Mucus-degrading Bacteroides link carbapenems to aggravated graft-versus-host disease.

The intestinal microbiota is an important modulator of graft-versus-host disease (GVHD), which often complicates allogeneic hematopoietic stem cell transplantation (allo-HSCT). Broad-spectrum antibiotics such as carbapenems increase the risk for intestinal GVHD, but mechanisms are not well understood. In this study, we found that treatment with meropenem, a commonly used carbapenem, aggravates colonic GVHD in mice via the expansion of Bacteroides thetaiotaomicron (BT). BT has a broad ability to degrade dietary polysaccharides and host mucin glycans. BT in meropenem-treated allogeneic mice demonstrated upregulated expression of enzymes involved in the degradation of mucin glycans. These mice also had thinning of the colonic mucus layer and decreased levels of xylose in colonic luminal contents. Interestingly, oral xylose supplementation significantly prevented thinning of the colonic mucus layer in meropenem-treated mice. Specific nutritional supplementation strategies, including xylose supplementation, may combat antibiotic-mediated microbiome injury to reduce the risk for intestinal GVHD in allo-HSCT patients.

Pyrrolidine dithiocarbamate and dexamethasone are novel treatments of Acute Exogenous Lipoid Pneumonia.

BACKGROUND: Acute exogenous lipoid pneumonia (AELP) is characterized by pulmonary inflammation. This mainly occur in children who have ingested sewing machine oil or other mineral oils accidentally. Despite emerging evidences revealing that inhibiting inflammation improves acute exogenous lipoid pneumonia, the actual process of inhibiting inflammation remains unknown. This study aimed to evaluate the effects of PDTC and dexamethasone on AELP to gain insight into the mechanism of AELP. METHODS: The experimental rats were randomly divided into 10 groups: NS control group (NS3 group, NS5 group), Oil inhalation group (AE3 group, AE5 group), PDTC intervention group (PDTC3 group, PDTC5 group), DXM intervention group (DXM3 group, DXM5 group), PDTC + DXM combined intervention group (PDTC + DXM3 group, PDTC + DXM 5 group). Enzyme-linked immunosorbent assay (ELISA) was used to determine concentrations of macrophage migration inhibitory factor (MIF), interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) in bronchoalveolar lavage fluid (BALF) and serum samples. On the other hand, western blotting was used to measure the expression levels of nuclear factor-κB p65 (NF-κB p65) and b-cell leukemia 2 (Bcl-2) in the lungs. Hematoxylin and Eosin (H&E) staining was performed to evaluate changes in the lung tissue. The wet-to-dry lung weight ratio was subsequently used to determine the pulmonary edema of the lungs. RESULTS: There were increased MIF levels in both serum and BALF samples of the AE group. Pyrrolidine dithiocarbamate (PDTC) and dexamethasone (DXM) independently and in combination reduced pulmonary inflammation induced by the sewing machine oil by regulating MIF expression. TNF-α and IL-6 levels in serum and BALF samples of the AE group were higher than those of the NS control animals. However, their levels decreased after treatment with either PDTC, DXM or PDTC + DXM. Similarly, NF-κBp65 expression increased after oil inhalation but decreased after treatment with either PDTC, DXM or PDTC + DXM. PDTC, DXM and PDTC + DXM treatment significantly reduced pulmonary inflammation and pulmonary edema of the lung tissue following induction of acute exogenous lipoid pneumonia. CONCLUSIONS: Individual or combined use of PDTC and DXM can ameliorate pulmonary inflammation induced by inhalation of sewing machine oil by inhibiting the NF-κB pathway in young rats. These findings provide novel insights that will greatly contribute in treatment of AELP.

Transgelin 2 is required for embryo implantation by promoting actin polymerization.

Infertility has been a great challenge in reproductive medicine. At least 40% of human pregnancy losses are clinically unrecognized and occur because of embryo implantation failure. Identification of the proteins and biochemical factors involved in embryo implantation and that are essential for crosstalk between the embryo and uterus can further increase female fertility rates. The actin cytoskeleton and actin-binding proteins (ABPs) are of great importance for cell morphology and rearrangement, which is crucial for trophoblast adhesion and invasion. However, the research on ABPs in embryo implantation is insufficient. In this report, we found that transgelin (TAGLN)2 is highly expressed in mouse blastocyst trophoblasts. Notably, inhibition of mouse blastocyst trophoblast TAGLN2 by lentivirus-mediated RNA interference significantly impaired embryo adhesion and implantation ability. Further in vitro experiments demonstrated that TAGLN2 knockdown with small interfering RNA observably decreased the invasion and migration abilities of human trophoblast cells. Immunofluorescence colocalization and microscale thermophoresis analysis showed that TAGLN2 directly binds to actin. In addition, knockdown of TAGLN2 in trophoblast cells resulted in a remarkable reduction in F-actin rather than G-actin. Our findings reveal an unidentified role of TAGLN2 in regulation of trophoblast invasion and adhesion by promoting actin polymerization.-Liang, X., Jin, Y., Wang, H., Meng, X., Tan, Z., Huang, T., Fan, S. Transgelin 2 is required for embryo implantation by promoting actin polymerization.

Down-regulation of Xist and Mir-7a-5p improves LPS-induced myocardial injury.

Background: X-inactive specific transcript (Xist) is a lncRNA, which plays a significant role in X-chromosome inactivation, regulates cell proliferation in tumor cells, and inhibits apoptosis in acute myocardial infarction. On the other hand, miR-7a-5p is involved in cardiomyocytes injury in myocardial ischemia/reperfusion. However, their roles in LPS-induced damage remain unclear. Objectives: This study aimed at using siRNA transfection and lentivirus infection to regulate the expression of xist and miR-7a-5p, and to evaluate their effects on LPS-induced myocardial damage. Method: Mice cardiomyocytes (MCM) cells were divided into six groups, namely the control group, the LPS group, the LPS + lncRNA- group, the LPS + lncRNA+ group, the LPS + miRNA- group, and the LPS + miRNA+ group. Quantitative real-time PCR (qRT-PCR) was performed to assay for the RNA expressions of xist, miR-7a-5p, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and recombinant mitochondrial transcription factor A (Tfam) in all the groups. The ATP level was determined using the adenosine triphosphate (ATP) assay kit according to the manufacturer's instructions. Flow cytometry was performed to estimate the level of apoptosis and proliferation in cells in each group. Results: The level of xist in the myocardial cells was markedly higher in the LPS group compared with the control group; however, it was reduced in the LPS+ lncRNA- group. There was no significant difference in the expression of xist among the LPS+miRNA-, LPS+miRNA+, and LPS groups. Moreover, the expression of mir-7a-5p was significantly reduced in myocardial cells in the LPS group, and moderately reduced in the LPS+ miRNA- group, but remarkably elevated in the LPS+ miRNA+ group (P<0.05). The expression of mir-7a-5p was comparably similar in the LPS+ lncRNA- group, LPS+ lncRNA+ group, and LPS groups. Further, the levels of PGC-1a, and Tfam were determined. In the LPS group, the expression of PGC-1α was significantly reduced but elevated in the LPS+lncRNA- and LPS+ miRNA- groups (P<0.05). There was no significant difference in the level of PGC-1α among the LPS, LPS+ lncRNA+, and LPS+ miRNA+ groups. The expression of Tfam was markedly reduced in the LPS group (P < 0.05), but elevated after the suppression of xist and mir-7a-5p. The expression of Tfam was not significantly different among the LPS group, LPS+ lncRNA+ and LPS+ miRNA+ groups. Notably, overexpression of mir-7a-5p had a mild effect on the expression of Tfam in the LPS+ miRNA+ group compared with the control group. Besides, ATP expression in the LPS group was markedly reduced, but elevated after the inhibition of xist and mir-7a-5p. Suppressing the expression of xist or mir-7a-5p resulted in reduced cell apoptosis and increased cell proliferation. Conclusions: In this study, we established that down-regulation of xist and mir-7a-5p reduces apoptosis in response to LPS.

Fbxo30 regulates chromosome segregation of oocyte meiosis.

As the female gamete, meiotic oocytes provide not only half of the genome but also almost all stores for fertilization and early embryonic development. Because de novo mRNA transcription is absent in oocyte meiosis, protein-level regulations, especially the ubiquitin proteasome system, are more crucial. As the largest family of ubiquitin E3 ligases, Skp1-Cullin-F-box complexes recognize their substrates via F-box proteins with substrate-selected specificity. However, the variety of F-box proteins and their unknown substrates hinder our understanding of their functions. In this report, we find that Fbxo30, a new member of F-box proteins, is enriched in mouse oocytes, and its expression level declines substantially after the metaphase of the first meiosis (MI). Notably, depletion of Fbxo30 causes significant chromosome compaction accompanied by chromosome segregation failure and arrest at the MI stage, and this arrest is not caused by over-activation of spindle assembly checkpoint. Using immunoprecipitation and mass spectrometric analysis, we identify stem-loop-binding protein (SLBP) as a novel substrate of Fbxo30. SLBP overexpression caused by Fbxo30 depletion results in a remarkable overload of histone H3 on chromosomes that excessively condenses chromosomes and inhibits chromosome segregation. Our finding uncovers an unidentified pathway-controlling chromosome segregation and cell progress.

The role of SCF ubiquitin-ligase complex at the beginning of life.

As the largest family of E3 ligases, the Skp1-cullin 1-F-box (SCF) E3 ligase complex is comprised of Cullins, Skp1 and F-box proteins. And the SCF E3 ubiquitin ligases play an important role in regulating critical cellular processes, which promote degradation of many cellular proteins, including signal transducers, cell cycle regulators, and transcription factors. We review the biological roles of the SCF ubiquitin-ligase complex in gametogenesis, oocyte-to-embryo transition, embryo development and the regulation for estrogen and progestin. We find that researches about the SCF ubiquitin-ligase complex at the beginning of life are not comprehensive, thus more in-depth researches will promote its eventual clinical application.

The efficacy and safety of coenzyme Q10 in Parkinson's disease: a meta-analysis of randomized controlled trials.

The objective of this meta-analysis was to evaluate the effects of coenzyme Q10 (CoQ10) for the treatment of Parkinson's disease (PD) patients in order to arrive at qualitative and quantitative conclusions about the efficacy of CoQ10. Databases searched included PubMed, Google scholar, CNKI, Wan-Fang, and the Cochrane Library from inception to March 2016. We only included sham-controlled, randomized clinical trials of CoQ10 intervention for motor dysfunction in patients with PD. Relevant measures were extracted independently by two investigators. Weighted mean differences (WMD) were calculated with random-effects models. Eight studies with a total of 899 patients were included. Random-effects analysis revealed a pooled WMD of 1.02, indicating no significant difference when CoQ10 treatment compared with placebo in terms of UPDRS part 3 (p = 0.54). Meanwhile, the effect size of UPDRS part 1, UPDRS part 2, and total UPDRS scores were similar in CoQ10 group with in placebo group (p > 0.05). Moreover, we found CoQ10 was well tolerated compared with placebo group. Subgroup analysis showed that the effect size of CoQ10 in monocentric studies was larger than in multicenter studies. Using the GRADE criteria, we characterized the quality of evidence presented in this meta-analysis as moderate to high level. The current meta-analysis provided evidence that CoQ10 was safe and well tolerated in participants with PD and no superior to placebo in terms of motor symptoms. According to these results, we cannot recommend CoQ10 for the routine treatment of PD right now.

Changes in the osmolarity of the embryonic microenvironment induce neural tube defects.

Many maternal disorders that modify the embryonic microenvironment, such as a change in osmolarity, can affect development, but how these changes influence the early embryo remains obscure. Neural tube defects, for example, are common congenital disorders found in fetus and neonates. In this study, we investigated the impact of anisotonic osmolarity (unequal osmotic pressures) on neural tube development in the early chick embryo, finding that neuronal cell differentiation was impaired in the neural tube due to enhanced apoptosis and repressed cell proliferation. Anisotonic osmolarity also affected normal development of the neural crest, which in turn influenced abnormal development of the neural tube. As neural tube development is highly dependent on the proper expression of bone morphogenetic protein 4 (BMP4), paired box 7 (PAX7), and sonic hedgehog (SHH) genes in the dorsal and ventral regions along the tube, we investigated the impact of anisotonic osmolarity on their expression. Indeed, small changes in osmolarity could positively and negatively impact the expression of these regulatory genes, which profoundly affected neural tube development. Thus, both the central and peripheral nervous systems were perturbed by anisotonic consitions as a consequence of the abnormal expression of key genes within the developing neural tube.

The impact of high-salt exposure on cardiovascular development in the early chick embryo.

In this study, we show that high-salt exposure dramatically increases chick mortality during embryo development. As embryonic mortality at early stages mainly results from defects in cardiovascular development, we focused on heart formation and angiogenesis. We found that high-salt exposure enhanced the risk of abnormal heart tube looping and blood congestion in the heart chamber. In the presence of high salt, both ventricular cell proliferation and apoptosis increased. The high osmolarity induced by high salt in the ventricular cardiomyocytes resulted in incomplete differentiation, which might be due to reduced expression of Nkx2.5 and GATA4. Blood vessel density and diameter were suppressed by exposure to high salt in both the yolk sac membrane (YSM) and chorioallantoic membrane models. In addition, high-salt-induced suppression of angiogenesis occurred even at the vasculogenesis stage, as blood island formation was also inhibited by high-salt exposure. At the same time, cell proliferation was repressed and cell apoptosis was enhanced by high-salt exposure in YSM tissue. Moreover, the reduction in expression of HIF2 and FGF2 genes might cause high-salt-suppressed angiogenesis. Interestingly, we show that high-salt exposure causes excess generation of reactive oxygen species (ROS) in the heart and YSM tissues, which could be partially rescued through the addition of antioxidants. In total, our study suggests that excess generation of ROS might play an important role in high-salt-induced defects in heart and angiogenesis.

Tsyn-Seq: a T-cell Synapse-Based Antigen Identification Platform.

Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen derived from human papillomavirus type 16 (HPV16), Tsyn-seq successfully enriched the correct cognate antigen from a cDNA library derived from an HPV16-positive cervical cancer cell line. Tsyn-seq provides a method for rapidly identifying antigens recognized by TCRs of interest from a tumor cDNA library. See related Spotlight by Makani and Joglekar, p. 515.

MCC950 Ameliorates Acute Exogenous Lipoid Pneumonia Induced by Sewing Machine Oil in Rats via the NF-κB/NLRP3 Inflammasome Pathway.

BACKGROUND/AIM: Acute exogenous lipoid pneumonia (AELP) is a rare disorder caused by intake of lipid formulations and is often underdiagnosed. Meanwhile, the mechanism of AELP is still underlying. MCC950, was previously found to significantly suppress the release of inflammatory cytokines IL-18 and IL-1ß. However, the effect of MCC950 on AELP induced by sewing machine oil has not been reported. MATERIALS AND METHODS: The NLRP3, NF-[Formula: see text]B p65, caspase-1 and IL-1ß expression in lung tissues were compared between a rat model of AELP and control rats using western blotting and real-time quantitative assay. Moreover, haematoxylin and eosin (H&E) staining was performed to elucidate the mechanisms by which MCC950 ameliorates sewing machine oil-induced AELP in vivo. RESULTS: MCC950 reduced the expression of NF-[Formula: see text]B p65 in the lung samples of the treatment group and further down-regulated the NLRP3 and caspase-1 levels while inhibited the production of IL-1ß. Besides, decreases in inflammatory cell infiltration in the lung were shown using H&E staining. CONCLUSION: MCC950 ameliorates sewing machine oil-induced acute exogenous lipoid pneumonia in rats through inhibition of the NF-[Formula: see text]B/NLRP3 inflammasome pathway.

Protective Effects of NaHS/miR-133a-3p on Lipopolysaccharide-Induced Cardiomyocytes Injury.

Objective: The aim of this study was to investigate the effects of sodium hydrosulfide (NaHS) on Lipopolysaccharide (LPS)-induced cardiomyocyte injury in H9c2 cells. Methods: H9c2 cardiomyocytes cultivated with medium containing 10 µg/mL LPS were used to recapitulate the phenotypes of those in sepsis. Two sequential experiments were performed. The first contained a control group, a LPS group, and a LPS + NaHS group, with the aim to assure the protective effects of NaHS on LPS-treated cardiomyocytes. The second experiment added a fourth group, the LPS + NaHS + miR-133a-3p inhibition group, with the aim to preliminarily explore whether miR-133-3p exerts a protective function downstream of NaHS. The adenosine triphosphate (ATP) kit was used to detect ATP content; real-time quantitative polynucleotide chain reaction (qPCR) was used to measure the levels of mammalian targets of rapamycin (mTOR), AMP-dependent protein kinase (AMPK), and miR-133a-3p, and Western blot (WB) was used to detect protein levels of mTOR, AMPK, myosin-like Bcl2 interacting protein (Beclin-1), microtubule-associated protein 1 light chain 3 (LC3I/II), and P62 (sequestosome-1, sqstm-1/P62). Results: Compared with the control group, the expressions of miR-133a-3p (P < 0.001), P62 (P < 0.001), and the content of ATP (P < 0.001) decreased, while the expressions of Beclin-1 (P = 0.023) and LC3I/II (P = 0.048) increased in the LPS group. Compared with the LPS group, the expressions of miR-133a-3p (P < 0.001), P62 (P < 0.001), and the content of ATP (P < 0.001) in the NaHS + LPS group increased, while the expressions of Beclin-1 (P = 0.023) and LC3I/II (P = 0.022) decreased. Compared with the NaHS + LPS group, the expression levels of miR-133a-3p (P < 0.001), P62 (P = 0.001), and the content of ATP (P < 0.001) in the LPS + NaHS + miR-133a-3p inhibition group were downregulated, and the expression levels of Beclin-1 (P = 0.012) and LC3I/II (P = 0.010) were upregulated. The difference was statistically significant. There was no significant difference in the expression of AMPK and mTOR between groups. Conclusion: Our research demonstrated that NaHS relieved LPS-induced myocardial injury in H9c2 by promoting the expression of miR-133a-3p, inhibiting autophagy in cardiomyocytes, and restoring cellular ATP levels.

Bacteroides ovatus alleviates dysbiotic microbiota-induced intestinal graft-versus-host disease.

Acute gastrointestinal intestinal GVHD (aGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation, and the intestinal microbiota is known to impact on its severity. However, an association between treatment response of aGI-GVHD and the intestinal microbiota has not been well-studied. In a cohort of patients with aGI-GVHD (n=37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and loss of Bacteroides ovatus from the microbiome. In a mouse model of carbapenem-aggravated GVHD, introducing Bacteroides ovatus reduced severity of GVHD and improved survival. Bacteroides ovatus reduced degradation of colonic mucus by another intestinal commensal, Bacteroides thetaiotaomicron, via its ability to metabolize dietary polysaccharides into monosaccharides, which then inhibit mucus degradation by Bacteroides thetaiotaomicron and reduce GVHD-related mortality.

Diet-derived metabolites and mucus link the gut microbiome to fever after cytotoxic cancer treatment.

Not all patients with cancer and severe neutropenia develop fever, and the fecal microbiome may play a role. In a single-center study of patients undergoing hematopoietic cell transplant (n = 119), the fecal microbiome was characterized at onset of severe neutropenia. A total of 63 patients (53%) developed a subsequent fever, and their fecal microbiome displayed increased relative abundances of Akkermansia muciniphila, a species of mucin-degrading bacteria (P = 0.006, corrected for multiple comparisons). Two therapies that induce neutropenia, irradiation and melphalan, similarly expanded A. muciniphila and additionally thinned the colonic mucus layer in mice. Caloric restriction of unirradiated mice also expanded A. muciniphila and thinned the colonic mucus layer. Antibiotic treatment to eradicate A. muciniphila before caloric restriction preserved colonic mucus, whereas A. muciniphila reintroduction restored mucus thinning. Caloric restriction of unirradiated mice raised colonic luminal pH and reduced acetate, propionate, and butyrate. Culturing A. muciniphila in vitro with propionate reduced utilization of mucin as well as of fucose. Treating irradiated mice with an antibiotic targeting A. muciniphila or propionate preserved the mucus layer, suppressed translocation of flagellin, reduced inflammatory cytokines in the colon, and improved thermoregulation. These results suggest that diet, metabolites, and colonic mucus link the microbiome to neutropenic fever and may guide future microbiome-based preventive strategies.

[Risk factors for death in children with septic shock].

OBJECTIVE: To identify the risk factors for death in children with septic shock. METHODS: Clinical data of 53 children with septic shock admitted to the Yuying Children's Hospital between January 2006 and July 2008 were retrospectively studied. Risk factors for death were assessed using univariate analysis and logistic regression analysis. RESULTS: Nineteen cases died out of 53 children with septic shock. Univariate analysis and logistic regression analysis showed that arterial blood pH value<7.0 (OR=89.66), hypotension (OR=84.00), the pediatric critical illness score<70 (OR=60.00), the number of organ dysfunction>or=3 (OR=38.98), incompletion of volume resuscitation within 6 hrs after shock (OR=26.41), and no administration of effective antibiotics within 1 hr after shock (OR=11.43) and of vasoactive drugs (OR=75.68) were risk factors for death in children with septic shock. CONCLUSIONS: A low arterial blood pH value (<7.0), hypotension, a pediatric critical illness score (<70) and the number of organ dysfunction>or=3 are related to a high mortality in children with septic shock. If the volume resuscitation can be completed within 6 hrs after shock, effective antibiotics can be administered within 1 hr after shock, and vasoactive drugs can be used properly, the outcome of children with septic shock may be improved.

Efficacy of levofloxacin on macrolide-unresponsive and corticosteroid-resistant refractory Mycoplasma pneumoniae pneumonia in children.

BACKGROUND: This study aimed to summarize the experience in treatment of Mycoplasma pneumoniae pneumonia (MPP) with worsening lung shadow despite treatment with appropriate antimicrobials and corticosteroid in children. METHODS: All patients satisfied refractory MP pneumonia (RMPP) diagnostic criteria were enrolled. The clinical manifestations, laboratory findings, imaging features, treatments, and outcomes were retrospectively reviewed. RESULTS: Six patients with an average age of 7.83±3.13 years old were included in this study. All the patients were non-responsive to macrolide (ML) and glucocorticoids treatment shown by aggravated clinical symptoms and chest radiographies. The average total duration of fever was 19.5±8.34 days and the average time before levofloxacin (LVX) therapy was 10±2.97 days. After LVX treatment, the time of fever was from 1 to 3 days in five cases and 11 days in one case. The MP-DNA copies in the sputum decreased slowly after ML treatment in six patients, while they decreased quickly after LVX treatment in 5 children. A2063G mutation of domain V of 23SrRNA gene was found in five cases. Five patients recovered completely 16-32 days after treatment. One patient developed acute disseminated encephalomyelitis (ADEM) with abnormal brain magnetic resonance imaging and occurred serious sequelae. CONCLUSIONS: The sputum MP-DNA copies and clinical symptoms have a positive correlation with therapeutic efficacy. LVX may be beneficial in treatment of ML-unresponsive and corticosteroid-resistant RMPP in children. RMPP can be gradually cured by effective treatment of LVX, while which can damage the nervous system and lead to severe complications once MP invades brain tissues.

Clinical characteristics and effective treatments of scrub typhus-associated hemophagocytic lymphohistiocytosis in children.

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon and life-threatening disorder that may rarely complicate the clinical course of Orientia tsutsugamushi disease (scrub typhus). Here, we describe the clinical features, laboratory parameters, management, and outcome of 16 children with scrub typhus-associated HLH. All patients satisfied the HLH-2004 diagnostic criteria. All patients had fever of unknown origin and multisystem damage. Raised hepatic transaminases and abnormalities in routine blood test were observed in all children. Imaging tests showed abnormalities in 10 cases. Six patients were treated with intravenous azithromycin for 5 days, and 10 with intravenous chloramphenicol for 7-10 days because of non-response to 3-day azithromycin treatment. Five patients were treated with intravenous albumin and 3 with intravenous immunoglobulin. Two patients with severe symptoms (shortness of breath, cyanosis) were treated with dexamethasone (0.3 mg/kg/d). Fifteen patients recovered completely after 8-22 days of treatment. One patient died. The occurrence of severe complications draws attention to the need for early diagnosis and effective treatment. Anti-rickettsial antibiotic treatment (azithromycin or chloramphenicol) without the need for chemotherapy may be beneficial in such cases, instead of treatment according to the 2004 HLH protocol.

Inhibition of neddylation causes meiotic arrest in mouse oocyte.

Mammalian oocyte meiosis is a special form of cell division that provides haploid gametes for fertilization. Unlike in mitosis, post-translational modifications (PTMs) are more crucial during meiosis because of the absence of de novo mRNA transcription. As a classic PTM, protein neddylation is a biological process that mediates protein degradation by modifying cullin proteins and activating the Cullin-Ring E3 ligases. This process plays important roles in various biological processes such as autophagy and tumorigenesis. However, the function of neddylation in germ cells is unknown. In this study, we observed that the inhibition of neddylation by its specific inhibitor MLN4924 significantly arrests mouse oocyte at the stage of metaphase during meiosis. The arrested oocytes display impaired spindles with over-activation of spindle assembly checkpoint (SAC). Accordingly, we identified early mitosis inhibitor 1 (Emi1), a key inhibitor of anaphase-promoting complex/cyclosome (APC/CFzr1), as a substrate of neddylation-mediated protein degradation. Thus, our study uncovered an unknown role of neddylation in female germ cells and suggests that proper neddylation is essential for oocyte maturation.

High Glucose Level Induces Cardiovascular Dysplasia During Early Embryo Development.

The incidence of gestational diabetes mellitus (GDM) has increased dramatically amongst multiethnic population. However, how gestational diabetes mellitus damages the developing embryo is still unknown. In this study, we used yolk sac membrane (YSM) model to investigate angiogenesis in the developing chick embryo. We determined that in the presence of high glucose, it retarded the growth and extension of the embryonic vascular plexus and it also reduced the density of the vasculature in yolk sac membrane model. Using the same strategy, we used the chorioallantoic membrane (CAM) as a model to investigate the influence of high glucose on the vasculature. We established that high glucose inhibited development of the blood vessel plexus and the blood vessels formed had a narrower diameter than control vessels. Concurrent with the abnormal angiogenesis, we also examined how it impacted cardiogenesis. We determined the myocardium in the right ventricle and left atrium were significantly thicker than the control and also there was a reduction in glycogen content in cardiomyocytes. The high glucose also induced excess reactive oxygen species (ROS) production in the cardiomyocytes. We postulated that it was the excess reactive oxygen species that damaged the cardiomyocytes resulting in cardiac hyperplasia.

Protective effects of exogenous NaHS against sepsis-induced myocardial mitochondrial injury by enhancing the PGC-1α/NRF2 pathway and mitochondrial biosynthesis in mice.

This study aimed to examine whether exogenous NaHS can protect myocardial mitochondrial injury from sepsis by enhancing the peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α)/ nuclear factor erythroid-2-related factor 2 (NRF2) pathway and mitochondrial biosynthesis in mice. Animals were divided into sham-operated, sepsis, sepsis + 25 µmol/L NaHS, sepsis + 50 µmol/L NaHS, sepsis + 100 µmol/L NaHS, and sepsis + 200 µmol/L NaHS groups. The myocardial damage was evaluated by hematoxylin and eosin staining for myocardial microstructure and serum cardiac troponin I (cTnI) detection. The myocardial mitochondrial damage was evaluated through transmission electron microscopic observation of mitochondrial microstructure and detection of the degree of myocardial mitochondrial swelling. The adenosine triphosphate (ATP) level was used to appraise the mitochondrial function. The mRNA expression levels of Nrf2, PGC-1α, and Tfam were analyzed to explore the molecular mechanism. RESULTS: In the sepsis group, the structure of myocardial tissue and mitochondria were significantly damaged, the serum cTnI level increased (P < 0.05), the ATP level reduced, the degree of myocardial mitochondrial swelling aggravated, and the mRNA expression levels of Nrf2, PGC-1α, and Tfam increased (P < 0.05). After NaHS treatment, the structure of myocardial tissue and mitochondria improved, the cTnI level reduced, the ATP level increased, the degree of myocardial mitochondrial swelling alleviated, and the mRNA expression level of Nrf2, PGC-1α, and Tfam increased continuously in a dose-dependent manner (P < 0.05). CONCLUSIONS: Exogenous NaHS had a protective effect against myocardial mitochondrial injury in sepsis. The mechanism might lie in enhancing the PGC-1α/NRF2 pathway and mitochondrial biosynthesis.