The neuroprotection of controlled decompression after traumatic epidural intracranial hypertension through suppression of autophagy via PI3K/Akt signaling pathway.

Acute intracranial hypertension (AIH) is a common and tricky symptom that inflicts upon patients after traumatic brain injury (TBI). A variety of clinical options have been applied for the management of AIH, such as physiotherapy, medication, surgery and combination therapy. Specifically, controlled decompression (CDC) alleviates the extent of brain injury and reduces the incidence of a series of post-TBI complications, thereby enhancing the prognosis of patients suffering from acute intracranial hypertension. The objective of the present project is to illuminate the potential molecular mechanism that underlies the neuroprotective effects of CDC in a rat model of traumatic epidural intracranial hypertension (TEIH). Herein, we observed the functional recovery, the degree of brain edema, the level of apoptosis, the expressions of neuronal cell autophagy-related signaling pathway proteins (including Akt, p-Akt, LC3 and Beclin-1) in rat TEIH model at 24 h post-surgery. The results showed in comparison with rapid decompression (RDC), CDC reduced the degree of brain edema, diminished the level of cellular apoptosis and enhanced neurological function, and whereas the neuroprotective effect of CDC could be reversed by rapamycin (Rap). The expressions of Beclin-1 and LC3 in CDC group were significantly lower than those of RDC group, and the expression levels of these two proteins were significantly elevated after the addition of Rap. The expression of p-Akt in CDC group was considerably enhanced than RDC group. After the addition of LY294002, a PI3K/Akt pathway inhibitor, p-Akt protein expression was reduced, and the neuroprotective effect of the rats was markedly inhibited. Taken together, our data demonstrate the superior neuroprotective effect of CDC with regard to alleviating early brain edema, improving the neurological status, suppressing apoptosis and inhibiting neuronal autophagy via triggering PI3K/Akt signaling pathway.

Controlled Decompression Alleviates Motor Dysfunction by Regulating Microglial Polarization via the HIF-1α Signaling Pathway in Intracranial Hypertension.

Decompressive craniectomy (DC) is a major form of surgery that is used to reduce intracranial hypertension (IH), the most frequent cause of death and disability following severe traumatic brain injury (sTBI) and stroke. Our previous research showed that controlled decompression (CDC) was more effective than rapid decompression (RDC) with regard to reducing the incidence of complications and improving outcomes after sTBI; however, the specific mechanisms involved have yet to be elucidated. In the present study, we investigated the effects of CDC in regulating inflammation after IH and attempted to identify the mechanisms involved. Analysis showed that CDC was more effective than RDC in alleviating motor dysfunction and neuronal death in a rat model of traumatic intracranial hypertension (TIH) created by epidural balloon pressurization. Moreover, RDC induced M1 microglia polarization and the release of pro-inflammatory cytokines. However, CDC treatment resulted in microglia primarily polarizing into the M2 phenotype and induced the significant release of anti-inflammatory cytokines. Mechanistically, the establishment of the TIH model led to the increased expression of hypoxia-inducible factor-1α (HIF-1α); CDC ameliorated cerebral hypoxia and reduced the expression of HIF-1α. In addition, 2-methoxyestradiol (2-ME2), a specific inhibitor of HIF-1α, significantly attenuated RDC-induced inflammation and improved motor function by promoting M1 to M2 phenotype transformation in microglial and enhancing the release of anti-inflammatory cytokines. However, dimethyloxaloylglycine (DMOG), an agonist of HIF-1α, abrogated the protective effects of CDC treatment by suppressing M2 microglia polarization and the release of anti-inflammatory cytokines. Collectively, our results indicated that CDC effectively alleviated IH-induced inflammation, neuronal death, and motor dysfunction by regulating HIF-1α-mediated microglial phenotype polarization. Our findings provide a better understanding of the mechanisms that underlie the protective effects of CDC and promote clinical translational research for HIF-1α in IH.

Retraction Notice to: Exosomes Derived from miR-143-Overexpressing MSCs Inhibit Cell Migration and Invasion in Human Prostate Cancer by Downregulating TFF3.

[This retracts the article DOI: 10.1016/j.omtn.2019.08.010.].

A newborn with convulsions 12 days after birth was misdiagnosed as neonatal intracranial hemorrhage: Case report.

INTRODUCTION: Cases with early diagnosis of neonatal tuberous sclerosis syndrome (TSC) are relatively seldom seen, and misdiagnosis of intracranial hemorrhage is even more rare. We retrospectively analyzed the clinical data of a case of neonatal tuberous sclerosis with atypical early symptoms and misdiagnosed as more common intracranial hemorrhage of the newborn. PATIENT CONCERNS: The child was female and had no obvious cause of convulsion 12 days after birth. The local hospital was initially diagnosed as "neonatal intracranial hemorrhage, congenital heart disease," and still had convulsions after 5 days of treatment, so it was transferred to neonatal intensive care unit of our hospital. DIAGNOSIS: After admission, cardiac color ultrasound, magnetic resonance imaging, and electroencephalogram were performed, and TSC was diagnosed in combination with clinical symptoms. However, no known pathogenic mutations such as TSC1 and TSC2 were detected by peripheral blood whole exon sequencing. INTERVENTION: After a clear diagnosis, sirolimus, and vigabatrin were given. But there were still convulsions. Topiramate, valproic acid, and oxcarbazepine were successively added to the outpatient department for antiepileptic treatment, and vigabatrin gradually decreased. OUTCOME: Up to now, although the seizures have decreased, they have not been completely controlled. CONCLUSIONS: The TSC of neonatal tuberous sclerosis is different from that of older children. It is usually characterized by respiratory distress and arrhythmia, and may be accompanied by convulsions, but the activity between attacks is normal. However, neonatal intracranial hemorrhage can be caused by premature delivery, birth injury, hypoxia, etc. Its characteristics are acute onset, severe illness, and rapid progression. Consequently, the diagnosis of these 2 diseases should not only be based on medical imaging, but also be combined with their clinical characteristics. When the imaging features are inconsistent with the clinical diagnosis, a comprehensive evaluation should be made again. The timing and pattern of onset of neonatal convulsions can help in differential diagnosis. If there is cardiac rhabdomyoma, subependymal or cortical nodule, skin low melanoma, etc, the possibility of neonatal TSC should be considered, and the diagnosis should be made according to its diagnostic criteria to avoid or reduce misdiagnosis.

IP3R-mediated activation of BK channels contributes to mGluR5-induced protection against spinal cord ischemia-reperfusion injury.

Spinal cord ischemia-reperfusion injury (SCIRI) can cause dramatic neuron loss and lead to paraplegia in patients. In this research, the role of mGluR5, a member of the metabotropic glutamate receptors (mGluRs) family, was investigated both in vitro and in vivo to explore a possible method to treat this complication. In vitro experiment, after activating mGluR5 via pretreating cells with (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG) and 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), excitotoxicity induced by glutamate (Glu) was attenuated in primary spinal cord neurons, evidenced by higher neuron viability, decreased lactate dehydrogenase (LDH) release and less detected TUNEL-positive cells. According to Western Blot (WB) results, Glu treatment resulted in a high level of large-conductance Ca2+- and voltage-activated K+ (BK) channels, with activation relying on the mGluR5-IP3R (inositol triphosphate) pathway. In vivo part, a rat model of SCIRI was built to further investigate the role of mGluR5. After pretreating them with CHPG and CDPPB, the rats showed markedly lower spinal water content, attenuated motor neuron injury in the spinal cord of L4 segments, and better neurological function. This effect could be partially reversed by paxilline, a blocker of BK channels. In addition, activating BK channels alone using specific openers: NS1619 or NS11021 can protect spinal cord neurons from injury induced by either SCIRI or Glu. In conclusion, in this research, we proved that mGluR5 exerts a protective role in SCIRI, and this effect partially works via IP3R-mediated activation of BK channels.

Dexmedetomidine-mediated regulation of miR-17-3p in H9C2 cells after hypoxia/reoxygenation injury.

Patients with heart disease often suffer from ischemia, which can be treated by reperfusion. However, this treatment can lead to the development of ischemia/reperfusion (I/R) injury, an inflammatory condition that can cause further heart damage. Dexmedetomidine (Dex), an α2-adrenoceptor agonist, and the microRNA (miR)-17-3p, have both been suggested to alleviate I/R injury and cardiac tissue inflammation. The aim of the present study was to investigate whether Dex and miR-17-3p could act together to prevent I/R injury. H9C2 cells, a myoblast cell line used as a model of rat cardiomyocytes, were cultured in a hypoxic environment for 3 h, and then reoxygenated for 3 h. This hypoxia/reoxygenation (H/R) was used to model I/R. Cell Counting kit-8 was used to determine cell viability and an annexin V-FITC/propidium iodide apoptosis kit used to analyze cell apoptosis. A dual luciferase reporter assay was used to determine the interaction between miR-17-3p and toll-like receptor 4 (TLR4). Western blotting and reverse transcription-quantitative PCR were used to determine protein levels and mRNA expression of TLR4 and galectin-3. A concentration of 0.1-10 µmol/l Dex attenuated H/R injury, which was accompanied by increased miR-17-3p levels. Additionally, the inhibition of miR-17-3p exacerbated H/R injury and reduced the effect of Dex on H/R injury. H/R led to an increased galectin-3 level compared with that in control cells, and Dex or miR-17-3p inhibitor did not markedly affect the level of galectin-3, indicating that Dex alleviated the effects of I/R injury through other pathways. Inhibition of miR-17-3p in Dex-induced H9C2 cells during H/R increased the expression of inflammatory mediators including tumor necrosis factor-α, interleukin (IL)-6, IL-1ß and phosphorylated NFκB subunit p65, while Dex reduced the H/R-induced expression of these inflammatory mediators. Inhibition of TLR4 also attenuated H/R injury. In summary, the findings of the present study indicated that Dex reduced H/R injury in H9C2 cell via the modulation of inflammatory signaling pathways, and these inflammatory factors could be regulated by miR-17-3p.

Resveratrol prevents liver damage in MCD-induced steatohepatitis mice by promoting SIGIRR gene transcription.

Persistent inflammation is one of the main reasons that nonalcoholic fatty liver disease develops into cirrhosis and liver cancer, and reducing the expression of inflammatory factors may be an effective strategy to alleviate the development of nonalcoholic steatohepatitis (NASH). SIGIRR, a member of the interleukin-1 receptor family, has been shown to inhibit the production of inflammatory cytokines, and its down-regulation or deletion has been suggested to be an important cause of inflammatory damage to organs. In this study, we identified that resveratrol efficiently induced the transcriptional activity of the SIGIRR promoter and also increased SIGIRR mRNA levels in human hepatocytes and mouse livers. Furthermore, the potential effects of resveratrol on a methionine/choline-deficient diet-induced NASH mouse model were investigated. Resveratrol maintained the expression level of SIGIRR in the mouse liver. Resveratrol intervention alleviated NASH progression; decreased the levels of alanine aminotransferase and aspartate aminotransferase; and down-regulated tumor necrosis factor-α, interleukin (IL)-6, IL-1ß and transforming growth factor-ß mRNA and protein levels. Additionally, increased SIGIRR potentially blocked the activity of the Toll-like receptor/nuclear factor-κB signaling pathway both in vivo and in vitro. In vitro, resveratrol pretreatment protected against hepatocyte injury caused by foamy macrophage-released inflammatory cytokines, which are involved in the development of NASH. However, resveratrol did not effectively induce hepatocyte SIGIRR gene transcription in the inflammatory cytokine microenvironment. In conclusion, resveratrol is practical and acts as an agonist of the SIGIRR protein to negatively regulate the expression of inflammatory factors in liver, suggesting that appropriate intake may be a potential way to prevent the occurrence and development of NASH.

Improved drug delivery and anti-tumor efficacy of combinatorial liposomal formulation of genistein and plumbagin by targeting Glut1 and Akt3 proteins in mice bearing prostate tumor.

Despite the plethora of significant research progress made to develop novel strategies for the treatment of prostate cancer, this disease remains one of the major global health challenges among men. However, using a co-treatment approach utilizing two or more anticancer drugs has shown tremendous success in the treatment of many cancer types. Nanoliposomes are well known to encapsulate multiple drugs and deliver them at the desired site. In this work, we report the synthesis of nanoliposomes (∼100 nm) encapsulating two drugs, plumbagin, and genistein, to synergistically inhibit the growth of prostate cancer cells. The combination of plumbagin and genistein drugs was found inhibiting xenograft prostate tumor growth by ∼80 % without any appreciable toxicity. Mechanistically, the combination of plumbagin and genistein containing nanoliposomes leads to the inhibition of PI3K/AKT3 signaling pathway as well as the decreased population of Glut-1 transporters to impart the retardation in tumor growth. Decrease in proliferative cells and blood vessels are early biological processes that laid the foundation of the observed anti-tumor effect. Thus, a novel, and non-toxic liposomal formulation, containing plumbagin and genistein drugs, is reported, which can deliver anticancer agents to prostate tumors and inhibit the growth.

Effect of lung recruitment on blood gas index, hemodynamics, lung compliance, and rehabilitation index in children with acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a common pediatric disease, with an increasing mortality rate in recent years. This study aims to explore the effects of lung recruitment on blood gas indexes, hemodynamics, lung compliance, and rehabilitation index in children with ARDS. METHODS: Seventy children with ARDS admitted to our hospital from December 2017 to December 2018 were selected as the study subjects, and were divided into a study group (35 cases, treated with lung recruitment strategy) and a control group (35 cases, treated with routine therapy). The changes of blood gas indexes, such as partial pressure of oxygen (PO2), partial pressure of carbon dioxide (PCO2), and partial pressure of oxygen/fraction of inspired oxygen (PO2/FiO2) levels, as well as hemodynamic indexes, including cardiac output (CO), heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), were compared before and after treatment in the two groups. RESULTS: Results showed that the difference in blood gas indexes between the two groups was statistically significant after treatment (P<0.05), and that the levels of PaO2, PaCO2, pondus Hydrogenii (pH), and PO2/FiO2 in the study group were all higher compared to the control group (P<0.05). The hemodynamic indexes showed that CO was significantly different between the two groups (P<0.05), but HR, MAP, and CVP were not (P>0.05). The lung compliance values of the two groups continued to increase at different time points after treatment (P<0.05), and the lung compliance of the study group was higher than that of the control group immediately after recruitment, as well as at 10 and 60 min of lung recruitment (P<0.05). In addition, the ventilator use, ICU stay, and hospital stay times of the study group were shorter than those in the control group (P<0.05), and the mortality rate of the study group was lower than that of the control group (P>0.05). CONCLUSIONS: The lung recruitment strategy has a significant therapeutic effect on children with ARDS. It can effectively improve blood and gas function and lung compliance, and has a positive effect on the hemodynamic stability of children with ARDS.

Exosomes Derived from miR-143-Overexpressing MSCs Inhibit Cell Migration and Invasion in Human Prostate Cancer by Downregulating TFF3.

Exosomes are membrane-enclosed nanovesicles that shuttle active cargoes, such as mRNAs and microRNAs (miRNAs), between different cells. Mesenchymal stem cells (MSCs) are able to migrate to the tumor sites and exert complex functions over tumor progress. We investigated the effect of human bone marrow-derived MSC (BMSC)-derived exosomal miR-143 on prostate cancer. During the co-culture experiments, we disrupted exosome secretion by the inhibitor GW4869 and overexpressed exosomal miR-143 using miR-143 plasmid. miR-143 was involved in the progression of prostate cancer via trefoil factor 3 (TFF3). Moreover, miR-143 was downregulated while TFF3 was upregulated in prostate cancer cells and tissues, and miR-143 was found to specifically inhibit TFF3 expression. Human MSC-derived exosomes enriched miR-143 and transferred miR-143 to prostate cancer cells. Furthermore, elevated miR-143 or exosome-miR-143 or silencing TFF3 inhibited the expression of TFF3, proliferating cell nuclear antigen (PCNA), matrix metalloproteinase (MMP)-2, and MMP-9 and PC3 cell proliferation, migration, invasion, and tumor growth, whereas it promoted apoptosis. In conclusion, hMSC-derived exosomal miR-143 directly and negatively targets TFF3 to suppress prostate cancer.

Interactive Aggregation-Induced Emission Systems Controlled by Dynamic Covalent Chemistry.

Aggregation-induced emission (AIE) molecules show all kinds of application in biological research, chemical sensing, and medical study. However, most of the reported molecules are based on the performance of the single molecular entity. In this paper, a molecular system for real-time sensing through combination of dynamic covalent chemistry and aggregation-induced emission was rationally designed and tested. The aggregated particles exhibit different fluorescence emission colors upon the addition of various kinds of chemical reagents. The LC-MS analysis reveals that the breakage, formation, and exchange of the disulfide bonds in the molecular system occur spontaneously upon different reagents (base/acid and cysteine), which leads to a change in the proportion of different components in the system accordingly. Meanwhile, the fluorescence emission of the AIE system exhibits blue/red shift accompanied by intensity changes. Moreover, the particle size of the aggregated molecules gradually increased with the change of the chemical environment, which could be the result of the nucleus growing through intermolecular hydrogen bonding among molecular components. Thus, the chemical environment change results in the interactions of molecules, which further leads to the variation of dynamic fluorescence emission and morphology. The result represents a promising future for a dynamic AIE molecular system in the bioimaging and sensing study.

Relationship of serum inflammatory cytokines with anemia and vascular endothelial function in children with systemic lupus erythematosus.

OBJECTIVE: To analyze the relationship of the serum levels of inflammatory cytokines with the degree of anemia and vascular endothelial function in children with systemic lupus erythematosus (SLE), as well as to explore the predictive value of risk factors for SLE in children. METHODS: A total of 88 patients with SLE diagnosed in the Pediatric Department of our hospital from March 2015 to February 2017 were selected as the observation group, and 30 healthy controls with comparable age were selected as the control group. Basic characteristics of all enrolled individuals, such as age, sex, height and weight, and the related biochemical indexes, including the levels of inflammatory cytokines [C-reactive protein (CRP), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR)], blood routine test including hemoglobin (Hb), platelet (PLT) and mean corpuscular volume as well as related indexes of vascular endothelial function, such as homocysteine (Hcy), carbonic oxide (NO), endothelial nitric oxide synthase (eNOS) were measured. In addition, the SLE disease activity index (SLEDAI) score of patients was also recorded. RESULTS: There were no significant differences regarding age, sex, body mass index (BMI), triglyceride (TG), low density lipoprotein-cholesterol (LDL-C) and high density lipoprotein-cholesterol (HDL-C) between observation group and control group (p > 0.05), but the total cholesterol (TC) level in observation group was significantly higher than that in control group (p < 0.05). In addition, the levels of CRP, TNF-α, IL-6 and ESR in serum in observation group were significantly higher than those in control group (p < 0.05). However, the Hb, PLT and mean corpuscular volume in observation group were significantly lower than those in control group (p < 0.05). Moreover, the levels of Hcy, NO and eNOS in observation group were significantly higher than those in control group (p < 0.05). Furthermore, correlation analyses showed that CRP was positively correlated with SLEDAI score (r = 0.791, p < 0.001) and Hcy level (r = 0.817, p < 0.001), but negatively correlated with Hb level (r = -0.663, p < 0.001). CONCLUSION: There is a close relationship between serum inflammatory cytokines and SLE severity, Hcy or Hb level in children, suggesting these inflammatory cytokines might be novel indicators for evaluating the severity of SLE.

Elevated levels of cerebrospinal fluid and plasma interleukin-37 in patients with Guillain-Barré syndrome.

UNLABELLED: AIMS. Interleukin-37 (IL-37) is an anti-inflammatory cytokine. This study aims to investigate the concentrations of plasma and cerebrospinal fluid (CSF) IL-37 in patients with Guillain-Barré Syndrome (GBS). METHODS: The levels of plasma and CSF IL-37, IL-17A, IFN- γ , and TNF- α in 25 GBS patients and 20 healthy controls (HC) were determined by enzyme-linked immunoabsorbent assay and flow cytometric bead array assay, respectively. The values of clinical parameters in the patients were also measured. RESULTS: The concentrations of plasma IL-37, IL-17A, IFN- γ , and TNF- α and CSF IL-37 and IL-17A in patients at the acute phase of GBS were significantly higher than those in the HC. The levels of plasma IL-37, IL-17A, IFN- γ , and TNF- α were positively correlated in those patients, and the levels of CSF IL-37 and IL-17A as well as the levels of plasma TNF- α were correlated positively with the GBS disability scale scores (GDSs) in those patients. Treatment with intravenous immunoglobulin significantly reduced the levels of plasma IL-37, IL-17A, IFN- γ , and TNF- α in the drug-responding patients. CONCLUSIONS: Our findings indicate higher levels of plasma and CSF IL-37 and IL-17A and other proinflammatory cytokines in patients with GBS.

DNA vaccine expressing repeated carcinoembryonic antigen (CEA)(625-667) induces strong immunity in mice.

The efficacy of immunization with DNA plasmids for single truncated carcinoembryonic antigen (CEA) peptide or triple repeated CEA peptides in mice was evaluated. A DNA fragment the truncated CEA gene (nucleotide 625-667) encoding two helper T lymphocyte (HTL) epitopes was amplified by PCR and cloned for generating recombinant plasmids for single CEA(625-667) (pcDNA-CEA(625-667)) or triple CEA(625-667) (pcDNA-triCEA(625-667)), respectively. Subsequently, groups of BALB/c female mice were intramuscularly injected with pcDNA-CEA(625-667,) pcDNA-triCEA(625-667) or control pcDNA3.0 vector, respectively. Ten days after the last immunization, the frequency of splenic CD4(+) and CD8(+) T cells in the mice was determined by flow cytometry. The antigen-specific proliferation of splenic T cells and cytokine production ex vivo were analyzed by (3)H-TdR uptake and cytokine ELISA, respectively. The levels of serum antibodies against CEA in the mice were detected by Western blot and ELISA. Although immunization with plasmid for the CEA(625-667) peptide(s) did not alter the frequency of CD4(+) and CD8(+) T cells in mice, vaccination with plasmid for CEA peptide induced strong antigen-specific T cell proliferation, particularly for the plasmid encoding the triple-repeated CEA peptides, accompanied by significantly elevated levels of IFN-γ secreted by T cells from the mice immunized with triple-repeated peptides. Furthermore, immunization with the plasmid for CEA peptide stimulated higher levels of antigen-specific antibody responses in mice. Vaccination with the plasmid for the triple repeated CEA peptides induced stronger Th1 responses. Our findings may be useful for the development of effective DNA vaccine for the immunotherapy of cancer.