INTRODUCTION: Sepsis is defined as a life-threatening complication that occurs when the body responds to an infection attacking the host. Sepsis rapidly progresses and patients deteriorate and develop septic shock, with multiple organ failure, if not promptly treated. Currently no effective therapy is available for sepsis; therefore, early diagnosis is crucial to decrease the high mortality rate. Genome-wide expression analyses of patients in critical conditions have confirmed that the expression levels of the majority of genes are changed, suggesting that the molecular basis of sepsis is at the gene level. This review aims to elucidate the role of circular (circ) RNAs in the pathogenesis of sepsis and sepsis-induced organ damage. In addition, the feasibility of using circRNAs as novel diagnostic biomarkers for sepsis is also discussed, as well as circRNA-based therapy. METHOD: This narrative review is based on a literature search using Medline database. Search terms used were "circular RNAs and sepsis", "circRNAs and sepsis", "non-coding RNAs and sepsis", "ncRNAs and sepsis", "circRNAs and septic pathogenesis", "circRNAs and septic model", "circRNAs and septic shock" and "circRNAs, biomarker, and sepsis". RESULTS: Numerous studies indicate that circRNAs might exert pivotal roles in regulating the immune system of the host against various pathogens, such as bacteria and viruses. Dysregulation of circRNA expression levels has been confirmed as an early event in sepsis and associated with the inflammatory response, immunosuppression and coagulation dysfunction. This impairment in regulation eventually leads to multiple organ dysfunctions, including of the kidneys, lungs and heart. CONCLUSION By investigating the regulation of circRNAs in sepsis, new molecular targets for the diagnosis and intervention of sepsis can be identified. Such an understanding will be important for the development of therapeutic drugs.
Biomarkers ; Humans ; RNA, Circular ; Shock, Septic/genetics*

AIMThe role of activated nuclear factor-kappa B(NF-kappaB) on the expression of heme oxygenase-1 induced by lipopolysaccharide (LPS) in rats' myocardium was obversed, and the effect exerted in endotoxic shock was explored.

METHODSThe changes in mean arterial pressure within 12 hours were recorded on a polygraph. The protein expression of NF-kappaB p65 in rats'myocardium, which were induced by lipopolysaccharide were measured with immunochemistry. The changes both of protein and gene expression of heme oxygenase-1 in rats' myocardium, which were induced by injection of LPS or preadministration of the specific inhibitor of NF-kappaB, pyrrolidine dithiocarbamate(PDTC), were examined by immunochemistry of reverse transcripted polymerase chain reaction.

RESULTS(1) LPS caused a rapid decrease of MAP within 12 h( P < 0.01). (2) After LPS was administration, the protein expression of NF-kappaB p65 in both of micrangium endothelium within myocardium markedly increased at 0.5 h and 2 h, while decreased gradually at 6 h and 12 h. (3) ES group expressed as migration of acute inflammatory cells and dilation and stagnation in blood capillary, while the increase of HO-1 mRNA induced by LPS didn't change at the first 0.5 h, began at 2 h, peaked at 6 h, and declined at 12 h, respectively. The protein expression of HO-1 in micrangium endothelium within myocardium markedly increased and emerged in myocardium, and kept a high level at 6 h and 12 h. (4) When a specific inhibitor of NF-kappaB, PDTC, was applied to inhibit the level of NF-kappaB, we found that the pathomorphological changes of myocardium in ES rats were improved and both HO-1 mRNA and protein expression in myocardium markedly failed at 6 h.

CONCLUSIONNF-kappaB was activated on the stimulation of LPS, which brought about its translocation to the nucleus to act on transcription activity of HO-1 gene. NF-kappaB might be involved in its signal transductive mechanisms, which might be one of the important mechanism of LPS inducing the refractory low arterial pressure in ES rats.

Animals ; Heme Oxygenase-1 ; genetics ; metabolism ; Lipopolysaccharides ; adverse effects ; Male ; Myocardium ; metabolism ; NF-kappa B ; metabolism ; Rats ; Rats, Sprague-Dawley ; Shock, Septic ; metabolism

To investigate the changes of intestinal microcirculation in endotoxic shock and the effect of inducible nitric oxide synthase (iNOS) on intestinal microcirculation, endotoxic shock was induced by intravenous injection of lipopolysaccharide (LPS) in mice. Mean arterial pressure (MAP) was monitored throughout the experimental procedure. The velocity and flux of red blood cell (RBC) in villus tip arteriole and capillaries were measured by FITC-labeled erythrocytes and intravital microscopy. The effect of iNOS was determined by targeted disruption of mice iNOS-gene and administration of S-methylthiourea sulfate (SMT), a selective inhibitor of iNOS, before LPS injection. No significant differences in MAP, RBC velocity and flux at baseline were found among wild type mice, SMT pretreated mice and iNOS-gene knockout mice. LPS induced a dramatic fall of MAP in wild type mice. The decrease of MAP was significantly restored in iNOS-gene knockout mice and in wild type mice received SMT before LPS injection. The velocity and flux of RBC in villus tip arteriole and capillaries decreased markedly after LPS injection in wild type mice, while significantly higher velocity and flux of RBC were found in iNOS-gene knockout mice and SMT-pretreated mice both 60 and 120 min after LPS injection. The results demonstrate that iNOS plays an essential role in the intestinal microcirculation disturbance which occurs in endotoxic shock.
Animals ; Intestines ; blood supply ; Lipopolysaccharides ; Male ; Mice ; Mice, Knockout ; Microcirculation ; physiology ; Nitric Oxide Synthase Type II ; genetics ; physiology ; Shock, Septic ; chemically induced ; physiopathology

OBJECTIVETo investigate the antagonistic effect and mechanism of the effect of cyproheptadine (Cyp) on endotoxic shock in rats.

METHODSEndotoxic shock was produced in rats by i.v. injection of lipopolysaccharides (LPS) (5 mg/kg). Tumor necrosis factor (TNF(alpha)) mRNA expression was assessed by Northern blot. Plasma TNF(alpha) content was measured by radioimmunoassay. Plasma superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured. The intracellular free calcium concentration ([Ca(2+)](i)) in single endothelial cells was determined by laser scanning confocal microscopy (LSCM).

RESULTSCyp 5 mg/kg injected immediately after i.v. LPS raised the mean arterial blood pressure (MABP) of shocked rats and improved their 24 h survival rate. Meanwhile, Cyp markedly decreased TNF(alpha) mRNA levels in rat liver (18 +/- 10 vs. LPS + saline 38 +/- 10, P < 0.01) as well as plasma TNF(alpha) content [(7.8 +/- 2.4) microg/L vs. LPS + saline (21.5 +/- 3.2) microg/L, P < 0.01)]. It enhanced plasma SOD activity [(1037.2 +/- 112.8) NU/L vs LPS + saline (615.4 +/- 92.6) NU/L, P < 0.01], reduced the MDA content [(5.2 +/- 1.1) micromol/L vs. LPS + saline (9.8 +/- 1.5) micromol/L, P < 0.01], and inhibited TNF(alpha)-induced [Ca(2+)](i) elevation.

CONCLUSIONCyp exerts an anti-endotoxic shock effect by inhibiting TNF(alpha) gene expression, enhancing SOD activity, reducing lipid peroxidation, and preventing [Ca(2+)](i) overload.

Animals ; Cyproheptadine ; pharmacology ; Histamine H1 Antagonists ; pharmacology ; Malondialdehyde ; blood ; Rats ; Rats, Wistar ; Shock, Septic ; drug therapy ; metabolism ; Superoxide Dismutase ; blood ; Tumor Necrosis Factor-alpha ; biosynthesis ; genetics

PURPOSE: High mobility group box 1 (HMGB1) plays a central role in the pathogenesis of sepsis and multiple organ dysfunction syndromes. We investigated the associations of a single nucleotide polymorphism (SNP; rs1045411) in HMGB1 with various clinical parameters, severity, and prognosis in patients with sepsis, severe sepsis, or septic shock. MATERIALS AND METHODS: We enrolled 212 adult patients followed for 28 days. All patients were genotyped for rs1045411, and the serum levels of HMGB1 and several cytokines were measured. RESULTS: The proportions of patients according to genotype were GG (71.2%), GA (26.4%), and AA (2.4%). Among patients with chronic lung disease comorbidity, patients with a variant A allele had higher positive blood culture rates and higher levels of various cytokines [interleukin (IL)-1beta, IL-6, IL-10, IL-17, and tumor necrosis factor-alpha] than those with the GG genotype. In the analysis of those with diabetes as a comorbidity, patients with a variant A allele had higher blood culture and Gram-negative culture rates than those with GG genotypes; these patients also had a higher levels of IL-17. In the analysis of those with sepsis caused by a respiratory tract infection, patients with a variant A allele had higher levels of IL-10 and IL-17 (all p<0.05). This polymorphism had no significant impact on patient survival. CONCLUSION: The variant A allele of rs1045411 appears to be associated with a more severe inflammatory response than the GG genotype under specific conditions.
Adult ; Aged ; Alleles ; Asian Continental Ancestry Group/genetics ; China/epidemiology ; Cytokines/*blood/*genetics ; Female ; Genotype ; HMGB1 Protein/blood/*genetics ; Humans ; Interleukin-10/genetics ; Interleukin-17/genetics ; Interleukin-6/blood ; Male ; Middle Aged ; Polymorphism, Genetic/*genetics ; Polymorphism, Single Nucleotide/*genetics ; Prognosis ; Republic of Korea ; Sepsis/immunology/*metabolism/mortality ; Shock, Septic/immunology/*metabolism/mortality ; Survival ; Tumor Necrosis Factor-alpha/genetics

Clostridium difficile (C. difficile) is a common causative agent of pseudomembranous colitis (PMC). C. difficile-associated diarrhea (CDAD) ranges from mild diarrhea to life threatening PMC. Recently, a highly virulent strain of C. difficile polymerase chain reaction ribotype 027 was found in North America, Europe, and Japan. A 52-yr-old woman with anti-tuberculosis medication and neurogenic bladder due to traffic accident experienced five episodes of C. difficile PMC after taking antibiotics for pneumonia along with septic shock and acute renal failure. She was readmitted to the intensive care unit and treated with oral vancomycin with refractory of oral metronidazole, inotropics and probiotics for over 60 days. C. difficile isolated both at the first and the last admission was identified as C. difficile ribotype 027 by ribotyping, toxinotyping, and tcdC gene sequencing, which turned out the same pathogen as the epidemic hypervirulent B1/NAP1 strain. This is the first case of C. difficile PCR ribotype 027 in Korea. After discharge, she was maintained on probiotics and rifaximin for 3 weeks. She had no relapse for 6 months.
Accidents, Traffic ; Antitubercular Agents/therapeutic use ; Base Sequence ; Clostridium difficile/*classification/genetics/isolation & purification ; Enterocolitis, Pseudomembranous/*diagnosis/drug therapy/*microbiology ; Female ; Humans ; Kidney Failure, Acute/diagnosis ; Korea ; Middle Aged ; Molecular Sequence Data ; Polymerase Chain Reaction ; Ribotyping ; Shock, Septic/diagnosis

ATP-sensitive potassium (K(ATP)) channels are widely distributed in vasculatures, and play an important role in the vascular tone regulation. The K(ATP) channels consist of 4 pore-forming inward rectifier K(+) channel (Kir) subunits and 4 regulatory sulfonylurea receptors (SUR). The major vascular isoform of K(ATP) channels is composed of Kir6.1/SUR2B, although low levels of other subunits are also present in vascular beds. The observation from transgenic mice and humans carrying Kir6.1/SUR2B channel mutations strongly supports that normal activity of the Kir6.1/SUR2B channel is critical for cardiovascular function. The Kir6.1/SUR2B channel is regulated by intracellular ATP and ADP. The channel is a common target of several vasodilators and vasoconstrictors. Endogenous vasopressors such as arginine vasopressin and α-adrenoceptor agonists stimulate protein kinase C (PKC) and inhibit the K(ATP) channels, while vasodilators such as β-adrenoceptor agonists and vasoactive intestinal polypeptide increase K(ATP) channel activity by activating the adenylate cyclase-cAMP-protein kinase A (PKA) pathway. PKC phosphorylates a cluster of 4 serine residues at C-terminus of Kir6.1, whereas PKA acts on Ser1387 in the nucleotide binding domain 2 of SUR2B. The Kir6.1/SUR2B channel is also inhibited by oxidants including reactive oxygen species allowing vascular regulation in oxidative stress. The molecular basis underlying such a channel inhibition is likely to be mediated by S-glutathionylation at a few cysteine residues, especially Cys176, in Kir6.1. Furthermore, the channel activity is augmented in endotoxemia or septic shock, as a result of the upregulation of Kir6.1/SUR2B expression. Activation of the nuclear factor-κB dependent transcriptional mechanism contributes to the Kir6.1/SUR2B channel upregulation by lipopolysaccharides and perhaps other toll-like receptor ligands as well. In this review, we summarize the vascular K(ATP) channel regulation under physiological and pathophysiological conditions, and discuss the importance of K(ATP) channel as a potentially useful target in the treatment and prevention of cardiovascular diseases.
ATP-Binding Cassette Transporters ; genetics ; physiology ; Animals ; Endotoxemia ; metabolism ; physiopathology ; Humans ; KATP Channels ; genetics ; physiology ; Mice ; Mice, Transgenic ; Muscle, Smooth, Vascular ; metabolism ; physiology ; Potassium Channels, Inwardly Rectifying ; genetics ; physiology ; Receptors, Drug ; genetics ; physiology ; Shock, Septic ; metabolism ; physiopathology ; Sulfonylurea Receptors ; Vasoconstriction ; physiology ; Vasodilation ; physiology ; Vasomotor System ; physiology

The association of hematological malignancies with a mediastinal germ cell tumor (GCT) is very rare. We report one case of a young adult male with primary mediastinal GCT who subsequently developed acute megakaryoblastic leukemia involving isochromosome (12p). A 25-yr-old man had been diagnosed with a mediastinal GCT and underwent surgical resection and adjuvant chemotherapy. At 1 week after the last cycle of chemotherapy, his peripheral blood showed leukocytosis with blasts. A bone marrow study confirmed the acute megakaryoblastic leukemia. A cytogenetic study revealed a complex karyotype with i(12p). Although additional chemotherapy was administered, the patient could not attain remission and died of septic shock. This case was definitely distinct from therapy-related secondary leukemia in terms of clinical, morphologic, and cytogenetic features. To our knowledge, this is the first case report of a patient with mediastinal GCT subsequently developing acute megakaryoblastic leukemia involving i(12p) in Korea.
Adult ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Bleomycin/administration & dosage ; Bone Marrow/pathology ; *Chromosomes, Human, Pair 12 ; Cisplatin/administration & dosage ; Etoposide/administration & dosage ; Humans ; Isochromosomes ; Karyotyping ; Leukemia, Megakaryoblastic, Acute/drug therapy/etiology/*genetics ; Male ; Mediastinal Neoplasms/*diagnosis/drug therapy/surgery ; Neoplasms, Germ Cell and Embryonal/*diagnosis/drug therapy/surgery ; Neoplasms, Second Primary/drug therapy/etiology/*genetics ; Republic of Korea ; Shock, Septic/pathology

Sphingobacterium spiritivorum has been rarely isolated from clinical specimens of immunocompromised patients, and there have been no case reports of S. spiritivorum infection in Korea to our knowledge. We report a case of S. spiritivorum bacteremia in a 68-yr-old woman, who was diagnosed with acute myeloid leukemia and subsequently received chemotherapy. One day after chemotherapy ended, her body temperature increased to 38.3degrees C. A gram-negative bacillus was isolated in aerobic blood cultures and identified as S. spiritivorum by an automated biochemical system. A 16S rRNA sequencing analysis confirmed that the isolate was S. spiritivorum. The patient received antibiotic therapy for 11 days but died of septic shock. This is the first reported case of human S. spiritivorum infection in Korea. Although human infection is rare, S. spiritivorum can be a fatal opportunistic pathogen in immunocompromised patients.
Aged ; Anti-Bacterial Agents/therapeutic use ; Bacteremia/*complications/drug therapy/*microbiology ; Bone Marrow Cells/pathology ; Fatal Outcome ; Female ; Humans ; Immunocompromised Host ; Leukemia, Myeloid, Acute/*complications ; Phylogeny ; RNA, Ribosomal, 16S/genetics ; Sequence Analysis, DNA ; Shock, Septic/etiology/microbiology ; Sphingobacterium/classification/genetics/isolation & purification/*physiology

OBJECTIVETo observe the influence of treatment with the inhibitor of extracellular-signal regulated protein kinase (ERK) signal transduction pathway on the expression of biopterin/nitric oxide (NO) as well as the activation of nuclear factor-kappaB (NF-kappaB), and to clarify the potential cross-talk regulation mechanisms between ERK and NF-kappaB pathway in biopterin-mediated NO induction in rats with endotoxic shock.

METHODSUsing an endotoxic shock model, 60 male Wistar rats were randomly divided into normal controls (n = 8), endotoxic shock group (n = 32) and PD98059 treatment group (n = 20). At serial time points animals in each group were sacrificed, and tissue samples from liver, lungs as well as kidneys were harvested to detect NF-kappaB activity, guanosine triphosphate-cyclohydrolase (GTP-CHI) and inducible nitric oxide synthase (iNOS) mRNA expression. Biopterin and NO levels in plasma and tissues were also assayed.

RESULTSIt was found that after lipopolysaccharide (LPS) challenge, GTP-CHI mRNA expression and biopterin levels significantly elevated in liver, lungs and kidneys, keeping at high values up to 24 h, so did the values of iNOS mRNA expression and NO levels. NF-kappaB DNA binding activity was enhanced rapidly in various tissues, peaking at 2 h after LPS challenge. Treatment with PD98059, an inhibitor of ERK signal transduction pathway, could significantly inhibit GTP-CHI mRNA expression in kidneys, and GTP-CHI mRNA expression in liver and lungs showed certain down-regulation tendency. At the same time, biopterin level was significantly decreased in plasma, liver and kidneys at 12 h. Similarly, iNOS/NO induction at early stage markedly decreased in various tissues. In addition, treatment with PD98059 reduced NF-kappaB DNA binding activity in liver, lungs, as well as kidneys at 2-6 h, 2 h, 24 h and 24 h after LPS challenge, respectively.

CONCLUSIONSInhibition of ERK pathway could partially inhibit the production of biopterin/NO as well as the activation of NF-kappaB pathway, which indicated that cross-talk regulation seems to be existed between ERK and NF-kappaB pathway, and they might be involved in the regulatory process of biopterin-mediated nitric oxide induction in rats with endotoxic shock.

Animals ; Biopterin ; metabolism ; physiology ; Disease Models, Animal ; Extracellular Signal-Regulated MAP Kinases ; physiology ; GTP Cyclohydrolase ; biosynthesis ; genetics ; Male ; NF-kappa B ; metabolism ; Nitric Oxide ; biosynthesis ; Nitric Oxide Synthase Type II ; biosynthesis ; genetics ; Random Allocation ; Rats ; Rats, Wistar ; Shock, Septic ; physiopathology ; Signal Transduction