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.

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.

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.

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.

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.

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.

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.

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.

The psychological status of 8817 hospital workers during COVID-19 Epidemic: A cross-sectional study in Chongqing.

BACKGROUND: There was an outbreak of COVID-19 towards the end of 2019 in China, which spread all over the world rapidly. The Chinese healthcare system is facing a big challenge where hospital workers are experiencing enormous psychological pressure. This study aimed to (1) investigate the psychological status of hospital workers and (2) provide references for psychological crisis intervention in the future. METHOD: An online survey was conducted to collect sociodemographic features, epidemic-related factors, results of PHQ-9, GAD-7, PHQ-15, suicidal and self-harm ideation (SSI), and the score of stress and support scales. Chi-square test, t-test, non-parametric, and logistic regression analysis were used to detect the risk factors to psychological effect and SSI. RESULTS: 8817 hospital workers participated in this online survey. The prevalence of depression, anxiety, somatic symptoms, and SSI were 30.2%, 20.7%, 46.2%, and 6.5%, respectively. Logistic regression analysis showed that female, single, Tujia minority, educational background of junior or below, designated or county hospital, need for psychological assistance before or during the epidemic, unconfident about defeating COVID-19, ignorance about the epidemic, willingness of attending parties, and poor self-rated health condition were independent factors associated with high-level depression, somatic symptom, and SSI among hospital workers (P<0.05). LIMITATIONS: This cross-sectional study cannot reveal the causality, and voluntary participation could be prone to selection bias. A modified epidemic-related stress and support scale without standardization was used. The number of hospital workers in each hospital was unavailable. CONCLUSION: There were a high level of psychological impact and SSI among hospital workers, which needed to be addressed. County hospital workers were more severe and easier to be neglected. More studies on cognitive and behavioral subsequence after a public health disaster among hospital workers are needed.

Recurrent positive nucleic acid detection in a recovered COVID-19 patient: A case report and literature review.

OBJECTIVE: To describe a case of recurrent positive nucleic acid detection in a recovered coronavirus disease 2019 (COVID-19) patient and to provide clinical data for the further study of COVID-19. METHODS: A case of COVID-19 was retrospectively analyzed, and the relevant literature was reviewed. RESULTS: Based on the 6th edition of the COVID-19 treatment plan, the patient met the discharge standards after treatment and was discharged after consultation with the expert panel. Two weeks after discharge, nucleic acid testing of a sputum sample for severe acute respiratory coronavirus 2 (SARS-CoV-2) was positive again. There may be various reasons. CONCLUSION: Recurring positive SARS-CoV-2 nucleic acid tests pose a formidable challenge, and more stringent discharge standards should be considered. When considering recurrent positive nucleic acid results in COVID-19 patients, the clinicians should have a rational judgment.

Simple hypertrophic tonsils have more active innate immune and inflammatory responses than hypertrophic tonsils with recurrent inflammation in children.

BACKGROUND: Tonsil hypertrophy has negative impact on children's health, but its pathogenesis remains obscure despite the fact that numerous bacteriological studies have been carried out. Understanding the innate immune and inflammatory states of hypertrophic tonsils with different clinical manifestations is of great significance for defining the pathogenesis of tonsil hypertrophy and establishing treatment strategies. The present study was undertaken to examine the characteristics of innate immunity and inflammation in children with hypertrophic palatine tonsils and different clinical manifestations. METHODS: Tonsil tissues were surgically removed from the patients and classified based on the patients' clinical manifestations. The patients were divided into three groups: 1) Control group; 2) Tonsil Hypertrophy (TH) group; and 3) Tonsil Hypertrophy combined with Recurrent Infection (TH + RI) group. The immune and inflammatory statuses of these tissues were characterized using qRT-PCR and ELISA methods. RESULTS: Viral protein 1 (VP1) was highly expressed in TH group, but not in TH + RI group. In TH group, elevated expression was observed in the innate immune mediators, including retinoic acid-inducible gene I (RIG-I), interferon alpha (IFN-α), mitochondrial antiviral-signaling protein (MAVS), NLR family pyrin domain containing 3 (NLRP3), toll-like receptor (TLR) 4 and TLR7. Consistent with the innate immune profile, the expression of inflammatory markers (IL-1ß, NF-κB and IL-7) was also significantly elevated in TH group. Meanwhile, the COX-2/PGE2/EP4 signaling pathway was found to be involved in the inflammatory response and the formation of fibroblasts. CONCLUSIONS: Innate immune and inflammatory responses are more active in simple hypertrophic tonsils, rather than hypertrophic tonsils with recurrent inflammation. A local relative immune deficiency in the hypertrophic tonsils may be a causative factor for recurrent tonsillitis in TH + RI. These differences, together with the patient's clinical manifestations, suggest that tonsillar hypertrophy might be regulated by diverse immune and/or inflammatory mechanism through which novel therapeutic strategies might be created.

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.

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.

Inhibition of the mitochondrial complex-1 protects against carbon tetrachloride-induced acute liver injury.

Mitochondrial dysfunction has been documented to play a crucial role in the pathogenesis of liver injury. In the present study, we investigated the role of rotenone, a mitochondrial complex-1 inhibitor, in carbon tetrachloride (CCl4) -induced acute liver injury, as well as the underlying mechanisms. Before CCl4 administration, the mice were pretreated with rotenone at a dose of 250 ppm in food for three days. Then CCl4 was administered to the mice for 16 h by intraperitoneal injection. The liver injury, mitochondrial status, oxidative stress, and inflammation were examined. Strikingly, CCl4 treatment markedly induced liver injury as shown by enhanced serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and morphological lesions (HE stating), which was significantly attenuated by rotenone treatment in line with the reduced activity of mitochondrial complex-1. Meanwhile, oxidative stress markers of malondialdehyde (MDA), 4-hydroxynonenal (HNE), and dihydroethidium (DHE) and the inflammatory markers of IL-1ß, MCP-1, TNF-α, TLR-4, and IL-6 were also significantly suppressed by rotenone. More importantly, the mitochondrial abnormalities shown by the reduction of SOD2, mitochondrial transcription factor A (TFAM), mitochondrial NADH dehydrogenase subunit 1 (mtND1), and Cytb were significantly restored, indicating that rotenone protected against mitochondrial damage induced by CCl4 in liver. Moreover, rotenone treatment alone did not significantly alter liver morphology and liver enzymes ALT and AST. CYP2E1, a metabolic enzyme of CCl4, was also not significantly affected by rotenone. In conclusion, rotenone protected the liver from CCl4-induced damage possibly by inhibiting the mitochondrial oxidative stress and inflammation.

Shikonin attenuates acetaminophen-induced acute liver injury via inhibition of oxidative stress and inflammation.

Acetaminophen (APAP) overdose causes acute liver injury and leads to fatal liver damage. However, the therapies are quite limited. Shikonin is a natural product with antioxidant and anti-inflammatory activities. In the present study, the hepatoprotective effects and the underlying mechanisms of shikonin in APAP-induced hepatotoxicity in vivo and in vitro were investigated. APAP-induced acute liver injury and shikonin pretreatment models were established in vivo and in vitro, as evidenced by serum hepatic enzymes, histological changes, oxidative stress indicators and proinflammatory cytokines. The results revealed that shikonin pretreatment prevented the elevation of serum alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels and markedly reduced APAP-induced histological alterations in liver tissues. Additionally, shikonin restored superoxide dismutase (SOD) expression and glutathione (GSH) content in line with the blockade of oxidative stress. The changes in gene expression involved in oxidative stress including methionine sulfoxide reductase (such as MsrA and MsrB1), heme oxygenase-1 (HO-1), SOD2 and cytochrome P450 2E1 (CYP2E1), were markedly reversed after shikonin therapy. Furthermore, shikonin markedly attenuated the APAP-induced production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) and suppressed the expression of genes related to inflammation. In AML-12 cells, shikonin pretreatment decreased APAP-induced cytotoxicity as measured by CCK-8 assay and LDH release. The changes in gene expression involved in oxidative stress and the inflammatory response were consistent with those in mouse livers. This study indicated that shikonin attenuated APAP-induced acute liver injury via inhibiting oxidative stress and inflammatory responses in vivo and in vitro. These findings offer new insights into the potential therapy for APAP hepatotoxicity.

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.

Inhibition of mitochondrial complex I by rotenone protects against acetaminophen-induced liver injury.

Acetaminophen (APAP) is widely used as an antipyretic analgesic in clinic. However, overdose-related severe liver injury is a major concern of this drug. Recently, accumulating evidence indicated an important role of mitochondrial abnormality in the pathogenesis of APAP hepatoxicity. Thus, the present investigation was undertaken to evaluate the effect of mitochondrial complex I inhibition by rotenone on APAP hepatoxicity. In this study, male BALB/c mice were pretreated with 250 ppm of rotenone in food for 3 days, then the animals were intraperitoneally injected with 300 mg/kg APAP. After 24 h APAP administration, animals developed severe liver injury as shown by the remarkable elevation of ALT and AST and hepatic centrilobular necrosis in line with the reduced liver GSH content. Strikingly, rotenone treatment markedly attenuated liver injury as shown by the improved liver enzyme release and liver morphology and enhanced liver GSH content. Meanwhile, rotenone ameliorated mitochondrial abnormality, inflammatory response and oxidative stress. Moreover, the downregulation of NOX4, a documented protector against APAP hepatotoxicity, was significantly restored by rotenone. However, mitochondrial complex III inhibitor AZOX failed to protect liver against APAP-induced injury. Together, these results suggested that inhibition of mitochondrial complex I but not mitochondrial complex III played a potent role in protecting against APAP hepatotoxicity.