Association of lipid accumulation product with all-cause and cardiovascular disease mortality: Result from NHANES database.

BACKGROUND AND AIM: At present, there are few studies on the relationship between lipid accumulation product (LAP) and mortality. This study aims to explore the relationship between adult LAP and all-cause and cardiovascular disease (CVD) mortality. METHODS AND RESULTS: The study people from the National Health and Nutrition Examination Survey (NHANES). Results of the mortality study were based on death data up to December 31, 2019. Cox proportional risk model was used to estimate the risk ratio (HR) and 95 % CI of all-cause and CVD mortality. A total of 50162 people were included in the study (the weighted average age and male proportion were 48.14 years and 48.64 % respectively). During the follow-up of 203460871 person-years, 6850 deaths were recorded, including 1757 CVD deaths. After multivariable adjustment, the increase of LAP was significantly correlated with all-cause and CVD mortality. Compared with the participants of Quartile 1 of LAP, the multivariable adjusted HRs and 95 % CI of the participants of Quartile 4 of LAP were 1.54 (1.32, 1.80) all-cause mortality (P for trend<0.001), and 1.55 (1.16, 2.09) CVD mortality (P for trend = 0.04). For every increase of natural log-transformed LAP, the all-cause mortality increased by 22 %, and the CVD mortality increased by 14 % (both P < 0.05). CONCLUSIONS: Our cohort study based on NHANES showed that higher LAP was significantly associated with higher all-cause and CVD mortality. Maintaining a low LAP status may reduce the risk of death.

METTL16 inhibits papillary thyroid cancer tumorigenicity through m6A/YTHDC2/SCD1-regulated lipid metabolism.

Papillary thyroid carcinoma (PTC) stands as the leading cancer type among endocrine malignancies, and there exists a strong correlation between thyroid cancer and obesity. However, the clinical significance and molecular mechanism of lipid metabolism in the development of PTC remain unclear. In this study, it was demonstrated that the downregulation of METTL16 enhanced lipid metabolism and promoted the malignant progression of PTC. METTL16 was expressed at lower levels in PTC tissues because of DNMT1-mediated hypermethylation of its promoter. Loss- and gain-of-function studies clarified the effects of METTL16 on PTC progression. METTL16 overexpression increased the abundance of m6A in SCD1 cells, increasing RNA decay via the m6A reader YTHDC2. The SCD1 inhibitor A939572 inhibited growth and slowed down lipid metabolism in PTC cells. These results confirm the crucial role of METTL16 in restraining PTC progression through SCD1-activated lipid metabolism in cooperation with YTHDC2. This suggests that the combination of METTL16 and anti-SCD1 blockade might constitute an effective therapy for PTC.

Targeting STAT6 to mitigate sepsis-induced muscle atrophy and weakness: Modulation of mitochondrial dysfunction, ferroptosis, and CHI3L1-Mediated satellite cell loss.

Sepsis-induced muscle weakness is a debilitating consequence of prolonged critical illness, often associated with a poor prognosis. While recent research has shown that STAT6 functions as an inhibitor of myogenesis, its role in sepsis-induced muscle weakness remains unclear. In this study, we hypothesized that inhibiting STAT6 could attenuate sepsis-induced muscle atrophy and weakness, and we explored the underlying mechanisms. Leveraging a microarray dataset from sepsis patients, we identified significant enrichment of genes related to muscle function, ferroptosis, and the p53 signalling pathway in muscle tissue from sepsis patients. Using a murine sepsis model induced by cecum ligation and puncture (CLP), we explore the multifaceted role of STAT6 inhibition. Our findings demonstrate that STAT6 inhibition effectively attenuates muscle atrophy, enhances grip strength, preserves mitochondrial integrity, and modulates ferroptosis in septic mice. Additionally, we identify elevated levels of CHI3L1 in septic muscle tissue, which are significantly reduced by STAT6 inhibition. In-depth analysis of primary muscle satellite cells reveals that CHI3L1 overexpression is associated with increased expression of key regulators of satellite cell myogenicity, while negatively impacting cell viability. Silencing CHI3L1 expression mitigates satellite cell injury and loss, highlighting its pivotal role in sepsis-induced muscle damage. In summary, this study unveils the potential of STAT6 as a therapeutic target for mitigating sepsis-induced muscle atrophy and weakness. Our findings underscore the regulation of mitochondrial dysfunction, ferroptosis, and CHI3L1-mediated satellite cell damage by STAT6, offering promising avenues for therapeutic intervention in the management of sepsis-induced muscle weakness.

Analysis of sleep for the American population: Result from NHANES database.

OBJECTIVES: To assess the contemporary prevalence and decade-long trends of sleep duration, sleep disorders and trouble sleeping among adults in the United States, as well as their risk factors, from 2005 to 2018. MATERIALS AND METHODS: We used National Health and Nutrition Examination Survey data to calculate the sleep duration and weighted prevalence of sleep disorders and trouble sleeping in adults aged 20 years or older. Sleep duration, sleep disorders and trouble sleeping were assessed by questionnaire. RESULTS: A total of 27,399 people were included in the survey on sleep duration, with a weighted percentage of normal sleep (7-8 h/night) of 56.33 % (95 % CI, 53.06-59.60 %) and a weighted percentage of short sleep (5-6 h/night) of 31.73 %. In stratified descriptions, participants aged 40-49 years were more likely to sleep less than five hours, while women aged 80 years and older were more likely to sleep longer and blacks were more likely to sleep shorter. A total of 27,406 participants were included in the survey for sleep disorders. The weighted proportion of the population with sleep disorders was 8.44 % (95 % CI, 7.79-9.8 %). Independent risk factors for sleep disorders were being 40-69 years old, being white, having a high education level, smoking, having hypertension, diabetes, heart disease, and BMI ≥ 25. From 2005 to 2014, the prevalence of sleep disorders increased year by year, from 7.44 % in 2005-2006 to 10.40 % in 2013-2014 (P for Trend<0.001). A total of 38,165 participants were included in the survey on trouble sleeping. The weighted proportion of the population with troubled sleeping was 27.30 % (25.70-28.90 %). Independent risk factors for troubled sleeping were being 30-79 years old, being white, having a high education level, smoking, drinking, having hypertension, diabetes, heart disease and BMI ≥ 25. From 2005 to 2018, the prevalence of trouble sleeping increased annually, from 24.44 % in 2005-2006 to 30.58 % in 2017-2018 (P for trend<0.001). CONCLUSION: Adults in the United States are likely to have abnormal sleep durations, and the prevalence of sleep disorders and troubled sleeping is on the rise.

A Mammalian Conserved Circular RNA CircLARP1B Regulates Hepatocellular Carcinoma Metastasis and Lipid Metabolism.

Circular RNAs (circRNAs) have emerged as crucial regulators in physiology and human diseases. However, evolutionarily conserved circRNAs with potent functions in cancers are rarely reported. In this study, a mammalian conserved circRNA circLARP1B is identified to play critical roles in hepatocellular carcinoma (HCC). Patients with high circLARP1B levels have advanced prognostic stage and poor overall survival. CircLARP1B facilitates cellular metastatic properties and lipid accumulation through promoting fatty acid synthesis in HCC. CircLARP1B deficient mice exhibit reduced metastasis and less lipid accumulation in an induced HCC model. Multiple lines of evidence demonstrate that circLARP1B binds to heterogeneous nuclear ribonucleoprotein D (HNRNPD) in the cytoplasm, and thus affects the binding of HNRNPD to sensitive transcripts including liver kinase B1 (LKB1) mRNA. This regulation causes decreased LKB1 mRNA stability and lower LKB1 protein levels. Antisense oligodeoxynucleotide complementary to theHNRNPD binding sites in circLARP1B increases the HNRNPD binding to LKB1 mRNA. Through the HNRNPD-LKB1-AMPK pathway, circLARP1B promotes HCC metastasis and lipid accumulation. Results from AAV8-mediated hepatocyte-directed knockdown of circLARP1B or Lkb1 in mouse models also demonstrate critical roles of hepatocytic circLARP1B regulatory pathway in HCC metastasis and lipid accumulation, and indicate that circLARP1B may be potential target of HCC treatment.

Regulation of the stem­like properties of estrogen receptor­positive breast cancer cells through NR2E3/NR2C2 signaling.

Cancer stem cells (CSCs) are major drivers of metastasis, drug resistance and recurrence in numerous cancers. However, critical factors that can modulate CSC stemness have not been clearly identified. Nuclear receptor subfamily 2 group E member 3 (nr2e3) expression has been previously reported to be positively associated with drug sensitivity and favorable clinical outcomes in patients with estrogen receptor (ER)+ breast cancer. This suggests that nr2e3 expression may be inversely associated with CSC stemness in this type of tumor cells. The present study aimed to investigate the regulatory roles of NR2E3 in the stem-like properties of ER+ breast cancer cells and to identify the underlying mechanisms. Bioinformatics analysis was performed using the data derived from the Cancer Genome Atlas database. Nr2e3-specific shRNA and nuclear receptor subfamily 2 group C member 2 (nr2c2) overexpressed plasmids were constructed to silence and enhance the expression of nr2e3 and nr2c2, respectively. Transwell and wound healing experiments were conducted to evaluate the migration and invasion ability of MCF7 cells, while colony formation tests were used to evaluate the clonality. Flow cytometry was used to detect the percentage of CD44+CD24-/low cells. Reverse transcription-quantitative PCR and western blotting were performed to detect expression at the mRNA and protein levels. The results showed that compared with normal breast tissues and MCF10A cells, the expression of nr2e3 was increased in ER+ breast tumor tissues and cell lines. Nr2e3 silencing promoted the migration, invasion and colony-forming ability of the ER+ MCF7 cells. It also increased the expression of epithelial-mesenchymal transition markers and stem cell-related transcription factors, in addition to the percentage of CD44+CD24-/low cells. The expression of nr2e3 and nr2c2 was found to be positively correlated. Nr2e3 knockdown decreased the mRNA and protein expression levels of nr2c2, whereas nr2c2 overexpression reversed the elevated CD44+CD24-/low cell ratio and the increased migratory activity caused by nr2e3 silencing. The results of the present study suggest that NR2E3 may serve an important role in modulating the stem-like properties of ER+ breast cancer cells, where NR2E3/NR2C2 signaling may be a therapeutic target in ER+ breast cancer.

Case report: COVID-19-associated refractory thrombotic thrombocytopenic purpura complicated with Guillain-Barré syndrome.

Thrombotic thrombocytopenic purpura (TTP), a rare and lethal thrombotic microangiopathy, is an autoimmune disease that can be triggered by viral infections such as COVID-19. This condition is characterized by hemolytic microangiopathy, thrombocytopenia, and neurologic alterations, possibly accompanied by fever and renal damage. Moreover, more than 220 patients with Guillain-Barré syndrome (GBS) have been reported in association with the COVID-19 infection. In this report, we present a case of a patient who developed refractory TTP complicated by GBS following a SARS-CoV-2 infection. We aimed to highlight the importance of accurately diagnosing neurological complications associated with a COVID-19 infection and to demonstrate our strategies for treating a patient with COVID-19 infection-related refractory TTP complicated by GBS.

The RING-domain E3 ubiquitin ligase RNF146 promotes cardiac hypertrophy by suppressing the LKB1/AMPK signaling pathway.

The RING-domain E3 ubiquitin ligase RNF146 is an enzyme that plays an important role in ubiquitin-proteasomal protein degradation and participates in various pathophysiological processes. However, its role in cardiac hypertrophy is unclear. In the present work, thoracic transverse aortic constriction (TAC) was performed in transgenic mice with RNF146 knockout mice (KO) and wild-type mice, and neonatal rat cardiomyocytes (NRCMs) were subjected to angiotensin II (Ang II) stimulation to induce cardiac hypertrophy in vitro and in vivo. RNF146 expression was significantly increased in hypertrophied murine hearts and Ang II-stimulated NRCMs. RNF146-KO mice and knockdown of RNF146 NRCMs attenuated TAC- or Ang II-stimulated cardiac hypertrophy. Conversely, enforced expression of RNF146 aggravated these changes. Mechanistically, we found that RNF146 KO or knockdown increased the activation of the AMP-activated protein kinase (AMPK) pathway. Furthermore, we found that RNF146 KO or knockdown decreased ubiquitination of Liver kinase B1 (LKB1), which promoted the activation of the AMPK pathway in a dependent manner. In conclusion, RNF146 targets LKB1 protein for ubiquitin-proteasome degradation in cardiomyocytes and subsequently promotes cardiac hypertrophy by suppressing the activation of the AMPK signaling pathway.

Identification of microRNA hsa-miR-30c-5p as an inhibitory factor in the progression of hepatocellular carcinoma and investigation of its regulatory network via comprehensive analysis.

Hepatocellular carcinoma (HCC) is a primary liver cancer with high morbidity and mortality. An increasing number of abnormal gene expressions were identified to be associated with the progression of HCC. Previous studies showed that the hsa-miR-30 c-5p (miR-30 c), one of the miR-30 family members, might play a role in suppressing tumor progression in a variety of tumors. The present study aims to examine miR-30 c effects in the development of HCC. The role of miR-30 c in HCC was comprehensively investigated by using bioinformatics and experiments in vitro. The multiple databases were combined to predict and screen the target genes and upstream lncRNAs of miR-30 c, and then constructed a competitive endogenous RNA (ceRNA) regulatory network with miR-30 c as the central miRNA. The miR-30 c-related ceRNA regulatory network was also initially validated in vitro. The results showed that miR-30 c over-expression could inhibit proliferation, migration, invasion, induce apoptosis, and increase G0/G1 phase ratio of HCC cells. Three miR-30 c upstream lncRNAs and 12 miR-30 c target genes were expressed in HCC cells with increased expression and poor prognosis, and a miR-30 C-related ceRNA regulatory network was constructed. This study verified miR-30 c as an inhibitory factor in the progression of HCC and performed analyses on the miR-30 c regulatory network, which might provide potential target information for HCC prognoses and therapies. However, further experiments in vivo and studies including clinical trials will be conducted to validate our results.

De-ubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced cardiac hypertrophy.

Stresses, such as neurohumoral activation, induced pathological cardiac hypertrophy is the main risk factor for heart failure. The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role and mechanism of deubiquitinating enzymes (DUBs) in cardiac hypertrophy is limited. Here, we observe that the deubiquitinating enzyme ubiquitin-specific protease 12(USP12) is upregulated in Ang II-induced hypertrophic hearts and primary neonatal rat cardiomyocytes (NRCMs). Inhibition of USP12 ameliorate Ang II-induced myocardial hypertrophy, while overexpression of USP12 have the opposite effect. USP12 deficiency also significantly attenuate the phenotype of Ang II-induced cardiac hypertrophy in vivo. Moreover, we demonstrate that USP12 aggravate Ang II-induced cardiac hypertrophy by enhancing METTL3, a methyltransferase which catalyze N6-methyladenosine (m6A) modification on messenger RNA and acts as a harmful factor in pathological cardiac hypertrophy. Upregulation of METTL3 reverse the reduction of myocardial hypertrophy induced by USP12 silencing in NRCMs. In contrast, knockdown of METTL3 attenuate the aggravation of myocardial hypertrophy in USP12-overexpressing NRCMs. Furthermore, we discover that USP12 promote the expression of METTL3 via upregulating p300. Mechanistically, USP12 binds and stabilizes p300, thereby activating the transcription of its downstream gene METTL3. Finally, our data show that USP12 is partially dependent on the stabilization of p300 to activate METTL3 expression and promote myocardial hypertrophy. Taken together, our results demonstrate that USP12 acts as a pro-hypertrophic deubiquitinating enzyme via enhancing p300/METTL3 axis, indicating that targeting USP12 could be a potential treatment strategy for pathological cardiac hypertrophy.

Immunomodulatory property and its regulatory mechanism of double network hydrogel on dendritic cells.

Modulation of the key immune cell subsets by biomaterial has emerged as a potential target to promote tissue repair and regeneration. Based on calcium alginate (Alg) and glycol chitosan (GC), an injectable double-network (DN) hydrogel has been developed as a scaffold for cell delivery and cell cocultured system. Previous studies have documented the interaction between dendritic cells (DCs) and GC or Alg hydrogel, but the potential effect of DN hydrogel on activation of DCs still remains unclear. This research was conducted to explore the immunomodulatory influence and underlying mechanisms of GC/Alg DN hydrogel on DCs in vitro and in vivo. Stimulation of DCs with DN hydrogel obviously induced the maturation of DCs in vitro. In vivo, DN hydrogel did not have obvious influence on the maturation of splenic DCs on postimplantation days 3, 10, and 30. Mechanistically, we found that DN hydrogel induced the maturation of DCs via phosphorylation of phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin in vitro. It provides a novel understanding of the immunomodulatory property of DN hydrogel on DCs, which may serve as potential target for designing immune-mediated regenerative strategies.

[Effects of chitinase-3-like protein 1 on the expression of inflammatory damage-related molecules in mouse skeletal muscle satellite cells induced by lipopolysaccharide].

OBJECTIVE: To explore the potential mechanism of chitinase-3-like protein 1 (CHI3L1) involved in skeletal muscle stem cell injury induced by sepsis. METHODS: Six different concentrations of lipopolysaccharide (LPS) were used to stimulate mouse skeletal muscle satellite cells cultured in vitro. Enzyme linked immunosorbent assay (ELISA) and cell counting kit-8 (CCK-8) were used to determine the optimal concentration. The overexpression and interference vectors of CHI3L1 were constructed to transfect skeletal muscle satellite cells, and the transfection efficiency was verified by polymerase chain reaction (PCR) and Western blotting. The cells were randomly divided into blank control group (cells without any intervention), model group (LPS-stimulated untransfected cells), overexpressing CHI3L1 group (LPS-stimulated cells transfected with CHI3L1 plasmid), overexpressing CHI3L1 control group [LPS-stimulated cells transfected with negative control (NC) plasmid], CHI3L1 interference group [LPS-stimulated cells transfected with CHI3L1 small interfering RNA (siRNA)], CHI3L1 interference control group (LPS-stimulated cells transfected with CHI3L1-siRNA NC). The levels of extracellular caspase-1 and interleukin-1ß (IL-1ß) were detected by ELISA. The protein expressions of intracellular IL-1ß, signal transducters and activator of transcription 3 (STAT3), protein kinase B (Akt) and phosphorylated Akt (p-Akt) were detected by Western blotting. RESULTS: According to the results of CCK-8 and ELISA, the best concentration of 5 mg/L LPS was selected for the subsequent experiment. The transfection was validated by PCR and Western blotting. Compared with the blank control group, the levels of extracellular IL-1ß, caspase-1 and the protein expressions of intracellular Akt, p-Akt, and IL-1ß were significantly increased in the model group [IL-1ß (ng/L): 11.22±0.55 vs. 8.63±0.63, caspase-1 (pmol/L): 9.47±0.22 vs. 8.65±0.15, Akt/GAPDH: 1.36±0.12 vs. 1.06±0.15, p-Akt/GAPDH: 0.78±0.07 vs. 0.09±0.01, IL-1ß/GAPDH: 1.38±0.12 vs. 0.18±0.03, all P < 0.05]. Compared with the model group and the overexpressing CHI3L1 control group, the levels of extracellular IL-1ß, caspase-1 and the protein expressions of intracellular p-Akt and IL-1ß were significantly increased in the overexpressing CHI3L1 group [IL-1ß (ng/L): 14.93±0.97 vs. 11.22±0.55, 9.38±0.40, caspase-1 (pmol/L): 10.35±0.03 vs. 9.47±0.22, 8.46±0.24, p-Akt/GAPDH: 1.21±0.04 vs. 0.78±0.07, 0.63±0.04, IL-1ß/GAPDH: 1.87±0.08 vs. 1.38±0.12, 1.51±0.17, all P < 0.05]. Compared with the model group and the CHI3L1 interference control group, the levels of extracellular IL-1ß, caspase-1 and the protein expressions of intracellular p-Akt and IL-1ß were significantly decreased in the CHI3L1 interference group [IL-1ß (ng/L): 8.98±0.73 vs. 11.22±0.55, 10.44±0.65, caspase-1 (pmol/L): 7.61±0.63 vs. 9.47±0.22, 8.37±0.38, p-Akt/GAPDH: 0.50±0.04 vs. 0.78±0.07, 0.94±0.06, IL-1ß/GAPDH: 0.77±0.02 vs. 1.38±0.12, 1.13±0.07, all P < 0.05]. CONCLUSIONS: CHI3L1 may mediate the damage of skeletal muscle stem cells in sepsis by increasing the expression of caspase-1 and IL-1ß. CHI3L1 may be involved in the regulation of Akt signaling pathway in skeletal muscle stem cells, but has no significant effect on STAT3 signaling pathway.

Sevoflurane-induced cognitive decline in aged mice: Involvement of toll-like receptors 4.

Toll-like receptors 4 (TLR4) contributes to the pathogenesis of some neurodegenerative diseases. However, little is known about whether TLR4 is associated with sevoflurane-induced cognitive decline. This investigation aims to address the effect of global TLR4 gene knockout on cognitive decline following sevoflurane exposure to mice. Wild-type and TLR4-/- mice were exposed to 3% sevoflurane. Novel object recognition test and Y-maze test were used to analyze cognitive function. Tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in plasma and hippocampus were measured by ELISA. Peripheral administration of recombinant TNF-α to TLR4-/- mice was used to observed the role of TNF-α in cognitive function following sevoflurane. Our results showed that, in contrast to wild-type mice, TLR4 deficiency protected against the cognitive function impairment following sevoflurane exposure, and abrogated IL-1ß, IL-6 and TNF-α response to sevoflurane in the system and the hippocampus. Subcutaneous administration of recombinant TNF-α elevated these cytokine levels in the hippocampus, and resulted in cognitive decline in TLR4-/- mice exposed to sevoflurane. Taken together, our results identify the crucial role of TLR4 in sevoflurane-induced cognitive decline, and showed that TLR4 mediated pro-inflammatory cytokine response to sevoflurane, and consequent cognitive decline in aged mice exposed to sevoflurane, and imply a novel target for improvement and therapy of sevoflurane-associated cognitive decline.

Downregulated CHI3L1 alleviates skeletal muscle stem cell injury in a mouse model of sepsis.

Sepsis is an acute systemic inflammatory response of the body to microbial infection and a life-threatening condition associated with multiple organ failure. Recent data suggest that sepsis survivors present with long-term myopathy due to the dysfunction of skeletal muscle stem cells and satellite cells. Accumulating studies have implicated chitinase-3-like-1 protein (CHI3L1) in a variety of infectious diseases, specifically sepsis. Therefore, the aim of the present study is to elucidate the potential mechanism by which CHI3L1 is involved in the injury of skeletal muscle stem cells in mouse models of sepsis. An in vitro cell model was developed by lipopolysaccharide (LPS) and in vivo mouse model of sepsis was induced by CRP-like protein (CLP). To elucidate the biological significance behind the silencing of CHI3L1, modeled skeletal muscle stem cells and mice were treated with siRNA against CHI3L1 or overexpressed CHI3L1. Highly expressed CHI3L1 was found in skeletal muscle tissues of mice with sepsis. Besides, siRNA-mediated silencing of CHI3L1 was revealed to increase Bcl-2 expression along with cell proliferation, while diminishing Bax expression, cell apopstosis as well as serum levels of TNF-α, IL-1ß, INF-γ, IL-10, and IL-6. Taken conjointly, this present study provided evidence suggesting that downregulation of CHI3L1 has the potential to prevent the injury of skeletal muscle stem cells in mice with sepsis. Collectively, CHI3L1 may serve as a valuable therapeutic strategy in alleviating sepsis.

Crebanine N-oxide, a natural aporphine alkaloid isolated from Stephania hainanensis, induces apoptosis and autophagy in human gastric cancer SGC-7901 cells

Objective: To investigate the cytotoxic effects and the potential mechanisms of crebanine N-oxide in SGC-7901 gastric adenocarcinoma cells. Methods: The cytotoxicity of crebanine N-oxide was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay and cellular morphology was observed under a microscope. Cell apoptosis was determined by flow cytometry using propidium iodide staining. The expression levels of apoptotic-related proteins, cleaved caspase-3, cytochrome C, p53 and Bax, and autophagyrelated proteins p62, beclin1 and LC3 were detected by Western blotting assays. Results: Crebanine N-oxide treatment significantly inhibited the proliferation of SGC-7901 cells in a dose-dependent and timedependent manner via induction of G2-phase cell cycle arrest, apoptosis, and autophagy in SGC-7901 cells. Conclusions: Crebanine N-oxide could inhibit the growth of gastric cancer cells by promoting apoptosis and autophagy and could be used as a potential agent for treating gastric cancer.

NEDD4 protects vascular endothelial cells against Angiotensin II-induced cell death via enhancement of XPO1-mediated nuclear export.

NEDD4 is an E3 ubiquitin ligase containing the HECT domain, which regulates various cellular processes, but its role in vascular endothelial cells is unknown. In the present study, we found that NEDD4 bound directly to XPO1 by co-immunoprecipitation screening. In HUVECs (human umbilical vein endothelial cells), overexpression of NEDD4 reduced Ang II-induced ROS level and cell apoptosis. Ang II stimulation led to nuclear accumulation of cargoes, while overexpression of NEDD4 enhanced the XPO1-dependent nuclear export of its cargoes. KPT185, an inhibitor of XPO1, can abolished the protective effect of NEDD4 under Ang II treatment. In addition, NEDD4 could promote the interaction between XPO1 and RanBP3 via K63-linked ubiquitination of XPO1. These results suggested that NEDD4 played a protective role in vascular endothelial cell injury through regulating XPO1-mediated nuclear export.

[Update in immune regulatory pathway of tumor necrosis factor-α-induced protein 8-like 2].

OBJECTIVE: The tumor necrosis factor-α-induced protein 8-like (TNFAIP8, TIPE) family is recently identified proteins consisting of four highly homologous mammalian proteins: TIPE, TIPE1, TIPE2, and TIPE3. Although the four members share similar molecular structure and function, involving effects in pathophysiological processes of inflammation, immunity, tumors, stroke, angiogenesis, and other diseases, they have individual characteristics. Many studies have shown that TIPE2 is an essential negative regulator of both innate and adaptive immunity. Up-regulation of TIPE2 expression can alleviate excessive inflammation during septic shock and maintain hemostasis of macrophages, neutrophils, dendritic cells, T cells, and B cells. In this review, we summarize the current literature for structure feature, immune function, and regulatory mechanism of TIPE2, together with its clinical significance in the pathogenesis of immune disorders of a wide array of human diseases. Understanding the basic biology of this new molecule might help us to seek novel strategies for the immunomodulation of human diseases.

Analyses of a Panel of Transcripts Identified From a Small Sample Size and Construction of RNA Networks in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Dysregulation of mRNAs and non-coding RNAs (ncRNAs) plays critical roles in the progression of HCC. Here, we investigated HCC samples by RNA-seq and identified a series of dysregulated RNAs in HCC. Various bioinformatics analyses established long non-coding RNA (lncRNA)-mRNA co-expression and competing endogenous RNA (ceRNA) networks in circRNA-miRNA-mRNA axis, indicating the potential cis and/or trans regulatory roles of lncRNAs and circRNAs. Moreover, GO pathway analysis showed that these identified RNAs were associated with many biological processes that were related to tumorigenesis and tumor progression. In conclusion, we systematically established functional networks of lncRNA-mRNA, circRNA-miRNA-mRNA to further unveil the potential interactions and biological processes in HCC. These results provide further insights into gene expression network of HCC and may assist future diagnosis of HCC.

Role of dendritic cells in the host response to biomaterials and their signaling pathways.

Strategies to enhance, inhibit, or qualitatively modulate immune responses are important for diverse biomedical applications such as vaccine adjuvant, drug delivery, immunotherapy, cell transplant, tissue engineering, and regenerative medicine. However, the clinical efficiency of these biomaterial systems is affected by the limited understanding of their interaction with complex host microenvironments, for example, excessive foreign body reaction and immunotoxicity. Biomaterials and biomedical devices implanted in the body may induce a highly complicated and orchestrated series of host responses. As macrophages are among the first cells to infiltrate and respond to implanted biomaterials, the macrophage-mediated host response to biomaterials has been well studied. Dendritic cells (DCs) are the most potent antigen-presenting cells that activate naive T cells and bridge innate and adaptive immunity. The potential interaction of DCs with biomaterials appears to be critical for exerting the function of biomaterials and has become an important, developing area of investigation. Herein, we summarize the effects of the physicochemical properties of biomaterials on the immune function of DCs together with their receptors and signaling pathways. This review might provide a complete understanding of the interaction of DCs with biomaterials and serve as a reference for the design and selection of biomaterials with particular effects on targeted cells. STATEMENT OF SIGNIFICANCE: Biomaterials implanted in the body are increasingly applied in clinical practice. The performance of these implanted biomaterials is largely dependent on their interaction with the host immune system. As antigen-presenting cells, dendritic cells (DCs) directly interact with biomaterials through pattern recognition receptors (PRRs) recognizing "biomaterial-associated molecular patterns" and generate a battery of immune responses. In this review, the physicochemical properties of biomaterials that regulate the immune function of DCs together with their receptors and signaling pathways of biomaterial-DC interactions are summarized and discussed. We believe that knowledge of the interplay of DC and biomaterials may spur clinical translation by guiding the design and selection of biomaterials with particular effects on targeted cell for tissue engineering, vaccine delivery, and cancer therapy.

CSN5 attenuates Ang II-induced cardiac hypertrophy through stabilizing LKB1.

CSN5 is a critical subunit of the COP9 signalosome (CSN) and has been involved in various cellular processes, but little is known about the role of CSN5 in cardiac disease. In the present study, we found that the expression of CSN5 was increased in Angiotensin II (Ang II)-induced cardiac hypertrophic mice hearts and Ang II-treated cardiomyocytes. We also observed that overexpression of CSN5 significantly inhibited Ang II-induced cardiac hypertrophy, whereas CSN5 silence exhibited the opposite phenotypes. Further investigation demonstrated that CSN5 maintained the activity of AMP-activated protein kinase (AMPK) in cardiomyocyte by enhancement of LKB1. Mechanistically, we found that CSN5 directly interacted and deubiquitinated LKB1 for its stabilization in cardiomyocytes. Finally, our results demonstrated that the anti-hypertrophic effect of CSN5 was partially dependent on stabilization of LKB1. Collectively, these findings suggested that strategies based on activation of CSN5/LKB1 axis might be promising in the treatment of hypertrophic cardiomyopathy.