative phosphorylation, but their mitochondrial regulators are poorly understood. Here we report that, proline dehydrogenase (PRODH), a mitochondria-localized proline metabolism enzyme, is dramatically upregulated in naive hESCs compared to their primed counterparts. The upregulation of PRODH is induced by a reduction in c-Myc expression that is dependent on PD0325901, a MEK inhibitor routinely present in naive hESC culture media. PRODH knockdown in naive hESCs significantly promoted mitochondrial oxidative phosphorylation (mtOXPHOS) and reactive oxygen species (ROS) production that triggered autophagy, DNA damage, and apoptosis. Remarkably, MitoQ, a mitochondria-targeted antioxidant, effectively restored the pluripotency and proliferation of PRODH-knockdown naive hESCs, indicating that PRODH maintains naive pluripotency by preventing excessive ROS production. Concomitantly, PRODH knockdown significantly slowed down the proteolytic degradation of multiple key mitochondrial electron transport chain complex proteins. Thus, we revealed a crucial role of PRODH in limiting mtOXPHOS and ROS production, and thereby safeguarding naive pluripotency of hESCs.

Semaphorin 1a-mediated dendritic wiring of the Drosophila mushroom body extrinsic neurons.

SignificanceThe adult Drosophila mushroom body (MB) is one of the most extensively studied neural circuits. However, how its circuit organization is established during development is unclear. In this study, we provide an initial characterization of the assembly process of the extrinsic neurons (dopaminergic neurons and MB output neurons) that target the vertical MB lobes. We probe the cellular mechanisms guiding the neurite targeting of these extrinsic neurons and demonstrate that Semaphorin 1a is required in several MB output neurons for their dendritic innervations to three specific MB lobe zones. Our study reveals several intriguing molecular and cellular principles governing assembly of the MB circuit.

Tissue-derived extracellular vesicles in cancer progression: mechanisms, roles, and potential applications.

Extracellular vesicles (EVs) are small lipid bilayer-enclosed vesicles that mediate vital cellular communication by transferring cargo between cells. Among these, tissue-derived extracellular vesicles (Ti-EVs) stand out due to their origin from the tissue microenvironment, providing a more accurate reflection of changes in this setting. This unique advantage makes Ti-EVs valuable in investigating the intricate relationship between extracellular vesicles and cancer progression. Despite considerable research efforts exploring the association between Ti-EVs and cancers, a comprehensive clustering or grouping of these studies remains lacking. In this review, we aim to fill this gap by presenting a comprehensive synthesis of the mechanisms underlying Ti-EV generation, release, and transport within cancer tissues. Moreover, we delve into the pivotal roles that Ti-EVs play in cancer progression, shedding light on their potential as diagnostic and therapeutic tools. The review culminates in the construction of a comprehensive functional spectrum of Ti-EVs, providing a valuable reference for future research endeavors. By summarizing the current state of knowledge on Ti-EVs and their significance in tumor biology, this work contributes to a deeper understanding of cancer microenvironment dynamics and opens up avenues for harnessing Ti-EVs in diagnostic and therapeutic applications.

Circulating small extracellular vesicle-based miRNA classifier for follicular thyroid carcinoma: a diagnostic study.

BACKGROUND: The diagnosis of follicular thyroid carcinoma (FTC) prior to surgery remains a major challenge in the clinic. METHODS: This multicentre diagnostic study involved 41 and 150 age- and sex-matched patients in the training cohort and validation cohort, respectively. The diagnostic properties of circulating small extracellular vesicle (sEV)-associated and cell-free RNAs were compared by RNA sequencing in the training cohort. Subsequently, using a quantitative real-time polymerase chain reaction (qRT‒PCR) assay, high-quality candidates were identified to construct an RNA classifier for FTC and verified in the validation cohort. The parallel expression, stability and influence of the RNA classifier on surgical strategy were also investigated. RESULTS: The diagnostic properties of sEV long RNAs, cell-free long RNAs and sEV microRNAs (miRNAs) were comparable and superior to those of cell-free miRNAs in RNA sequencing. Given the clinical application, the circulating sEV miRNA (CirsEV-miR) classifier was developed from five miRNAs based on qRT‒PCR data, which could well identify FTC patients (area under curve [AUC] of 0.924 in the training cohort and 0.844 in the multicentre validation cohort). Further tests revealed that the CirsEV-miR score was significantly correlated with the tumour burden, and the levels of sEV miRNAs were also higher in sEVs from the FTC cell line, organoid and tissue. Additionally, circulating sEV miRNAs remained constant after different treatments, and the addition of the CirsEV-miR classifier as a biomarker improves the current surgical strategy. CONCLUSIONS: The CirsEV-miR classifier could serve as a noninvasive, convenient, specific and stable auxiliary test to help diagnose FTC following ultrasonography.

m 6 A-mediated gluconeogenic enzyme PCK1 upregulation protects against hepatic ischemia-reperfusion injury.

BACKGROUND AND AIMS: Ischemia-reperfusion (I/R) injury frequently occurs during liver surgery, representing a major reason for liver failure and graft dysfunction after operation. The metabolic shift from oxidative phosphorylation to glycolysis during ischemia increased glucose consumption and accelerated lactate production. We speculate that donor livers will initiate gluconeogenesis, the reverse process of glycolysis in theory, to convert noncarbohydrate carbon substrates (including lactate) to glucose to reduce the loss of hepatocellular energy and foster glycogen storage for use in the early postoperative period, thus improving post-transplant graft function. APPROACH AND RESULTS: By analyzing human liver specimens before and after hepatic I/R injury, we found that the rate-limiting enzyme of gluconeogenesis, PCK1, was significantly induced during liver I/R injury. Mouse models with liver I/R operation and hepatocytes treated with hypoxia/reoxygenation confirmed upregulation of PCK1 during I/R stimulation. Notably, high PCK1 level in human post-I/R liver specimens was closely correlated with better outcomes of liver transplantation. However, blocking gluconeogenesis with PCK1 inhibitor aggravated hepatic I/R injury by decreasing glucose level and deepening lactate accumulation, while overexpressing PCK1 did the opposite. Further mechanistic study showed that methyltransferase 3-mediated RNA N6-methyladinosine modification contributes to PCK1 upregulation during hepatic I/R injury, and hepatic-specific knockout of methyltransferase 3 deteriorates liver I/R injury through reducing the N6-methyladinosine deposition on PCK1 transcript and decreasing PCK1 mRNA export and expression level. CONCLUSIONS: Our study found that activation of the methyltransferase 3/N6-methyladinosine-PCK1-gluconeogenesis axis is required to protect against hepatic I/R injury, providing potential intervention approaches for alleviating hepatic I/R injury during liver surgery.

Efficacy of revascularization in CTO patients based on hibernating myocardium therapy.

BACKGROUND: The effectiveness of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) is still uncertain, especially for patients with ischemic left ventricular dysfunction. This study aimed to assess hibernating myocardium (HM), as determined by single-photon emission computed tomography (SPECT) and 18F-FDG positron emission tomography (PET), and to compare the benefits of PCI and optimal medical therapy (OMT). METHODS: A retrospective study collected data from 332 patients with CTO and ischemic left ventricular dysfunction. The study compared patients who underwent PCI or OMT via propensity score matching (PSM) analysis which was performed with a 1:2 matching protocol using the nearest neighbour matching algorithm. The primary endpoint of the study was the occurrence of major adverse cardiac events (MACE), defined as a composite of cardiac death, readmission for worsening heart failure (WHF), revascularization and myocardial infarction (MI). RESULTS: After PSM, there were a total of 246 individuals in the PCI and OMT groups. Following Cox regression, hibernating myocardium/total perfusion defect (HM/TPD) was identified as an independent risk factor (hazard ratio (HR): 1.03, 95% confidence interval (CI): 1.008-1.052, p = .007). The cut-off value of HM/TPD was 38%. The results of the subgroup analysis suggest that for patients with HM/TPD >38%, the OMT group had a greater risk of MACE (p = .035). A sensitivity analysis restricting patients with single-vessel CTO lesions, HM/TPD remained an independent predictor (HR 1.025, 95% CI 1.008-1.043, p = .005). CONCLUSION: HM/TPD is an independent predictor of MACE, and for patients with HM/TPD > 38%, CTO-PCI had a lower risk of MACE compared with OMT. However, further validation is still needed through large-scale studies.

Directional emission of a three-dimensional connection-type metamaterial.

Directional emission of electromagnetic waves plays an essential role in laser radar and free-space communication. For most directional antennas, bandwidth and miniaturization are a pair of contradictions due to their underlying interference mechanism. Connection-type metamaterials exhibit exotic electromagnetic response near zero-frequency, which relies on the global topology of mesh connectivity rather than resonance and thus has a broad working bandwidth. In this Letter, we investigate the broadband orientation-dependent coupling effect of a 3D double mesh metamaterial. Based on this effect, we achieve a broadband directional emission (relative bandwidth of 37.72%) using a compact structure (compared to twice working wavelength). Our work provides a novel, to the best of our knowledge, scheme to manipulate a long-wavelength wave and may pave the way to a miniaturized directional antenna.

Exploring the Dual Functions of Distal Acyl Group Direction in Various Nucleophilic Environments.

A universal glycosylation strategy could significantly simplify glycoside synthesis. One approach to achieving this goal is through acyl group direction for the corresponding 1,2-, 1,3-, 1,4-, or 1,6-trans glycosylation; however, this approach has been challenging for glycosidic bonds that require distal equatorial-acyl group direction. We developed an approach in weakly nucleophilic environments for selective 1,4-trans glycosylation directed by the equatorial-4-O-acyl group. Here, we explored this condition in other distal acyl groups and found that, besides 1,n-trans direction, acyl groups also mediated hydrogen bonding between acyl groups and alcohols. The latter showed a diverse effect and classified the acyl group direction into axial and equatorial categories. Corresponding glycosylation conditions were distinguished as guidance for acyl group direction from either category. Hence, acyl group direction may serve as a general glycosylation strategy.

Recombinantly expressed rhFEB remodeled the skin defect of db/db mice.

Fibronectin (FN) and collagen are vital components of the extracellular matrix (ECM). These proteins are essential for tissue formation and cell alignment during the wound healing stage. In particular, FN interacts with collagens to activate various intracellular signaling pathways to maintain ECM stability. A novel recombinant extra domain-B fibronectin (EDB-FN)-COL3A1 fusion protein (rhFEB) was designed to mimic the ECM to promote chronic and refractory skin ulcer wound healing. rhFEB significantly enhanced cell adhesion and migration, vascular ring formation, and the production of new collagen I (COL1A1) in vitro. rhFEB decreased M1 macrophages and further modulated the wound microenvironment, which was confirmed by the treatment of db/db mice with rhFEB. Accelerated wound healing was shown during the initial stages in rhFEB-treated db/db mice, as was enhanced follicle regeneration, re-epithelialization, collagen deposition, granulation, inflammation, and angiogenesis. The wound chronicity of diabetic foot ulcers (DFUs) remains the main challenge in current and future treatment. rhFEB may be a candidate molecule for regulating M1 macrophages during DFU healing. KEY POINTS: • A recombinant protein EDB-FN-collagen III (rhFEB) was highly expressed in Escherichia coli • rhFEB protein induces COL1A1 secretion in human skin fibroblasts • rhFEB protein accelerates diabetic wound healing.

The effects of hyaluronan and proteoglycan link protein 1 (HAPLN1) in ameliorating spinal cord injury mediated by Nrf2.

Excessive inflammatory response and oxidative stress (OS) play an important role in the pathogenesis of spinal cord injury (SCI). Balance of inflammation and prevention of OS have been considered an effective strategy for the treatment of SCI. Hyaluronan and proteoglycan link protein 1 (HAPLN1), also known as cartilage link protein, has displayed a wide range of biological and physiological functions in different types of tissues and cells. However, whether HAPLN1 regulates inflammation and OS during SCI is unknown. Therefore, we aimed to examine whether HAPLN1 can have a protective effect on SCI. In this study, both in vitro and in vivo SCI models were established. Nissl staining and terminal deoxynucleotidyl transferase dUTP nick end labeling staining assays were used. Western blotting and enzyme-linked immunosorbent assay were employed to assess the expression of proteins. Our results demonstrate that the administration of HAPLN1 promoted the recovery of motor neurons after SCI by increasing the Basso mouse scale score, increasing the numbers of motor neurons, and preventing apoptosis of spinal cord cells. Additionally, HAPLN1 mitigated OS in spinal cord tissue after SCI by increasing the content of superoxide dismutase SOD and the activity of glutathione peroxidase but reducing the levels of malondialdehyde. Importantly, we found that HAPLN1 stimulated the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway and stimulated the expression of heme oxygenase-1 and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase-1, which mediated the attenuation of HAPLN1 in activation of the NOD-like receptor protein 3 (NLRP3) inflammasome by reducing the levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1ß. Correspondingly, in vitro experiments show that the presence of HAPLN1 suppressed the NLRP3 inflammasome and prevented cell injury against H2O2 in PC12 cells. These effects were mediated by the Nrf2/ARE pathway, and inhibition of Nrf2 with ML385 abolished the beneficial effects of HAPLN1. Based on these findings, we conclude that HAPLN1 inhibits the NLRP3 inflammasome through the stimulation of the Nrf2/ARE pathway, thereby suppressing neuroinflammation, enhancing motor neuronal survival, and improving the recovery of nerve function after SCI.

Development of a Novel Nomogram to Predict Major Adverse Cardiac Events in Patients with Chronic Total Occlusion.

Objectives: To create a nomogram using single photon emission computed tomography (SPECT) myocardial perfusion imaging and 18F-FDG positron emissions tomography (PET) gated myocardial metabolism imaging to forecast major adverse cardiovascular events (MACE) in chronic total occlusion (CTO) patients treated with optimal medical therapy (OMT). Methods: A total of 257 patients who received OMT between January 2016 and December 2021 were included in this retrospective study. Patients were randomly divided into development (n=179) and validation (n=78) cohorts. A thorough evaluation was conducted, encompassing clinical features and imaging analysis, which involved assessing myocardial perfusion and metabolism. Independent risk factors were identified using least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses. Calibration curves and decision curve analysis (DCA) were used to evaluate the clinical usefulness. Results: In the development cohort, 53 patients (29.6%) experienced MACE out of 179 patients, while in the validation cohort, MACE occurred in 23 (29.5%) patients out of 78. The PET-left ventricular end-systolic volume (P-ESV) (HR 1.01; 95% CI 1.003-1.017; p=0.003), hibernating myocardium / total perfusion defect (HM/TPD) (HR 1.053; 95% CI 1.038-1.069; p<0.001), PET-left ventricular ejection fraction (P-LVEF) (HR 0.862; 95% CI 0.788-0.943; p=0.001), and left anterior descending branch (LAD) (HR 2.303; 95% CI 1.086-4.884; p=0.03) were significantly associated with MACE and were used to develop the nomogram. The nomogram demonstrated excellent discrimination with C-indexes of 0.931 and 0.911 in the development and validation cohorts. DCA determined that the model exhibited a considerably superior net advantage in predicting MACE. Conclusion: A new nomogram integrating clinical factors and imaging features was created to predict the risk of MACE in patients with CTO.

Development and external validation of a nomogram for the early prediction of acute kidney injury in septic patients: a multicenter retrospective clinical study.

Background and purpose: Acute kidney injury (AKI) is a common serious complication in sepsis patients with a high mortality rate. This study aimed to develop and validate a predictive model for sepsis associated acute kidney injury (SA-AKI). Methods: In our study, we retrospectively constructed a development cohort comprising 733 septic patients admitted to eight Grade-A tertiary hospitals in Shanghai from January 2021 to October 2022. Additionally, we established an external validation cohort consisting of 336 septic patients admitted to our hospital from January 2017 to December 2019. Risk predictors were selected by LASSO regression, and a corresponding nomogram was constructed. We evaluated the model's discrimination, precision and clinical benefit through receiver operating characteristic (ROC) curves, calibration plots, decision curve analysis (DCA) and clinical impact curves (CIC) in both internal and external validation. Results: AKI incidence was 53.2% in the development cohort and 48.2% in the external validation cohort. The model included five independent indicators: chronic kidney disease stages 1 to 3, blood urea nitrogen, procalcitonin, D-dimer and creatine kinase isoenzyme. The AUC of the model in the development and validation cohorts was 0.914 (95% CI, 0.894-0.934) and 0.923 (95% CI, 0.895-0.952), respectively. The calibration plot, DCA, and CIC demonstrated the model's favorable clinical applicability. Conclusion: We developed and validated a robust nomogram model, which might identify patients at risk of SA-AKI and promising for clinical applications.

Heterogeneity of work alienation and its relationship with job embeddedness among Chinese nurses: a cross-sectional study using latent profile analysis.

OBJECTIVE: To identify the distinct profiles of work alienation among Chinese nurses, examine the demographic factors associated with profile memberships, and then explore the relationship between latent categories of work alienation and job embeddedness. METHODS: A cross-sectional survey of 523 nurses was conducted from July to August 2023. Latent profile analysis (LPA) was performed to identify distinct profiles of nurses based on three aspects: powerlessness, helplessness, and meaningfulness. A multinomial logistic regression analysis was conducted to explore the predictors of profile membership. Hierarchical regression analysis was carried out to examine the association between profile memberships and job embeddedness. RESULTS: Three subgroups of work alienation of nurses were identified: 23.1%, 57.8%, and 19.1% in the low work alienation group (profile 1), the moderate work alienation group (profile 3), and the high work alienation group (profile 2), respectively. Nurses with college degrees were more likely to be grouped into moderate work alienation. Nurses who did not work night shifts were more likely to have low or moderate levels of work alienation. Nurses earning 2,000-3,000 and 3,001-5,000 yuan per month were likely to be in the low work alienation group. The different categories of work alienation significantly predicted job embeddedness among nurses (ΔR2 = 0.103, p < 0.001). CONCLUSIONS: Work alienation has an important impact on clinical nurses' job embeddedness. Nursing managers should pay attention to the differences in individual work alienation status and adopt reasonable management strategies to improve the level of job embeddedness, ensure the quality of care, and reduce nursing turnover.

Trade-offs between the accumulation of cuticular wax and jasmonic acid-mediated herbivory resistance in maize.

Plants have evolved complex physical and chemical defense systems that allow them to withstand herbivory infestation. Composed of a complex mixture of very-long-chain fatty acids (VLCFAs) and their derivatives, cuticular wax constitutes the first physical line of defense against herbivores. Here, we report the function of Glossy 8 (ZmGL8), which encodes a 3-ketoacyl reductase belonging to the fatty acid elongase complex, in orchestrating wax production and jasmonic acid (JA)-mediated defenses against herbivores in maize (Zea mays). The mutation of GL8 enhanced chemical defenses by activating the JA-dependent pathway. We observed a trade-off between wax accumulation and JA levels across maize glossy mutants and 24 globally collected maize inbred lines. In addition, we demonstrated that mutants defective in cuticular wax biosynthesis in Arabidopsis thaliana and maize exhibit enhanced chemical defenses. Comprehensive transcriptomic and lipidomic analyses indicated that the gl8 mutant confers chemical resistance to herbivores by remodeling VLCFA-related lipid metabolism and subsequent JA biosynthesis and signaling. These results suggest that VLCFA-related lipid metabolism has a critical role in regulating the trade-offs between cuticular wax and JA-mediated chemical defenses.

Dietary sodium butyrate positively modulated intestinal microbial community, but did not promote growth of largemouth bass (Micropterus salmoides).

This study investigated the effects of dietary sodium butyrate (NaB) on growth, serum biochemical indices, intestine histology, and gut microbiota of largemouth bass (Micropterus salmoides). A basal diet was formulated and used as the control diet (Con), and five additional diets were prepared by supplementing NaB (50%) in the basal diet at 2.0, 4.0, 8.0, 12.0, and 16.0 g/kg inclusion (NaB-2, NaB-4, NaB-8, NaB-12, and NaB-16 diets). Then, the six diets were fed to triplicate groups of largemouth bass juveniles (2.4 ± 0.1 g) for 8 weeks. NaB supplementation linearly and quadratically affected weight gain (WG) and feed intake (FI) (P < 0.05). The NaB-16 group displayed lower WG (- 6.8%) and FI than the Con group (P < 0.05), while no differences were found in WG and feed conversion ratio between the other NaB groups and Con group (P > 0.05). Serum alkaline phosphatase and lysozyme activities were higher in the NaB groups (P < 0.05), and D-lactate content was lower in the NaB-12 group (P < 0.05) than the control. Intestinal lipase activity in NaB-2, NaB-4 group, and villi width in NaB-8 group were also higher than those in the Con group (P < 0.05). Compared to the Con group, the intestinal abundances of Firmicutes and Mycoplasma were increased and the abundances of Proteobacteria, Achromobacter and Plesiomonas were decreased in NaB-4 and NaB-16 groups (P < 0.05). In conclusion, dietary NaB did not promote the growth of juvenile largemouth bass, but positively modulated the intestinal microbial community.

Enhanced organic degradation and microbial community cooperation by inoculating Bacillus licheniformis in low temperature composting.

Microbial activity and interaction are the important driving factors in the start-up phase of food waste composting at low temperature. The aim of this study was to explore the effect of inoculating Bacillus licheniformis on the degradation of organic components and the potential microbe-driven mechanism from the aspects of organic matter degradation, enzyme activity, microbial community interaction, and microbial metabolic function. The results showed that after inoculating B. licheniformis, temperature increased to 47.8°C on day 2, and the degradation of readily degraded carbohydrates (RDC) increased by 31.2%, and the bioheat production increased by 16.5%. There was an obvious enhancement of extracellular enzymes activities after inoculation, especially amylase activity, which increased by 7.68 times on day 4. The inoculated B. licheniformis colonized in composting as key genus in the start-up phase. Modular network analysis and Mantel test indicated that inoculation drove the cooperation between microbial network modules who were responsible for various organic components (RDC, lipid, protein, and lignocellulose) degradation in the start-up phase. Metabolic function prediction suggested that carbohydrate metabolisms including starch and sucrose metabolism, glycolysis / gluconeogenesis, pyruvate metabolism, etc., were improved by increasing the abundance of related functional genes after inoculation. In conclusion, inoculating B. licheniformis accelerated organic degradation by driving the cooperation between microbial network modules and enhancing microbial metabolism in the start-up phase of composting.

The role of extracellular vesicles in circulating tumor cell-mediated distant metastasis.

Current research has demonstrated that extracellular vesicles (EVs) and circulating tumor cells (CTCs) are very closely related in the process of distant tumor metastasis. Primary tumors are shed and released into the bloodstream to form CTCs that are referred to as seeds to colonize and grow in soil-like distant target organs, while EVs of tumor and nontumor origin act as fertilizers in the process of tumor metastasis. There is no previous text that provides a comprehensive review of the role of EVs on CTCs during tumor metastasis. In this paper, we reviewed the mechanisms of EVs on CTCs during tumor metastasis, including the ability of EVs to enhance the shedding of CTCs, protect CTCs in circulation and determine the direction of CTC metastasis, thus affecting the distant metastasis of tumors.

Piezo1 alleviates acetaminophen-induced acute liver injury by activating Nrf2 and reducing mitochondrial reactive oxygen species.

Acetaminophen (APAP) overdose is the most common cause for acute liver failure (ALF) in the developed countries, with limited treatment options. Piezo1 is a mechanosensitive cation channel. We found that APAP caused upregulation of Piezo1 in both an APAP-induced acute liver injury (ALI) animal model and a mouse hepatocyte cell line AML12. Activation of Piezo1 by its activator Yoda1 reduced APAP-induced hepatotoxicity and ROS level. Mechanistically, activation of Piezo1 led to accumulation of the antioxidant regulator Nrf2 and upregulation of its target genes Nqo1 and Gsta1, while knockdown of Piezo1 downregulated this pathway. Finally, injection of Yoda1 decreased serum AST and ALT levels, reduced cell death and rescued liver injury in the APAP-induced ALI mouse model. Our findings suggested a previously undiscovered protective role of Piezo1 in APAP-induced ALI, which might shed light on a new therapeutic target for this disease.

Acupuncture exerts preventive effects in rats of chronic unpredictable mild stress: The involvement of inflammation in amygdala and brain-spleen axis.

BACKGROUND: Acupuncture has shown the preventive effects on depression in rats with chronic unpredictable mild stress (CUMS). However, the mechanisms of acupuncture for preventing depression still need to be explored. In the study, acupuncture was applied to a rat depression model of CUMS, high-mobility group box 1(HMGB1)/toll-like receptor 4 (TLR4) and brain-spleen axis were assessed. METHODS: Male Sprague Dawley (SD) rats were exposed to CUMS with two stressors per day for 28 days. In the meantime, manual acupuncture (at GV16 and GV23 acupoints, once every other day) and fluoxetine gavage (2.1 mg/kg, 0.21 mg/mL) were administered daily post CUMS stressors. Behavioral tests and biological detection methods were conducted in sequence to evaluate depression-like phenotypes in rats. RESULTS: The results showed CUMS induced depression-like behaviors, hyper-activation of HMGB1/TLR4 signaling pathway, elevated inflammation in amygdala and peripheral blood, and hyperactivation of hypothalamic-pituitary-adrenal (HPA) axis. These changes could be prevented and reversed by acupuncture to varying extents. CONCLUSION: Acupuncture prevented and ameliorated depression-like symptoms induced by CUMS, possibly via regulating inflammation through brain-spleen axis mediated by HMGB1/TLR4 signaling pathway and HPA axis regulation.

miR-142-3p encapsulated in T lymphocyte-derived tissue small extracellular vesicles induces Treg function defect and thyrocyte destruction in Hashimoto's thyroiditis.

BACKGROUND: Hashimoto's thyroiditis (HT) is an organ-specific autoimmune disease characterized by lymphocyte infiltration that destroys thyrocyte cells. The aim of the present study was to elucidate the role and mechanisms of tissue small extracellular vesicle (sEV) microRNAs (miRNAs) in the pathogenesis of HT. METHODS: Differentially expressed tissue sEV miRNAs were identified between HT tissue and normal tissue by RNA sequencing in the testing set (n = 20). Subsequently, using quantitative real-time polymerase chain reaction (qRT‒PCR) assays and logistic regression analysis in the validation set (n = 60), the most relevant tissue sEV miRNAs to HT were verified. The parental and recipient cells of that tissue sEV miRNA were then explored. In vitro and in vivo experiments were further performed to elucidate the function and potential mechanisms of sEV miRNAs that contribute to the development of HT. RESULTS: We identified that miR-142-3p encapsulated in T lymphocyte-derived tissue sEVs can induce Treg function defect and thyrocyte destruction through an intact response loop. Inactivation of miR-142-3p can effectively protect non-obese diabetic (NOD).H-2h4 mice from HT development display reduced lymphocyte infiltration, lower antibody titers, and higher Treg cells. Looking at the mechanisms underlying sEV action on thyrocyte destruction, we found that the strong deleterious effect mediated by tissue sEV miR-142-3p is due to its ability to block the activation of the ERK1/2 signaling pathway by downregulating RAC1. CONCLUSIONS: Our findings highlight the fact that tissue sEV-mediated miR-142-3p transfer can serve as a communication mode between T lymphocytes and thyrocyte cells in HT, favoring the progression of HT.