E3 ubiquitin ligase RNF128 attenuates colitis and colorectal tumorigenesis by triggering the degradation of IL-6 receptors.

INTRODUCTION: Intestinal immune dysregulation is strongly linked to the occurrence and formation of tumors. RING finger protein 128 (RNF128) has been identified to play distinct immunoregulatory functions in innate and adaptive systems. However, the physiological roles of RNF128 in intestinal inflammatory conditions such as colitis and colorectal cancer (CRC) remain controversial. OBJECTIVES: To elucidate the function and mechanism of RNF128 in colitis and CRC. METHODS: Animal models of dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced CRC were established in WT and Rnf128-deficient mice and evaluated by histopathology. Co-immunoprecipitation and ubiquitination analyses were employed to investigate the role of RNF128 in IL-6-STAT3 signaling. RESULTS: RNF128 was significantly downregulated in clinical CRC tissues compared with paired peritumoral tissues. Rnf128-deficient mice were hypersusceptible to both colitis induced by DSS and CRC induced by AOM/DSS or APC mutation. Loss of RNF128 promoted the proliferation of CRC cells and STAT3 activation during the early transformative stage of carcinogenesis in vivo and in vitro when stimulated by IL-6. Mechanistically, RNF128 interacted with the IL-6 receptor α subunit (IL-6Rα) and membrane glycoprotein gp130 and mediated their lysosomal degradation in ligase activity-dependent manner. Through a series of point mutations in the IL-6 receptor, we identified that RNF128 promoted K48-linked polyubiquitination of IL-6Rα at K398/K401 and gp130 at K718/K816/K866. Additionally, blocking STAT3 activation effectively eradicated the inflammatory damage of Rnf128-deficient mice during the transformative stage of carcinogenesis. CONCLUSION: RNF128 attenuates colitis and colorectal tumorigenesis by inhibiting IL-6-STAT3 signaling, which sheds novel insights into the modulation of IL-6 receptors and the inflammation-to-cancer transition.

AIM2 enhances Candida albicans infection through promoting macrophage apoptosis via AKT signaling.

Candida albicans is among the most prevalent invasive fungal pathogens for immunocompromised individuals and novel therapeutic approaches that involve immune response modulation are imperative. Absent in melanoma 2 (AIM2), a pattern recognition receptor for DNA sensing, is well recognized for its involvement in inflammasome formation and its crucial role in safeguarding the host against various pathogenic infections. However, the role of AIM2 in host defense against C. albicans infection remains uncertain. This study reveals that the gene expression of AIM2 is induced in human and mouse innate immune cells or tissues after C. albicans infection. Furthermore, compared to their wild-type (WT) counterparts, Aim2-/- mice surprisingly exhibit resistance to C. albicans infection, along with reduced inflammation in the kidneys post-infection. The resistance of Aim2-/- mice to C. albicans infection is not reliant on inflammasome or type I interferon production. Instead, Aim2-/- mice display lower levels of apoptosis in kidney tissues following infection than WT mice. The deficiency of AIM2 in macrophages, but not in dendritic cells, results in a phenocopy of the resistance observed in Aim2-/- mice against C. albican infection. The treatment of Clodronate Liposome, a reagent that depletes macrophages, also shows the critical role of macrophages in host defense against C. albican infection in Aim2-/- mice. Furthermore, the reduction in apoptosis is observed in Aim2-/- mouse macrophages following infection or treatment of DNA from C. albicans in comparison with controls. Additionally, higher levels of AKT activation are observed in Aim2-/- mice, and treatment with an AKT inhibitor reverses the host resistance to C. albicans infection. The findings collectively demonstrate that AIM2 exerts a negative regulatory effect on AKT activation and enhances macrophage apoptosis, ultimately compromising host defense against C. albicans infection. This suggests that AIM2 and AKT may represent promising therapeutic targets for the management of fungal infections.

IRF7 Exacerbates Candida albicans Infection by Compromising CD209-Mediated Phagocytosis and Autophagy-Mediated Killing in Macrophages.

IFN regulatory factor 7 (IRF7) exerts anti-infective effects by promoting the production of IFNs in various bacterial and viral infections, but its role in highly morbid and fatal Candida albicans infections is unknown. We unexpectedly found that Irf7 gene expression levels were significantly upregulated in tissues or cells after C. albicans infection in humans and mice and that IRF7 actually exacerbates C. albicans infection in mice independent of its classical function in inducing IFNs production. Compared to controls, Irf7-/- mice showed stronger phagocytosis of fungus, upregulation of C-type lectin receptor CD209 expression, and enhanced P53-AMPK-mTOR-mediated autophagic signaling in macrophages after C. albicans infection. The administration of the CD209-neutralizing Ab significantly hindered the phagocytosis of Irf7-/- mouse macrophages, whereas the inhibition of p53 or autophagy impaired the killing function of these macrophages. Thus, IRF7 exacerbates C. albicans infection by compromising the phagocytosis and killing capacity of macrophages via regulating CD209 expression and p53-AMPK-mTOR-mediated autophagy, respectively. This finding reveals a novel function of IRF7 independent of its canonical IFNs production and its unexpected role in enhancing fungal infections, thus providing more specific and effective targets for antifungal therapy.

Knockdown of LCN2 Attenuates Brain Injury After Intracerebral Hemorrhage via Suppressing Pyroptosis.

Objective: The aims of this study are to screen novel differentially expressed genes (DEGs) for intracerebral hemorrhage (ICH) and reveal the role of Lipocalin-2 (LCN2) in ICH. Methods: We constructed the ICH model by injection of autologous whole blood into the right basal ganglia in rats. RNA-sequencing and bioinformatics analyses were performed to identify the DEGs between ICH and sham rats, and some important ones were confirmed using quantitative real-time PCR (qRT-PCR). LCN shRNA was used to knockdown of LCN2 in ICH rats. Pathological examination was carried out using 2,3,5-triphenyltetrazolium chloride (TTC) staining and Hematoxylin-eosin (HE) staining. Immunohistochemistry detected Caspase-3, and co-staining of Terminal dUTP nick end labeling (TUNEL) and NEUN staining were performed for neuron apoptosis assessment. Western blot analysis was performed to quantify pyroptosis-related proteins. Enzyme-linked immunosorbent assay (ELISA) was used to measure inflammatory cytokine levels. Results: ICH rats exhibited significant hematomas, higher brain water content, obvious interstitial edema, and inflammatory infiltration, as well as more apoptotic cells in brain tissues. RNA-seq analysis identified 103 upregulated and 81 downregulated DEGs. The expression of LCN2, HSPB1, CXCL10, and MEF2B were upregulated in ICH rats. ICH triggered the release of interleukin (IL)-1ß, tumor necrosis factor-α (TNF-α), and IL-18, and promoted the expression of pyroptosis-related proteins Caspase-1, GSDMD, NLRP3, and ASC. LCN2 knockdown attenuated the pathological characteristics of ICH, and also reduced pyroptosis in brain tissues. Conclusion: Inhibition of LCN2 attenuates brain injury after ICH via suppressing pyroptosis, which provide guidance for ICH management.

MDA5 Enhances Invasive Candida albicans Infection by Regulating Macrophage Apoptosis and Phagocytosis/Killing Functions.

Candida albicans is a common opportunistic pathogenic fungus. The innate immune system provides the first-line host defense against fungal infection. Innate immune receptors and downstream molecules have been shown to play various roles during fungal infection. The innate immune receptor MDA5, encoded by the gene Ifih1, enhances host resistance against viral and Aspergillus fumigatus infection by inducing the production of interferons (IFNs). However, the role of MDA5 in C. albicans infection is still unclear. Here, we found that the gene expression levels of IFIH1 were significantly increased in innate immune cells after C. albicans stimulation through human bioinformatics analysis or mouse experiments. Through in vivo study, MDA5 was shown to enhance host susceptibility to C. albicans infection independent of IFN production. Instead, MDA5 exerted its influence on macrophages and kidneys by modulating the expression of Noxa, Bcl2, and Bax, thereby promoting apoptosis. Additionally, MDA5 compromised killing capabilities of macrophage by inhibition iNOS expression. The introduction of the apoptosis inducer PAC1 further impaired macrophage functions, mimicking the enhancing effect of MDA5 on C. albicans infection. Furthermore, the administration of macrophage scavengers increased the susceptibility of Ifih1-/- mice to C. albicans. The founding suggests that MDA5 promote host susceptibility to invasive C. albicans by enhancing cell apoptosis and compromising macrophage functions, making MDA5 a target to treat candidiasis.

Intestinal epithelial SNAI1 promotes the occurrence of colorectal cancer by enhancing EMT and Wnt/ß-catenin signaling.

Colorectal cancer (CRC) is a prevalent cause of cancer and mortality on a global scale. SNAI1, a member of the zinc finger transcription superfamily, is a significant contributor to embryonic development and carcinogenesis through the process of epithelial-mesenchymal transition (EMT). While prior research utilizing CRC cells and clinical data has demonstrated that SNAI1 facilitates CRC progression through diverse mechanisms, the precise manner in which epithelial SNAI1 regulates CRC development in vivo remains unclear. In this study, colitis and colitis-associated CRC were induced through the use of intestinal epithelium-specific Snai1 knockout (Snai1 cKO) mice. Our findings indicate that Snai1 cKO mice exhibit a reduced susceptibility to acute colitis and colitis-associated CRC compared to control mice. Western-blot analysis of colon tissues revealed that Snai1 cKO mice exhibited a higher overall apoptosis level during tumor formation than control mice. No significant differences were observed in the activation of the classical p53 signaling pathway. However, Snai1 cKO mice exhibited weakened EMT and Wnt/ß-catenin pathway activation. In summary, our study has provided evidence in vivo that the intestinal epithelial SNAI1 protein suppresses apoptosis, amplifies the EMT, and activates the Wnt/ß-catenin signaling pathways in both early and late phases of CRC formation, thus promoting the development and progression of colitis-associated CRC.

Inhibition of FNDC1 suppresses gastric cancer progression by interfering with Gßγ-VEGFR2 complex formation.

Gastric cancer (GC) is a prevalent digestive tract malignant tumor characterized by an insidious onset, ease of metastasis, rapid growth, and poor prognosis. Here, we report that fibronectin type III domain containing 1 (FNDC1) has high expression in GC and indicates poor outcomes in patients with GC. FNDC1 over-expression or knockdown promotes or inhibits tumorigenesis and metastasis, respectively. The expression of FNDC1 is upregulated by TWIST1, strengthening its interaction with Gßγ and VEGFR2. The formation of the trimers, TWIST1 plus Gßγ and VEGFR2, increases VEGFR2 phosphorylation and Gßγ trafficking, which activates RAS-MAPK and PI3K-AKT signaling, benefiting GC progression. In this study, we demonstrated that arsenite can efficiently suppress FNDC1 expression, attenuating the formation of the trimers and downstream pathways. Altogether, our results indicate that FNDC1 might be a promising target for clinical treatment and prognostic judgment, while FNDC1 inhibition by arsenite provides a new opportunity for overcoming this fatal disease.

Deferoxamine in intracerebral hemorrhage: Systematic review and meta-analysis.

BACKGROUND: Intracerebral hemorrhage (ICH) is a stroke with a high morbidity and mortality rate. Deferoxamine (DFX) is thought to be effective in treating Intracerebral Hemorrhage. In our study, we performed a meta-analysis to evaluate the treatment effects of DFX. METHODS: We systematically searched PubMed, Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Chinese Biomedical Literature Database in Jan 2022 for studies on DFX for ICH patients. Outcome measures included relative hematoma volume, relative edema volume, good neurological functional outcome and adverse events. Odds risk (OR) and weighted mean difference (WMD) were used to evaluate clinical outcomes. RESULTS: After searching 636 articles, 4 RCTs, 2 NRCTs, and 1cohort study were included. We found that DFX was effective in hematoma absorption on day 7 after onset, but the difference was not significant on day 14. DFX could suppress edema expansion on days 3, 7, and 14 after onset. DFX did not contribute to better outcomes after 3 and 6 months when used the modified Rankin Scale and the Glasgow Outcome Scale to evaluate neurological prognosis. The pooled results showed no statistically significant difference in Serious adverse events between the experimental and control groups. CONCLUSIONS: DFX could limit edema expansion on days 3, 7, and 14 after commencement and facilitate hematoma absorption at week 1 without significantly increasing the risk of adverse events, but it did not improve neurological prognosis.

Akkermansia muciniphila administration exacerbated the development of colitis-associated colorectal cancer in mice.

Colorectal cancer (CRC) is one of the most common digestive tract malignancies and inflammation and gut microbiota are well-known key factors to influence CRC development. Akkermansia mucinipila is an important gram-negative anaerobic bacterium that can degrade mucin in gut. Previous studies suggested that A. muciniphila may affect inflammation and cell proliferation, but the relationship between A. muciniphila and CRC is not clarified. Here C57BL/6 mice were administrated with A. muciniphila or PBS and then treated with azoxymethane (AOM)/dextran sodium sulphate (DSS) to induce CRC. The mice receiving A. muciniphila administration had more serious weight loss, shorter colon length and more intestinal tumors than those receiving PBS administration after AOM/DSS treatment. More colon damage and less goblet cells were also observed in A. muciniphila treated mice. Furthermore, A. muciniphila administration induced more Ki67+ proliferating cells, higher PCNA expression and elevated gene expression of proliferation-associated molecules including Snrpd1, Dbf4 or S100A9. At early stage of CRC development, in comparison with controls, the mice receiving A. muciniphila administration also had more body weight loss and shorter colon length, as well as higher gene expression of inflammatory cytokines. Furthermore, the in vitro experimental results showed that the co-culture of colon epithelial cells with A. muciniphila enhanced the cell proliferation and gene expression of proliferation-associated molecules. Therefore, A. mucinipila may promote the formation of CRC in mice through increasing the early level of inflammation and the proliferation of intestinal epithelial cells.

Efficacy and Safety of Glucocorticoids Versus Placebo as an Adjuvant Treatment to Surgery in Chronic Subdural Hematoma: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.

BACKGROUND: Chronic subdural hematoma (CSDH) is a common neurosurgical disease with a high recurrence rate, especially among the elderly. Glucocorticoids have been tested for the treatment of CSDH in observational studies and randomized clinical trials. METHODS: We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials database for randomized trials from the earliest date available to May 23, 2021 that had compared glucocorticoids and placebo as a postoperative treatment of CSDH. Trials were included if the study participants were aged ≥18 years and had had CSDH after surgery. The relative risk (RR) was used to evaluate the clinical outcomes. RESULTS: We included 5 eligible randomized controlled trials with a total of 1251 patients. The findings showed that the use of adjuvant glucocorticoid therapy can effectively reduce the recurrence risk of CSDH compared with placebo (RR, 0.40; 95% confidence interval [CI], 0.28-0.58; P < 0.001). No significant differences were found between the glucocorticoid and placebo groups regarding favorable neurological outcomes (RR, 1; 95% CI, 0.93-1.08; P = 0.92). We found that the use of adjuvant glucocorticoids resulted in a significant increase in psychiatric symptoms (RR, 3.22; 95% CI, 1.83-5.64; P < 0.001). No significant differences were found for infection between the 2 groups (RR, 1.86; 95% CI, 0.56-6.14; P = 0.31). CONCLUSIONS: Glucocorticoid therapy can effectively reduce the recurrence risk of CSDH after surgery without an increase in the postoperative infection rate. However, significantly increased psychiatric symptoms were reported in the glucocorticoid group.

Endovascular coiling versus surgical clipping for aneurysmal subarachnoid hemorrhage: A meta-analysis of randomized controlled trials.

BACKGROUND: Aneurysmal subarachnoid hemorrhage is a relatively rare cause of stroke, carrying a bad prognosis of mortality and disability. The current standard procedure, neurosurgical clipping, has failed to achieve satisfactory outcomes. Therefore, endovascular detachable coils have been tested as an alternative. This meta-analysis was aimed to compare the outcomes of surgical clipping and endovascular coiling in aneurysmal subarachnoid hemorrhage. MATERIALS AND METHODS: Relevant randomized trials up to June 2018 were identified from Medline, Central, and Web of Science. Data for poor outcomes (Modified Rankin Scale [mRS] scores 3 to 6) at 2-3 months, 1 year, and 3-5 years were extracted and analyzed as odds ratios (ORs) with 95% confidence intervals (CIs), using RevMan software. RESULTS: Five studies (2780: 1393 and 1387 patients in the coiling and clipping arms, respectively) were included in the current analysis. The overall effect estimate favored endovascular coiling over surgical clipping in terms of reducing poor outcomes (death or dependency, mRS > 2) at 1 year (OR = 0.67, 95% CI: 0.57-0.79) and 3-5 years (OR = 0.8, 95% CI: 0.67-0.96). Moreover, coiling was associated with a significantly lower rate of cerebral ischemia (OR = 0.37, 95% CI: 0.16-0.86). Postprocedural mortality (OR = 0.79, 95% CI: 0.6-1.05) and rebleeding (OR = 1.15, 95% CI: 0.75-1.78) rates were comparable between the two groups. However, technical failure was significantly more common with coiling interventions than with clipping surgeries (OR = 2.84, 95% CI: 1.86-4.34). CONCLUSION: Our analysis suggests that coiling can be a better alternative to clipping in terms of surgical outcomes. Further improvements in the coiling technique and training may improve the outcomes of this procedure.

Anti-vascular endothelial growth factor in glioblastoma: a systematic review and meta-analysis.

Glioblastoma is one of the most common primary brain tumors in adults. The current treatment strategies failed to achieve satisfactory outcomes. Anti-vascular endothelial growth factor (anti-VEGF) agents have been proposed to enhance the survival and quality of life in these patients. To investigate this, different databases were searched in addition to hand searching. Relevant studies were screened and only ten randomized controlled trials (RCTs) met the eligibility criteria; six of them were considered for meta-analysis. Eligible RCTs were assessed regarding risk of bias using the Cochrane tool. Relevant data were extracted and meta-analysis was conducted using the random effects model analysis on RevMan software. One thousand seventy-eight patients in the anti-VEGF group and 946 patients in the control group were available for analysis. No statistically significant improvement in the overall survival (OS) was detected for anti-VEGF (OR 0.87, 95% CI 0.7-1.09, p = 0.23) or bevacizumab subgroup (OR 0.84, 95% CI 0.65-1.08, p = 0.17) compared to standard therapy alone. However, the progression-free survival (PFS) showed a significant improvement with both anti-VEGF (OR 0.76, 95% CI 0.65-0.89, p = 0.0007) and bevacizumab subgroup (OR 0.75, 95% CI 0.65-0.87, p = 0.0001). In conclusion, anti-VEGF agents can improve the PFS but not OS in glioblastoma patients. The current evidence is not satisfactory to declare a new therapeutic line. Further RCTs with sharply determined outcomes and assessment methods are required.

[The effects of protooncogene on oocyte maturation mediated by cytokines].

AIM: The mechanisms of cytokines in regulating oocyte maturation is still little known. The present study attempt to investigate whether the protooncogene of c-erbB2, c-myb are involved in introducing of cytokines to regulate oocyte maturation. METHODS: This research used mouse GV stage oocyte culture model in vitro and RT-PCR, Western blotting method to explore the effect of EGF, TNFalpha, ET-1 and NO on oocyte maturation; to analyze the c-erbB2 mRNA and c-myb mRNA expression and the phosphorylation of MAPK and cyclinB1 expression in oocytes affected by above cytokines. RESULTS: EGF(10 microg/L) stimulated meiosis of oocytes significantly, the level of c-erbB2 mRNA, c-myb mRNA were increased, and promoted the phosphorylation of MAPK and cyclinB1 expression; TNFalpha (1 microg/L) and ET-1 ((10(-1) mol/L) had the results to EGF. Low dose of SNP (10(-5)mol/L) had no effect on oocyte maturation, but could significantly reverse the suppression of dbcAMP on oocyte maturation. CONCLUSION: c-erbB2 and c-myb were involved in introducing of cytokines to regulate oocyte maturation, might be the middle link in connection of the cytokines with MAPK and MPF in regulation oocyte maturation.