Disruption of CerS6-mediated sphingolipid metabolism by FTO deficiency aggravates ulcerative colitis.

BACKGROUND AND AIMS: Deregulation of RNA N6-methyladenosine (m6A) modification in intestinal epithelial cells (IECs) influences intestinal immune cells and leads to intestinal inflammation. We studied the function of fat mass-and obesity-associated protein (FTO), one of the m6A demethylases, in patients with ulcerative colitis (UC). METHODS: We analysed colon tissues of Ftoflox/flox; Villin-cre mice and their Ftoflox/flox littermates with dextran sulfate sodium (DSS) using real-time PCR and 16s rRNA sequencing. RNA and methylated RNA immunoprecipitation sequencing were used to analyse immunocytes and IECs. Macrophages were treated with conditioned medium of FTO-knockdown MODE-K cells or sphingosine-1-phosphate (S1P) and analysed for gene expression. Liquid chromatograph mass spectrometry identified C16-ceramide. RESULTS: FTO downregulation was identified in our in-house cohort and external cohorts of UC patients. Dysbiosis of gut microbiota, increased infiltration of proinflammatory macrophages, and enhanced differentiation of Th17 cells were observed in Ftoflox/flox;Villin-cre mice under DSS treatment. FTO deficiency resulted in an increase in m6A modification and a decrease in mRNA stability of CerS6, the gene encoding ceramide synthetase, leading to the downregulation of CerS6 and the accumulation of S1P in IECs. Subsequentially, the secretion of S1P by IECs triggered proinflammatory macrophages to secrete serum amyloid A protein 1/3, ultimately inducing Th17 cell differentiation. In addition, through bioinformatic analysis and experimental validation, we identified UC patients with lower FTO expression might respond better to vedolizumab treatment. CONCLUSIONS: FTO downregulation promoted UC by decreasing CerS6 expression, leading to increased S1P accumulation in IECs and aggravating colitis via m6A-dependent mechanisms. Lower FTO expression in UC patients may enhance their response to vedolizumab treatment.

Targeting Nrf2 may reverse the drug resistance in ovarian cancer.

BACKGROUND: Acquired resistance to therapeutic drugs has become an important issue in treating ovarian cancer. Studies have shown that the prevalent chemotherapy resistance (cisplatin, paclitaxel etc.) for ovarian cancer occurs partly because of decreased production of reactive oxygen species within the mitochondria of ovarian cancer cells. MAIN BODY: Nuclear erythroid-related factor-2 (Nrf2) mainly controls the regulation of transcription of genes through the Keap1-Nrf2-ARE signaling pathway and protects cells by fighting oxidative stress and defending against harmful substances. This protective effect is reflected in the promotion of tumor cell growth and their resistance to chemotherapy drugs. Therefore, inhibition of the Nrf2 pathway may reverse drug resistance. In this review, we describe the functions of Nrf2 in drug resistance based on Nrf2-associated signaling pathways determined in previous studies. CONCLUSIONS: Further studies on the relevant mechanisms of Nrf2 may help improve the outcomes of ovarian cancer therapy.

Gastric Mammalian Target of Rapamycin Signaling Contributes to Inhibition of Ghrelin Expression Induced by Roux-En-Y Gastric Bypass.

BACKGROUND/AIMS: Roux-en-Y Gastric Bypass, RYGB, is the most effective strategy to control body weight in morbid obesity. RYGB leads to rapid improvement of glycemic status and weight loss, which are largely attributed to the alteration of gastrointestinal hormones including ghrelin. The current study examined potential mechanisms of altered ghrelin synthesis after RYGB. METHODS: Gastric mammalian target of rapamycin (mTOR) signaling, ghrelin synthesis and secretion were determined in lean or obese male mice with or without RYGB operation, as well as in obese patients pre- and post-RYGB surgery. Ghrelin expression and mTOR signaling were investigated by western blotting and immunohistochemistry. Ghrelin mRNA levels were detected by real-time PCR. Plasma ghrelin was measured by enzyme immunoassay. RESULTS: mTOR activity in the gastric fundus was significantly lower than in the forestomachs. Both of them were decreased after 24h fasting. A significant negative correlation was found between gastric levels of phospho-S6 (phospho-S6 ribosomal protein) and proghrelin during changes of energy status. mTOR activity was activated, whereas ghrelin expression was inhibited by Roux-en-Y Gastric Bypass in both rodents and human beings. Increment of ghrelin synthesis and decline of mTOR signaling induced by rapamycin were significantly reversed by RYGB in both lean and obese mice. Administration of Ad-S6K1 (adenovirus-mediated p70 ribosomal protein subunit 6 kinase 1) from tail vein suppressed the expression of ghrelin in RYGB-operated mice relative to control animals. CONCLUSION: mTOR is therefore a gastric fuel sensor whose activity is linked to the regulation of ghrelin after Roux-en-Y Gastric Bypass.

Optical coherence tomography patterns and outcomes of contusion maculopathy caused by impact of sporting equipment.

BACKGROUND: To describe the patterns and outcomes of contusion maculopathy after ocular contusions resulting from accidental impact with sporting equipment. METHODS: We conducted a retrospective study of interventional case series. PATIENT POPULATION: Twenty-one eyes of 21 patients who sustained blunt ocular trauma while playing a sport. Intervention/Observation Procedure(s): Surgery or observation by optical coherence tomography (OCT). MAIN OUTCOME MEASURE(S): The morphologic changes within the macula in the early stages after injury and changes in visual function in the early and recovery stages after injury. RESULTS: In the early stage, OCT visualized four injury patterns: type Ι, commotio retinae (14.3%, 3 eyes) with increased reflectivity of the ellipsoid zone and retinal pigment epithelium; type II, incomplete macular hole(38.1%, 8 eyes) with three structural changes, i.e., a partial V-shaped macular hole, a jar-shaped macular hole with retinal tissue at the bottom, and a connective bridge attached to retinal tissues; type III, full-thickness macular hole (33.3%, 7 eyes); and type IV, foveal hemorrhage (14.3%, 3 eyes). During recovery, OCT images of types Ι and II showed almost normal macular morphology with better visual acuity (mean ± SD,0.02 ± 0.1 and 0.14 ± 0.21logMAR.). In types III and IV, the visual prognosis was poor (0.52 ± 0.34 and 0.22 ± 0.16), OCT images showed retinal atrophy at the fovea despite vitrectomy and sulfur hexafluoride (SF6) gas tamponade. CONCLUSION: Early OCT images identified four patterns of contusion maculopathy with different treatment outcomes. In types Ι and II, the visual function and retinal morphology remained intact. With types III and IV, respectively, the treatments of vitrectomy and SF6 gas tamponade for patients were effective.

Acute ganglion cell loss during rapid visual recovery in optic neuritis.

PURPOSE: To report dynamic changes in the retinal ganglion cell layer (GCL) and visual function in acute and chronic optic neuritis (ON). METHODS: Sixteen eyes (15 patients) with acute ON were followed for 3.5 to 31 months (average, 10.2). The best-corrected visual acuity (BCVA) and thickness of the GCL plus the inner plexiform layer (GCL+IPL) were measured 4 to 13 times between baseline and the final visit using the ganglion cell analysis software in the Cirrus HD-OCT [high-definition optical coherence tomography] instrument. Goldmann perimetry was performed at baseline and at the final visit. RESULTS: The thickness of the GCL+IPL at baseline was within normal limits in the affected (80.4 ± 4.9 microns) and unaffected fellow eyes (80.5 ± 5.0 microns). Rapid thinning to 69 ± 7.3 microns occurred during month 1 in the affected eyes, slowing during month 2, and then reaching a minimum level (63.6 ± 8.7 microns). In contrast, BCVA was lowest (mean ± standard deviation logarithm of the minimum angle of resolution, -1.29 ± 0.96) in 11 eyes at baseline, increased markedly to -0.15 ± 0.37 during month 1, and reached a maximum level (-0.18 ± 0.19) during month 2 and (-0.02 ± 0.23) at the final visit. The BCVA in the other five eyes fluctuated during month 1, increased markedly during month 2, and then reached a maximum plateau (-0.07 ± 0.20). The patterns of visual field defects at baseline were varied, and were determinants of BCVA. The visual field largely recovered in 11 eyes, but small central scotomas in four eyes and an enlarged blind spot in one eye remained at the final visit. Eyes with the least GCL+IPL thinning at month 1 or 2 had the least depression in the final deviation map. CONCLUSIONS: In acute ON, the progression toward irreversible ganglion cell loss occurs rapidly during months 1 and 2. In contrast, visual function recovers rapidly during the same period. Remodeling of the neural network may occur between the photoreceptors and the reduced numbers of ganglion cells during the first months of ON. The small number of residual ganglion cells appears to compensate for the initial visual dysfunction.

Retinal ganglion cell analysis in multiple evanescent white dot syndrome.

BACKGROUND: Multiple evanescent white dot syndrome (MEWDS) is an acute and usually unilateral retinopathy that occurs predominantly in young adults. This report presents the outcomes of ganglion cell analysis (GCA) in MEWDS. CASE PRESENTATION: A 41-year-old woman was diagnosed as MEWDS in right eye. At her initial visit, the deviation map of the ganglion cell analysis showed there was a decrease of the ganglion cell layer (GCL) + inner plexiform layer (IPL) thickness in both eyes, even though her left eye was not affected. A 29-year-old woman was also diagnosed as MEWDS in right eye. Although the deviation map of ganglion cell analysis showed there was a decrease of the GCL + IPL thickness in both eyes at her initial visit, her right eye was not affected. CONCLUSION: GCA indicated there was a decrease (<1% of the distribution of normals) of the ganglion cell layer + inner plexiform layer thickness in both the affected and fellow eyes in 7 of 9 patients diagnosed as MEWDS in our hospital. Although the lesions responsible for MEWDS are thought to disrupt the photoreceptor outer segments, we observed changes in the inner retina in both the affected and fellow eye of MEWDS patients.

Effects of oregano essential oil Pickering emulsion and ZnO nanoparticles on the properties and antibacterial activity of konjac glucomannan/carboxymethyl chitosan nanocomposite films.

Green and environmentally friendly natural bio-based food packaging films are increasingly favored by consumers. This study incorporated carboxylated-cellulose nanocrystal stabilized oregano essential oil (OEO) Pickering emulsion and ZnO nanoparticles (ZNPs) into konjac glucomannan (KGM)/carboxymethyl chitosan (CMCS) complexes to develop active food packaging films. The effects of OEO Pickering emulsion and ZNPs on the physical, structural, and antimicrobial activities of the nanocomposite films were evaluated. The OEO Pickering emulsion had a droplet size of 48.43 ± 3.56 µm and showed excellent dispersion and stability. Fourier transform infrared and X-ray diffraction analyses suggested that the interactions between the Pickering emulsion, ZNPs and KGM/CMCS matrix were mainly through hydrogen bonding. SEM observations confirmed that the Pickering emulsion and ZNPs were well incorporated into the KGM/CMCS matrix, forming tiny pores within the nanocomposite films. The incorporation of the OEO Pickering emulsion and/or ZNPs obviously increased the light and water vapor barrier ability, thermal stability, mechanical strength and antimicrobial properties of the KGM/CMCS nanocomposite film. Notably, KGM/CMCS/ZNPs/OEO Pickering emulsion films exhibited the highest barrier, and mechanical and antimicrobial activities due to the synergistic effect between the OEO Pickering emulsion and ZNPs. These results suggest that KGM/CMCS/ZNPs/OEO Pickering emulsion films can be utilized as novel active food packaging materials to extend the shelf life of packaged foods.

Enhanced stabilization of multifunctional phenolic acids-grafted chitin nanofibers for Pickering emulsions.

The objective of this study was to develop novel functional stabilizers for Pickering emulsions using phenolic acids-grafted chitin nanofibers (phenolic acids-g-ChNF), which were fabricated by grafting ferulic acid (FA), sinapic acid (SA) and caffeic acid (CA) onto ChNF via free radical-mediated method. The Fourier transform infrared spectrum and Proton nuclear magnetic resonance showed that graft copolymerization occurred between the amino groups of ChNF and the carbonyl of the phenolic acids. Further, it was revealed that CA-g-ChNF and SA-g-ChNF possessed stronger antioxidant and antibacterial properties than the original ChNF and FA-g-ChNF. Additionally, we applied phenolic acids-g-ChNF to develop Pickering emulsions and found that SA-g-ChNF- and CA-g-ChNF-stabilized emulsions displayed reduced droplet sizes compared to FA, the main reason for which was that SA and CA had a rather close bonding relationship with ChNF. Taken together, SA-g-ChNF and CA-g-ChNF as novel multi-functional particles can be employed for facilitating the stability of Pickering emulsions.

Effects of lower limb exoskeleton gait orthosis compared to mechanical gait orthosis on rehabilitation of patients with spinal cord injury: A systematic review and future perspectives.

OBJECTIVE: We aimed to systematically evaluate the walking efficiency of lower limb exoskeleton gait orthosis and mechanical gait orthosis in patients with spinal cord injury. DATA SOURCES: Databases searched included: Web of Science, MEDLINE, Cochrane Library and Google Scholar. STUDY SELECTION: Articles published in English from 1970 to 2022 investigating the impact of lower limb exoskeleton gait orthosis versus mechanical gait orthosis on gait outcomes in patients with spinal cord injury were considered. DATA EXTRACTION: Two researchers independently extracted data and filled out predesigned forms. Information including authors, year of study, methodological quality, participant characteristics, intervention and comparison details, outcomes and results. The primary outcomes were kinematic data; the secondary outcomes were clinical tests. DATA SYNTHESIS: Data synthesis using meta-analysis was not possible due to the diversity of study designs, methodologies, and outcome measures. RESULTS: A total of 11 trials and 14 types of orthotics were included. The information gathered generally supported the gait improving effects of lower limb exoskeleton gait orthosis and mechanical gait orthosis in both kinematic data and clinical tests among patients with spinal cord injury. CONCLUSIONS: This systematic review compared walking efficiency of patients with spinal cord injury wearing powered exoskeleton gait orthosis and non-powered mechanical gait orthosis. Due to the limited quality and quantity of the included studies, more high-quality studies are needed to verify the above conclusions. Future research should focus on improving trial quality and comprehensive parametric analysis of subjects with different physical conditions.

MC4R in Central and Peripheral Systems.

Obesity has emerged as a critical and urgent health burden during the current global pandemic. Among multiple genetic causes, melanocortin receptor-4 (MC4R), involved in food intake and energy metabolism regulation through various signaling pathways, has been reported to be the lead genetic factor in severe and early onset obesity and hyperphagia disorders. Most previous studies have illustrated the roles of MC4R signaling in energy intake versus expenditure in the central system, while some evidence indicates that MC4R is also expressed in peripheral systems, such as the gut and endocrine organs. However, its physiopathological function remains poorly defined. This review aims to depict the central and peripheral roles of MC4R in energy metabolism and endocrine hormone homeostasis, the diversity of phenotypes, biased downstream signaling caused by distinct MC4R mutations, and current drug development targeting the receptor.

UBE2E2 enhances Snail-mediated epithelial-mesenchymal transition and Nrf2-mediated antioxidant activity in ovarian cancer.

Dissemination of ovarian cancer (OvCa) cells can lead to inoperable metastatic lesions in the bowel and omentum, which have a poor prognosis despite surgical and chemotherapeutical options. A better understanding of the mechanisms underlying metastasis is urgently needed. In this study, bioinformatics analyses revealed that UBE2E2, a less-studied ubiquitin (Ub)-conjugating enzyme (E2), was upregulated in OvCa and was associated with poor prognosis. Subsequently, we performed western blot analysis and IHC staining with 88 OvCa and 26 normal ovarian tissue samples, which further confirmed that UBE2E2 protein is highly expressed in OvCa tissue but weakly expressed in normal tissue. Furthermore, the silencing of UBE2E2 blocked OvCa cell migration, epithelial-mesenchymal transition (EMT) and metastasis in vitro, whereas UBE2E2 overexpression exerted the opposite effects. Mechanistically, UBE2E2 promoted p62 accumulation and increased the activity of the Nrf2-antioxidant response element (ARE) system, which ultimately activated the Snail signaling pathway by inhibiting the ubiquitin-mediated degradation of Snail. Additionally, co-IP and immunofluorescence demonstrated that a direct interaction exists between UBE2E2 and Nrf2, and the N-terminal of UBE2E2 (residues 1-52) is required and sufficient for its interaction with Nrf2 protein. Mutations in the active site cysteine (Cys139) impaired both the function and cellular distribution of UBE2E2. More importantly, the deletion of UBE2E2 reduced tumorigenicity and metastasis in xenograft OvCa mouse models. Taken together, our findings reveal the role of the UBE2E2-Nrf2-p62-Snail signaling axis in OvCa and thus provides novel therapeutic targets for the prevention of OvCa metastasis.

Preparation, characterization and biological activity of phosphorylated surface deacetylated chitin nanofibers.

Phosphorylation is a key route to achieve varieties of biological activities for polysaccharides. Here, we report the phosphorylated surface deacetylated chitin nanofibers (PS-ChNFs) using the sodium tripolyphosphate/sodium trimetaphosphate (STPP/STMP) method. Response surface methodology (RSM) was employed to optimize in this study. Under optimal conditions, a maximum degree of substitution (DS) of 0.13 was obtained. In addition, the structures of PS-ChNFs were investigated by Fourier transform infrared spectroscopy (FT-IR), Nuclear Magnetic Resonance spectra (NMR), X-ray photoelectron spectroscopy (XPS), Scanning electron microscope (SEM) and (Energy Dispersive Spectroscopy-mapping) EDS-mapping. The findings revealed that the FT-IR spectroscopy and XPS analysis confirmed the appearance of phosphate groups in PS-ChNFs. The 31P NMR results indicate that the PS-ChNFs structure has characteristic peaks of P elements. SEM images showed that PS-ChNFs had a rough surface with many cavities, but the P elements on the surface of the EDS-mapping are uniformly distributed throughout the sample without any enrichment. Antioxidant and antibacterial test showed that PS-ChNFs had significant scavenging effect on free radicals and antibacterial effect. The above results indicate that the chemical modification of PS-ChNFs was successful.

Physiological but not morphological adjustments along latitudinal gradients in a human commensal species, the Eurasian tree sparrow.

Human commensal species take advantage of anthropogenic conditions that are less likely to be challenged by the selective pressures of natural environments. Their morphological and physiological phenotypes can therefore dissociate from habitat characteristics. Understanding how these species adjust their morphological and physiological traits across latitudinal gradients is fundamental to uncovering the eco-physiological strategies underlying coping mechanisms. Here, we studied morphological traits in breeding Eurasian tree sparrows (ETSs; Passer montanus) among low-latitude (Yunnan and Hunan) and middle-latitude (Hebei) localities in China. We then compared body mass; lengths of bill, tarsometatarsus, wing, total body, and tail feather; and baseline and capture stress-induced levels of plasma corticosterone (CORT) and the metabolites including glucose (Glu), total triglyceride (TG), free fatty acid (FFA), total protein, and uric acid (UA). None of the measured morphological parameters varied with latitude except in the Hunan population, which demonstrated longer bills than those in other populations. Stress-induced CORT levels significantly exceeded baseline levels and decreased with increasing latitude, but total integrated CORT levels did not vary with latitude. Capture stress-induced significantly increased Glu levels and decreased TG levels, independent of site. However, the Hunan population had significantly higher baseline CORT, baseline and stress-induced FFA levels, but lower UA levels, which differed from other populations. Our results suggest that rather than morphological adjustments, physiological adjustments are mainly involved in coping mechanisms for middle-latitude adaptation in ETSs. It is worth investigating whether other avian species also exhibit such dissociation from external morphological designs while depending on physiological adjustments.

The rs1421085 variant within FTO promotes brown fat thermogenesis.

One lead genetic risk signal of obesity-the rs1421085 T>C variant within the FTO gene-is reported to be functional in vitro but lacks evidence at an organism level. Here we recapitulate the homologous human variant in mice with global and brown adipocyte-specific variant knock-in and reveal that mice carrying the C-allele show increased brown fat thermogenic capacity and resistance to high-fat diet-induced adiposity, whereas the obesity-related phenotypic changes are blunted at thermoneutrality. Both in vivo and in vitro data reveal that the C-allele in brown adipocytes enhances the transcription of the Fto gene, which is associated with stronger chromatin looping linking the enhancer region and Fto promoter. Moreover, FTO knockdown or inhibition effectively eliminates the increased thermogenic ability of brown adipocytes carrying the C-allele. Taken together, these findings identify rs1421085 T>C as a functional variant promoting brown fat thermogenesis.

Inverse pattern of photoreceptor abnormalities in retinitis pigmentosa and cone-rod dystrophy.

PURPOSE: To determine the characteristics of the photoreceptor abnormalities in retinitis pigmentosa (RP) and cone-rod dystrophy (CRD). METHODS: We evaluated the photoreceptor abnormalities using spectral-domain optical coherence tomography (SD-OCT) in 28 patients with RP and 17 patients with CRD. The OCT images and full-field electroretinograms were obtained from 21 eyes in normal subjects who were age-matched to patients with RP and CRD and served as controls. RESULTS: Eyes with RP and CRD had markedly decreased rod responses (6.5 and 57.5 % of normal value), maximal responses (9.6 and 51.6 %), cone (16.5 and 25.8 %), and 30-Hz flicker responses (17.8 and 30.1 % of normal value), and their P values were smaller than 0.0003. On comparison of ERG data between RP and CRD, they had statistically significant differences in rod responses (P < 0.0003) and maximal responses (P < 0.0003). However, there were no statistical differences in cone response and a weak difference in 30-Hz flicker responses (P < 0.017). The best-corrected visual acuity was -0.03 ± 0.09 (logMAR, mean ± standard deviation [SD]) in eyes with RP, but 0.57 ± 0.54 in eyes with CRD. SD-OCT showed that eyes with RP had an intact reflective line at the junction between the photoreceptor inner and outer segment (IS/OS) at the fovea, while eyes with CRD had no IS/OS. The extent of the central visual field was correlated with the IS/OS length at the macula in eyes with RP. CONCLUSION: The distribution patterns of the IS/OS line help to differentiate between RP and CRD.

Nrf2 Signaling Pathway Mediates the Protective Effects of Daphnetin Against D-Galactose Induced-Premature Ovarian Failure.

Oxidative damage can lead to severe ovarian dysfunctions and even premature ovarian failure. Nrf2, a significant transcription factor that regulates the oxidative stress response of cells, declines with age. Daphnetin, as a kind of natural Chinese herbal medicine, can activate Nrf2 and further promote the antioxidant defense of cells. However, whether Daphnetin treatment can protect ovary from premature ovarian failure and the specific mechanism involved are not understood. This study aimed to investigate the protective function of Daphnetin against the ovarian aging induced by D-galactose in wild-type and Nrf2-/- mice. Female C57BL/6 mice with Wild-type and Nrf2-/- were divided into five groups separately and the premature ovarian failure model were established by D-galactose and then Daphnetin and VE were given for treatment. After 42 days, ovaries tissue and serum were collected for biochemical determination, H&E staining, Immunohistochemical staining and western blot analysis. In the WT-POF group, ovarian function was broke, and the expression of the ovarian senescence-associated protein P16 and the level of oxidative stress were significantly increased, while the expression of the anti-senescence protein klotho was significantly decreased. In addition, the expression of Nrf2 and the antioxidases GCLC, HO-1 and NQO1 were decreased, but TXNIP and NLRP3 were significantly increased. Furthermore, the characteristics of premature ovarian failure were more significant in Nrf2 knockout mice than in wild-type mice, especially the expression of NLRP3 and TXNIP. Moreover, daphnetin, an Nrf2 activator, rescued d-gal-induced POF in a dose-dependent manner, while the protective effect was weakened or even lost in Nrf2 knockout mice. Our results suggested that daphnetin is likely to be a candidate drug for premature ovarian failure treatment and it is mostly possible referred to the molecular mechanism of increasing Nrf2 expression and inhibiting NLRP3 activation in the ovarian aging process.

Oxidized Chitin Nanocrystals Greatly Strengthen the Stability of Resveratrol-Loaded Gliadin Nanoparticles.

Resveratrol (RES) is a natural polyphenol with a variety of health beneficial properties, but its application is greatly limited due to low aqueous solubility and poor bioavailability. This study aims to address these issues via gliadin nanoparticles stabilized with oxidized chitin nanocrystals (O-ChNCs) as a delivery system for RES. RES-loaded gliadin nanoparticles (GRNPs) were fabricated by an antisolvent method, and their formation mechanism was elucidated using zeta-potential, FTIR, XRD, and TEM. Furthermore, the effect of O-ChNCs on the colloidal stability and bioactiveness of GRNPs was discussed. The results demonstrate that O-ChNCs are adsorbed onto the surface of GRNPs through hydrogen bonding and electrostatic interactions, leading to the enhanced absolute potential and the improved hydrophobicity of the particles, which in turn facilitates the stability of the GRNPs. Furthermore, the changes in the release profile and antioxidant activity of RES in the simulated gastric and intestinal tracts indicate that the adsorption of O-ChNCs not only delays the release of RES but also has a protective effect on the antioxidant capacity of RES. This study provides significant implications for developing stable gliadin nanoparticles as delivery vehicles for bioactive substances.

GREM2 is associated with human central obesity and inhibits visceral preadipocyte browning.

BACKGROUND: Some circulating proteins are linked to central adiposity. Gremlin 2 (GREM2) functions as a secreted factor involved in osteogenesis and adipogenesis. Here, we investigated the association of blood GREM2 levels and central adiposity, and the biological roles of GREM2 in the browning program of visceral preadipocytes. METHODS: Three independent cohorts were applied to detect circulating GREM2 levels. Recombinant Grem2 protein, Grem2 overexpression and knockout mouse models, and preadipocyte-specific Bmpr2 knockout mice were used to assess the roles of Grem2 in the browning program. FINDINGS: We detected the presence of GREM2 protein in human serum using an ELISA approach. We revealed elevated GREM2 levels in severely obese subjects and validated this finding in a large-scale community population involving 10,327 subjects. Notably, serum GREM2 was positively associated with visceral fat volume, as quantified by 3D reconstruction methods. In mice, Grem2 was highly expressed in visceral fat and liver tissues, while surgical removal of visceral fat lowered circulating Grem2 levels. Visceral fat secreted more Grem2 in obese mice. Grem2-overexpressed mice exhibited a reduced browning ability of visceral fat, whereas Grem2 ablation enhanced the browning capacity and reduced visceral fat content. Mechanistically, Grem2 attenuated the browning program of visceral preadipocytes partially by antagonizing BMP4/7-SMAD1/5/8 signaling pathway. Further, genetic deletion of Bmpr2 in Pdgfrα+ preadipocytes abolished the antagonistic effect of Grem2. INTERPRETATION: These findings indicate that GREM2 might function as a circulating protein factor associated with human visceral adiposity, and Grem2 inhibits the browning capacity of visceral preadipocytes partially by BMP4/7-BMPR2 signaling pathway. FUNDING: The complete list of funders can be found in the Acknowledgement section.

Effect of Massive Transfusion Protocol on Coagulation Function in Elderly Patients with Multiple Injuries.

OBJECTIVE: To evaluate the effect of massive transfusion protocol on coagulation function in elderly patients with multiple injuries. METHODS: In this retrospective cohort study, clinical data were collected from a total of 94 elderly patients with multiple injuries, including 44 cases who received routine transfusion protocol (control group) and 50 cases who concurrently received massive transfusion protocol in our hospital (research group). The changes in platelet parameters, coagulation function, and organ dysfunction scores at admission and 24 h after transfusion were compared between the two groups. The 24-hour plasma and red blood cell transfusion volume, length of stay, complications, and mortality of the two groups were analyzed statistically. RESULTS: Twenty-four hours after blood transfusion, the hematocrit, platelets, and hemoglobin in the research group were higher than those in the control group, while the activated partial thromboplastin time, prothrombin time, thrombin time, fibrinogen, and scores of Marshall scoring system and Sequential Organ Failure Assessment were lower than those in the control group (P < 0.01). The 24-hour plasma transfusion volume was higher, and the length of intensive care unit (ICU) stay and total length of stay were lower in the research group compared with the control group (P < 0.01). No significant difference was found in the mortality rate between the research group and the control group (10.00% vs. 13.64%, P > 0.05). The incidence of complications in the research group was lower than that in the control group (12.00% vs. 31.82%, P < 0.05). CONCLUSION: Massive transfusion protocol for elderly patients with multiple injuries can improve their coagulation function and platelet parameters, alleviate organ dysfunction, shorten length of ICU stay, and decrease the incidence of complications, which is conducive to improving the prognosis of patients.

Diosmetin induces apoptosis in ovarian cancer cells by activating reactive oxygen species and inhibiting the Nrf2 pathway.

The fatality rate of ovarian cancer ranks first among gynecological tumors, and the prognosis is poor. Diosmetin (Dio), a natural flavonoid obtained from citrus fruits, has been shown to have anti-tumor effects in lung, liver, and skin cancers. We aimed to investigate the effects of Dio on ovarian cancer A2780 and SKOV3 cells along with the underlying mechanisms. Our data showed that Dio inhibited the proliferation, migration, and invasion of these cells and induced their apoptosis. Moreover, Dio upregulated the levels of Bax and cleaved Caspase-3 and PARP while downregulating the level of Bcl2. Mechanistically, our results revealed that Dio inhibited Nrf2 and induced the production of reactive oxygen species (ROS). The ROS scavenger N-acetyl-L-cysteine (NAC) suppressed the inhibitory effect of Dio on the proliferation of the ovarian cancer cells. Additionally, overexpression of Nrf2 partially suppressed the Dio-induced apoptosis and proliferation inhibition in these cells. These findings indicate that Dio exerts an anti-tumor activity by upregulating ROS levels and inhibiting Nrf2, indicating that Dio is a promising chemotherapeutic candidate for the treatment of ovarian cancer.