Clinical characteristics and risk factors associated with diverse manifestations of COVID-19 in patients aged 85 years and older.

Objective: The goal of this study is to assess the clinical attributes exhibited by patients aged 85 years and older who present different manifestations of COVID-19, and to examine the factors influencing the classification of the disease severity. Method: This retrospective study was conducted at a single center, encompassing an analysis of clinical data obtained from patients with COVID-19 admitted to a general geriatric hospital in Hangzhou, Zhejiang, China, during the period from December 20, 2022, to February 1, 2023. The study focused on 91 eligible patients whose disease severity was compared based on the imaging findings. Results: A total of 91 patients aged 85 years and older, with a median age of 92, including 46 males, 10 exhibiting mild symptoms, 48 moderate cases, and 33 severe cases met the inclusion criteria. Notably, disease severity displayed a significant correlation with age (p < 0.011). All patients presented with complicated chronic underlying conditions and a history of prolonged medication use. Rheumatic immune diseases (p = 0.040) and endocrine medications, primarily hypoglycemic agents (p = 0.034), exhibited statistical significance. Additionally, markers such as lactate dehydrogenase (LDH) (p = 0.030), interleukin 6 (IL-6) (p = 0.014), and D-dimer (p = 0.007) revealed significant associations with disease severity. Chest computed tomography scans predominantly revealed inflammatory features (n = 81, 89.0%). Notably, patients classified as having mild or moderate conditions exhibited eventual improvement, while 13 patients (39.4%) among the severe cases succumbed to the disease. Conclusion: The classification of disease among patients aged 85 years or older old is correlated with advanced age, concurrent rheumatic immune diseases, and prolonged administration of endocrine medications. Furthermore, patients with elevated levels of LDH, IL-6, and D-dimer demonstrated a higher propensity for developing severe diseases.

Enzymatic TET-1 inhibition highlights different epigenetic behaviours of IL-1ß and TNFα in tumour progression of OS cell lines.

Osteosarcoma (OS) is the most frequent primary malignant bone tumour, whose heterogeneity represents a major challenge for common antitumour therapies. Inflammatory cytokines are known to be necessary for OS progression. Therefore, to optimise therapy, it is important to discover reliable biomarkers by identifying the mechanism generating OS and investigating the inflammatory pathways that support the undifferentiated state. In this work, we highlight the differences of epigenetic activities of IL-1ß and TNFα, and the susceptibility of TET-1 enzymatic inhibition, in tumour progression of three different OS cell lines. Investigating DNA methylation of IL-6 promoter and determining its expression, we found that TET enzymatic inhibition influences proliferation induced by inflammatory cytokines in OS cell lines. Moreover, Bobcat 339 treatment blocks IL-1ß epigenetic action on IL-6 promoter, while only partially those of TNFα as well as inhibits IL-1ß-dependent epithelial-mesenchymal transition (EMT) process, but only partially those of TNFα. In conclusion, this work highlights that IL-1ß and TNFα have different effects on DNA demethylation in OS cell lines, making DNA methylation a potential biomarker of disease. Specifically, in IL-1ß treatment, TET-1 inhibition completely blocks tumour progression, while in TNFα actions, it is only partially effective. Given that these two inflammatory pathways can be therapeutic targets for treating these tumours, knowledge of their distinct epigenetic behaviours can be useful for developing precise and specific therapeutic strategies for this disease.

Panel of serum biomarkers for differential diagnosis of idiopathic interstitial lung disease and interstitial lung disease-secondary to systemic autoimmune rheumatic disease.

BACKGROUND: Interstitial lung disease (ILD) may complicate the course of systemic autoimmune rheumatic disease (SARD) and diagnostic biomarkers are needed. Krebs von den Lungen-6 (KL-6), ferritin (FER) and interleukin 6 (IL-6) have been involved in the ILD development. Our study aimed to compare KL-6, FER, IL-6 and soluble mesothelin-related peptide (SMRP) concentrations in a cohort of idiopathic and SARD-ILD. METHODS: 3169 patients were enrolled in the "UK Biomarkers in Interstitial Lung Disease (UK-BILD) Study". We selected patients affected by SARD-ILD and idiopathic ILD (usual interstitial pneumonia-idiopathic pulmonary fibrosis and fibrotic non-specific interstitial pneumonia). Serum marker concentrations were measured through chemiluminescent assays (Fujirebio Europe, Ghent, Belgium). RESULTS: 1013 patients were selected for the study: 520 (51.3%) had idiopathic ILD and 493 (48.7%) SARD-ILD. Idiopathic ILD patients displayed higher KL-6 values than SARD-ILD (p = 0.0002). FER and SMRP, though within normal ranges, were significantly higher in idiopathic ILD (p<0.0001). Logistic regression showed good sensitivity (69.4%) and specificity (80.4%) selecting the variables FER and KL-6 concentrations, age and gender-male correlated with a diagnosis of idiopathic ILD. CONCLUSION: Our study showed the excellent diagnostic value of KL-6 for detecting ILD, which irrespective of the final diagnosis and extent of disease, is always elevated and is a reliable biomarker of lung fibrosis in various diseases, ranging from idiopathic to autoimmune forms. Our study proposed an ILD differentiation model including clinical background. In this context, combination of serum markers and clinical data, as seen in our cohort, may lead to a further improvement in diagnostic accuracy for ILD.

Protein Kinase C and Matrix Metalloproteinases Expression Using Phorbol Myristate Acetate in Degenerative Intervertebral Disc Cells.

Background: Degeneration of nucleus pulposus (NP) cells involves multiple factors. The relationship between the canonical Wnt/ß-catenin signaling pathway and matrix metalloproteinases (MMPs) is important in cellular senescence. Protein kinase C (PKC), an intermediate of the non-canonical Wnt pathway stimulated by phorbol myristate acetate (PMA), possibly prevents NP cell senescence, although not yet demonstrated in human-based studies. This study aimed to investigate the effect of PMA stimulation on the non-canonical and canonical Wnt pathways and MMP expression in human NP cells to ascertain its inhibitory effects on the senescence of NP cells. Methods: Human disc tissues of Pfirrmann grades 1 and 2 were collected from patients during spinal surgery and subsequently cultured. Protein and ribonucleic acid (RNA) were isolated from NP cells treated with PMA (400 nM) for 24 hours. Expression of MMP1, MMP13, tissue inhibitor of matrix metalloproteinase 1 (TIMP1), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), transient receptor potential vanilloid 4 (TRPV4), interleukin-6 (IL-6), and ß-catenin were detected using western blot analysis. Messenger RNA (mRNA) expression of type II collagen and glycosaminoglycan (GAG) were analyzed using reverse transcription polymerase chain reaction. IL-6 and prostaglandin E2 (PGE2) levels were measured using enzyme-linked immunosorbent assay. Results: Expression of PKC-δ (intermediate of the non-canonical Wnt pathway) and ß-catenin (intermediate of the canonical Wnt pathway) was increased by PMA treatment. The mRNA levels of type II collagen and GAG increased; however, their protein levels were not altered. PMA treatment increased the expression of MMP1, TIMP1, ADAMTS5, IL-6, PGE2, and TRPV4; however, the expression of MMP13 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was unaltered. Conclusions: PMA activated PKC-δ, affecting the non-canonical Wnt pathway; however, its effect on ß-catenin in the canonical Wnt pathway was limited. ß-catenin activation through the TRPV4 channel led to increased expression of MMP1 and ADAMTS5 and that of IL-6 and PGE2 owing to NF-κB expression. Consequently, the degeneration of NP cells was not prevented.

Role of endothelial dysfunction in sleep-disordered breathing in egyptian children with sickle cell disease.

BACKGROUND: Endothelial dysfunction is an integral pathophysiologic mechanism in sickle cell disease (SCD), and can lead to many complications. Sleep-disordered breathing (SDB) is a SCD complication with diverse incidence and pathophysiology. This study aimed to determine the prevalence of SDB in children with SCD and to assess its relation to endothelial dysfunction. METHODS: Sixty children with SCD and 60 healthy controls were enrolled. The levels of TNF-α, IL-6, and IL-17A were evaluated in the entire cohort using enzyme-linked immunosorbent assay (ELISA) kits. Polysomnography (PSG) was performed for all SCD patients after completion of the Pediatric Sleep Questionnaire (PSQ). RESULTS: TNF-α, IL-6, and IL-17A levels were significantly greater in children with SCD than in controls (p-values < 0.001, < 0.001, and 0.006, respectively). The PSQ revealed symptoms suggestive of SDB in 50 children with SCD (83.3%), and PSG revealed obstructive sleep apnea (OSA) in 44 children with SCD (73.3%); 22 patients had mild OSA, and 22 had moderate-to-severe OSA according to the apnea-hypopnea index (AHI). TNF-α was significantly greater in SCD children who reported heavy or loud breathing, trouble breathing or struggle to breathe, and difficulty waking up in the morning (p-values = 0.002, 0.002, and 0.031, respectively). The IL-6 levels were significantly greater in SCD children who stopped growing normally (p-value = 0.002). The levels of IL-6 and IL-17A were significantly greater in SCD children with morning headaches (p-values = 0.007 and 0.004, respectively). CONCLUSION: Children with SCD showed a high prevalence of SDB with significantly elevated levels of markers of endothelial function, highlighting the interplay of SDB and endothelial dysfunction in SCD.

Role of interleukin 6 polymorphism and inflammatory markers in outcome of pediatric Covid- 19 patients.

BACKGROUND: IL-6 polymorphisms were associated to viral infection outcomes through affection of IL-6 production and it is an early indicator of tissue injury and systemic inflammatory response. The study aimed to determine whether genetic IL-6 polymorphisms, serum interleukin-6 level and inflammatory markers (Presepsin, CXCL-10, C3, and C4) are associated with the prediction of disease severity in pediatric COVID-19 patients and its possible use as a prognostic tool in pediatric patients admitted to hospital. METHODS: This prospective cohort study was conducted on 150 children with COVID-19. Patients were divided according to the severity of infection into four groups: group I (mild) 67 cases; group II (moderate) 53 cases, group III (severe) 17 cases and group IV (critical) 14 cases. Serum Interleukin 6, CXCL-10, Presepsin, renal and liver functions, electrolytes, C3, C4, ferritin, and D dimer serum levels were assessed in all patients. The Kruskal Wallis test used to compare parametric quantitative data between studied groups and Mann Whitney test for each pair of groups. Non-parametric quantitative data was compared between studied groups using a one-way ANOVA test and post-hoc Bonferroni analysis for each pair of groups. RESULTS: Group I: 35 males and 32 females with a median age of 16 months. Group II: 17 males and 35 females with a median age of 13 months. Group III: 6 males and 11 females with a median age of 12 months and group IV: 3 males and 11 females with a median age of 12 months. There was no statistical difference between the studied groups regarding gender and age. Serum levels of IL- 6, serum ferritin; D-dimer, Presepsin and CXCL 10 were significantly higher in both severe and critical groups than the other 2 groups (mild and moderate). ROC curve analysis showed that interleukin-6 and Presepsin were good markers for prediction of severity of COVID-19 among the diseased children. For severe cases, the sensitivity of interleukin-6 was 76.47% and specificity was 92.31%. For critical cases, the sensitivity of interleukin-6 was 71.43% and specificity was 82.35%. The sensitivity of Presepsin was 76.47% and specificity was 88.46% in severe cases. For critical cases, the sensitivity of Presepsin was 78.57% and specificity of 91.2%. There was significant difference in IL-6 572 allelic among moderate cases with the most frequent 42.3% for genotype (GC) and allelic among severe cases with the most frequent 47.1% for genotype (GC). Significant difference in IL-6 174 allelic among critical cases with the most frequent 78.6% for genotype (CC). CONCLUSIONS: Children whom expressed GC genotypes of IL6 (-572G > C) polymorphism are at a considerably higher risk of developing a severe disease. This risk is significantly larger in the severe group of children than in children in critical condition who have GC genotypes of IL6 (-174 G > C) polymorphism. While IL6 (-597G > A) polymorphism has no role in COVID 19 severity in children.

Effect of napabucasin and doxorubicin via the Jak2/Stat3 signaling pathway in suppressing the proliferation of neuroblastoma cells.

PURPOSE: Napabucasin (NP) is a natural compound that can suppress cancer cell proliferation and cell cycle by inhibition of the signal transducer and activator of transcription 3 (STAT3) gene. We examined the effects of NP on the proliferation and invasion of neuroblastoma cells (SH-SY5Y). METHODS: Human neuroblastoma SH-SY5Y cell line was used in this study. NP was administered to groups at the doses of 0.3-1 µM. Cell viability was analyzed by MTT assay. Real-time quantitative reverse transcription polymerase chain reaction and western blot analysis assessed the expressions of interleukin (IL)-6 dependent Jak2/Stat3 signaling pathway. The MTT cell viability method was applied to determine the antagonistic-synergistic effects and inhibitory concentration (IC50) doses of doxorubicin (DX) and NP. RESULTS: It was determined that 0.3-1 µM doses of NP killed the cells almost completely after 48 hours, and also that Jak2/Stat3 expressions decreased dose-dependently via IL-6. At the protein level, NP and DX were found to reduce Jak2 and Stat3 levels. CONCLUSIONS: NP showed that it suppresses the proliferation of neuroblastoma cells. Due to its inhibitory effect on Jak2 and Stat3, it can be used to prevent invasion of SH-SY5Y cells. NP, which can inactivate Jak2/Stat3, can be used as a treatment agent by combining with DX in proliferation pathway in neuroblastoma.

Nicotine promotes pathogenic bacterial growth and biofilm formation in peri-implant.

Introduction. Peri-implantitis is a plaque-associated disease that leads to implant loss and arises from bacterial biofilms on the surface of the implant. Smoking is a risk factor for peri-implantitis and impedes treatment effectiveness. Additionally, aryl hydrocarbon receptor (AHR), IL-6, and IL-22 levels are related to peri-implantitis.Aim. We aimed to investigate the effects of nicotine on inflammatory response, bacterial growth and biofilm formation.Hypothesis/Gap Statement. We hypothesized that nicotine promoted pathogenic bacterial growth and biofilm formation, thereby aggravating inflammation.Methodology. The expression of AHR, IL-6 and IL-22 was measured in peri-implant sulci fluid using quantitative PCR and Western blot analyses. The cementum was incubated with bacterial suspension including Porphyromonas gingivalis, Streptococcus sanguinis and Fusobacterium nucleatum and treated with 100, 200, 250 and 300 µg ml-1 nicotine, and then, the absorbance and number of colony-forming units were detected. Biofilm formation was evaluated using the tissue culture plate method and safranin O staining. Carbohydrates and proteins were measured by the phenol-sulfuric acid method and the bicinchoninic acid method, respectively.Results. The results indicated that smoking increased the levels of AHR, IL-6 and IL-22. Functionally, nicotine promoted the growth of P. gingivalis, S. sanguinis and F. nucleatum. Additionally, it promoted the biofilm formation of these bacteria and increased the contents of carbohydrates and proteins.Conclusion. Nicotine promoted bacterial growth and biofilm build-up, suggesting that smoking may aggravate the progression of peri-implantitis.

Pharmacodynamic, prognostic, and predictive biomarkers in severe and critical COVID-19 patients treated with sirukumab.

We examined candidate biomarkers for efficacy outcomes in hospitalized COVID-19 patients who were treated with sirukumab, an IL-6 neutralizing antibody, in a randomized, double-blind, placebo-controlled, phase 2 trial. Between May 2020 and March 2021, 209 patients were randomized (sirukumab, n = 139; placebo, n = 70); 112 had critical COVID-19. Serum biomarkers were evaluated for the pharmacodynamic effect of sirukumab and for their potential prognostic and predictive effect on time to sustained clinical improvement up to Day 28, clinical improvement at Day 28, and mortality at Day 28. The absence of detectable IL-4 increase and smaller increases in CCL13 post-baseline were most significantly associated with better response to sirukumab (versus placebo) treatment for all clinical efficacy outcomes tested, especially in patients with critical COVID-19. These data suggest that patients with critical COVID-19 without detectable sirukumab-induced IL-4 levels are more likely to benefit from sirukumab treatment. ClinicalTrials.gov Identifier: NCT04380961.

Exploring the role of TNF-α, TGF-ß, and IL-6 serum levels in categorical and noncategorical models of mood and psychosis.

Psychotic and mood disorders are discussed as part of the same continuum. The potential role of immune dysregulation in defining their clinical presentations, however, remains unclear. Differences in TNF-α, IL-6 and TGF-ß levels were investigated in 143 patients with schizophrenia (SCH = 63) and bipolar disorder (BD = 80), in remission. Cytokines were evaluated against the dimensional assessment of psychosis and affective symptoms using the schizo-bipolar scale, together with the severity of the same symptom domains measured by the brief psychiatric rating scale (BPRS). Lower TGF-ß was associated with more lifetime episodes, family risk for psychosis, and more severe mood and psychotic symptoms in all patients. BPRS Affect symptoms domain correlated with lower TGF-ß levels in BD, and higher TGF-ß levels in SCH patients. Using moderated mediation analysis, TGF-ß was a relevant predictor only in the setting of non-categorical symptom distribution, with familial risk for psychosis confirmed as a significant moderator. Severity of BPRS Affect symptoms domain was an independent predictor of inclination towards the psychosis spectrum. The underlying immune dysregulation may be shared by the disorders, rather than a unique characteristic of each, having significant implications for our understanding of the continuum vs. categorical approach to psychosis and mood disorders.

Pro-inflammatory cytokines gene expression in liver and kidneys of rats exposed to a sub-lethal dose of Bitis arietans snake venom.

Bitis arietans (Puff adder) is a poisonous snake and its bite causes pain, edema, blistering, tissue damage and neutrophilia. There are limited studies on inflammatory process involved in Bitis arietans envenomation. We therefore investigated the role of proinflammatory cytokines in Bitis arietans venom (BAV)-induced liver and kidney toxicities in rats. Adult male Sprague Dawley rats were treated with BAV (0.5 mg/kg) and were sacrificed after specific time intervals (2 h, 24 h, 1 week). Blood samples were collected for liver and renal function tests and tissues were collected for histopathology and gene expression analysis of IL-1ß, IL-6, and TNF-α in liver and kidneys. There was no significant difference in serum ALT activities among different treatment groups. Serum AST was significantly increased at 24 h following BAV injection. In both organs, injection of BAV resulted in mild inflammatory cell infiltration at 2 h post-dosing which normalized after 1 week. In liver, there was a significant increase in IL-1ß expression in BAV-treated rats at 2 and 24 h post-dosing that reduced after one week. Significant increases in IL-6 and TNF-α were observed at 24 h and 1 week after BAV exposure. In kidneys, there were significant increases in IL-1ß and TNF-α expression at 24 h that subsided after 1 week. In conclusion, a single sub-lethal dose of BAV caused an acute phase inflammation in liver and kidneys. It is most probable that a higher dose of BAV may result in greater and irreversible damage to these organs.

[Study on the clinical effect of initiating continuous blood purification at different times for severe acute pancreatitis].

OBJECTIVE: To observe the clinical effect of initiating continuous blood purification (CBP) treatment at different times for patients with severe acute pancreatitis (SAP), and to explore the optimal timing for starting CBP treatment for SAP, so as to provide evidence for clinicians to start CBP treatment. METHODS: A retrospective cohort study was used to select patients with SAP who received CBP treatment in People's Hospital of Hunan Province from January 2020 to December 2023. According to the timing of CBP initiation, the patients were divided into early initiation group (diagnosis of SAP to the first CBP treatment time < 24 hours) and late initiation group (diagnosis of SAP to the first CBP treatment time of 24-48 hours). The general data, acute physiology and chronic health evaluation II (APACHE II), bedside index for severity in acute pancreatitis (BISAP) score and laboratory indicators, local complications and systemic complications, intensive care unit (ICU) treatment time, hospital stay, treatment cost, and clinical outcome of the two groups were collected and compared. RESULTS: A total of 130 patients with SAP who received CBP treatment were enrolled, including 90 patients in the early initiation group and 40 patients in the late initiation group. Before treatment, there were no significant differences in gender, age, APACHE II score, BISAP score, etiology and laboratory examination indexes between the early initiation group and late initiation group. At 48, 72, 96 hours after treatment, the blood calcium level of the two groups was significantly higher than that before treatment, and the levels of white blood cell count (WBC), C-reactive protein (CRP), lactic acid, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), APACHE II score and BISAP score were significantly lower than those before treatment. The WBC level, APACHE II score and BISAP score of the late initiation group were significantly lower than those of the early initiation group at 72 hours and 96 hours after treatment [WBC (×109/L): 10.96 (8.68, 13.04) vs. 12.45 (8.93, 16.30) at 72 hours after treatment, and 10.18 (8.68, 12.42) vs. 11.96 (8.81, 16.87) at 96 hours after treatment; APACHE II score: 9.50 (5.75, 12.00) vs. 11.00 (6.25, 14.00) at 72 hours after treatment, and 10.00 (4.00, 12.00) vs. 12.00 (7.00, 14.75) at 96 hours after treatment; BISAP score: 2.35±1.03 vs. 2.76±1.10 at 72 hours after treatment, and 2.08±1.21 vs. 2.70±1.11 at 96 hours after treatment], the differences were statistically significant (all P < 0.05). In terms of complications, the incidence of pancreatic abscess in the late initiation group was significantly lower than that in the early initiation group [5.00% (2/40) vs. 20.00% (18/90)], but the incidence of abdominal compartment syndrome was significantly higher than that in the early initiation group [42.50% (17/40) vs. 13.33% (12/90)], the differences were statistically significant (all P < 0.05). In addition, the ICU treatment time in the early initiation group was significantly shorter than that in the late initiation group [days: 11.00 (6.00, 20.00) vs. 15.00 (9.75, 25.00), P < 0.05], and there were no statistically significant differences in hospitalization costs, length of stay and mortality between the two groups. CONCLUSIONS: CBP can effectively increase the level of blood calcium and decrease the level of lactic acid and inflammatory factors. Starting CBP within 24-48 hours after diagnosis of SAP can reduce WBC level and disease severity score faster, and reduce the occurrence of pancreatic abscess. Initiation of CBP within 24 hours after diagnosis of SAP can reduce the incidence of abdominal compartment syndrome and shorten the duration of ICU treatment.

[Early diagnostic and prognosis prediction of circ_0054633 for acute lung injury/acute respiratory distress syndrome in children with severe pneumonia].

OBJECTIVE: To explore the value of circ_0054633 in early diagnosis and prognosis prediction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in children with severe pneumonia. METHODS: A retrospective case-control study was conducted on children with diagnosed severe pneumonia admitted to Tianjin Children's Hospital from July 1, 2022, to February 29, 2024. The clinical data was collected by electronic medical record system and clinical follow-up, including gender, age, lung injury prediction score (LIPS), pediatric critical illness score (PCIS), serum circ_0054633, interleukin-6 (IL-6), the indicators of the arterial blood-gas analysis, oxygenation index (PaO2/FiO2) within 24 hours of admission and the survival status of 28 days. According to whether ALI/ARDS occurred, they were divided into the ALI/ARDS group and the non-ALI/ARDS group. The differences of clinical data between the two groups were compared, and multivariate Logistic regression was used to analyze the risk factors for ALI/ARDS in children with severe pneumonia. The receiver operator characteristic curve (ROC curve) will be used to explore the early diagnostic value of ALI/ARDS in children with severe pneumonia. The patients of ALI/ARDS were divided into mild group, moderate group and severe group according to the level of PaO2/FiO2. The levels of serum circ_0054633 and IL-6 in various severity ALI/ARDS were compared. The differences of serum circ_0054633, IL-6 levels, PCIS score and LIPS score were compared between the two groups of ALI/ARDS patients according to different prognoses in 28 days, as well as the correlation between various risk factors and circ_0054633. RESULTS: A total 74 children with severe pneumonia were included, with 34 cases in the ALI/ARDS group and 40 cases in the non-ALI/ARDS group. In ALI/ARDS group, there were 9 cases in the mild group, 15 cases in the moderate group and 10 cases in the severe group; while 12 cases died and 22 cases survived after 28 days. The serum circ_0054633, IL-6 level and LIPS score were higher in the ALI/ARDS group than the non-ALI/ARDS group, while the PCIS score was lower, and the two groups had significant difference. Multivariate Logistic regression analysis showed that circ_0054633 was independent predictors of ALI/ARDS in children with severe pneumonia [odds ratio (OR) = 3.853, 95% confidence interval (95%CI) was 1.912-7.805, P = 0.017]. ROC curve analysis showed that the cut-off values for circ_0054633 in the diagnosis of ALI/ARDS were 3.955, sensitivity was 79.4%, specificity was 92.5%, area under the ROC curve (AUC) was 0.892. The serum circ_0054633 and IL-6 levels were higher in the children who died in 28 days than the children who were survived, while the PCIS score was lower, and the two groups had significant difference. Spearman correlation analysis showed that the level of circ_0054633 in children with ALI/ARDS was positively correlated with 28-day mortality and IL-6 (r value was 0.675, 0.763, respectively, all P < 0.001), but negatively correlated with PCIS score (r = -0.626, P < 0.001), while no significant correlation with LIPS score (r = 0.389, P = 0.023). CONCLUSIONS: The level of serum circ_0054633 has a better value in early diagnosis and prognosis prediction of ALI/ARDS caused in children with severe pneumonia.

[IDI2-AS1 influences the development of acute myocardial infarction by regulating NR4A2 through microRNA-33b-5p].

OBJECTIVE: To explore the effect and correlation of long non-coding RNA (lncRNA) IDI2-AS1/microRNA-33b-5p (miR-33b-5p)/nuclear receptor-associated protein NR4A2 competitive endogenous RNA (ceRNA) regulatory network on acute myocardial infarction (AMI), and to verify whether IDI2-AS1 regulates NR4A2 through miR-33b-5p to affect the occurrence and development of myocardial infarction. METHODS: The miRNA and mRNA expression chips related to myocardial infarction were obtained from gene expression omnibus (GEO), and the differential expression was analyzed. The upstream regulatory mechanism of NR4A2 was predicted using TargetScan database. Thirty-two male C57/BL6 mice were divided into Sham group, AMI model group, miR-33b-5p mimic group [miR-33b-5p mimic lentivirus (5×107 TU) was injected locally into the heart tissue during ligation] and miR-33b-5p inhibitor group [miR-33b-5p inhibitor lentivirus (5×107 TU) was injected locally into the heart tissue during ligation] according to random number table method, with 8 mice per group. Left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) were asseessed by echocardiography, left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF) were calculated. After the last weighing, the anesthetized mice were sacrificed and the heart tissues were taken. Masson staining of the heart tissues was observed under light microscope, myocardial collagen volume fraction (CVF) and infarct size were calculated. Cardiomyocytes of SPF grade SD rats were collected. They were divided into normal control group (control group), ischemia-hypoxia model group, miR-33b-5p mimic transfection group (miR-33b-5p mimic transfection group before ischemia and hypoxia treatment) and miR-33b-5p inhibitor transfection group (miR-33b-5p inhibitor transfection group before ischemia and hypoxia treatment). The activity of caspase-3/7 in cardiomyocytes was measured. The levels of interleukins (IL-1ß, IL-6) and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). The levels of malondialdehyde (MDA), superoxide dismutase (SOD), creatine kinase (CK), MB isoenzyme of creatine kinase (CK-MB) and lactate dehydrogenase (LDH) were detected by colorimetry. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of apoptosis-related proteins Bax and Bcl-2, cytochrome C (Cyt C) and IDI2-AS1/miR-33b-5p/NR4A2 regulatory axis genes. RESULTS: The myocardial infarction microarray analysis showed that NR4A2 expression was significantly up-regulated in myocardial infarction, with predicted upstream regulatory mechanisms indicating its possible influence through the IDI2-AS1/miR-33b-5p/NR4A2 regulatory axis. Echocardiographic detection showed that compared with AMI model group and miR-33b-5p inhibitor group, LVEF and LVFS in the heart tissue of mice in miR-33b-5p mimic group were significantly increased, while the levels of LVEDD, LVESD, CK, CK-MB and LDH were significantly decreased, with statistical significance. Light microscope showed myocardial fibrosis and myocardial infarction in AMI model group and miR-33b-5p inhibitor group. In the miR-33b-5p mimic group, the degree of myocardial fibrosis was decreased and the myocardial infarction size was significantly reduced. Compared with AMI model group and miR-33b-5p inhibitor group, the levels of MDA, IL-1ß, IL-6, TNF-α and the expressions of Bax and Cyt C in the heart tissue of mice in miR-33b-5p mimic group were significantly decreased, while the levels of SOD and Bcl-2 expression were significantly increased, and the differences were statistically significant. The expressions of IDI2-AS1 and NR4A2 in the heart tissue of mice in miR-33b-5p mimic group were significantly lower than those in AMI model group and miR-33b-5p inhibitor group [IDI2-AS1 (2-ΔΔCt): 1.96±0.08 vs. 2.73±0.08, 3.10±0.05, NR4A2 (2-ΔΔCt): 2.36±0.07 vs. 3.16±0.08, 3.80±0.08, all P < 0.01]. The expression of miR-33b-5p was significantly higher than that of AMI model group and miR-33b-5p inhibitor group (2-ΔΔCt: 0.88±0.07 vs. 0.57±0.07, 0.23±0.01, both P < 0.01). The cell experiment results showed that the caspase-3/7 activity of rat neonatal cardiomyocytes in the miR-33b-5p mimic transfection group was significantly lower than that in the ischemia-hypoxia model group and the miR-33b-5p inhibitor transfection group, suggesting that miR-33b-5p can significantly reduce the apoptosis level of the ischemia-hypoxia model. The levels of peroxidation and inflammation indexes, important genes of apoptosis pathway and the expression of IDI2-AS1/miR-33b-5p/NR4A2 regulatory axis of rat neonatal cardiomyocytes in all groups were consistent with the above. CONCLUSIONS: IDI2-AS1 can regulate NR4A2 through miR-33b-5p, thus affecting the occurrence and development of AMI.

Paraneoplastic renal dysfunction in fly cancer models driven by inflammatory activation of stem cells.

Tumors can induce systemic disturbances in distant organs, leading to physiological changes that enhance host morbidity. In Drosophila cancer models, tumors have been known for decades to cause hypervolemic "bloating" of the abdominal cavity. Here we use allograft and transgenic tumors to show that hosts display fluid retention associated with autonomously defective secretory capacity of fly renal tubules, which function analogous to those of the human kidney. Excretion from these organs is blocked by abnormal cells that originate from inappropriate activation of normally quiescent renal stem cells (RSCs). Blockage is initiated by IL-6-like oncokines that perturb renal water-transporting cells and trigger a damage response in RSCs that proceeds pathologically. Thus, a chronic inflammatory state produced by the tumor causes paraneoplastic fluid dysregulation by altering cellular homeostasis of host renal units.

Neuroprotective effect of Naochuxue prescription on intracerebral hemorrhage: inhibition of autophagy downregulating high mobility group box-1.

OBJECTIVE: To determine the molecular mechanisms underlying the neuroprotective effects of Naochuxue prescription (,NCXP) in rats with intracerebral hemorrhage (ICH). METHODS: Sprague-Dawley rats were injected with collagenase to generate ICH models, which were then randomly divided into six groups, including control, sham, model, and three intervention groups. The intervention groups received different doses of NCXP (0.13, 0.26, and 0.52 g/kg) daily for 10 d. High-performance liquid chromatography (HPLC) was used to analyze the chemical characteristics of NCXP. The neurobehavioral outcomes of the rats were evaluated using neurological deficit scores (Zea Longa 5) and the corner turn test. Pathomorphological changes in perihematomal tissues after ICH were observed using hematoxylin and eosin staining. Immunohistochemistry (IHC) was used to detect the inflammation expression of interleukin 6 (IL-6) and toll-like receptor 4 (TLR4). High mobility group box-1 (HMGB1), Beclin1, microtubule-associated protein 1 light chain 3 beta (LC3), and sequestosome 1 (p62) were detected using real-time quantitative polymerase chain reaction and Western blotting in perihematomal tissues. RESULTS: HPLC showed that the NCXP had good stability. Rats with ICH had severe neurological function deficits compared to the control group. IHC results showed that NCXP significantly downregulated the expression of the inflammatory proteins IL-6 and TLR4. ICH rats treated with NCXP showed less neurological injury than the model group, accompanied by a significantly decreased expression of HMGB1, Beclin1, and LC3 and an increased expression of p62. CONCLUSIONS: The neuroprotective effect of NCXP alleviated inflammation and autophagy possibly by downregulating HMGB1 expression. However, further research on the signaling pathways is required to verify this hypothesis.

Qingfei Zhisou oral liquid alleviates fever-induced inflammation by regulating arachidonic acid and lysophospholipids metabolism and inhibiting hypothalamus transient receptor potential ion channels expression.

OBJECTIVE: To explore how Qingfei Zhisou oral liquid (, QFZS) adjusts body temperature bias and the interaction of inflammatory factors levels and metabolomic differences. METHODS: Dry yeast was subcutaneously injected at 10 mL/kg to establish the pyrexia model. We randomly divided 60 Sprague-Dawley rats into five groups: control, model, positive, low dose of QFZS and high dose of QFZS. Inflammatory proteins were evaluated by Western blotting and immunohistochemistry. For the examination of the endogenous metabolites, enzyme linked immunosorbent assay and ultra-high-performance liquid chromatography high-resolution mass spectrometry were employed. RESULTS: QFZS significantly reduced rats' body temperature within 6 h after dry yeast injection and reduced the secretion of the arginine vasopressin, cyclic adenosine monophosphate, prostaglandin E-2, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß in serum. Meanwhile, we identified 41 metabolites between the model and QFZS groups, including arachidonic acid and lysophospholipids. QFZS restored normal arachidonic acid levels. Based on the differential metabolite enrichment analysis, QFZS's anti-inflammatory and anti-pyrexia effects might be related to the inflammatory pathway regulated by transient receptor potential. Additionally, QFZS treatment reduced transient receptor potential melastatin 2 ion channel expression and affected TNF-α, heat shock protein 70, and cyclooxygenase-2 expression in the hypothalamus. CONCLUSION: QFZS exerts its regulatory effects on fever by regulating the metabolism of lysophospholipids and arachidonic acid and the regulation of inflammation via transient receptor potential ion channels channels.

Examining the Relationship Between Polystyrene Microplastics and Male Fertility: Insights From an In Vivo Study and In Vitro Sertoli Cell Culture.

BACKGROUND: While polystyrene microplastics (PS-MPs) are emerging as potentially significant health threats, linked to cancer and reproductive dysfunction, their precise effects on human health remain largely unknown. We aimed to investigate the underlying mechanisms promoting microplastic-induced damage in the reproductive system. METHODS: Thirty C57BL/6 male mice were randomly allocated into six equal-sized groups. Mice were exposed to fluorescent PS-MPs (5 µm, < 18%, green) at a dose of 1 and 3 mg/dL via oral gavage for 28 and 56 days, respectively (control, 0 mg/dL). The presence of antibodies and inflammatory and oxidative stress markers were evaluated using western blotting. Sperm analysis was also performed. Mouse testis Sertoli TM4 cells were divided into two groups: control (medium only) and PS-MPs (medium containing, 1,000 µg/mL) groups and cultured in vitro for 1, 24, 48, or 72 hours. The cells were cultured in a Ham's F12: Dulbecco's Modified Eagle Medium medium with 0.25% fetal bovine serum at 37°C with humidified atmosphere of 5% carbon dioxide in the air. Protein analyses for interleukin (IL)-6, IL-10, NADPH-oxidase (NOX)-2, NOX-4, hypoxia-inducible transcription factor (HIF)-2α, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-ß were performed using western blotting. RESULTS: The testes were evaluated after 28 and 56 days of exposure. Varying sizes of PS-MPs were detected in the testes (ranging from 5.870 to 7.768 µm). Significant differences in sperm concentration, motility, and the proportion of normal sperm were observed between the two groups. An increase in TGF-ß, HIF-2α, and NOX-4 levels was observed using western blot analysis. However, no dose-dependent correlations were observed between the two groups. In vitro evaluation of the PS-MPs group displayed PS-MP penetration of the lumen of Sertoli cells after 1 hour. Further PS-MP aggregation within Sertoli cells was observed at 24, 48, and 72 hours. A significant increase in inflammatory protein expressions (IL-10, TGF-ß, MCP-1, IL-6, TNF-α, and HIF-2α) was observed through western blotting, although oxidative agents did not show a significant increase. CONCLUSION: PS-MPs induced reproductive dysfunction in male mice provide new insights into PS-MPs-associated toxicity in mammals.

Assessment of the circulating levels of immune system checkpoint selected biomarkers in patients with lung cancer.

BACKGROUND: Lung cancer is recognized as one of the leading causes of cancer-related deaths globally, with a significant increase in incidence and intricate pathogenic mechanisms. This study examines the expression profiles of Programmed Cell Death Protein 1 (PD-1), PD-1 ligand (PDL-1), ß-catenin, CD44, interleukin 6 (IL-6), and interleukin 10 (IL-10), as well as their correlations with the clinic-pathological features and diagnostic significance in lung cancer patients. METHODS AND RESULTS: The research involved lung cancer patients exhibiting various pathological characteristics, alongside demographically matched healthy controls. The expression levels of PD-1, PDL-1, ß-catenin, and CD44 were analyzed using Real-Time PCR, while circulating levels of IL-6 and IL-10 were assessed through ELISA assays. This investigation focused on peripheral blood mononuclear cells (PBMC) to evaluate these factors non-invasively. Findings indicated that levels of PD-1, PDL-1, and CD44 were significantly elevated in patients compared to controls, which coincided with a decrease in ß-catenin levels. Additionally, a concurrent rise in IL-6 and IL-10, both pro-inflammatory cytokines, was observed in patients, suggesting a potential regulatory role for these cytokines on the PD-1/PDL-1 axis, which may help tumors evade immune system checkpoints. The predictive value of these factors concerning lung tumors and metastasis was significant (Regression analysis). Furthermore, these markers demonstrated diagnostic potential in differentiating between patients and healthy controls, as well as between individuals with metastatic and non-metastatic tumors (ROC curve analysis). CONCLUSIONS: This study provides insights into the expression profiles of PD-1/PDL-1 immune system checkpoints and their regulatory factors in lung cancer, potentially paving the way for new therapeutic and diagnostic approaches.

Acetylcholine receptor-ß inhibition by interleukin-6 in skeletal muscles contributes to modulating neuromuscular junction during aging.

BACKGROUND: Aging-related strength decline contributes to physiological deterioration and is a good predictor of poor prognosis. However, the mechanisms underlying neuromuscular junction disorders affecting contraction in aging are not well described. We hypothesized that the autocrine effect of interleukin (IL)-6 secreted by skeletal muscle inhibits acetylcholine receptor (AChR) expression, potentially causing aging-related strength decline. Therefore, we investigated IL-6 and AChR ß-subunit (AChR-ß) expression in the muscles and sera of aging C57BL/6J mice and verified the effect of IL-6 on AChR-ß expression. METHODS: Animal experiments, in vitro studies, bioinformatics, gene manipulation, dual luciferase reporter gene assays, and chromatin immunoprecipitation experiments were used to explore the role of the transcription cofactor peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) and its interacting transcription factors in the IL-6-mediated regulation of AChR-ß expression. RESULTS: IL-6 expression gradually increased during aging, inhibiting AChR-ß expression, which was reversed by tocilizumab. Both tocilizumab and the PGC1α agonist reversed the inhibiting effect of IL-6 expression on AChR-ß. Compared to inhibition of signal transducer and activator of transcription 3, extracellular signal-regulated kinases 1/2 (ERK1/2) inhibition suppressed the effects of IL-6 on AChR-ß and PGC1α. In aging mouse muscles and myotubes, myocyte enhancer factor 2 C (MEF2C) was recruited by PGC1α, which directly binds to the AChR-ß promoter to regulate its expression. CONCLUSIONS: This study verifies AChR-ß regulation by the IL-6/IL-6R-ERK1/2-PGC1α/MEF2C pathway. Hence, evaluating muscle secretion, myokines, and AChRs at an earlier stage to determine pathological progression is important. Moreover, developing intervention strategies for monitoring, maintaining, and improving muscle structure and function is necessary.