LncRNA SNHG12 suppresses adipocyte inflammation and insulin resistance by regulating the HDAC9/Nrf2 axis.

Obesity is often associated with low-grade inflammation. The incidence of obesity has increased annually worldwide, which seriously affects human health. A previous study indicated that long noncoding RNA SNHG12 was downregulated in obesity. Nevertheless, the role of SNHG12 in obesity remains to be elucidated. In this study, qRT-PCR, western blot, and ELISA were utilized to examine the gene and protein expression. Flow cytometry was employed to investigate the M2 macrophage markers. RNA pull-down assay and RIP were utilized to confirm the interactions of SNHG12, hnRNPA1, and HDAC9. Eventually, a high-fat diet-fed mouse model was established for in vivo studies. SNHG12 overexpression suppressed adipocyte inflammation and insulin resistance and promoted M2 polarization of macrophages that was caused by TNF-α treatment. SNHG12 interacted with hnRNPA1 to downregulate HDAC9 expression, which activated the Nrf2 signaling pathway. HDAC9 overexpression reversed the effect of SNHG12 overexpression on inflammatory response, insulin resistance, and M2 phenotype polarization. Overexpression of SNHG12 improved high-fat diet-fed mouse tissue inflammation. This study revealed the protective effect of SNHG12 against adipocyte inflammation and insulin resistance. This result further provides a new therapeutic target for preventing inflammation and insulin resistance in obesity.

ZNF300 promotes proliferation and migration of hepatocellular carcinoma by upregulating c-MYC gene expression.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Currently, the treatments of HCC are limited to surgical resection and liver transplantation, and there is no effective systemic therapy. OBJECTIVES: To investigate the regulatory mechanism of zinc finger protein 300 (ZNF300) in hepatocellular carcinoma (HCC). METHODS: The expressions of ZNF300 in HCC tissue samples and HCC cell lines (Hep3B, Huh7, SNU-387) were detected. ZNF300 overexpression vector (ZNF300) or shRNAZNF300 (shZNF300) was transfected into HCC cells to increase or inhibit ZNF300 expression. 5-Ethynyl-2'-deoxyuridine assay (EdU), cell counting kit-8 assay (CCK-8) and transwell invasion assay were conducted to evaluate the proliferation, viability, migration, and invasion of HCC cells respectively. The expressions of tumor migration and invasion related proteins (matrix metallopeptidase 2 (MMP-2) and MMP-9), c-MYC, and MAPK/ERK signaling pathway related molecules (p-ERK1/2, ERK1/2, p-P38, P38) were determined by western blotting. Hep3B cells transfected with shZNF300 were subcutaneously injected into nude mice to perform tumor xenograft experiment. Tumor volume and weight were measured. RESULTS: ZNF300 was upregulated in HCC tissues and cells. The expressions of MMP-2 and MMP-9 were increased in HCC cells after transfecting with ZNF300 but reduced in HCC cells transfected with shZNF300. Downregulation of ZNF300 inhibited HCC cell proliferation, migration, and invasion, while overexpression of ZNF300 showed the opposite effects. Moreover, the expressions of c-MYC and MAPK/ERK signaling pathway related molecules were increased after overexpression of ZNF300 but reduced after downregulating ZNF300. In tumor xenograft experiment, downregulation of ZNF300 reduced tumor volume and weight. CONCLUSION: The present study proved that downregulation of ZNF300 inhibited HCC growth by reducing c-MYC expression and MAPK/ERK signaling pathway.

Derivation of water quality criteria for paraquat, bisphenol A and carbamazepine using quantitative structure-activity relationship and species sensitivity distribution (QSAR-SSD).

The risk assessment of an expanding array of emerging contaminants in aquatic ecosystems and the establishment of water quality criteria rely on species sensitivity distribution (SSD), necessitating ample multi-trophic toxicity data. Computational methods, such as quantitative structure-activity relationship (QSAR), enable the prediction of specific toxicity data, thus mitigating the need for costly experimental testing and exposure risk assessment. In this study, robust QSAR models for four aquatic species (Rana pipiens, Crassostrea virginica, Asellus aquaticus, and Lepomis macrochirus) were developed using leave-one-out (LOO) screening variables and the partial least squares algorithm to predict toxicity data for paraquat, bisphenol A, and carbamazepine. These predicted data can be integrated with experimental data to construct SSD models and derive hazardous concentration for 5 % of species (HC5) for the criterion maximum concentration. The chronic water quality criterion for paraquat, bisphenol A, and carbamazepine were determined at 6.7, 11.1, and 3.5 µg/L, respectively. The QSAR-SSD approach presents a viable and cost-effective method for deriving water quality criteria for other emerging contaminants.

Birth Weight and Risk of Cerebral Aneurysm: A Multivariable Mendelian Randomization Study.

BACKGROUND: Birth weight has been linked with various health outcomes. The association between birth weight and cerebral aneurysm remains unknown. METHODS: The two-sample Mendelian randomization (MR) approach was used to evaluate the causal effect of birth weight on cerebral aneurysm based on genome-wide association studies (GWAS), comprising 261,932 UKB participants for birth weight and 204,060 FinnGen participants for cerebral aneurysm. The inverse variance weighted (IVW) method was used as the primary method. Alternative methods were used for comparison. Sensitivity analysis was conducted to evaluate the robustness of the results. Multivariable MR (MVMR) was further conducted to evaluate the direct effect of the birth weight on cerebral aneurysm. RESULTS: The IVW detected a causal association between higher birth weight and increased risk of cerebral aneurysm (OR = 0.521, 95% CI = 0.356 ∼ 0.763, P = 7.88 × 10-4), which was supported by alternative MR models. Sensitivity analysis did not find any evidence of heterogeneity or pleiotropy. MVMR further identified a direct effect of birth weight on cerebral aneurysm, independent of obesity-related traits or smoking. CONCLUSION: This MR study found evidence of the association between birth weight and cerebral aneurysm, providing novel insight into the etiology of cerebral aneurysm, indicating the promising role of birth weight as a marker for screening populations at higher risk of cerebral aneurysm.

Architecting O3/P2 layered oxides by gradient Mn doping for sodium-ion batteries.

O3 phase layered oxides are highly attractive cathode materials for sodium-ion batteries because of their high capacity and decent initial Coulombic efficiency. However, their rate capability and long cycling life are unsatisfactory due to the narrow Na+ transfer channel and irreversible phase transitions of O3 phase during sodiation/desodiation process. Constructing O3/P2 multiphase structures has been proven to be an effective strategy to overcome these challenges. In this study, we synthesized bi-phasic structured O3/P2 Na(Ni2/9Fe1/3Cu1/9Mn1/3)1-xMnxO2 (x = 0.01, 0.02, 0.03, 0.04, 0.05) materials through Mn doping during sodiation process. Benefiting from surface P2 phase layer with the enhanced Na+ transfer dynamics and high structural stability, the Na(Ni2/9Fe1/3Cu1/9Mn1/3)0.98Mn0.02O2 (NFCM-M2) cathode delivers a reversible capacity of 139.1 mA h g-1 at 0.1 C, and retains 71.4 % of its original capacity after 300 cycles at 1 C. Our work provides useful guidance for designing multiphase cathodes and offers new insights into the structure-performance correlation for sodium-ion cathode materials.

Altered counts and mitochondrial mass of peripheral blood leucocytes in patients with chronic hepatitis B virus infection.

Hepatitis B virus (HBV) damages liver cells through abnormal immune responses. Mitochondrial metabolism is necessary for effector functions of white blood cells (WBCs). The aim was to investigate the altered counts and mitochondrial mass (MM) of WBCs by two novel indicators of mitochondrial mass, MM and percentage of low mitochondrial membrane potential, MMPlow%, due to chronic HBV infection. The counts of lymphocytes, neutrophils and monocytes in the HBV infection group were in decline, especially for lymphocyte (p = 0.034) and monocyte counts (p = 0.003). The degraded MM (p = 0.003) and MMPlow% (p = 0.002) of lymphocytes and MM (p = 0.005) of monocytes suggested mitochondrial dysfunction of WBCs. HBV DNA within WBCs showed an extensive effect on mitochondria metabolic potential of lymphocytes, neutrophils and monocytes indicated by MM; hepatitis B e antigen was associated with instant mitochondrial energy supply indicated by MMPlow% of neutrophils; hepatitis B surface antigen, antiviral therapy by nucleos(t)ide analogues and prolonged infection were also vital factors contributing to WBC alterations. Moreover, degraded neutrophils and monocytes could be used to monitor immune responses reflecting chronic liver fibrosis and inflammatory damage. In conclusion, MM combined with cell counts of WBCs could profoundly reflect WBC alterations for monitoring chronic HBV infection. Moreover, HBV DNA within WBCs may be a vital factor in injuring mitochondria metabolic potential.

Microstructure Evolution of TB18 Alloy after Thermal Treatment and the Effect of Recrystallization Texture on Mechanical Properties.

In industrial production, the deformation inhomogeneity after metal forging affects the mechanical properties of various parts of the forgings. The question of whether the organization and mechanical properties of ß-titanium alloy can be improved by controlling the amount of forging deformation needs to be answered. Therefore, in this paper, a new sub-stable ß-Ti alloy TB 18 (Ti-5.3Cr-4.9Mo4.9V-4.3Al-0.9Nb-0.3Fe) was subjected to three different levels of deformation, as well as solid solution-aging treatments, and the variation rules of microstructure and mechanical properties were investigated. During the solid solution process, the texture evolution pattern of the TB18 alloy at low deformation (20-40%) is mainly rotational cubic texture deviated into α-fiber texture; at high deformation (60%), the main components of the deformed texture are α-fiber texture with a specific orientation of (114)<113-3>. After subsequent static recrystallization, the α-fiber texture is deviated to an α*-fiber texture, while the specific orientation (114)<113-3> can still be inherited as a major component of the recrystallized texture. The plasticity of the alloy in the normal direction (ND) after the solid solution is influenced by the existence of the <110>//ND texture, and the plasticity of the alloy in the ND direction after aging is determined by a combination of the volume fraction of the <110>//ND texture in the matrix phase and the volume fraction of [112-0]α//ND in the α phase. The results show that it is feasible to change the characteristics of the recrystallization texture of TB18 by controlling the deformation level of hot forging, thus realizing the modulation of the mechanical properties.

Tendon extracellular-matrix-derived tissue engineering micro-tissue for Achilles tendon injury regeneration in rats.

BACKGROUND: Achilles tendon is vital in maintaining the stability and function of ankle joint. It is quite difficult to achieve the structural and functional repair of Achilles tendon in tissue engineering. METHODS: A tissue-engineered tendon micro-tissue was prepared using rat tail tendon extracellular matrix (TECM) combined with rat adipose stem cells (ADSCs) to repair Achilles tendon injuries. The TECM was prepared by repeated freezing and thawing. The in vitro characteristics of TECM and its effect on ADSCs proliferation were detected. This tissue-engineered tendon micro-tissue for Achilles tendon repair in vivo was evaluated based on general characteristics, gait analysis, ultrasound findings, histological analysis, and biomechanical testing. RESULTS: The results showed that the TECM scaffold had good biocompatibility for ADSCs. At 2 weeks post-surgery, collagen types I and III and tenomodulin expression were higher, and vascular endothelial growth factor expression was lower in the micro-tissue group than other groups. At 4 and 8 weeks post-surgery, the results of histological analysis and ultrasound findings showed that the repaired tendon tissue was smooth and lustrous, and was arranged regularly and evenly in the micro-tissue group. Gait analysis confirmed that better motor function recovery was noted in micro-tissue group than other groups. In addition, the mechanical properties of the repaired tendon tissue in micro-tissue group were better than other groups. CONCLUSION: Tissue-engineered tendon micro-tissue fabricated by TECM and ADSCs has good biocompatibility and can promote structural and functional repair of tendon in vivo. This composite biomaterial has broad application prospects in tissue engineering.

Vitamin D Relieves Epilepsy Symptoms and Neuroinflammation in Juvenile Mice by Activating the mTOR Signaling Pathway via RAF1: Insights from Network Pharmacology and Molecular Docking Studies.

Epilepsy is a common neurological disorder, and the exploration of potential therapeutic drugs for its treatment is still ongoing. Vitamin D has emerged as a promising treatment due to its potential neuroprotective effects and anti-epileptic properties. This study aimed to investigate the effects of vitamin D on epilepsy and neuroinflammation in juvenile mice using network pharmacology and molecular docking, with a focus on the mammalian target of rapamycin (mTOR) signaling pathway. Experimental mouse models of epilepsy were established through intraperitoneal injection of pilocarpine, and in vitro injury models of hippocampal neurons were induced by glutamate (Glu) stimulation. The anti-epileptic effects of vitamin D were evaluated both in vivo and in vitro. Network pharmacology and molecular docking analysis were used to identify potential targets and regulatory pathways of vitamin D in epilepsy. The involvement of the mTOR signaling pathway in the regulation of mouse epilepsy by vitamin D was validated using rapamycin (RAPA). The levels of inflammatory cytokines (TNF-α, IL-1ß, and IL-6) were assessed by enzyme-linked immunosorbent assay (ELISA). Gene and protein expressions were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining was used to analyze the apoptosis of hippocampal neurons. In in vivo experiments, vitamin D reduced the Racine scores of epileptic mice, prolonged the latency of epilepsy, and inhibited the production of TNF-α, IL-1ß, and IL-6 in the hippocampus. Furthermore, network pharmacology analysis identified RAF1 as a potential target of vitamin D in epilepsy, which was further confirmed by molecular docking analysis. Additionally, the mTOR signaling pathway was found to be involved in the regulation of mouse epilepsy by vitamin D. In in vitro experiments, Glu stimulation upregulated the expressions of RAF1 and LC3II/LC3I, inhibited mTOR phosphorylation, and induced neuronal apoptosis. Mechanistically, vitamin D activated the mTOR signaling pathway and alleviated mouse epilepsy via RAF1, while the use of the pathway inhibitor RAPA reversed this effect. Vitamin D alleviated epilepsy symptoms and neuroinflammation in juvenile mice by activating the mTOR signaling pathway via RAF1. These findings provided new insights into the molecular mechanisms underlying the anti-epileptic effects of vitamin D and further supported its use as an adjunctive therapy for existing anti-epileptic drugs.

Chemo-, Regio- and Stereoselective Preparation of (Z)-2-Butene-1,4-Diol Monoesters via Pd-Catalyzed Decarboxylative Acyloxylation.

(Z)-alkenes are useful synthons but thermodynamically less stable than their (E)-isomers and typically more difficult to prepare. The synthesis of 1,4-hetero-bifunctionalized (Z)-alkenes is particularly challenging due to the inherent regio- and stereoselectivity issues. Herein we demonstrate a general, chemoselective and direct synthesis of (Z)-2-butene-1,4-diol monoesters. The protocol operates within a Pd-catalyzed decarboxylative acyloxylation regime involving vinyl ethylene carbonates (VECs) and various carboxylic acids as the reaction partners under mild and operationally attractive conditions. The newly developed process allows access to a structurally diverse pool of (Z)-2-butene-1,4-diol monoesters in good yields and with excellent regio- and stereoselectivity. Various synthetic transformations of the obtained (Z)-2-butene-1,4-diol monoesters demonstrate how these synthons are of great use to rapidly diversify the portfolio of these formal desymmetrized (Z)-alkenes.

Potent human monoclonal antibodies targeting Epstein-Barr virus gp42 reveal vulnerable sites for virus infection.

Epstein-Barr virus (EBV) is linked to various malignancies and autoimmune diseases, posing a significant global health challenge due to the lack of specific treatments or vaccines. Despite its crucial role in EBV infection in B cells, the mechanisms of the glycoprotein gp42 remain elusive. In this study, we construct an antibody phage library from 100 EBV-positive individuals, leading to the identification of two human monoclonal antibodies, 2B7 and 2C1. These antibodies effectively neutralize EBV infection in vitro and in vivo while preserving gp42's interaction with the human leukocyte antigen class II (HLA-II) receptor. Structural analysis unveils their distinct binding epitopes on gp42, different from the HLA-II binding site. Furthermore, both 2B7 and 2C1 demonstrate potent neutralization of EBV infection in HLA-II-positive epithelial cells, expanding our understanding of gp42's role. Overall, this study introduces two human anti-gp42 antibodies with potential implications for developing EBV vaccines targeting gp42 epitopes, addressing a critical gap in EBV research.

Case report: Non-EBV associated cerebral vasculitis and cerebral hemorrhage in X-linked lymphoproliferative disease.

X-linked lymphoproliferative disease (XLP) is a rare genetic disorder characterized by immune dysregulation. The three most common clinical phenotypes are EBV-associated infectious mononucleosis (FIM), abnormal gammaglobulinemia, and lymphoma. We present a rare case of XLP1 with neurovasculitis, which is non-EBV-related and involves multiple systems, a condition rarely seen in children. The patient initially presented with an unsteady gait, which progressively evolved into language and consciousness disorders. Additionally, CT scans revealed multiple nodules in the lungs. Subsequent genetic testing and brain tissue biopsy confirmed the diagnosis: XLP1-related cerebral vasculitis and cerebral hemorrhage. Tragically, during the diagnostic process, the child experienced a sudden cerebral hemorrhage and herniation, ultimately resulting in fatality. This case offers a comprehensive insight into XLP1-related cerebral vasculitis and cerebral hemorrhage, underscoring the significance of early diagnosis and prompt treatment, while also imparting valuable clinical experience and lessons to the medical community.

Identification and analysis of immunogenicity and immunotherapy efficacy by fatty acid genes: a novel prognostic features of lumbar disc herniation and Mendelian randomization analysis.

BACKGROUND: Sciatica is a phrase used to describe radiating leg discomfort. The most common cause is lumbar disc herniation (LDH), which is considered to start in the nucleus pulposus. Advancements in lipidomics and metabolomics have unveiled the complex role of fatty acid metabolism (FAM) in both healthy and pathological states. However, the specific roles of fatty acid metabolism-related genes (FAMGs) in shaping therapeutic approaches, especially in LDH, remain largely unexplored and are a subject of ongoing research. METHODS: The junction of the weighted correlation network analysis (WGCNA) test with 6 FAMGs enabled the finding of FAMGs. Gene set variation analysis (GSVA) was used to identify the possible biological activities and pathways of FAMGs. LASSO was used to determine diagnostic effectiveness of the four FAMGs in diagnosing LDH. GSE124272, GSE147383, GSE150408, and GSE153761 were utilized to confirm the levels of expression of four FAMGs. RESULTS: Four FAMGs were discovered [Acyl-CoA Thioesterase 4 (ACOT4), Cytochrome P450 Family 4 Subfamily A Member 11 (CYP4A11), Acyl-CoA Dehydrogenase Long Chain (ACADL), Enoyl-CoA Hydratase and 3-Hydroxyacyl CoA Dehydrogenase (EHHADH)] For biological function analysis, mhc class ib receptor activity, response to thyroxine, response to l phenylalanine derivative were emphasized. CONCLUSIONS: FAMGs can help with prognosis and immunology, and provide evidence for fatty acid metabolism-related targeted therapeutics. In LDH, FAMGs and their interactions with immune cells might be therapeutic targets.

Deep burn surgery of the whole dorsum of the hand: Composite skin grafting over acellular dermal matrix versus thick split-thickness skin grafting.

Preservation and restoration of hand function after burn injuries are challenging yet imperative. This study aimed to assess the curative effect of a composite skin graft over an acellular dermal matrix (ADM) and a thick split-thickness skin graft (STSG) for treating deep burns on the hand. Patients who met the inclusion criteria at the First Affiliated Hospital of Wenzhou Medical University between September 2011 and January 2020 were retrospectively identified from the operative register. We investigated patient characteristics, time from operation to the start of active motion exercise, take rates of skin graft 7 days post-surgery, donor site recovery, complications and days to complete healing. Patients were followed up for 12 months to evaluate scar quality using the Vancouver Scar Scale (VSS) and hand function through total active motion (TAM) and the Jebsen-Taylor Hand Function Test (JTHFT). A total of 38 patients (52 hands) who received thin STSG on top of the ADM or thick STSG were included. The location of the donor sites was significantly different between Group A (thick STSG) and Group B (thin STSG + ADM) (p = 0.03). There were no statistical differences in age, gender, underlying disease, cause of burn, burn area, dominant hand, patients with two hands operated on and time from burn to surgery between the two groups (p > 0.05). The time from operation to the start of active motion exercise, take rates of skin graft 7 days post-surgery and days to complete healing were not significantly different between Group A and Group B (p > 0.05). The rate of donor sites requiring skin grafting was lower in Group B than in Group A (22.2% vs. 100%, p < 0.001). There were no statistically significant differences in complications between the groups (p = 0.12). Moreover, 12 months postoperatively, the pliability subscore in the VSS was significantly lower in Group A than in Group B (p = 0.01). However, there were no statistically significant differences in vascularity (p = 0.42), pigmentation (p = 0.31) and height subscores (p = 0.13). The TAM and JTHFT results revealed no statistically significant differences between the two groups (p = 0.22 and 0.06, respectively). The ADM combined with thin STSG is a valuable approach for treating deep and extensive hand burns with low donor site morbidity. It has a good appearance and function in patients with hand burns, especially in patients with limited donor sites.

Associations of systemic inflammatory regulators with CKD and kidney function: evidence from the bidirectional mendelian randomization study.

BACKGROUND: Previous observational studies have reported that systemic inflammatory regulators are related to the development of chronic kidney disease (CKD); however, whether these associations are causal remains unclear. The current study aimed to investigate the potential causal relationships between systemic inflammatory regulators and CKD and kidney function. METHOD: We performed bidirectional two-sample Mendelian randomization (MR) analyses to infer the underlying causal associations between 41 systemic inflammatory regulators and CKD and kidney function. The inverse-variance weighting (IVW) test was used as the primary analysis method. In addition, sensitivity analyses were executed via the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test and the weighted median test. RESULTS: The findings revealed 12 suggestive associations between 11 genetically predicted systemic inflammatory regulators and CKD or kidney function in the forward analyses, including 4 for CKD, 3 for blood urea nitrogen (BUN), 4 for eGFRcrea and 1 for eGFRcys. In the other direction, we identified 6 significant causal associations, including CKD with granulocyte-colony stimulating factor (GCSF) (IVW ß = 0.145; 95% CI, 0.042 to 0.248; P = 0.006), CKD with stem cell factor (SCF) (IVW ß = 0.228; 95% CI, 0.133 to 0.323; P = 2.40 × 10- 6), eGFRcrea with SCF (IVW ß =-2.90; 95% CI, -3.934 to -1.867; P = 3.76 × 10- 8), eGFRcys with GCSF (IVW ß =-1.382; 95% CI, -2.404 to -0.361; P = 0.008), eGFRcys with interferon gamma (IFNg) (IVW ß =-1.339; 95% CI, -2.313 to -0.366; P = 0.007) and eGFRcys with vascular endothelial growth factor (VEGF) (IVW ß =-1.709; 95% CI, -2.720 to -0.699; P = 9.13 × 10- 4). CONCLUSIONS: Our findings support causal links between systemic inflammatory regulators and CKD or kidney function both in the forward and reverse MR analyses.

Detecting Misfolded α-Synuclein in Blood Years before the Diagnosis of Parkinson's Disease.

BACKGROUND: Identifying individuals with Parkinson's disease (PD) already in the prodromal phase of the disease has become a priority objective for opening a window for early disease-modifying therapies. OBJECTIVE: The aim was to evaluate a blood-based α-synuclein seed amplification assay (α-syn SAA) as a novel biomarker for diagnosing PD in the prodromal phase. METHODS: In the TREND study (University of Tuebingen) biennial blood samples of n = 1201 individuals with/without increased risk for PD were taken prospectively over 4 to 10 years. We retrospectively analyzed blood samples of 12 participants later diagnosed with PD during the study to detect and amplify pathological α-syn conformers derived from neuronal extracellular vesicles using (1) immunoblot analyses with an antibody against these conformers and (2) an α-syn-SAA. Additionally, blood samples of n = 13 healthy individuals from the TREND cohort and n = 20 individuals with isolated rapid eye movement sleep behavior disorder (iRBD) from the University Hospital Cologne were analyzed. RESULTS: All individuals with PD showed positive immunoblots and a positive α-syn SAA at the time of diagnosis. Moreover, all PD patients showed a positive α-syn SAA 1 to 10 years before clinical diagnosis. In the iRBD cohort, 30% showed a positive α-syn SAA. All healthy controls had a negative SAA. CONCLUSIONS: We here demonstrate the possibility to detect and amplify pathological α-syn conformers in peripheral blood up to 10 years before the clinical diagnosis of PD in individuals with and without iRBD. The findings of this study indicate that this blood-based α-syn SAA assay has the potential to serve as a diagnostic biomarker for prodromal PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

STAT3 promotes cytoplasmic-nuclear translocation of RNA-binding protein HuR to inhibit IL-1ß-induced IL-8 production.

Signal transducer and activator of transcription 3 (STAT3) functions to regulate inflammation and immune response, but its mechanism is not fully understood. We report here that STAT3 inhibitors Stattic and Niclosamide up-regulated IL-1ß-induced IL-8 production in C33A, CaSki, and Siha cervical cancer cells. As expected, IL-1ß-induced IL-8 production was also up-regulated through the molecular inhibition of STAT3 by use of CRISPR/Cas9 technology. Unexpectedly, IL-1ß induced IL-8 production via activating ERK and P38 signal pathways, but neither STAT3 inhibitors nor STAT3 knockout affected IL-1ß-induced signal transduction, suggesting that STAT3 decreases IL-8 production not via inhibition of signal transduction. To our surprise, STAT3 inhibition increased the stabilization, and decreased the degradation of IL-8 mRNA, suggesting a post-transcriptional regulation of IL-1ß-induced IL-8. Moreover, Dihydrotanshinone I, an inhibitor of RNA-binding protein HuR, down-regulated IL-1ß-induced IL-8 dose-dependently. HuR inhibition by CRISPR/Cas9 also decreased IL-8 production induced by IL-1ß. Mechanistically, co-immunoprecipitation results showed that STAT3 did not react with HuR directly, but STAT3 inhibition increased the protein levels of HuR in cytoplasm. And IL-6 activation of STAT3 induced HuR cytoplasmic-nuclear transport. Taken together, these results suggest that STAT3 contributes to HuR nuclear localization and inhibits Il-1ß-induced IL-8 production through this non-transcriptional mechanism.

Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression.

Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.

ODF3B affects the proliferation and apoptosis of glioma via the JAK/STAT pathway.

The pathogenesis of glioma has remained unclear. In this study, it was found that high expression of the outer dense fibers of sperm tail 3B (ODF3B) in gliomas was positively correlated with the grade of glioma. The higher the grade, the worse the prognosis. ODF3B is closely related to the growth and apoptosis of glioma. In terms of mechanism, ODF3B was found to affect the proliferation and apoptosis of glioma through the JAK1 and JAK2/STAT3 pathways. ODF3B was also found to affect the growth and apoptosis of glioma in vivo. We conclude that ODF3B affects glioma proliferation and apoptosis via the JAK/STAT pathway and is a potential therapeutic target.