High mobility group AT-hook 2 promotes tumorigenicity of pancreatic cancer cells via upregulating ANLN.

HMGA2 is associated with the regulation of cellular biological processes in various human disorders and cancer progression, yet little is known about how HMGA2 controls tumorigenesis. This study uncovered the mechanism of HMGA2-mediated regulation of tumorigenicity in pancreatic cancer. We showed that HMGA2 was highly expressed in pancreatic cancer cells and correlated with poor prognosis. HMGA2 expression knockdown inhibited the tumorigenicity of pancreatic cancer cells. Conversely, overexpression of HMGA2 promoted tumorigenicity. Combination of ChIP-Seq, RNA-Seq and dual-luciferase reporter assays revealed HMGA2 could directly regulate ANLN expression. Furthermore, we found ANLN could mediate the HMGA2-induced effects on pancreatic cancer cells. The identification of the regulatory mechanism of HMGA2 and ANLN will provide insights into the progression for human pancreatic cancer.

Navigation-Guided Nasal Endoscopy to Remove the Cavernous Venous Malformation of the Orbital Apex Through the Sphenoid Approach.

OBJECTIVE: To explore the feasibility of navigation-guided sinus endoscopy to remove the cavernous vascular malformation of the orbital apex through the sphenoid approach. METHODS: A retrospective series of non-control cases were collected. From May 2012 to December 2019, patients with imaging findings of cavernous venous malformation in the orbital apex were collected at the Eye Hospital Affiliated to Nanchang University. All patients underwent navigation guided sinusoscopy through the sphenoid approach to remove the cavernous venous malformation of the orbital apex. Analyze the changes of visual function and postoperative complications before and after operation. RESULTS: Twelve patients were collected, including 3 males and 9 females aged between 32 and 59. In 3 patients without visual impairment, the postoperative visual function was still normal. The remaining 9 patients all had visual impairment. Among them, 3 patients had fully recovered normal visual function after operation, 2 patients had improved visual function compared with preoperative, and 4 patients had no change in postoperative visual acuity. There were no complications in 3 of the 12 patients, and 9 patients had transient limited intraocular rotation with mild limitation of diplopia after operation, and all returned to normal within 1 month after surgery. CONCLUSION: Navigation-guided sinus endoscopy through the sphenoid approach to remove the cavernous venous malformation of the orbital apex is an effective and feasible surgical method.

Artemisinin and dihydroartemisinin promote ß-cell apoptosis induced by palmitate via enhancing ER stress.

Artemisinin (ART) and dihydroartemisinin (DHA) are first-line antimalarial drugs and have been reported to have anti-obesity effects. Hyperlipidemia is associated with ß-cell damage in obese subjects, which could contribute to the pathogenesis of type 2 diabetes. In addition to their anti-obesity effects, ART and DHA also have protective roles in some diseases. Thus, we investigated the effects of ART and DHA in palmitate-induced ß-cell apoptosis and the underlying mechanism. In this study, the rat pancreatic ß-cell line INS-1 and mouse pancreatic ß-cell line MIN6 were cultured with palmitate (PA) (0.1 mM) to induce cell apoptosis in the presence or absence of ART or DHA. Cell apoptosis was investigated by using flow cytometry, and the expression of ER stress markers, including CHOP, GRP78 and PDI, was detected by Western blotting and/or qRT-PCR. The results showed that ART and DHA significantly increased the apoptosis of ß-cells induced by PA and exacerbated the ER stress caused by PA. An inhibitor of ER stress, 4-phenylbutyric acid (4-PBA), significantly ameliorated cell apoptosis caused by ART and DHA in PA-treated ß-cells, consistent with the inhibition of ER stress. Together, the findings from the current study suggested that ART and DHA may promote lipid disorder-associated ß-cell injury via enhancing ER stress when they were used to treat obesity.

Signature MicroRNA expression profile is associated with lipid metabolism in African green monkey.

BACKGROUND: Non-human primates (NHPs) are important models of medical research on obesity and cardiovascular diseases. As two of the most commonly used NHPs, cynomolgus macaque (CM) and African green monkey (AGM) own different capacities in lipid metabolism of which the mechanism is unknown. This study investigated the expression profiles of lipid metabolism-related microRNAs (miRNAs) in CM and AGM and their possible roles in controlling lipid metabolism-related gene expression. METHODS: By small RNA deep sequencing, the plasma miRNA expression patterns of CM and AGM were compared. The lipid metabolism-related miRNAs were validated through quantitative reverse-transcription (RT) polymerase chain reaction (PCR). Related-target genes were predicted by TargetScan and validated in Vero cells. RESULTS: Compared to CM, 85 miRNAs were upregulated with over 1.5-fold change in AGM of which 12 miRNAs were related to lipid metabolism. miR-122, miR-9, miR-185, miR-182 exhibited the greatest fold changes(fold changes are 51.2, 3.8, 3.7, 3.3 respectively; all P < 0.01). And 77 miRNAs were downregulated with over 1.5-fold change in AGM of which 3, miR-370, miR-26, miR-128 (fold changes are 9.3, 1.8, 1.7 respectively; all P < 0.05) were related to lipid metabolism. The lipid metabolism-related gene targets were predicted by TargetScan and confirmed in the Vero cells. CONCLUSION: We report for the first time a circulating lipid metabolism-related miRNA profile for CM and AGM, which may add to knowledge of differences between these two non-human primate species and miRNAs' roles in lipid metabolism.

Black rockfish C-type lectin, SsCTL4: A pattern recognition receptor that promotes bactericidal activity and virus escape from host immune defense.

C-type lectin (CTL) is an immune receptor and is received extensive attention of its important roles in immune response and immune escape. Some CTL, such as CTL4, has been well characterized in human and several other mammals, but much less documentation exists about the immunological function of CTL4 in lower vertebrates. In the present study, a C-type lectin domain family 4 member, SsCTL4, which is also high homology with CD209 antigen-like protein, from the teleost fish black rockfish (Sebastes schlegelii) was identified and examined at expression and functional levels. The open reading frame of SsCTL4 is 765 bp, and the deduced amino acid sequence of SsCTL4 shares 78%-84% overall identities with the C-type lectin of several fish species. In silico analysis identified several conserved C-type lectin features, including a carbohydrate-recognition domain and four disulfide bond-forming cysteine residues. Expression of SsCTL4 occurred in multiple tissues and was upregulated during bacterial and viral infection. Recombinant SsCTL4 (rSsCTL4) exhibited apparent binding activities against bacteria (Edwardsiella tarda and Vibrio anguillarum) and virus (infectious spleen and kidney necrosis virus, ISKNV). rSsCTL4 was able to agglutinate the Gram-negative and Gram-positive bacteria in a Ca2+-dependent manner. The agglutinating ability of rSsCTL4 was abolished in the absence of calcium or presence of mannose. rSsCTL4 also increased macrophage bactericidal activity. In the presence of rSsCTL4, fish exhibited enhanced resistance against bacterial infection but increased susceptibility to viral infections. Collectively, these results indicate that SsCTL4 serves as a pattern recognition receptor that not only promotes bactericidal activity, but may also serve as targets for virus manipulation of host defense system.

Rotenone Protects Against Acetaminophen-Induced Kidney Injury by Attenuating Oxidative Stress and Inflammation.

BACKGROUND/AIMS: In clinic, excessive acetaminophen (APAP) can cause kidney damage with uncertain mechanisms. Recently, accumulating evidence demonstrated a pathogenic role of mitochondrial dysfunction in the kidney injury. Thus, in this study, rotenone, a mitochondrial complex I inhibitor, was applied to the mice with APAP-induced acute kidney injury to evaluate the effect of mitochondrial complex I inhibition on APAP nephrotoxicity. METHODS: After 3 days of rotenone pretreatment, mice were administered with APAP (300mg/kg) by intraperitoneal injection for 24 h. Then the kidney injury, inflammation, and oxidative stress were evaluated. RESULTS: APAP significantly enhanced the BUN, serum creatine, and cystatin C levels in line with a moderate alteration of renal morphology. Strikingly, rotenone treatment normalized BUN, serum creatinine, and cystatin C levels, as well as the kidney morphology. Meanwhile, APAP enhanced tubular injury markers of NGAL and KIM-1 by 347- and 5-fold at mRNA levels, respectively. By Western blotting, we confirmed a 15-fold increment of NGAL in APAP-exposed kidneys. Importantly, rotenone treatment largely normalized NGAL and KIM-1 levels and attenuated inflammatory response in APAP-treated mice. Similarly, rotenone treatment enhanced the expressions of SOD1-3 compared with APAP group in line with a significant suppression of kidney MDA content. Finally, we observed that inhibition of mitochondrial complex III failed to protect against APAP-induced nephrotoxicity. CONCLUSION: Mitochondrial complex I inhibitor rotenone protected kidneys against APAP-induced injury possibly via the inhibition of mitochondrial oxidative stress and inflammation.

A high-mobility group box 1 that binds to DNA, enhances pro-inflammatory activity, and acts as an anti-infection molecule in black rockfish, Sebastes schlegelii.

High-mobility group box (HMGB) 1 is a chromosomal protein that plays critical roles in DNA transcription, replication and repair. In addition, HMGB1 functions as a pro-inflammatory molecule in many vertebrates and invertebrates. In teleosts, very limited studies of HMGB1 have been reported. In this study, we identified a HMGB1 homologue (SsHMGB1) from black rockfish (Sebastes schlegelii) and analyzed its structure, expression and biological function. The open reading frame of SsHMGB1 is 621 bp, with a 5'-untranslated region (UTR) of 62 bp and a 3'-UTR of 645 bp. SsHMGB1 contains two typical HMG boxes and an acidic C-terminal tail. The deduced amino acid sequence of SsHMGB1 shares the highest overall identity (89.4%) with the HMGB1 of Anoplopoma fimbria. The expression of SsHMGB1 occurred in multiple tissues and was highest in the brain. Moreover, the mRNA level of SsHMGB1 in head kidney (HK) macrophages could be induced by Listonella anguillarum in a time-dependent manner. Recombinant SsHMGB1 purified from Escherichia coli (i) bound DNA fragments in a dose-dependent manner; and (ii) induced the expression of cytokines in HK macrophages, including a significant increase in TNF-α activity and enhanced mRNA level of TNF13B and IL-1 ß, which are known to be involved in antibacterial defense; moreover, (iii) significantly improved the macrophage bactericidal activity together with reduced pathogen dissemination and replication of bacteria in fish kidney. These results indicated that SsHMGB1 is a novel HMGB1 that possesses apparent immunoregulatory properties and is likely to be involved in fighting bacterial infection.

The effects of combined hyperbaric oxygen therapy on patients with post-stroke depression.

[Purpose] To observe the effect of combined hyperbaric oxygen therapy on patients with post-stroke depression. [Subjects] Ninety patients with post-stroke depression were randomly divided into 3 groups: fluoxetine treatment group (n = 30), hyperbaric oxygen therapy group (n = 30), and hyperbaric oxygen combined treatment group (n = 30). [Methods] Fluoxetine treatment group received anti-depression drugs (fluoxetine, 20 mg/day), hyperbaric oxygen therapy group received hyperbaric oxygen (once a day, 5 days/week), hyperbaric oxygen combined treatment group received fluoxetine and hyperbaric oxygen treatments as described above. All patients received routine rehabilitation therapy. Hamilton Depression Scale (HAMD), and Scandinavian Stroke Scale (SSS) scores were evaluated before and at the end of 4th week. The total effective rate of depression release between the 3 groups was also compared at the end of study. [Results] The end scores of HAMD and SSS in the 3 groups were significantly lower than those before treatment. The total effective rate of combined hyperbaric oxygen therapy group after treatment was higher than the other two groups. [Conclusions] Combined hyperbaric oxygen therapy plays an important role in the treatment of patients with post-stroke depression. The total effective rate of combined hyperbaric oxygen therapy was higher than other routine anti post-stroke depression treatments.

Roxadustat ameliorates experimental colitis in mice by regulating macrophage polarization through increasing HIF level.

BACKGROUND: Gastro-intestinal (GI) tract inflammation is as a result of inflammatory hypoxia which is also induced by long-standing group of disorders like inflammatory-bowel disease (IBD). Regulation of GI immune homeostasis by macrophage involves hypoxia-inducible factor (HIF). As inhibitor of HIF prolyl hydroxylase, roxadustat (ROX) increases the levels of HIF. METHODS: We induced experimental colitis (EC) model in mice via dextran-sulfate sodium (DSS) to evaluate ROX role in above-mentioned disease. RESULTS: ROX ameliorated EC in mice by blocking colonic length shorten and loss of body weight, thereby reducing scores of disease-activity index (DAI) and histopathology. ROX significantly reduced inflammatory cytokines levels, suppressed M1 and increased M2 macrophage polarization in colonic tissues. Besides, ROX blocked declining hematocrit (HCT) level in blood and increased HIF-1-α and HIF-2-α level in colonic tissues. The inhibitor of HIF-1- α, KC7F2 decreased body weight and colonic length in ROX-treated DSS mice. Meanwhile, DAI scores and histopathology in KC7F2 treated DSS mice were markedly higher than that of treatment with ROX alone. KC7F2 treatments also significantly increased inflammatory cytokines levels, respectively promoted and reduced polarization of M1 and M2 macrophages in colonic tissue from ROX treated mice. Further, KC7F2 treatments inhibited ROX induced HCT level increasing in blood and decreased HIF-1-α and HIF-2-α level in colonic tissue. CONCLUSION: Collectively, we discovered that ROX ameliorated EC in mice by regulating macrophage polarization through promotion of HIF expression. GENERAL SIGNIFICANCE: Taken together, we developed a new application of ROX, which provides new ideas and a scientific basis for IBD treatment.

Genetic diversity of Bartonella quintana in macaques suggests zoonotic origin of trench fever.

Bartonella quintana is a bacterium that causes a broad spectrum of diseases in humans including trench fever. Humans were previously considered to be the primary, if not the only, reservoir hosts for B. quintana. To identify the animal reservoir and extend our understanding of the ecological and evolutionary history of B. quintana, we examined blood samples from macaques and performed multilocus sequence typing (MLST) analysis. We demonstrated the prevalence of B. quintana infection was common in macaques from main primate centres in mainland China. Overall, 18.0% (59/328) of rhesus macaques and 12.7% (39/308) of cynomolgus macaques were found to be infected with B. quintana by blood culture and/or polymerase chain reaction. The infection was more frequently identified in juvenile and young monkeys compared with adult animals. In contrast with the relatively low level of sequence divergence of B. quintana reported in humans, our investigation revealed much higher genetic diversity in nonhuman primates. We identified 44 new nucleotide variable sites and 14 novel sequence types (STs) among the B. quintana isolates by MLST analysis. Some STs were found only in cynomolgus macaques, while some others were detected only in rhesus macaques, suggesting evidence of host-cospeciation, which were further confirmed by phylogenetic analysis and Splits decomposition analysis. Our findings suggest that trench fever may primarily be a zoonotic disease with macaques as the natural hosts.

Anti-inflammatory role of fenofibrate in treating diseases.

Inflammation contributes to the pathogenesis of several diseases. Fenofibrate, known as a peroxisome proliferator-activated receptor - α (PPAR-α) agonist, is a classic drug for treating hyperlipidemia. In addition to its lipid-lowering effect, fenofibrate has also been reported to exert anti-inflammatory effects with complicated underlying mechanisms of action. In general, the anti-inflammatory effect of fenofibrate is secondary to its lipid-lowering effect, especially for the inflammation caused by hyperlipidemia in the circulatory system. Some anti-inflammatory actions may also come from its regulatory effects on intracellular lipid metabolism by activating PPAR-α. In addition, some roles in anti-inflammation might be mediated by its direct regulation of inflammatory signaling pathways. In order to understand anti-inflammatory activities and the underlying mechanisms of fenofibrate action in disease better, we herein reviewed and discussed the anti-inflammatory roles and its subserving mechanisms in various diseases of different organ systems. Thus, this review offers insights into the optimal use of fenofibrate in the clinical setting.

Reduction of NADPH oxidase 4 in adipocytes contributes to the anti-obesity effect of dihydroartemisinin.

Artemisinin derivatives have been found to have anti-obesity effects recently, but the mechanism is still controversial. Herein, long-term DHA treatment in obese mice significantly reduced the body weight and improved glucose metabolism. However, short-term DHA treatment did not affect glucose metabolism in obese mice, suggesting that the improved glucose metabolism in mice with DHA treatment could be secondary to body weight reduction. Consistent with previous reports, we observed that DHA inhibited the differentiation of adipocytes. Mechanistically, DHA significantly reduced the expression of NADPH oxidase 4 (NOX4) in white adipose tissue (WAT) of mice and differentiated adipocytes, and using NOX4 siRNA or the NOX4 inhibitor GKT137831 significantly attenuated adipocyte differentiation. Over-expression of NOX4 partially reversed the inhibition effect of DHA on adipogenic differentiation of preadipocytes. In addition, targeted proteomics analysis showed that DHA improved the abnormality of metabolic pathways. In conclusion, DHA significantly reduced fat mass and improved glucose metabolism in obese mice, possibly by inhibiting NOX4 expression to suppress adipocyte differentiation and lipid accumulation in adipocytes.

Endoscopic nasobiliary drainage and percutaneous transhepatic biliary drainage for the treatment of acute obstructive suppurative cholangitis: a retrospective study of 37 cases.

BACKGROUND/AIMS: This study compared the effectiveness and safety of endoscopic nasobiliary drainage(ENBD) to percutaneous transhepatic biliary drainage(PTBD) for the treatment of acute obstructive suppurative cholangitis (AOSC). METHODOLOGY: AOSC patients were assigned to undergo either ENBD (n=22) or PTBD(n=15). RESULTS: In the ENBD group, the procedure was successfully completed in 19 patients (86.4%), where- as it was converted to PTBD in 3 patients (13.6%) due to the failure of antegrade cholangiography. All the patients in the PTBD group underwent first- or second-look PTBD successfully. CONCLUSIONS: ENBD is effective for the treatment of AOSC, facilitating subsequent endoscopic or surgical intervention. PTBD is an effective and safe alternative to ENBD in patients unsuitable for ENBD.

The adsorption behaviors of N2O on penta-graphene and Ni-doped penta-graphene.

In order to develop the adsorption application of penta-graphene (PG) to N2O gas molecule, we calculated the sensing properties of PG and Ni-doped PG to N2O molecule via first-principles calculations. Based on the calculated adsorption energy, charge transfer, band gap, density of states and partial density of states, we observed that this gas molecule was weakly physically adsorbed on the surface of intrinsic PG, while the adsorption behaviors on the surface of Ni-doped PG were greatly influenced by the doping sites and adsorption orientations. With the Ni atom doped at the sp2 hybridized carbon site, strong chemical adsorption between the gas molecule and the substrate was induced. The adsorption structure of the N2O molecule with its N atom close to the substrate exhibited better stability. Moreover, an external perpendicular electric field could enhance the adsorption performance of the N2O molecule and adjust the charge transfer between the molecule and substrate. Our results broaden the adsorption applications of PG and indicate that Ni-doped PG is a potential candidate for N2O gas sensors.

Perfect spin Seebeck effect, spin-valve, spin-filter and spin-rectification based on the heterojunction of sawtooth graphene and graphyne nanoribbons.

In order to develop low-power-consumption electronic devices, we studied a heterojunction composed of a 5,4-sawtooth graphene nanoribbon and 6,6,12-graphyne nanoribbon by using first-principles calculations combined with the non-equilibrium Green's function approach. Some spin caloritronic and spintronic devices can be realized based on the heterojunction, exhibiting excellent and multifunctional properties: a net spin current and perfect spin Seebeck effect are generated, a thermal induced and bias induced colossal magnetoresistance is obtained, and a spin filter with 100% spin polarization and a spin rectification with a high rectification ratio are acquired. Our results indicate that the proposed heterojunction is a promising candidate for multi-effect and low-power-consumption electronic devices.

Acetaminophen-induced reduction of NIMA-related kinase 7 expression exacerbates acute liver injury.

Background & Aims: Acetaminophen (APAP)-induced acute liver injury (ALI) is a global health issue characterised by an incomplete understanding of its pathogenesis and unsatisfactory therapies. NEK7 plays critical roles in both cell cycle regulation and inflammation. In the present study, we investigated the role and mechanism of NEK7 in APAP-induced ALI. Methods: In mice with NEK7 overexpression (hydrodynamic tail vein injection of NEK7 plasmids), hepatocyte-specific NEK7 knockout (cKO), and inducible NEK7 knockout (iKO), an overdose of APAP was administered to induce ALI. Liver injury was determined by an analysis of serum liver enzymes, pathological changes, inflammatory cytokines, and metabonomic profiles. In vitro, hepatocyte damage was evaluated by an analysis of cell viability, the reactive oxygen species levels, and mitochondrial function in different cell lines. Hepatocyte proliferation and the cell cycle status were determined by Ki-67 staining, EdU staining, and the cyclin levels. Results: NEK7 was markedly downregulated in APAP-induced injured liver and damaged hepatocytes. NEK7 overexpression in the liver significantly alleviated APAP-induced liver injury, as shown by the restored liver function, reduced pathological injury, and decreased inflammation and oxidative stress, which was confirmed in a hepatocyte cell line. Moreover, both NEK7 cKO and iKO mice exhibited exacerbation of APAP-induced ALI. Finally, we determined that cyclin B1-mediated cell cycle progression could mediate the protective effect of NEK7 against APAP-induced ALI. Conclusions: Reduced NEK7 contributes to APAP-induced ALI, possibly by dysregulating cyclins and disturbing cell cycle progression. Lay summary: Acetaminophen-induced acute liver injury is one of the major global health issues, owing to its high incidence, potential severity, and limited therapeutic options. Our current understanding of its pathogenesis is incomplete. Herein, we have shown that reduced NEK7 (a protein with a key role in the cell cycle) exacerbates acetaminophen-induced acute liver injury. Hence, NEK7 could be a possible therapeutic target for the prevention or treatment of this condition.

The Strain-Tuned Spin Seebeck Effect, Spin Polarization, and Giant Magnetoresistance of a Graphene Nanobubble in Zigzag Graphene Nanoribbons.

By using first-principle calculations combined with the non-equilibrium Green's function approach, we studied the spin caloritronic properties of zigzag graphene nanoribbons with a nanobubble at the edge (NB-ZGNRs). The thermal spin-polarized currents can be induced by a temperature difference, and the spin Seebeck effect is found in the nanoribbon. The spin polarization, magnetoresistance, and Seebeck coefficients are discussed, which are strongly affected and can be tuned by the geometrical strain. Moreover, some novel spin caloritronic devices are designed, such as a device that generates bidirectional perfect spin currents and thermally induced giant magnetoresistances. Our results open up the possibility of tuning the spin caloritronic properties of the NB-ZGNR-based devices by changing the elastic strain on the graphene nanobubble.

Celastrol inhibits intestinal lipid absorption by reprofiling the gut microbiota to attenuate high-fat diet-induced obesity.

Celastrol, a compound extracted from traditional Chinese medicine, has been reported as a potent anti-obesity agent with controversial mechanisms. Here both C57BL/6J and leptin-deficient (ob/ob) mice fed a high-fat diet (HFD) displayed body weight loss after celastrol therapy, opposing the previous viewpoint that celastrol improves obesity by sensitizing leptin signaling. More importantly, celastrol downregulated lipid transporters in the intestine, increased lipid excretion in feces, and reduced body weight gain in HFD mice. Meanwhile, analysis of gut microbiota revealed that celastrol altered the gut microbiota composition in HFD-fed mice, and modulating gut microbiota by antibiotics or fecal microbiota transplantation blocked the celastrol effect on intestinal lipid transport and body weight gain, suggesting a critical role of the gut microbiota composition in mediating the anti-obesity role of celastrol under HFD. Together, the findings revealed that celastrol reduces intestinal lipid absorption to antagonize obesity by resetting the gut microbiota profile under HFD feeding.