SIRT7 promotes the proliferation and migration of anaplastic thyroid cancer cells by regulating the desuccinylation of KIF23.

OBJECTIVE: This study was designed to investigate the regulatory effects of kinesin family member (KIF) 23 on anaplastic thyroid cancer (ATC) cell viability and migration and the underlying mechanism. METHODS: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to analyze the levels of KIF23 in ATC cells. Besides, the effects of KIF23 and sirtuin (SIRT) 7 on the viability and migration of ATC cells were detected using cell counting kit-8, transwell and wound healing assays. The interaction between SIRT7 and KIF23 was evaluated by co-immunoprecipitation (Co-IP) assay. The succinylation (succ) of KIF23 was analyzed by western blot. RESULTS: The KIF23 expression was upregulated in ATC cells. Silencing of KIF23 suppressed the viability and migration of 8505C and BCPAP cells. The KIF23-succ level was decreased in ATC cells. SIRT7 interacted with KIF23 to inhibit the succinylation of KIF23 at K537 site in human embryonic kidney (HEK)-293T cells. Overexpression of SIRT7 enhanced the protein stability of KIF23 in HEK-293T cells. Besides, overexpression of KIF23 promoted the viability and migration of 8505C and BCPAP cells, which was partly blocked by silenced SIRT7. CONCLUSIONS: SIRT7 promoted the proliferation and migration of ATC cells by regulating the desuccinylation of KIF23.

MiR-34a ameliorates arterial blood flow in rats with lower limb arteriosclerosis obliterans via Sirt1 signaling pathway.

In this study, we investigated the impact of microRNA-34a (miR-34a) on lower limb arteriosclerosis obliterans in rats through the Sirtuin 1 (Sirt1) signaling pathway. Thirty-six Sprague-Dawley rats were divided into normal, model, and miR-34a mimics groups. Rats in the normal group were raised normally, while the model group underwent lower limb arteriosclerosis obliterans induction and received saline injections. The miR-34a mimics group also underwent arteriosclerosis obliterans modeling but received miR-34a mimics injections. Immunohistochemistry revealed significantly increased vascular endothelial growth factor (VEGF) expression in both model and miR-34a mimics groups compared to the normal group, with the miR-34a mimics group showing higher levels. Western blotting indicated elevated Sirt1 protein expression in both non-normal groups, with the miR-34a mimics group exhibiting significantly higher levels. Quantitative polymerase chain reaction (qPCR) demonstrated higher levels of miR-34a, VEGF mRNA, and Sirt1 mRNA in the model group compared to the normal group, but significantly lower levels than the miR-34a mimics group. Enzyme-linked immunosorbent assay (ELISA) showed increased VEGF content in the model group compared to the normal group but decreased compared to the miR-34a mimics group. Hemorrheological detection revealed a reduced PU index in both non-normal groups compared to the normal group, with a significant increase in the miR-34a mimics group compared to the model group. Overall, miR-34a upregulation enhanced VEGF expression in rat blood vessels, ameliorating arterial blood flow in lower limb arteriosclerosis obliterans through the Sirt1 signaling pathway.

CUL7 promotes cancer cell survival through promoting Caspase-8 ubiquitination.

The Cullin 7 (CUL7) gene encodes a member of the cullin family of E3 ubiquitin ligases. Accumulated evidence suggests that CUL7 is oncogenic. However, the mechanism by which CUL7 improves cancer cell survival has not been fully elucidated. Here, we reported that CUL7 confers anti-apoptotic functions by interacting with Caspase-8. CUL7 prevents Caspase-8 activation by promoting Caspase-8 modification with non-degradative polyubiquitin chains at K215. CUL7 knockdown sensitized cancer cells to TRAIL-induced apoptosis in vitro and in nude mice. These results suggest that CUL7 limits extrinsic apoptotic signaling by promoting Caspase-8 ubiquitination.

Accuracy of Fukuoka and American Gastroenterological Association Guidelines for Predicting Advanced Neoplasia in Pancreatic Cyst Neoplasm: A Meta-Analysis.

BACKGROUND: A differential diagnosis of advanced pancreatic cystic neoplasms (PCNs) is critical to determine optimal treatment. The Fukuoka and American Gastroenterological Association (AGA) guidelines are the most widely accepted criteria for the management of PCNs. OBJECTIVE: This study aimed to evaluate the diagnostic value of these guidelines in predicting advanced neoplasia (AN). METHODS: A comprehensive electronic search of the PubMed, EMBASE, Web of Science, Cochrane Library, and Scopus databases was conducted to identify all relevant studies evaluating the Fukuoka and AGA guidelines in surgically resected and histologically confirmed PCNs. Pooled sensitivity, specificity, and diagnostic odds ratios (DORs) were calculated as compound measures of diagnostic accuracy using the random-effects model. Summary of receiver operating characteristic (SROC) curves and the area under the curve (AUC) were also performed. RESULTS: A total of 21 studies with 3723 patients were included in this meta-analysis. Of these studies, 15, 4, and 2 evaluated the Fukuoka guidelines, the AGA guidelines, and both guidelines, respectively. For AN prediction, the Fukuoka guidelines had a pooled sensitivity of 0.67 (95% confidence interval [CI] 0.64-0.70), pooled specificity of 0.64 (95% CI 0.62-0.66), and pooled DOR of 6.28 (95% CI 4.38-9.01), with an AUC of the SROC of 0.78. AGA guidelines showed a pooled sensitivity of 0.59 (95% CI 0.52-0.65), pooled specificity of 0.77 (95% CI 0.74-0.80), and pooled DOR of 5.84 (95% CI 2.60-13.15), with an AUC of 0.79 (95% CI 0.70-0.88). CONCLUSION: When used alone, the Fukuoka and AGA guidelines showed similar but unsatisfactory diagnostic accuracy in the risk stratification of malignant potential of PCN. Thus, we recommend that they be applied only as a broad framework in clinical practice.

Zinc mediates the SREBP-SCD axis to regulate lipid metabolism in Caenorhabditis elegans.

Maintenance of lipid homeostasis is crucial for cells in response to lipid requirements or surplus. The SREBP transcription factors play essential roles in regulating lipid metabolism and are associated with many metabolic diseases. However, SREBP regulation of lipid metabolism is still not completely understood. Here, we showed that reduction of SBP-1, the only homolog of SREBPs in Caenorhabditis elegans, surprisingly led to a high level of zinc. On the contrary, zinc reduction by mutation of sur-7, encoding a member of the cation diffusion facilitator (CDF) family, restored the fat accumulation and fatty acid profile of the sbp-1(ep79) mutant. Zinc reduction resulted in iron overload, which thereby directly activated the conversion activity of stearoyl-CoA desaturase (SCD), a main target of SREBP, to promote lipid biosynthesis and accumulation. However, zinc reduction reversely repressed SBP-1 nuclear translocation and further downregulated the transcription expression of SCD for compensation. Collectively, we revealed zinc-mediated regulation of the SREBP-SCD axis in lipid metabolism, distinct from the negative regulation of SREBP-1 or SREBP-2 by phosphatidylcholine or cholesterol, respectively, thereby providing novel insights into the regulation of lipid homeostasis.

Propofol Through Upregulating Caveolin-3 Attenuates Post-Hypoxic Mitochondrial Damage and Cell Death in H9C2 Cardiomyocytes During Hyperglycemia.

BACKGROUND/AIMS: Hearts from diabetic subjects are susceptible to myocardial ischemia reperfusion (I/R) injury. Propofol has been shown to protect against myocardial I/R injury due to its antioxidant properties while the underlying mechanism remained incompletely understood. Thus, this study aimed to determine whether or not propofol could attenuate myocardial I/R injury by attenuating mitochondrial dysfunction/damage through upregulating Caveolin (Cav)-3 under hyperglycemia. METHODS: Cultured rat cardiomyocyte H9C2 cells were subjected to hypoxia/reoxygenation (H/R) in the absence or presence of propofol under high glucose (HG), and cell viability, lactate dehydrogenase (LDH) and mitochondrial viability as well as creatine kinase-MB (CK-MB), cardiac troponin I (cTnI) and intracellular adenosine triphosphate (ATP) content were measured with colorimetric Enzyme-Linked Immunosorbent Assays. Intracellular levels of oxidative stress was assessed using 2,7-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescent staining and mitochondrial-dependent apoptosis was assessed by detecting mitochondrial membrane potential and the activation of apoptotic caspases 3 and 9. RESULTS: Exposure of cells to HG without or with H/R both significantly increased cell injury, cell apoptosis and enhanced oxidative stress that were associated with mitochondrial dysfunction and decreased Cav-3 protein expression. All these changes were further exacerbated following H/R under HG. Administration of propofol at concentrations from 12.5 to 50 µM but not 100 µM significantly attenuated H/R injury that was associated with increased Cav-3 expression and activation of the prosurvival proteins Akt and STAT3 with the optimal protective effects seen at 50 µM of propofol (P25). The beneficial effects of propofol(P25) were abrogated by Cav-3 disruption with ß-methyl-cyclodextrin. CONCLUSION: Propofol counteracts cardiomyocyte H/R injury by attenuating mitochondrial damage and improving mitochondrial biogenesis through upregulating Cav-3 during hyperglycemia.

Angiotensin-(1-7) counteracts angiotensin II-induced dysfunction in cerebral endothelial cells via modulating Nox2/ROS and PI3K/NO pathways.

Angiotensin (Ang) II, the main effector of the renin-angiotensin system, has been implicated in the pathogenesis of vascular diseases. Ang-(1-7) binds to the G protein-coupled Mas receptor (MasR) and can exert vasoprotective effects. We investigated the effects and underlying mechanisms of Ang-(1-7) on Ang II-induced dysfunction and oxidative stress in human brain microvascular endothelial cells (HbmECs). The pro-apoptotic activity, reactive oxygen species (ROS) and nitric oxide (NO) productions in HbmECs were measured. The protein expressions of nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2), serine/threonine kinase (Akt), endothelial nitric oxide synthase (eNOS) and their phosphorylated forms (p-Akt and p-eNOS) were examined by western blot. MasR antagonist and phosphatidylinositol-3-kinase (PI3K) inhibitor were used for receptor/pathway verification. We found that Ang-(1-7) suppressed Ang II-induced pro-apoptotic activity, ROS over-production and NO reduction in HbmECs, which were abolished by MasR antagonist. In addition, Ang-(1-7) down-regulated the expression of Nox2, and up-regulated the ratios of p-Akt/Akt and its downstream p-eNOS/eNOS in HbmECs. Exposure to PI3K inhibitor partially abrogated Ang-(1-7)-mediated protective effects in HbmECs. Our data suggests that Ang-(1-7)/MasR axis protects HbmECs from Ang II-induced dysfunction and oxidative stress via inhibition of Nox2/ROS and activation of PI3K/NO pathways.

The Role of Coping Behavior in Severely Burned Patients With Posttraumatic Stress Disorder.

This multicenter cross-sectional study investigates the role of coping behaviors of inpatients with severe burn injuries that determined their development of post-traumatic stress disorder (PTSD) in burn specialty center in South China. Sixty-four subjects who were in their rehabilitation period were enrolled in the study. Self-report scales, such as the Post-traumatic Stress Disorder Checklist-Civilian Version and the Medical Coping Mode Questionnaire, were applied for evaluating PTSD symptoms with the severity and classifying coping behaviors. Regression analysis evaluated the association of severity of PTSD with coping behaviors. Outcomes indicated that coping behaviors could diagnose PTSD symptoms and predict the severity of PTSD to some extent. It suggested coping behaviors might intermediate the psychological outcomes of the severely burned patients.

MicroRNA-520c-3p inhibits hepatocellular carcinoma cell proliferation and invasion through induction of cell apoptosis by targeting glypican-3.

AIM: Glypican-3 (GPC3) is a membrane-associated heparan sulfate proteoglycan involved in regulation of cell proliferation, cell survival, cell migration and differentiation process. MicroRNAs (miRNAs) are single-stranded, non-coding functional RNAs that are important in many biological processes. GPC3 and miRNAs have been found to play essential roles in the development and progression of hepatocellular carcinoma (HCC). However, little information about the relationship between GPC3 and miRNAs is available nowadays. Therefore, this study aims to examine the relationship between GPC3 and miRNAs. METHODS: Dual-luciferase reporter assay was used to validate the direct target of GPC3. Fluorescence quantitative PCR and Western blotting were used to examined the gene expression at mRNA and protein levels. Cell apoptosis was evaluated by flow cytometric analysis and Annexin V-FITC staining. Invasion of cells was evaluated by Transwell matrigel assay. RESULTS: The results showed that miR-520c-3p could specifically target GPC3 in HCC cells. GPC3 protein levels decreased with unchanged transcription efficiency after miRNA transfection, and there was negative correlation of miR-520c-3p expression in HCC in relate to GPC3 protein levels. Moreover, miR-520c-3p not only induced HCC cell apoptosis, but also inhibited the growth and invasion of the cells. Interestingly, overexpression of GPC3 could effectively reverse apoptosis induced by miR-520c-3p transfection in HCC. CONCLUSIONS: Taken together, these results supported that miR-520c-3p may decrease GPC3 protein levels to inhibit proliferation of HCC cells. Therefore, GPC3 could be a new target for genetic diagnosis and treatment of HCC.

Comparison of laparoscopic radiofrequency ablation with percutaneous radiofrequency ablation in the treatment of chronic hepatitis B-related hepatocellular carcinoma involving specific sites: A retrospective cohort study.

BACKGROUND: This study compared the effectiveness and safety of laparoscopic radiofrequency ablation (LRFA) and percutaneous radiofrequency ablation (PRFA) in the treatment of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) involving specific sites. METHODS: This retrospective cohort study included patients with HBV-related HCC involving specific sites treated with LRFA or PRFA between January 2012 and December 2020. The overall survival (OS), disease-free survival (DFS), and complications were compared between the LRFA and PRFA groups. The Cox proportional-hazards regression model was used to determine the factors affecting prognosis. RESULTS: This study included 109 patients: 69 in the LRFA group and 40 cases in the PRFA group. No significant differences were found in the 3-year OS rate between the two groups (73.7% vs. 70.0%, P = 0.514), but the LRFA group showed a higher 3-year DFS rate than the PRFA group (58.2% vs. 42.5%, P = 0.018). The RFA method was not associated with OS but was independently associated with DFS (LRPA vs. PRFA, HR = 2.078, P = 0.012). The common complications were ascites, pleural effusion, and fever in the two groups. The occurrence of complications in patients treated with LRFA or PRFA was similar (15.9% vs. 12.5%, P = 0.785). CONCLUSION: LRFA was associated with a better DFS in patients with HBV-related HCC involving specific sites. Thus, LRFA might have more advantages in treating liver cancer involving specific sites.

Knockdown of GPC3 inhibits the proliferation of Huh7 hepatocellular carcinoma cells through down-regulation of YAP.

Glypican-3 (GPC3), a membrane-associated heparan sulfate proteoglycan, is frequently upregulated in hepatocellular carcinoma (HCC). Yes-associated protein (YAP) is also found over-expressed in HCC and has been identified as a key effector molecule in Hippo pathway, which could control the organ size in animals through the regulation of cell proliferation and apoptosis and plays an important role in the development of malignant tumors. Studies have reported that GPC3 and YAP might collaborate to regulate the development of HCC. To elucidate the role of GPC3 in the development of HCC and its relationship with YAP, siRNA technique was employed to knock down GPC3 in Huh7 HCC cells. Moreover, recombinant human YAP-1 was used to examine the effects of GPC3 on Huh7 cells. The results of flow cytometric analysis and Annexin-V-FLUOS apoptosis assay showed that knockdown of GPC3-induced apoptosis in Huh7 cells, resulting in inhibition of cell proliferation as examined by EdU incorporation assay, migration, and invasion. GPC3 knockdown also suppressed the expression of YAP in mRNA and protein levels, as examined by fluorescence quantitative PCR and Western blot analysis. Moreover, addition of recombinant human YAP-1 effectively rescued the cells from apoptosis triggered by GPC3 knockdown. Taken together, our findings suggest that GPC3 regulates HCC cell proliferation with the involvement of Hippo pathway.

Unraveling the enigma of tumor-associated macrophages: challenges, innovations, and the path to therapeutic breakthroughs.

Tumor-associated macrophages (TAMs) are integral to the tumor microenvironment (TME), influencing cancer progression significantly. Attracted by cancer cell signals, TAMs exhibit unparalleled adaptability, aligning with the dynamic tumor milieu. Their roles span from promoting tumor growth and angiogenesis to modulating metastasis. While substantial research has explored the fundamentals of TAMs, comprehending their adaptive behavior, and leveraging it for novel treatments remains challenging. This review delves into TAM polarization, metabolic shifts, and the complex orchestration of cytokines and chemokines determining their functions. We highlight the complexities of TAM-targeted research focusing on their adaptability and potential variability in therapeutic outcomes. Moreover, we discuss the synergy of integrating TAM-focused strategies with established cancer treatments, such as chemotherapy, and immunotherapy. Emphasis is laid on pioneering methods like TAM reprogramming for cancer immunotherapy and the adoption of single-cell technologies for precision intervention. This synthesis seeks to shed light on TAMs' multifaceted roles in cancer, pinpointing prospective pathways for transformative research and enhancing therapeutic modalities in oncology.

Short-term clinical effects and inflammatory response of natural orifice specimen extraction surgery versus conventional laparoscopic-assisted surgery for the treatment of sigmoid and rectal cancer.

Background: The clinical outcomes and benefits of natural orifice specimen extraction surgery (NOSES) in colorectal cancer have not been fully evaluated comparing to conventional laparoscopic-assisted radical resection. This retrospective study was conducted to investigate the short-term clinical benefits of NOSES versus conventional laparoscopic-assisted surgery for the treatment of sigmoid and rectal cancer. Methods: A total of 112 patients with sigmoid or rectal cancer were included in this retrospective study. The observation group (n=60) was treated with NOSES, and the control group (n=52) was treated with conventional laparoscopic-assisted radical resection. Following these interventions, the postoperative recovery and inflammatory response indexes were compared between the two groups. Results: In contrast with the control group, the observation group significantly had longer operation time (t=2.83, P=0.006), but shorter durations for the resumption of a semi-liquid diet (t=2.17, P=0.032), and length of postoperative hospital stay (t=2.74, P=0.007), as well as fewer postoperative incision infections (χ2=7.32, P=0.009). Moreover, the levels of immunoglobulin (Ig), including IgG (t=2.29, P=0.024), IgA (t=3.30, P=0.001), and IgM (t=3.38, P=0.001), in the observation group were markedly higher than those within the control group at 3 days postoperatively. Also, the levels of inflammatory indicators including interleukin (IL)-6 (t=4.22, P=5.02E-5), C-reactive protein (CRP) (t=3.73, P=3.5E-4), and tumor necrosis factor (TNF)-α (t=2.94, P=0.004) in the observation group were considerably lower than those in the control group at 3 days after the operation. Conclusions: NOSES can improve the postoperative recovery and has benefits in reducing the inflammatory response than conventional laparoscopic-assisted surgery.

The Unique Genetic Mutation Characteristics Based on Large Panel Next-Generation Sequencing (NGS) Detection in Multiple Primary Lung Cancers (MPLC) Patients.

BACKGROUND: With the wide application of multislice spiral computed tomography (CT), the frequency of detection of multiple lung cancer is increasing. This study aimed to analyze gene mutations characteristics in multiple primary lung cancers (MPLC) using large panel next-generation sequencing (NGS) assays. METHODS: Patients with MPLC surgically removed from the Affiliated Hospital of Guangdong Medical University from Jan 2020 to Dec 2021 enrolled the study. NGS sequencing of large panels of 425 tumor-associated genes was performed. RESULTS: The 425 panel sequencing of 114 nodules in 36 patients showed that epidermal growth factor receptor (EGFR) accounted for the largest proportion (55.3%), followed by Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2) (9.6%), v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), and Kirsten rat sarcoma viral oncogene (KRAS) (8.8%). Fusion target variation was rare (only 2, 1.8%). ERBB2 Y772_A775dup accounted for 73%, KRAS G12C for about 18%, and BRAF V600E for only 10%. AT-rich interaction domain 1A (ARID1A) mutations were significantly higher in invasive adenocarcinoma (IA) which contained solid/micro-papillary malignant components (p = 0.008). The tumor mutation burden (TMB) distribution was low, with a median TMB of 1.1 MUTS/Mb. There were no differences in the TMB distribution of different driver genes. In addition, 97.2% of MPLC patients (35/36) had driver gene mutations, and 47% had co-mutations, mainly in IA (45%) and invasive adenocarcinoma (MIA) (37%) nodule, with EGFR (39.4%), KRAS (9.1%), ERBB2 (6.1%), tumor protein 53 (TP53) (6.1%) predominately. CONCLUSIONS: MPLC has a unique genetic mutation characteristic that differs from advanced patients and usually presents with low TMB. Comprehensive NGS helps to diagnose MPLC and guides the MPLC clinical treatment. ARID1A is significantly enriched in IA nodules containing micro-papillary/solid components, suggesting that these MPLC patients may have a poor prognosis.

Significance of exosomes in hepatocellular carcinoma.

Among the most prevalent cancers in the world, hepatocellular carcinoma (HCC) has a high mortality rate. The diagnosis and management of HCC are presently hindered by difficulties in early detection and suboptimal treatment outcomes. Exosomes have been shown to play an important role in hepatocarcinogenesis and can also be used for diagnosis and treatment. In this review, we discussed the research progress on exosomes in hepatocarcinogenesis development, tumor microenvironment remodeling, treatment resistance, and immunosuppression. HCC can be diagnosed and treated by understanding the pathogenesis and identifying early diagnostic markers. This review will be a significant reference for scholars with an initial understanding of the field to fully understand the role of exosomes in the organism.

PKIB involved in the metastasis and survival of osteosarcoma.

Osteosarcoma is frequently metastasized at the time of diagnosis in patients. However, the underlying mechanism of osteosarcoma metastasis remains poorly understood. In this study, we evaluated DNA methylation profiles combined with gene expression profiles of 21 patients with metastatic osteosarcoma and 64 patients with non-metastatic osteosarcoma from TARGET database and identified PKIB and AIM2 as hub genes related to the metastasis of osteosarcoma. To verify the effects of PKIB on migration and invasion of osteosarcoma, we performed wound-healing assay and transwell assay. The results showed that PKIB significantly inhibited the migration and invasion of osteosarcoma cells, and the Western blot experiments showed that the protein level of E-cad was upregulated and of VIM was downregulated in 143-B cell recombinant expression PKIB. These results indicate that PKIB inhibit the metastasis of osteosarcoma. CCK-8 assay results showed that PKIB promote the proliferation of osteosarcoma. In addition, the Western blot results showed that the phosphorylation level of Akt was upregulated in 143-B cells overexpressing PKIB, indicating that PKIB promotes the proliferation of osteosarcoma probably through signaling pathway that Akt involved in. These results give us clues that PKIB was a potential target for osteosarcoma therapy. Furthermore, combined clinical profiles analysis showed that the expression of AIM2- and PKIB- related risk scores was significantly related to the overall survival of patients with osteosarcoma. Thus, we constructed a nomogram based on AIM2 and PKIB expression-related risk scores for osteosarcoma prognostic assessment to predict the 1-, 2-, 3-, and 5-year overall survival rate of patients with metastatic osteosarcoma, assisting clinicians in the diagnosis and treatment of metastatic osteosarcoma.

Chemoprotective effect of boeravinone B against 1,2-dimethyl hydrazine induced colorectal cancer in rats via suppression of oxidative stress and inflammatory reaction.

Background: Colorectal cancer (CRC) has few or no symptoms and is often diagnosed at its end stage. Boeravinone B (BB) is a natural rotenoid which induces an antioxidative effect and has been used in cancer prevention. In this study, we scrutinized the chemoprotective effect of BB against 1,2dimethyl hydrazine (DMH) induced CRC in rats. Methods: Subcutaneous administration of DMH (40 mg/kg) was used for the induction of CRC in rats, followed by oral administration of BB. The body weight, tumor volume, tumor incidence, and total number of tumors were estimated in all rat groups rats except the normal group. Antioxidant parameters, phase I and II enzymes, and inflammatory cytokines and parameters were estimated at the completion of the study. Results: DMH induced group rats exhibited a tumor incidence of 100% along with several tumors/polyps per tumor­bearing rat, while BB treatment remarkably suppressed the incidence of tumors and suppressed polyps per tumor bearing rat. BB treatment significantly (P<0.001) altered the level of antioxidant parameters, phase I and phase II enzymes, and cytokines such as TNF-α, IL-1ß, IL-4, IL-6, and IL-10, and treatment significantly (P<0.001) suppressed the level of inflammatory cytokines, including cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and inducible nitric oxide synthase (iNOS). Conclusions: BB treatment considerably suppresses colon cancer via its antioxidant and anti-inflammatory mechanism.

The Calcium Binding Protein S100A11 and Its Roles in Diseases.

The calcium binding protein S100 family in humans contains 21 known members, with each possessing a molecular weight between 10 and 14 kDa. These proteins are characterized by a unique helix-loop-helix EF hand motif, and often form dimers and multimers. The S100 family mainly exists in vertebrates and exerts its biological functions both inside cells as a calcium sensor/binding protein, as well as outside cells. S100A11, a member of the S100 family, may mediate signal transduction in response to internal or external stimuli and it plays various roles in different diseases such as cancers, metabolic disease, neurological diseases, and vascular calcification. In addition, it can function as chemotactic agent in inflammatory disease. In this review, we first detail the discovery of S100 proteins and their structural features, and then specifically focus on the tissue and organ expression of S100A11. We also summarize its biological activities and roles in different disease and signaling pathways, providing an overview of S100A11 research thus far.

S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is becoming a severe liver disorder worldwide. Autophagy plays a critical role in liver steatosis. However, the role of autophagy in NAFLD remains exclusive and under debate. In this study, we investigated the role of S100 calcium binding protein A11 (S100A11) in the pathogenesis of hepatic steatosis. METHODS: We performed liver proteomics in a well-established tree shrew model of NAFLD. The expression of S100A11 in different models of NAFLD was detected by Western blot and/or quantitative polymerase chain reaction. Liver S100A11 overexpression mice were generated by injecting a recombinant adenovirus gene transfer vector through the tail vein and then induced by a high-fat and high-cholesterol diet. Cell lines with S100a11 stable overexpression were established with a recombinant lentiviral vector. The lipid content was measured with either Bodipy staining, Oil Red O staining, gas chromatography, or a triglyceride kit. The autophagy and lipogenesis were detected in vitro and in vivo by Western blot and quantitative polymerase chain reaction. The functions of Sirtuin 1, histone deacetylase 6 (HDAC6), and FOXO1 were inhibited by specific inhibitors. The interactions between related proteins were analyzed by a co-immunoprecipitation assay and immunofluorescence analysis. RESULTS: The expression of S100A11 was up-regulated significantly in a time-dependent manner in the tree shrew model of NAFLD. S100A11 expression was induced consistently in oleic acid-treated liver cells as well as the livers of mice fed a high-fat diet and NAFLD patients. Both in vitro and in vivo overexpression of S100A11 could induce hepatic lipid accumulation. Mechanistically, overexpression of S100A11 activated an autophagy and lipogenesis process through up-regulation and acetylation of the transcriptional factor FOXO1, consequently promoting lipogenesis and lipid accumulation in vitro and in vivo. Inhibition of HDAC6, a deacetylase of FOXO1, showed similar phenotypes to S100A11 overexpression in Hepa 1-6 cells. S100A11 interacted with HDAC6 to inhibit its activity, leading to the release and activation of FOXO1. Under S100A11 overexpression, the inhibition of FOXO1 and autophagy could alleviate the activated autophagy as well as up-regulated lipogenic genes. Both FOXO1 and autophagy inhibition and Dgat2 deletion could reduce liver cell lipid accumulation significantly. CONCLUSIONS: A high-fat diet promotes liver S100A11 expression, which may interact with HDAC6 to block its binding to FOXO1, releasing or increasing the acetylation of FOXO1, thus activating autophagy and lipogenesis, and accelerating lipid accumulation and liver steatosis. These findings indicate a completely novel S100A11-HDAC6-FOXO1 axis in the regulation of autophagy and liver steatosis, providing potential possibilities for the treatment of NAFLD.

Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C.

BACKGROUNDMultisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Kawasaki disease (KD) shares several clinical features with MIS-C, which prompted the use of intravenous immunoglobulin (IVIG), a mainstay therapy for KD. Both diseases share a robust activation of the innate immune system, including the IL-1 signaling pathway, and IL-1 blockade has been used for the treatment of both MIS-C and KD. The mechanism of action of IVIG in these 2 diseases and the cellular source of IL-1ß have not been defined.METHODSThe effects of IVIG on peripheral blood leukocyte populations from patients with MIS-C and KD were examined using flow cytometry and mass cytometry (CyTOF) and live-cell imaging.RESULTSCirculating neutrophils were highly activated in patients with KD and MIS-C and were a major source of IL-1ß. Following IVIG treatment, activated IL-1ß+ neutrophils were reduced in the circulation. In vitro, IVIG was a potent activator of neutrophil cell death via PI3K and NADPH oxidase, but independently of caspase activation.CONCLUSIONSActivated neutrophils expressing IL-1ß can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDINGPatient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation.