Human-Derived Induced GABAergic Progenitor Cells Improve Cognitive Function in Mice and Inhibit Astrocyte Activation with Anti-Inflammatory Exosomes.

OBJECTIVE: The role of gamma-aminobutyric acid-ergic (GABAergic) neuron impairment in Alzheimer's disease (AD), and if and how transplantation of healthy GABAergic neurons can improve AD, remain unknown. METHODS: Human-derived medial ganglionic eminence progenitors (hiMGEs) differentiated from programmed induced neural precursor cells (hiNPCs) were injected into the dentate gyrus region of the hippocampus (HIP). RESULTS: We showed that grafts migrate to the whole brain and form functional synaptic connections in amyloid precursor protein gene/ presenilin-1 (APP/PS1) chimeric mice. Following transplantation of hiMGEs, behavioral deficits and AD-related pathology were alleviated and defective neurons were repaired. Notably, exosomes secreted from hiMGEs, which are rich in anti-inflammatory miRNA, inhibited astrocyte activation in vitro and in vivo, and the mechanism was related to regulation of CD4+ Th1 cells mediated tumor necrosis factor (TNF) pathway. INTERPRETATION: Taken together, these findings support the hypothesis that hiMGEs transplantation is an alternative treatment for neuronal loss in AD and demonstrate that exosomes with anti-inflammatory activity derived from hiMGEs are important factors for graft survival. ANN NEUROL 2024.

Necroptosis-Mediated Synergistic Photodynamic and Glutamine-Metabolic Therapy Enabled by a Biomimetic Targeting Nanosystem for Cholangiocarcinoma.

Targeted delivery of glutamine metabolism inhibitors holds promise for cholangiocarcinoma therapy, yet effective delivery vehicles remain a challenge. This study reports the development of a biomimetic nanosystem, termed R-CM@MSN@BC, integrating mesoporous organosilicon nanoparticles with reactive oxygen species-responsive diselenide bonds for controlled release of the glutamine metabolism inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and the photosensitizer Ce6. Erythrocyte membrane coating, engineered with Arg-Gly-Asp (RGD) peptides, not only enhanced biocompatibility but also improved tumor targeting and tissue penetration. Upon laser irradiation, R-CM@MSN@BC executed both photodynamic and glutamine-metabolic therapies, inducing necroptosis in tumor cells and triggering significant immunogenic cell death. Time-of-flight mass cytometry analysis revealed that R-CM@MSN@BC can remodel the immunosuppressive tumor microenvironment by polarizing M1-type macrophages, reducing infiltration of M2-type and CX3CR1+ macrophages, and decreasing T cell exhaustion, thereby increasing the effectiveness of anti-programmed cell death ligand 1 immunotherapy. This strategy proposed in this study presents a viable and promising approach for the treatment of cholangiocarcinoma.

A randomized trial of the inflammatory cytokines levels and the blood transfusion rate between miniaturized tubing group and conventional tubing group in congenital heart disease open heart surgeries.

INTRODUCTION: We aimed to compare the inflammatory cytokines levels of the miniaturized and conventional extracorporeal circuit system. The miniaturized extracorporeal circuit system may be fewer possible inflammation-induced or blood transfusion-related complications. METHODS: We performed a prospective randomized controlled trial (RCT) of 101 patients undergoing congenital heart surgery with CPB (cardiopulmonary bypass, weight ≤15 kg, age ≤2 years). Patients were divided into two different CPB groups randomly by random data form. Blood samples at five different time points and the ultrafiltration fluid before and after CPB were collected in all patients. IL-6, IL-8, and TNF alpha were respectively tested with Abcam ELISA kit. RESULTS: The IL-6 level of blood serum in two groups had no statistical differences between the two groups at all time points. The IL-8 level of blood serum in two groups had no statistical differences right after anesthesia and 5 min after CPB. However, IL-8 level was significantly higher in conventional extracorporeal circuit group than that in miniaturized extracorporeal circuit group at 6 h, 12 h and 24 h after CPB. Blood serum TNF alpha in conventional extracorporeal circuit group was significantly higher at 6 h after CPB than that in miniaturized extracorporeal circuit group. No statistical differences in TNF alpha were found between two groups right after anesthesia and at 5 min after CPB, 12 h and 24 h after CPB. In ultrafiltration fluid, no statistical differences were found in IL-6, IL-8 nor TNF alpha between two groups in all time. No statistical differences were found in ICU (intensive care unit) stay and mechanical ventilation time between the two groups. The blood transfusion rate was significantly lower in miniaturized extracorporeal circuit group. CONCLUSION: Implementing the miniaturized extracorporeal circuit system could decrease the inflammatory cytokines at a certain level. The blood transfusion rate is significantly lower in miniaturized extracorporeal circuit group This indicates the miniaturized extracorporeal circuit system might be a safer CPB strategy with fewer possible inflammation-induced or blood transfusion-related complications.

The predictive value of γ-glutamyl transferase to serum albumin ratio in hepatocellular carcinoma patients after liver transplantation.

Background: Elevated preoperative γ-glutamyl transferase (GGT) levels or reduced serum albumin levels have been established as negative prognostic factors for patients with hepatocellular carcinoma (HCC) and various other tumors. Nonetheless, the prognostic significance of the GGT to serum albumin ratio (GAR) in liver transplantation (LT) therapy for HCC is still not well-defined. Methods: A retrospective analysis was conducted on the clinical data of 141 HCC patients who underwent LT at Shulan (Hangzhou) Hospital from June 2017 to November 2020. Using the receiver operating characteristic (ROC) curve, the optimal GAR cutoff value to predict outcomes following LT was assessed. Univariate and multivariate Cox proportional hazards regression analyses were used to identify independent risk factors associated with both overall survival (OS) and recurrence-free survival (RFS). Results: A GAR value of 2.04 was identified as the optimal cutoff for predicting both OS and RFS, with a sensitivity of 63.2% and a specificity of 74.8%. Among these patients, 80 (56.7%) and 90 (63.8%) met the Milan and the University of California San Francisco (UCSF) criteria, respectively. Univariate Cox regression analysis showed that microvascular invasion (MVI), maximum tumor size (>5 cm), total tumor size (>8 cm), liver cirrhosis, TNM stage (III), and GAR (≥2.04) were significantly associated with both postoperative OS and RFS in patients with HCC (all p < 0.05). Multivariate Cox regression analysis indicated that GAR (≥2.04) was independently linked with RFS and OS. Conclusion: Pre-transplant GAR ≥2.04 is an independent correlate of prognosis and survival outcomes after LT for HCC and can be used as a prognostic indicator for both mortality and tumor recurrence following LT.

Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis.

BACKGROUND: Acute liver failure (ALF) has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis. The silent information regulator sirtuin 1 (SIRT1)-mediated deacetylation affects multiple biological processes, including cellular senescence, apoptosis, sugar and lipid metabolism, oxidative stress, and inflammation. AIM: To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms. METHODS: This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing. C57BL/6 mice were also intraperitoneally pretreated with SIRT1, p53, or glutathione peroxidase 4 (GPX4) inducers and inhibitors and injected with lipopolysaccharide (LPS)/D-galactosamine (D-GalN) to induce ALF. Gasdermin D (GSDMD)-/- mice were used as an experimental group. Histological changes in liver tissue were monitored by hematoxylin and eosin staining. ALT, AST, glutathione, reactive oxygen species, and iron levels were measured using commercial kits. Ferroptosis- and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction. SIRT1, p53, and GSDMD were assessed by immunofluorescence analysis. RESULTS: Serum AST and ALT levels were elevated in patients with ALF. SIRT1, solute carrier family 7a member 11 (SLC7A11), and GPX4 protein expression was decreased and acetylated p5, p53, GSDMD, and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein levels were elevated in human ALF liver tissue. In the p53 and ferroptosis inhibitor-treated and GSDMD-/- groups, serum interleukin (IL)-1ß, tumour necrosis factor alpha, IL-6, IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated. In mice with GSDMD knockout, p53 was reduced, GPX4 was increased, and ferroptotic events (depletion of SLC7A11, elevation of ACSL4, and iron accumulation) were detected. In vitro, knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels, the cytostatic rate, and GSDMD expression, restoring SLC7A11 depletion. Moreover, SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group, accompanied by reduced p53, GSDMD, and ACSL4, and increased SLC7A11 and GPX4. Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalN-induced in vitro and in vivo models. CONCLUSION: SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

Arginase 2 is a Diagnostic and Prognostic Marker for Prostate Cancer and Is Associated with Metabolism.

Objective: Metabolism, a basic need and biochemical process for cell survival and proliferation, is closely connected with the pathogenesis and progression of prostate cancer. Methods: A four-gene signature construct that includes CKM (CKM), CD38, Enoyl Coenzyme A(EHHADH), and Arginase 2(ARG2) was created by bioinformatics. Finally, hub genes were validated by IHC and in vitro experiments. Results: The results showed the AUCs of the logistic regression and neural networks diagnostic model for the diagnosis of two subtypes were 0.920 and 0.936, respectively. The risk score demonstrated by univariable and multivariable Cox analysis is an independent predictive component of the prognostic signature for DFS. According to immunohistochemical analyses, ARG2 and CD38 expression levels were considerably under-expressed, but CKM and EHHADH expression levels were significantly overexpressed. Furthermore, The expression of ARG2 was significantly down-regulated in the late Gleason score. Finally, we found that ARG2 is lowly expressed in prostate cancer cells. Furthermore, based on the effect of ARG2 on the malignant phenotype of PCa in vitro, we also found that ARG2 may be a tumor suppressor that plays an important role in inhibiting proliferation, migration, and invasion. Conclusions: These findings suggest that ARG2 has been tentatively identified as a new target for research into how PCa develops in metabolism and for the development of innovative targeted treatments.

Autoimmune hepatitis-primary biliary cholangitis overlap syndrome complicated by various autoimmune diseases: A case report.

BACKGROUND: Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are two common clinical autoimmune liver diseases, and some patients have both diseases; this feature is called AIH-PBC overlap syndrome. Autoimmune thyroid disease (AITD) is the most frequently overlapping extrahepatic autoimmune disease. Immunoglobulin (IgG) 4-related disease is an autoimmune disease recognized in recent years, characterized by elevated serum IgG4 levels and infiltration of IgG4-positive plasma cells in tissues. CASE SUMMARY: A 68-year-old female patient was admitted with a history of right upper quadrant pain, anorexia, and jaundice on physical examination. Laboratory examination revealed elevated liver enzymes, multiple positive autoantibodies associated with liver and thyroid disease, and imaging and biopsy suggestive of pancreatitis, hepatitis, and PBC. A diagnosis was made of a rare and complex overlap syndrome of AIH, PBC, AITD, and IgG4-related disease. Laboratory features improved on treatment with ursodeoxycholic acid, methylprednisolone, and azathioprine. CONCLUSION: This case highlights the importance of screening patients with autoimmune diseases for related conditions.

IFIT1 modulates the proliferation, migration and invasion of pancreatic cancer cells via Wnt/ß-catenin signaling.

OBJECTIVES: Previously, Interferon-induced Protein with Tetratricopeptide Repeats 1 (IFIT1) has been shown to promote cancer development. Here, we aimed to explore the role of IFIT1 in the development and progression of pancreatic cancer, including the underlying mechanisms. METHODS: We explored IFIT1 expression in pancreatic cancer samples using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Cell Counting Kit-8 (CCK8), colony formation, scratch wound-healing and Transwell assays were performed to assess the proliferation, migration and invasion abilities of pancreatic cancer cells. Gene Set Enrichment Analysis (GSEA) and Western blotting were performed to assess the regulatory effect of IFIT1 on the Wnt/ß-catenin pathway. RESULTS: We found that upregulation of IFIT1 expression is common in pancreatic cancer and is negatively associated with overall patient survival. Knockdown of IFIT1 expression led to decreased proliferation, migration and invasion of pancreatic cancer cells. We also found that IFIT1 could regulate Wnt/ß-catenin signaling, and that a Wnt/ß-catenin agonist could reverse this effect. In addition, we found that IFIT1 can promote epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. CONCLUSIONS: Our data indicate that IFIT1 increases pancreatic cancer cell proliferation, migration and invasion by activating the Wnt/ß-catenin pathway. In addition, we found that EMT could be regulated by IFIT1. IFIT1 may serve as a potential therapeutic target for pancreatic cancer.

Anti-inflammatory mechanisms of neutrophil membrane-coated nanoparticles without drug loading.

Neutrophil membrane-coated nanoparticles (NM-NPs) are nanomedicines with traits of mimicking the surface properties and functions of neutrophils, which are the most abundant type of white blood cells in the human body. NM-NPs have been widely used as targeted drug delivery systems for various inflammatory diseases, but their intrinsic effects on inflammation are not fully characterized yet. This study found that NM-NPs could modulate inflammation by multiple mechanisms without drug loading. NM-NPs could inhibit the recruitment of neutrophils and macrophages to the inflamed site by capturing chemokines and blocking their adhesion to inflamed endothelial cells. After internalized by macrophages and other phagocytic cells, NM-NPs could alter their phenotype by phosphatidylserine and simultaneously degrade the sequestered and neutralized cytokines and chemokines by lysosomal degradation. Under these effects, NM-NPs exhibited significant anti-inflammatory effects on LPS-induced inflammatory liver injury in vivo without drug loading. Our study unveiled the anti-inflammatory effects and mechanisms of NM-NPs without drug loading, and provided new insights and evidence for understanding their biological effects and safety, as well as developing more effective and safe targeted drug delivery systems.

A novel DDIT3 activator dehydroevodiamine effectively inhibits tumor growth and tumor cell stemness in pancreatic cancer.

BACKGROUND: The existence of pancreatic cancer stem cells (PCSCs) results in limited survival benefits from current treatment options. There is a scarcity of effective agents for treating pancreatic cancer patients. Dehydroevodiamine (DeHE), a quinazoline alkaloid isolated from the traditional Chinese herb Evodiae fructus, exhibited potent inhibition of pancreatic ductal adenocarcinoma (PDAC) cell proliferation and tumor growth both in vitro and in vivo. METHODS: The cytotoxic effect of DeHE on PDAC cells was assessed using CCK-8 and colony formation assays. The antitumor efficacy of DeHE were appraised in human PANC-1 xenograft mouse model. Sphere formation assay and flow cytometry were employed to quantify the tumor stemness. RNA-Seq analysis, drug affinity responsive target stability assay (DARTS), and RNA interference transfection were conducted to elucidate potential signaling pathways. Western blotting and immunohistochemistry were utilized to assess protein expression levels. RESULTS: DeHE effectively inhibited PDAC cell proliferation and tumor growth in vitro and in vivo, and exhibited a better safety profile compared to the clinical drug gemcitabine (GEM). DeHE inhibited PCSCs, as evidenced by its suppression of self-renewal capabilities of PCSCs, reduced the proportion of ALDH+ cells and downregulated stemness-associated proteins (Nanog, Sox-2, and Oct-4) both in vitro and in vivo. Furthermore, there is potential involvement of DDIT3 and its downstream DDIT3/TRIB3/AKT/mTOR pathway in the suppression of stemness characteristics within DeHE-treated PDAC cells. Additionally, results from the DARTS assay indicated that DeHE interacts with DDIT3, safeguarding it against degradation mediated by pronase. Notably, the inhibitory capabilities of DeHE on PDAC cell proliferation and tumor stemness were partially restored by siDDIT3 or the AKT activator SC-79. CONCLUSION: In summary, our study has identified DeHE, a novel antitumor natural product, as an activator of DDIT3 with the ability to suppress the AKT/mTOR pathway. This pathway is intricately linked to tumor cell proliferation and stemness characteristics in PDAC. These findings suggest that DeHE holds potential as a promising candidate for the development of innovative anticancer therapeutics.

An Integrated Clinical and Computerized Tomography-Based Radiomic Feature Model to Separate Benign from Malignant Pleural Effusion.

INTRODUCTION: Distinguishing between malignant pleural effusion (MPE) and benign pleural effusion (BPE) poses a challenge in clinical practice. We aimed to construct and validate a combined model integrating radiomic features and clinical factors using computerized tomography (CT) images to differentiate between MPE and BPE. METHODS: A retrospective inclusion of 315 patients with pleural effusion (PE) was conducted in this study (training cohort: n = 220; test cohort: n = 95). Radiomic features were extracted from CT images, and the dimensionality reduction and selection processes were carried out to obtain the optimal radiomic features. Logistic regression (LR), support vector machine (SVM), and random forest were employed to construct radiomic models. LR analyses were utilized to identify independent clinical risk factors to develop a clinical model. The combined model was created by integrating the optimal radiomic features with the independent clinical predictive factors. The discriminative ability of each model was assessed by receiver operating characteristic curves, calibration curves, and decision curve analysis (DCA). RESULTS: Out of the total 1,834 radiomic features extracted, 15 optimal radiomic features explicitly related to MPE were picked to develop the radiomic model. Among the radiomic models, the SVM model demonstrated the highest predictive performance [area under the curve (AUC), training cohort: 0.876, test cohort: 0.774]. Six clinically independent predictive factors, including age, effusion laterality, procalcitonin, carcinoembryonic antigen, carbohydrate antigen 125 (CA125), and neuron-specific enolase (NSE), were selected for constructing the clinical model. The combined model (AUC: 0.932, 0.870) exhibited superior discriminative performance in the training and test cohorts compared to the clinical model (AUC: 0.850, 0.820) and the radiomic model (AUC: 0.876, 0.774). The calibration curves and DCA further confirmed the practicality of the combined model. CONCLUSION: This study presented the development and validation of a combined model for distinguishing MPE and BPE. The combined model was a powerful tool for assisting in the clinical diagnosis of PE patients.

RIRS with FV-UAS vs. MPCNL for 2-3-cm upper urinary tract stones: a prospective study.

To observe the efficacy and safety of retrograde intrarenal surgery (RIRS) combined with flexible vacuum-assisted ureteral access sheath (FV-UAS) and minimally invasive percutaneous nephrolithotomy (MPCNL) in patients with 2-3 cm upper urinary tract stones. A total of 160 patients with 2-3 cm upper urinary tract stones were prospectively randomized into 2 groups-80 in the FV-UAS group and 80 cases as control in the MPCNL group. The stone-free rates (SFRs) at different times (postoperative 1st day and 4th week) were considered as the primary outcome of the study. The secondary end points were operative time, hemoglobin decrease, postoperative hospital stay, and operation-related complications. There was no obvious difference between the two groups in patient's demographics and preoperative clinical characteristics (all P > 0.05). Postoperative data showed that mean decrease in hemoglobin level was less in FV-UAS group than that in MPCNL group (5.3 vs. 10.8 g/L, P < 0.001). Postoperative hospital stay in FV-UAS group was more shorten than that in MPCNL group (2.7 vs. 4.9 days, P < 0.001). There was no statistical significance between the two groups in SFRs during postoperative 1st day and 4th week (both P > 0.05). However, in terms of the rates of bleeding and pain, MPCNL group were both significantly higher than FV-UAS group (6.2 vs. 0.0%, P = 0.023; 16.2 vs. 2.5%, P = 0.003; respectively). Our study showed that RIRS with FV-UAS, a new partnership to treat 2-3 cm upper urinary tract stones, was satisfying as it achieved a high SFR rate and a low rate of complications. This method was safe and reproducible in clinical practice.

Establishment and comparison of different procedures for modeling intrauterine adhesion in rats: A preliminary study.

The establishment of a stable animal model for intrauterine adhesion (IUA) can significantly enhance research on the pathogenesis and pathological changes of this disease, as well as on the development of innovative therapeutic approaches. In this study, three different modeling methods, including phenol mucilage combined mechanical scraping, ethanol combined mechanical scraping and ethanol modeling alone were designed. The morphological characteristics of the models were evaluated. The underlying mechanisms and fertility capacity of the ethanol modeling group were analyzed and compared to those of the sham surgery group. All three methods resulted in severe intrauterine adhesions, with ethanol being identified as a reliable modeling agent and was subsequently subjected to further evaluation. Immunohistochemistry and RT-PCR results indicated that the ethanol modeling group exhibited an increase in the degree of fibrosis and inflammation, as well as a significant reduction in endometrial thickness, gland number, vascularization, and endometrial receptivity, ultimately resulting in the loss of fertility capacity. The aforementioned findings indicate that the intrauterine perfusion of 95 % ethanol is efficacious in inducing the development of intrauterine adhesions in rats. Given its cost-effectiveness, efficacy, and stability in IUA formation, the use of 95 % ethanol intrauterine perfusion may serve as a novel platform for evaluating innovative anti-adhesion materials and bioengineered therapies.

Resveratrol prevents age-related heart impairment through inhibiting the Notch/NF-κB pathway.

Resveratrol (RSV) is a natural polyphenol compound found in various plants that has been shown to have potential benefits for preventing aging and supporting cardiovascular health. However, the specific signal pathway by which RSV protects the aging heart is not yet well understood. This study aimed to explore the protective effects of RSV against age-related heart injury and investigate the underlying mechanisms using a D-galactose-induced aging model. The results of the study indicated that RSV provided protection against age-related heart impairment in mice. This was evidenced by the reduction of cardiac histopathological changes as well as the attenuation of apoptosis. RSV-induced cardioprotection was linked to a significant increase in antioxidant activity and mitochondrial transmembrane potential, as well as a reduction in oxidative damage. Additionally, RSV inhibited the production of pro-inflammatory cytokines such as interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). Furthermore, the expression of toll-like receptor 4 (TLR4), nuclear factor kappa-B p65 (NF-κB p65), and notch 1 protein were inhibited by RSV, indicating that inhibiting the Notch/NF-κB pathway played a critical role in RSV-triggered heart protection in aging mice. Moreover, further data on intestinal function demonstrated that RSV significantly increased short-chain fatty acids (SCFAs) in intestinal contents and reduced the pH value in the feces of aging mice. RSV alleviated aging-induced cardiac dysfunction through the suppression of oxidative stress and inflammation via the Notch/NF-κB pathway in heart tissue. Furthermore, this therapeutic effect was found to be associated with its protective roles in the intestine.

Neutrophil Nanodecoys Inhibit Tumor Metastasis by Blocking the Interaction between Tumor Cells and Neutrophils.

Cancer metastasis is the main cause of cancer-related deaths and involves the interaction between tumor cells and neutrophils. In this study, we developed activated neutrophil membrane-coated nanoparticles (aNEM NPs) as nanodecoys to block neutrophil-mediated cancer metastasis. The aNEM NPs were fabricated by cloaking poly(lactic acid) nanoparticles with membranes derived from activated neutrophils and inherited the functional proteins of activated neutrophils. We demonstrated that aNEM NPs could interfere with the recruitment of neutrophils to the primary tumor and premetastatic niches, inhibit the adhesion of neutrophils to tumor vascular endothelium and circulating tumor cells (CTCs), and disrupt the formation of CTC-neutrophil clusters in vitro and in vivo. In 4T1-bearing mice, aNEM NPs could effectively reduce breast cancer metastasis to various organs in mice. Our results suggest that aNEM NPs are a promising nanomedicine for preventing or treating cancer metastasis by acting as neutrophil nanodecoys.

Increased expression of NLRP3 associated with elevated levels of HMGB1 in children with febrile seizures: a case-control study.

BACKGROUND: High mobility group box-1 (HMGB1) is an endogenous danger signal that mediates activation of the innate immune response including NLR pyrin domain containing 3 (NLRP3) inflammasome activation and proinflammatory cytokine release. Although HMGB1 and NLRP3 have been implicated in the pathophysiology of seizures, the correlation between HMGB1 and NLRP3 expression has not been determined in children with febrile seizures (FS). To explore the relationship between extra-cellular HMGB1 and NLRP3 in children with FS, we analyzed serum HMGB1, NLRP3, caspase-1, and proinflammatory cytokines in patients with FS. METHODS: Thirty children with FS and thirty age-matched febrile controls were included in this study. Blood was obtained from the children with FS within 1 h of the time of the seizure; subsequently, the serum contents of HMGB1, NLRP3, caspase-1, interleukin (IL)-1ß, interleukin (IL)-6, and tumour necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. The Mann‒Whitney U test was used to compare serum cytokine levels between FS patients and controls. Spearman's rank correlation coefficient was calculated to detect significant correlations between cytokine levels. RESULTS: Serum levels of HMGB1, NLRP3, caspase-1, IL-1ß, IL-6, and TNF-α were significantly higher in FS patients than in febrile controls (p < 0.05). Serum levels of HMGB1 were significantly correlated with levels of NLRP3 and caspase-1 (both, p < 0.05). Serum levels of caspase-1 were significantly correlated with levels of IL-1ß (p < 0.05). Serum levels of IL-1ß were significantly correlated with levels of IL-6 and TNF-α (p < 0.05). CONCLUSIONS: HMGB1 is up-regulated in the peripheral serum of FS patients, which may be responsible, at least in part, for the increased expression of NLRP3 and Caspase-1. Increased expression of caspase-1 was significantly associated with elevated serum levels of IL-1ß. Given that activated Caspase-1 directly regulates the expression of mature IL-1ß and positively correlates with activation of the NLRP3 inflammasome, our data suggest that increased levels of peripheral HMGB1 possibly mediate IL-1ß secretion through the activation of the NLRP3 inflammasome in children with FS. Thus, both HMGB1 and NLRP3 might be potential targets for preventing or limiting FS.

Simplicispira sedimenti sp. nov., isolated from a sediment of drainage ditch in winery.

A Gram-stain-negative, motile (by single polar flagellum) and rod-shaped bacterium, designated W1-6T, was isolated from a sediment of drainage ditch in winery in Guiyang, south-western China. Strain W1-6T showed the highest 16S rRNA gene sequence similarities with the type strain of Acidovorax wautersii (98.1%) and Simplicispira lacusdiani (97.9%). Phylogenetic analysis based on 16S rRNA gene sequences showed that strain W1-6T was placed adjacent to the members of the genus Simplicispira and formed a separat subclade. Cells showed oxidase and catalase negative reactions. The only respiratory quinone detected was ubiquinone-8 (Q-8). Summed feature 3 (C16:1 ω7c and/or C16:1 ω6c), C16:0 and summed feature 8 (C18:1 ω7c and/or C18:1 ω6c) were predominant cellular fatty acids (> 10%) of strain W1-6T. Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and five unidentified phospholipids were found in the polar lipid extraction. The genomic DNA G + C content was 65.6%. Strain W1-6T shared the highest digital DNA-DNA hybridization [dDDH, (27.6%)] and average nucleotide identity [ANI (84.3%)] values with the type strain of S. lacusdiani. The dDDH and ANI values were below the cutoff level (dDDH 70%; ANI 95-96%) for species delineation. The polyphasic characteristics indicated that the strain W1-6T represents a novel species of the genus Simplicispira, for which the name Simplicispira sedimenti sp. nov. is proposed. The type strain is W1-6T (= CGMCC 1.16274T = NBRC 115624T).

lncRNA UCA1 promotes tumor progression by targeting SMARCD3 in cervical cancer.

Long noncoding RNA urothelial carcinoma associated 1 (UCA1) has been identified as a key molecule in human cancers. However, its functional implications remain unspecified in the context of cervical cancer (CC). This research aims to identify the regulatory mechanism of UCA1 in CC. UCA1 was identified through microarray and confirmed through a quantitative real-time polymerase chain reaction. Proteins that bind with UCA1 were recognized using RNA pull-down assays along with RNA immunoprecipitation. Ubiquitination assays and coimmunoprecipitation were performed to explore the molecular mechanisms of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily d, member 3 (SMARCD3) downregulated in CC. The effects of UCA1 and SMARCD3 on the progression of CC were investigated through gain- and loss-of-function assays and xenograft tumor formation in vivo. In this study, UCA1 was found to be upregulated in CC cells as well as in human plasma exosomes for the first time. Functional studies indicated that UCA1 promotes CC progression. Mechanically, UCA1 downregulated the SMARCD3 protein stabilization by promoting SMARCD3 ubiquitination. Taken together, we revealed that the UCA1/SMARCD3 axis promoted CC progression, which could provide a new therapeutic target for CC.

FARSB Facilitates Hepatocellular Carcinoma Progression by Activating the mTORC1 Signaling Pathway.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality. Human phenylalanine tRNA synthetase (PheRS) comprises two α catalytic subunits encoded by the FARSA gene and two ß regulatory subunits encoded by the FARSB gene. FARSB is a potential oncogene, but no experimental data show the relationship between FARSB and HCC progression. We found that the high expression of FARSB in liver cancer is closely related to patients' low survival and poor prognosis. In liver cancer cells, the mRNA and protein expression levels of FARSB are increased and promote cell proliferation and migration. Mechanistically, FARSB activates the mTOR complex 1 (mTORC1) signaling pathway by binding to the component Raptor of the mTORC1 complex to play a role in promoting cancer. In addition, we found that FARSB can inhibit erastin-induced ferroptosis by regulating the mTOR signaling pathway, which may be another mechanism by which FARSB promotes HCC progression. In summary, FARSB promotes HCC progression and is associated with the poor prognosis of patients. FARSB is expected to be a biomarker for early screening and treatment of HCC.

Associations of serum cortisol and inflammatory marker features with depression and anxiety in young women with gynecologic cancer.

PURPOSE: Serum cortisol and inflammatory markers may play a role in depression and anxiety, but little is known about whether various features of serum cortisol and inflammatory markers have different associations with depression and anxiety. This study examines the associations of serum cortisol and inflammatory marker features with depression and anxiety in young women with gynecologic cancer. METHODS: Sixty-four young women with gynecologic cancer, aged 15-39 years, were recruited in a tertiary general hospital and a tertiary hospital specializing in oncology in China from May to December 2021. The Hospital Anxiety and Depression Scale was used to evaluate depression and anxiety. Blood samples were taken at 8 am, 4 pm, and 10 pm on the same day to examine the various features (average, variability, and diurnal patterns) of serum cortisol and inflammatory markers, namely C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). RESULTS: Young women with gynecologic cancer who reported depression/anxiety had significantly higher average levels of serum cortisol, IL-6 and TNF-α than those who did not. The dysregulations in the diurnal patterns of serum cortisol and IL-6 were associated with depression and anxiety. Serum cortisol levels were significantly higher in the depression/anxiety group at 10 pm. Depression and anxiety were associated with elevated levels of IL-6 and TNF-α at each time point. CONCLUSION: This study revealed various associations of serum cortisol and inflammatory marker features with depression and anxiety in young women with gynecologic cancer. Further research is needed to understand the role of serum cortisol and inflammatory marker features in the progression of depression and anxiety.