A preliminary probabilistic nomogram model for predicting renal arteriolar damage in IgA nephropathy from clinical parameters.

Background: IgA nephropathy (IgAN) is a significant contributor to chronic kidney disease (CKD). Renal arteriolar damage is associated with IgAN prognosis. However, simple tools for predicting arteriolar damage of IgAN remain limited. We aim to develop and validate a nomogram model for predicting renal arteriolar damage in IgAN patients. Methods: We retrospectively analyzed 547 cases of biopsy-proven IgAN patients. Least absolute shrinkage and selection operator (LASSO) regression and logistic regression were applied to screen for factors associated with renal arteriolar damage in patients with IgAN. A nomogram was developed to evaluate the renal arteriolar damage in patients with IgAN. The performance of the proposed nomogram was evaluated based on a calibration plot, ROC curve (AUC) and Harrell's concordance index (C-index). Results: In this study, patients in the arteriolar damage group had higher levels of age, mean arterial pressure (MAP), serum creatinine, serum urea nitrogen, serum uric acid, triglycerides, proteinuria, tubular atrophy/interstitial fibrosis (T1-2) and decreased eGFR than those without arteriolar damage. Predictors contained in the prediction nomogram included age, MAP, eGFR and serum uric acid. Then, a nomogram model for predicting renal arteriolar damage was established combining the above indicators. Our model achieved well-fitted calibration curves and the C-indices of this model were 0.722 (95%CI 0.670-0.774) and 0.784 (95%CI 0.716-0.852) in the development and validation groups, respectively. Conclusion: With excellent predictive abilities, the nomogram may be a simple and reliable tool to predict the risk of renal arteriolar damage in patients with IgAN.

Off-the-shelf CAR-NK cells targeting immunogenic cell death marker ERp57 execute robust antitumor activity and have a synergistic effect with ICD inducer oxaliplatin.

BACKGROUND: Chimeric antigen receptor natural killer (CAR-NK) therapy holds great promise for treating hematologic tumors, but its efficacy in solid tumors is limited owing to the lack of suitable targets and poor infiltration of engineered NK cells. Here, we explore whether immunogenic cell death (ICD) marker ERp57 translocated from endoplasmic reticulum to cell surface after drug treatment could be used as a target for CAR-NK therapy. METHODS: To target ERp57, a VHH phage display library was used for screening ERp57-targeted nanobodies (Nbs). A candidate Nb with high binding affinity to both human and mouse ERp57 was used for constructing CAR-NK cells. Various in vitro and in vivo studies were performed to assess the antitumor efficacy of the constructed CAR-NK cells. RESULTS: We demonstrate that the translocation of ERp57 can not only be induced by low-dose oxaliplatin (OXP) treatment but also is spontaneously expressed on the surface of various types of tumor cell lines. Our results show that G6-CAR-NK92 cells can effectively kill various tumor cell lines in vitro on which ERp57 is induced or intrinsically expressed, and also exhibit potent antitumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models. Additionally, the antitumor activity of G6-CAR-NK92 cells is synergistically enhanced by the low-dose ICD-inducible drug OXP. CONCLUSION: Collectively, our findings suggest that ERp57 can be leveraged as a new tumor antigen for CAR-NK targeting, and the resultant CAR-NK cells have the potential to be applied as a broad-spectrum immune cell therapy for various cancers by combining with ICD inducer drugs.

Nanobody-Engineered Biohybrid Bacteria Targeting Gastrointestinal Cancers Induce Robust STING-Mediated Anti-Tumor Immunity.

Bacteria can be utilized for cancer therapy owing to their preferential colonization at tumor sites. However, unmodified non-pathogenic bacteria carry potential risks due to their non-specific targeting effects, and their anti-tumor activity is limited when used as monotherapy. In this study, a biohybrid-engineered bacterial system comprising non-pathogenic MG1655 bacteria modified with CDH17 nanobodies on their surface and conjugated with photosensitizer croconium (CR) molecules is developed. The resultant biohybrid bacteria can efficiently home to CDH17-positive tumors, including gastric, pancreatic, and colorectal cancers, and significantly suppress tumor growth upon irradiation. More importantly, biohybrid bacteria-mediated photothermal therapy (PTT) induced abundant macrophage infiltration in a syngeneic murine colorectal model. Further, that the STING pathway is activated in tumor macrophages by the released bacterial nucleic acid after PTT is revealed, leading to the production of type I interferons. The addition of CD47 nanobody but not PD-1 antibody to the PTT regimen can eradicate the tumors and extend survival. This results indicate that bacteria endowed with tumor-specific selectivity and coupled with photothermal payloads can serve as an innovative strategy for low-immunogenicity cancers. This strategy can potentially reprogram the tumor microenvironment by inducing macrophage infiltration and enhancing the efficacy of immunotherapy targeting macrophages.

Delta-radiomics Analysis Based on Multi-phase Contrast-enhanced MRI to Predict Early Recurrence in Hepatocellular Carcinoma After Percutaneous Thermal Ablation.

RATIONALE AND OBJECTIVES: It is critical to predict early recurrence (ER) after percutaneous thermal ablation (PTA) for hepatocellular carcinoma (HCC). We aimed to develop and validate a delta-radiomics nomogram based on multi-phase contrast-enhanced magnetic resonance imaging (MRI) to preoperatively predict ER of HCC after PTA. MATERIALS AND METHODS: We retrospectively enrolled 164 patients with HCC and divided them into training, temporal validation, and other-scanner validation cohorts (n = 110, 29, and 25, respectively). The volumes of interest of the intratumoral and/or peritumoral regions were delineated on preoperative multi-phase MR images. Original radiomics features were extracted from each phase, and delta-radiomics features were calculated. Logistic regression was used to train the corresponding radiomics models. The clinical and radiological characteristics were evaluated and combined to establish a clinical-radiological model. A fusion model comprising the best radiomics scores and clinical-radiological risk factors was constructed and presented as a nomogram. The performance of each model was evaluated and recurrence-free survival (RFS) was assessed. RESULTS: Child-Pugh grade B, high-risk tumor location, and an incomplete/absent tumor capsule were independent predictors of ER. The optimal radiomics model comprised 12 delta-radiomics features with areas under the curve (AUCs) of 0.834, 0.795, and 0.769 in the training, temporal validation, and other-scanner validation cohorts, respectively. The nomogram showed the best predictive performance with AUCs as 0.893, 0.854, and 0.827 in the three datasets. There was a statistically significant difference in RFS between the risk groups calculated using the delta-radiomics model and nomogram. CONCLUSIONS: The nomogram combined with the delta-radiomic score and clinical-radiological risk factors could non-invasively predict ER of HCC after PTA.

Cadherin 17 Nanobody-Mediated Near-Infrared-II Fluorescence Imaging-Guided Surgery and Immunotoxin Delivery for Colorectal Cancer.

Surgery and targeted therapy are of equal importance for colorectal cancer (CRC) treatment. However, complete CRC tumor resection remains challenging, and new targeted agents are also needed for efficient CRC treatment. Cadherin 17 (CDH17) is a membrane protein that is highly expressed in CRC and, therefore, is an ideal target for imaging-guided surgery and therapeutics. This study utilizes CDH17 nanobody (E8-Nb) with the near-infrared (NIR) fluorescent dye IRDye800CW to construct a NIR-II fluorescent probe, E8-Nb-IR800CW, and a Pseudomonas exotoxin (PE)-based immunotoxin, E8-Nb-PE38, to evaluate their performance for CRC imaging, imaging-guided precise tumor excision, and antitumor effects. Our results show that E8-Nb-IR800CW efficiently recognizes CDH17 in CRC cells and tumor tissues, produces high-quality NIR-II images for CRC tumors, and enables precise tumor removal guided by NIR-II imaging. Additionally, fluorescent imaging confirms the targeting ability and specificity of the immunotoxin toward CDH17-positive tumors, providing the direct visible evidence for immunotoxin therapy. E8-Nb-PE38 immunotoxin markedly delays the growth of CRC through the induction of apoptosis and immunogenic cell death (ICD) in multiple CRC tumor models. Furthermore, E8-Nb-PE38 combined with 5-FU exerts synergistically antitumor effects and extends survival. This study highlights CDH17 as a promising target for CRC imaging, imaging-guided surgery, and drug delivery. Nanobodies targeting CDH17 hold great potential to construct NIR-II fluorescent probes for surgery navigation, and PE-based toxins fused with CDH17 nanobodies represent a novel therapeutic strategy for CRC treatment. Further investigation is warranted to validate these findings for potential clinical translation.

Expression and clinical role of PRDX6 in lung adenocarcinoma.

OBJECTIVE: To explore the levels of expression and clinical role of peroxiredoxin 6 (PRDX6) in lung adenocarcinoma. METHODS: This retrospective study used a series of bioinformatics methods to detect the levels of expression of and mutations in the PRDX6 gene in a range of cancers and lung adenocarcinoma. Immunohistochemistry was used to verify the levels of expression of PRDX6 protein in samples of lung adenocarcinoma compared with normal adjacent tissue. The effect of PRDX6 gene knockdown on the in vitro proliferation of a lung adenocarcinoma cell line was measured. Bioinformatics methods were used to determine the diagnostic value and impact on survival of the PRDX6 gene in patients with lung adenocarcinoma. RESULTS: The results showed that the PRDX6 gene was highly expressed in lung adenocarcinoma and there were five mutations at different sites on the gene. PRDX6 promoted the proliferation of the lung adenocarcinoma cell line. The survival duration of lung adenocarcinoma patients with high levels of PRDX6 gene expression was significantly shorter than that of patients with low PRDX6 gene expression. CONCLUSION: PRDX6 is highly expressed in lung adenocarcinoma and higher levels of expression of the PRDX6 gene were associated with a poorer prognosis.

Investigation of the relationship between the changes in vaginal microecological enzymes and human papillomavirus (HPV) infection.

This study aims to investigate the relationship between the human papillomavirus (HPV) infection and the altered vaginal microecological environment of patients. Initially, HPV genotyping and microecological detection were performed in 1281 subjects in the Department of Obstetrics and Gynecology of The First Hospital of Qinhuangdao (Qinhuangdao, China). The relationship between the enzymes of vaginal microecology, that is, proline aminopeptidase and acetylglucosaminidase, and vaginal inflammatory diseases, as well as the prognosis of HPV infection, was analyzed. The experimental findings indicated a close relationship between the expression of positive prolyl aminopeptidase and trichomonas vaginitis, as well as bacterial vaginitis. In addition, the expression of acetylglucosaminidase is closely associated with trichomonas vaginitis and vulvovaginal candidiasis. Furthermore, the observations indicated that positive prolyl aminopeptidase and acetylglucosaminidase could increase the risk of various subtypes of HPV infection in patients. The receiver operating characteristic curve analysis presented that the expression of prolyl aminopeptidase and acetylglucosaminidase could offer exceptional diagnostic efficacy, indicating their association with persistent HPV infection. In summary, our results highlighted that the expression of positive prolyl aminopeptidase and acetylglucosaminidase in the vaginal microecology could be substantially correlated to the occurrence and the development of vaginal inflammatory diseases, as well as the outcome and the risk of persistent HPV infection.

ACUM, an easily underdiagnosed cause of dysmenorrhea-A case report.

This report described three cases with long-term severe dysmenorrhea, and these cases were referred to our department for medical help. The diagnosis of accessory cavitated uterine malformation (ACUM) was considered based on symptoms and ultrasound/MRI findings. Moreover, a combined approach involving hysteroscopic surgery and laparoscopic surgery was undertaken, and no complications occurred during surgery and in the post-operative period. It is important to consider ACUM in patients with severe dysmenorrhea that does not respond to medical management. Surgery is the most effective treatment for this anomaly.

Reshaped DNA methylation cooperating with homoeolog-divergent expression promotes improved root traits in synthesized tetraploid wheat.

Polyploidization is a major event driving plant evolution and domestication. However, how reshaped epigenetic modifications coordinate gene transcription to generate phenotypic variations during wheat polyploidization is currently elusive. Here, we profiled transcriptomes and DNA methylomes of two diploid wheat accessions (SlSl and AA) and their synthetic allotetraploid wheat line (SlSlAA), which displayed elongated root hair and improved root capability for nitrate uptake and assimilation after tetraploidization. Globally decreased DNA methylation levels with a reduced difference between subgenomes were observed in the roots of SlSlAA. DNA methylation changes in first exon showed strong connections with altered transcription during tetraploidization. Homoeolog-specific transcription was associated with biased DNA methylation as shaped by homoeologous sequence variation. The hypomethylated promoters showed significantly enriched binding sites for MYB, which may affect gene transcription in response to root hair growth. Two master regulators in root hair elongation pathway, AlCPC and TuRSL4, exhibited upregulated transcription levels accompanied by hypomethylation in promoter, which may contribute to the elongated root hair. The upregulated nitrate transporter genes, including NPFs and NRTs, also are significantly associated with hypomethylation, indicating an epigenetic-incorporated regulation manner in improving nitrogen use efficiency. Collectively, these results provided new insights into epigenetic changes in response to crop polyploidization and underscored the importance of epigenetic regulation in improving crop traits.

Ramelteon alleviates myocardial ischemia/reperfusion injury (MIRI) through Sirt3--dependent regulation of cardiomyocyte apoptosis.

Reperfusion stands as a pivotal intervention for ischemic heart disease. However, the restoration of blood flow to ischemic tissue always lead to further damage, which is known as myocardial ischemia/reperfusion injury (MIRI). Ramelteon is an orally administered drug used to improve sleep quality, which is famous for its high bioadaptability and absence of notable addictive characteristics. However, the specific mechanism by which it improves MIRI is still unclear. Sirtuin-3 (Sirt3), primarily located in mitochondria, is crucial in mitigating many cardiac diseases, including MIRI. Based on the structure of Sirt3, we simulated molecular docking and identified several potential amino acid binding sites between it and ramelteon. Therefore, we propose a hypothesis that ramelteon may exert cardioprotective effects by activating the Sirt3 signaling pathway. Our results showed that the activation levels and expression level of Sirt3 were significantly decreased in MIRI tissue and H2O2 stimulated H9C2 cells, while ramelteon treatment upregulated Sirt3 activity and expression. After treat with 3-TYP, a classic Sirt3 activity inhibitor, we constructed myocardial ischemia/reperfusion surgery in vivo and induced H9C2 cells with H2O2 in vitro. The results showed that the myocardial protection and anti-apoptotic effects of ramelteon were antagonized by 3-TYP, indicating that the activation of Sirt3 is a key mechanism for ramelteon to exert myocardial protection. In summary, our results confirm a novel mechanism by which ramelteon improves MIRI by activating Sirt3 signaling pathway, providing strong evidence for the treatment of MIRI with ramelteon.

Severe zoonotic viruses carried by different species of bats and their regional distribution.

BACKGROUND: Bats have garnered increased attention in the field of life sciences for their typical biological characteristics of carrying a variety of zoonotic viruses without disease, long lifespans, low tumorigenesis rates, and high metabolism. When it was found that bats can carry the rabies virus, over 60 years of research revealed that bats host over 4100 distinct viruses, including Ebola virus and SARS-CoV. OBJECTIVES: This paper primarily reviews the profiles of zoonotic viruses carried by bats across various regions globally. The review aims to provide a foundation and reference for future research on monitoring zoonotic viruses in diverse global regions and bat species, exploring the coevolutionary relationship between bats and viruses, understanding the tolerance mechanisms of bat B cells, prevention, and treatment of zoonotic diseases caused by bats. SOURCES: The search used 'bat', 'bats', 'rabies virus', 'Dengue virus', 'West Nile virus', 'Zika virus', 'St. Louis encephalitis virus', 'Japanese encephalitis virus', 'Hantavirus', 'Novel hantavirus', 'Rift Valley fever virus', 'Crimean Congo hemorrhagic fever virus', 'Paramyxovirus', 'Nipah virus', 'Hendra virus', 'Menangle virus', 'Tioman virus', 'Marburg Virus', 'Bombali virus', 'Ebola virus', 'Influenza A virus', 'coronavirus', 'Hepatitis B virus', and 'Hepatitis E virus' as text in PubMed. CONTENT: A total of 147 references were obtained. Surveys on severe zoonotic virus carriage have been limited to only 83 bat species belonging to nine families, which are distributed all over the world. We also briefly describe the antibody responses and B-cell molecules in bats. IMPLICATIONS: Several viruses have been found in different species of bats. This suggests that bats may be important hosts for future viral infectious diseases. Particularly in recent years, the close correlation between human infection pandemics caused by coronaviruses and bats highlights the pressing need to comprehend the species, tolerance, and coevolutionary mechanisms of zoonotic viruses carried by different bat species.

ZnO-rGO-based electrochemical biosensor for the detection of organophosphorus pesticides.

The accurate determination of organophosphorus pesticide residues is of great importance for human disease monitoring and environmental safety. Numerous detection methods exist, among which sensitive monitoring of organophosphorus compounds using electrochemical sensors has gradually become a research hotspot. This paper used acetylcholinesterase (AChE) as an indicator anchored on a zinc oxide-reduced graphene oxide (ZnO-rGO) composite rich in active sites, in which green non-toxic zinc oxide (ZnO) nanomaterials were uniformly distributed on the reduced graphene for rapid detection of organophosphorus. The effects of different ratios of ZnO to reduced graphene on the performance of ZnO-rGO nanocomposites were investigated. The AChE/ZnO-rGO biosensor detects organophosphorus by electrochemical inhibition of acetylcholinesterase in the presence of organophosphorus. The developed electrochemical biosensor has high selectivity and good linearity, and the ZnO-rGO nanocomposite as a matrix for immobilization of acetylcholinesterase and detection of organophosphorus has the potential for highly sensitive pesticide detection.

Elevated serum uric acid is associated with renal arteriolopathy and predict poor outcome in patients with lupus nephritis.

OBJECTIVES: Increased serum uric acid (SUA) levels are well known to be concomitant of cardiovascular and kidney diseases, and have been proposed to be implicated in the development of arteriolar damage. The aim of the present study was to assess the association between SUA levels, renal damage and its implication for outcome in patients with lupus nephritis (LN). METHODS: This retrospective study included 194 cases with biopsy proven LN at the Affiliated Hospital of Qingdao University between January 2013 and June 2021. We reviewed clinical, laboratory and histologic data of patients and analysed the correlation between SUA levels, renal damage and the primary outcome (death or ESRD). Biopsy-proven arteriolar damage was defined by the presence of arteriolar hyalinosis and/or intimal thickening. RESULTS: Compared to LN patients without hyperuricemia, LN patients with hyperuricaemia presented with higher BP, hyperlipidaemia, lower eGFR, lower haemoglobin, lower serum albumin, worse renal arteriolar damage and proteinuria, and also higher SLEDAI score, activity index and chronicity index (p<0.05). At logistic regression analysis, SUA was independently related to the presence of arteriolar damage. For each 100 µmol/L increase in SUA levels the risk for arteriolar damage raised by 53.8% (hazard ratio [HR] =1.538; 95% CI: 1.147-2.063; p=0.004) after adjustment for haemoglobin, serum creatinine and erythrocyte sedimentation rate. Cox regression analysis showed that female (HR=3.180; 95% CI: 1.216-8.313; p=0.018), white blood cell count (HR=1.111; 95% CI: 1.027-1.202; p=0.009), SUA (HR=1.100; 95% CI: 1.023-1.253; p=0.035), serum creatinine (HR=1.800; 95% CI: 1.348-2.404; p<0.001), and renal arteriolar damage (HR=3.117; 95% CI: 1.022-9.511; p=0.046) was significantly associated with development of ESRD or death in patients with LN after adjustment for several potential confounding factors. Furthermore, for each 100 µmol/L increase in SUA levels, the risk of ESRD or death increased by 10%. CONCLUSIONS: SUA levels are directly associated with renal arteriolar damage and poor prognosis in LN patients. Hyperuricaemia is an important predictor for poor prognosis in patients with LN.

LncRNA xist regulates sepsis associated neuroinflammation in the periventricular white matter of CLP rats by miR-122-5p/PKCη Axis.

Background: Neuroinflammation is a common feature of many neurological diseases, and remains crucial for disease progression and prognosis. Activation of microglia and astrocytes can lead to neuroinflammation. However, little is known about the role of lncRNA xist and miR-122-5p in the pathogenesis of sepsis-associated neuroinflammation (SAN). This study aims to investigate the role of lncRNA xist and miR-122-5p in the pathogenesis of SAN. Methods: Levels of miR-122-5p and proinflammatory mediators were detected in the cerebrospinal fluid (CSF) of patients with intracranial infection (ICI) by ELISA and qRT-PCR. miRNA expression in the periventricular white matter (PWM) in rats was analyzed by high-throughput sequencing. Levels of lncRNA xist, miR-122-5p and proinflammatory mediators in the PWM were measured using qRT-PCR and western blot. Bioinformatics analysis was used to predict the upstream and downstream of miR-122-5p. The interaction between miR-122-5p and its target protein was validated using luciferase reporter assay. BV2 and astrocytes were used to detect the expression of lncRNA xist, miR-122-5p. Results: The level of miR-122-5p was significantly decreased in the CSF of ICI patients, while the expression of IL-1ß and TNF-α were significantly upregulated. Furthermore, it was found that the expression of IL-1ß and TNF-α were negatively correlated with the level of miR-122-5p. A high-throughput sequencing analysis showed that miR-122-5p expression was downregulated with 1.5-fold changes in the PWM of CLP rats compared with sham group. Bioinformatics analysis found that lncRNA xist and PKCη were the upstream and downstream target genes of miR-122-5p, respectively. The identified lncRNA xist and PKCη were significantly increased in the PWM of CLP rats. Overexpression of miR-122-5p or knockdown of lncRNA xist could significantly downregulate the level of PKCη and proinflammatory mediators from activated microglia and astrocytes. Meanwhile, in vitro investigation showed that silencing lncRNA xist or PKCη or enhancing the expression of miR-122-5p could obviously inhibit the release of proinflammatory mediators in activated BV2 cells and astrocytes. Conclusion: LncRNA xist could regulate microglia and astrocytes activation in the PWM of CLP rats via miR-122-5p/PKCη axis, further mediating sepsis associated neuroinflammation.

Targeted delivery of organic small-molecule photothermal materials with engineered extracellular vesicles for imaging-guided tumor photothermal therapy.

Imaging-guided photothermal therapy (PTT) for cancers recently gathered increasing focus thanks to its precise diagnosis and potent therapeutic effectiveness. Croconaine (CR) dyes demonstrate potential in expanding utility for near infrared (NIR) dyes in bio-imaging/theranostics. However, reports on CR dyes for PTT are scarce most likely due to the short of the efficacious delivery strategies to achieve specific accumulation in diseased tissues to induce PTT. Extracellular vesicles (EVs) are multifunctional nanoparticle systems that function as safe platform for disease theragnostics, which provide potential benefits in extensive biomedical applications. Here, we developed a novel delivery system for photothermal molecules based on a CR dye that exerts photothermal activity through CDH17 nanobody-engineered EVs. The formed CR@E8-EVs showed strong NIR absorption, excellent photothermal performance, good biological compatibility and superb active tumor-targeting capability. The CR@E8-EVs can not only visualize and feature the tumors through CR intrinsic property as a photoacoustic imaging (PAI) agent, but also effectively retard the tumor growth under laser irradiation to perform PTT. It is expected that the engineered EVs will become a novel delivery vehicle of small organic photothermal agents (SOPTAs) in future clinical PTT applications.

Expression and clinical significance of RHCG in endometrial cancer.

Endometrial cancer (EC) is the most common gynecological cancer. Rhesus family, C glycoprotein (RHCG) has been evidenced to be involved in the occurrence and development of various tumors. This study aimed to investigate the expression and clinical significance of RHCG in EC. Bioinformatics analysis was based on the RNAseq counts data from TCGA database, and the prognosis analysis was performed using the Kaplan-Meier method; 4 cases of endometrioid adenocarcinomas samples and 4 cases of normal proliferative endometrium were collected for qPCR and western blot; immunohistochemistry analysis was employed to assess the expression of RHCG in a tissue microarray; the correlation between RHCG and clinicopathological factors was analyzed through Mann-Whitney U test. The lentiviral interference vector was further constructed. The results demonstrated that RHCG was highly expressed in EC tissues, and RHCG was an independent factor affecting the overall survival of patients. Additionally, the expression of RHCG was related to FIGO stage and tumor infiltrate. After interfering with shRHCG, the proliferation activity of EC cells decreased, the migration ability of cells decreased, the apoptosis of cells increased, and the tumor outgrowth was arrested. In summary, RHCG promotes the malignant proliferation and migration of EC, and makes the cells have anti-apoptotic activity. Our study provides a theoretical basis for RHCG to become a potential therapeutic target for EC in the future.

Mesenchymal stem cell-derived exosomal miR-548x-3p inhibits pyroptosis of vascular endothelial cells through HMGB1 in heat stroke.

Heat stroke (HS) is an acute physical illness associated with a higher risk of organ dysfunction. This study is the first to explore exosomal miR-548x-3p derived from human bone marrow mesenchymal stem cells (BMSCs) in the pyroptosis of vascular endothelial cells (VECs) associated with HS. Human BMSCs-derived exosome alleviated the injury of the heart, liver, kidney and ileum tissues, the increase of IL-1ß, IL-18 and TNF-α levels, pyroptosis of endothelial cells and the increase of HGMB1, NLRP3, ASC, caspase1 and GSDMD-N protein expression in HS mice and HS-induced human umbilical vein endothelial cells (HUVECs). miR-548x-3p was down-expressed in HS patients, while up-expressed in BMSCs-derived exosome. BMSCs-ExomiR-548x-3p mimics to inhibit pyroptosis, inflammation and HGMB1/NLRP3 activation in HS-induced HUVECs and HS mice, which were blocked by overexpression of HMGB1. In conclusion, human BMSCs-derived exosomes carried miR-548x-3p mimics to inhibit pyroptosis of VECs through HMGB1 in HS mice.

Value of T lymphocyte subset detection in cervical intraepithelial neoplasia.

OBJECTIVE: This study aimed to explore the value of T lymphocyte subset detection in cervical intraepithelial neoplasia (CIN). METHODS: In this retrospective analysis, T lymphocyte subsets in 186 CIN patients were detected. Venous blood T lymphocyte subsets were analyzed in patients with different CIN grades, and Spearman correlation analysis was conducted between CIN grade and T lymphocyte subsets. RESULTS: (1) There were significant differences in the CD3+, CD4+, CD8+, and CD4+/CD8+ levels before and 1, 2, and 3 months after treatment (P<0.05). Furthermore, significant differences were found in CD3+, CD4+, CD8+, and CD4+/CD8+ between every pair of time points (P<0.05). (2) Comparison of human papillomavirus distribution in patients with different CIN grades showed P<0.05. (3) The level of T lymphocyte subsets in the venous blood of patients with different CIN grades was compared, and significant differences were found, P<0.05. Higher CIN grade was associated with lower levels of CD3+, CD4+ and CD4+/CD8+, as well as higher level of CD8+. (4) Spearman analysis showed that CIN grade was negatively correlated with the levels of CD3+, CD4+, and CD4+/CD8+ (P<0.05) and positively correlated with the level of CD8+ (P<0.05). CONCLUSION: The levels of T lymphocyte subsets were found to be closely associated with the severity of CIN. Therefore, the detection of T lymphocyte subsets in venous blood could be a valuable clinical tool for predicting the presence and degree of CIN.

MiRNA-338-3p Inhibits Neuroinflammation in the Corpus Callosum of LCV-LPS Rats Via STAT1 Signal Pathway.

Neuroinflammation is a common characteristic of intracranial infection (ICI), which is associated with the activation of astrocytes and microglia. MiRNAs are involved in the process of neuroinflammation. This study aimed to investigate the potential mechanism by which miR-338-3p negatively modulate the occurrence of neuroinflammation. We here reported that the decreased levels of miR-338-3p were detected using qRT-PCR and the upregulated expression of TNF-α and IL-1ß was measured by ELISA in the cerebrospinal fluid (CSF) in patients with ICI. A negative association between miR-338-3p and TNF-α or IL-1ß was revealed by Pearson correlation analysis. Sprague-Dawley (SD) rats were injected with LPS (50 µg) into left cerebral ventricule (LCV), following which the increased expression of TNF-α and IL-1ß and the reduction of miR-338-3p expression were observed in the corpus callosum (CC). Moreover, the expression of TNF-α and IL-1ß in the astrocytes and microglia in the CC of LCV-LPS rats were saliently inhibited by the overexpression of miR-338-3p. In vitro, cultured astrocytes and BV2 cells transfected with mimic-miR-338-3p produced less TNF-α and IL-1ß after LPS administration. Direct interaction between miR-338-3p and STAT1 mRNA was validated by biological information analysis and dual luciferase assay. Furthermore, STAT1 pathway was found to be implicated in inhibition of neuroinflammation induced by mimic miR-338-3p in the astrocytes and BV2 cells. Taken together, our results suggest that miR-338-3p suppress the generation of proinflammatory mediators in astrocyte and BV2 cells induced by LPS exposure through the STAT1 signal pathway. MiR-338-3p could act as a potential therapeutic strategy to reduce the neuroinflammatory response. Diagram describing the cellular and molecular mechanisms associated with LPS-induced neuroinflammation via the miR-338-3p/STAT1 pathway. LPS binds to TLRs on astrocytes or microglia to activate the STAT1 pathway and upregulate the production of pro-inflammatory cytokines. However, miR-338-3p inhibits the expression of STAT1 and reduces the production of inflammatory mediators.

Chemical characterization, antioxidant and immunomodulatory activities of acetylated polysaccharides from Cyperus esculentus.

This research was designed to characterize the structure of Cyperus esculentus polysaccharide (CEP) and its acetylated one (ACEP), and then investigated the effects of acetylation on the changes in physicochemical properties, thermal stability, antioxidant and immunomodulatory activities. Results showed that CEP and ACEP were heteropolysaccharides consisting of glucose, mannose, arabinose and xylose. The main chain of CEP included α-1,4-Glcp residues with the branching points at the O-6 position of the α-1,6-Manp residues. Acetyl groups were substituted at the O-2 and O-6 positions of some glucose residues. Meanwhile, the acetylation remarkably improved the polysaccharides thermal stability, and the ACEP exhibited a greater antioxidant activity. Furthermore, CEP and ACEP were proved to protect RAW 264.7 cells against LPS-induced inflammation by improving cellular morphology and decreasing reactive oxygen species secretion. This study may highlight a new approach for developing a high value-added ingredient from C. esculentus for functional food industry.