naphthoquinones and Sepsis

Pyruvate kinase M2 is a critical enzyme that regulates cell metabolism and growth under different physiological conditions. In its metabolic role, pyruvate kinase M2 catalyzes the last glycolytic step which converts phosphoenolpyruvate to pyruvate with the generation of ATP. Beyond this metabolic role in glycolysis, PKM2 regulates gene expression in the nucleus, phosphorylates several essential proteins that regulate major cell signaling pathways, and contribute to the redox homeostasis of cancer cells. The expression of PKM2 has been demonstrated to be significantly elevated in several types of cancer, and the overall inflammatory response. The unusual pattern of PKM2 expression inspired scientists to investigate the unrevealed functions of PKM2 and the therapeutic potential of targeting PKM2 in cancer and other disorders. Therefore, the purpose of this review is to discuss the mechanistic and therapeutic potential of targeting PKM2 with the focus on cancer metabolism, redox homeostasis, inflammation, and metabolic disorders. This review highlights and provides insight into the metabolic and non-metabolic functions of PKM2 and its relevant association with health and disease.

Topics: Adenosine Triphosphate; Atherosclerosis; Carrier Proteins; Cell Proliferation; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Glycolysis; Homeostasis; Humans; Inflammation; Inflammatory Bowel Diseases; Insulin; Kidney Diseases; Liver; Membrane Proteins; Metabolic Diseases; Naphthoquinones; Neoplasm Metastasis; Neoplasms; Neuralgia; Oxidants; Oxidation-Reduction; Protein Isoforms; Sepsis; Signal Transduction; Thyroid Hormone-Binding Proteins; Thyroid Hormones; Tissue Distribution

Natural compounds were used in the treatment of acute kidney injury (AKI) caused by sepsis. This study investigated the function of shikonin from the roots of Arnebia purpurea in sepsis-induced AKI model. The target genes of shikonin were predicted by traditional Chinese medicine integrative database (TCMID). The markers of kidney injury, oxidative stress, and inflammatory factors were measured by enzyme-linked immunosorbent assay (ELISA). The pathological changes of kidney tubules were assessed by Hematoxylin and Eosin staining. Apoptosis of kidney tubular epithelial cells (KTECs) was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Protein expression was measured by western blot. Shikonin significantly improved kidney injury induced by cecal ligation and perforation (CLP). Besides, shikonin reduced KTECs apoptosis, malondialdehyde (MDA), reactive oxygen species (ROS), interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) levels, while augmented SOD and IL-10 levels. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase4 (NOX4) was predicted a target gene of shikonin. The expression of NOX4 was significantly inhibited in shikonin-treated group and the levels of phosphatidylinositol 3,4,5-trisphosphate 3-phosphate and dual specificity protein phosphate (PTEN) and p-p65 were decreased, while level of p-Akt was elevated. In vitro experiments, shikonin inhibited cell apoptosis, inflammatory, and ROS in human HK-2 cells and rat TECs. Shikonin downregulated expression of NOX4, PTEN and p-p65, and upregulated p-AKT and Bcl-2 expression in HK2 cells treated with lipopolysaccharide (LPS). Moreover, overexpression of NOX4 enhanced the effect of LPS on the expression level of PTEN, p-p65, p-AKT, and Bcl-2, which was reversed by the addition of shikonin. Taken together, shikonin could improve sepsis-induced AKI in rats, and attenuate the LPS induced KTECs apoptosis, oxidative stress, and inflammatory reaction via modulating NOX4/PTEN/AKT pathway.

Topics: Acute Kidney Injury; Animals; Apoptosis; Epithelial Cells; Humans; Kidney; Lipopolysaccharides; NADPH Oxidase 4; Naphthoquinones; Oxidative Stress; Phosphates; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; PTEN Phosphohydrolase; Rats; Reactive Oxygen Species; Sepsis

Shikonin is an anti-inflammatory agent extracted from natural herbs. The aim of this study is to explain the treatment effects and mechanism of Shikonin in acute lung injury induced by sepsis. In this study, first, we evaluate different Shikonin concentrations for the anti-inflammation of acute lung injury induced by sepsis in an in vivo study. On the basis of the results, we confirm that 50.0 mg/kg was the best therapeutic Shikonin concentration. As a second step, we discuss the mechanism of Shikonin by a vitro cell experiment. Finaly, we validate that Shikonin has effective treatment effects on acute lung injury via regulation of microRNA-140-5p/toll-like receptor 4 (miRNA-140-5p/TLR4) in the in vivo study. The results of vitro and vivo study showed that Shikonin could improve acute lung injury induced by sepsis. The mechanism might be correlation miRNA-140-5p expression increasing, and regulated targeted gene TLR4, with TLR4 expression depressing, the downstream myeloid differentiation protein 88 and nuclear factor κB proteins expression were suppressed. In conclusion, Shikonin improved sepsis induced lung injury by regulation miRNA-140-5p/TLR4.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cell Proliferation; Cells, Cultured; Gene Expression Regulation; Male; MicroRNAs; Naphthoquinones; Rats; Sepsis; Specific Pathogen-Free Organisms; Toll-Like Receptor 4

Sepsis is an infection-induced aggressive and life-threatening organ dysfunction with high morbidity and mortality worldwide. Infection-associated inflammation and coagulation promote the progression of adverse outcomes in sepsis. Here, we report that phospho-Tyr705 of STAT3 (pY-STAT3), not total STAT3, contributes to systemic inflammation and coagulopathy in sepsis.. Cecal ligation and puncture (CLP)-induced septic mice were treated with BP-1-102, Napabucasin, or vehicle control respectively and then assessed for systemic inflammation, coagulation response, lung function and survival. Human pulmonary microvascular endothelial cells (HPMECs) and Raw264.7 cells were exposed to lipopolysaccharide (LPS) with pharmacological or genetic inhibition of pY-STAT3. Cells were assessed for inflammatory and coagulant factor expression, cell function and signaling.. Pharmacological inhibition of pY-STAT3 expression by BP-1-102 reduced the proinflammatory factors, suppressed coagulation activation, attenuated lung injury, alleviated vascular leakage and improved the survival rate in septic mice. Pharmacological or genetic inhibition of pY-STAT3 diminished LPS-induced cytokine production in macrophages and protected pulmonary endothelial cells via the IL-6/JAK2/STAT3, NF-κB and MAPK signaling pathways. Moreover, the increase in procoagulant indicators induced by sepsis such as tissue factor (TF), the thrombin-antithrombin complex (TAT) and D-Dimer were down-regulated by pY-STAT3 inhibition.. Our results revealed a therapeutic role of pY-STAT3 in modulating the inflammatory response and defective coagulation during sepsis. Video Abstract.

Topics: Aminosalicylic Acids; Animals; Benzofurans; Blood Coagulation; Cecum; Cell Membrane Permeability; Endothelial Cells; Humans; Inflammation; Inflammation Mediators; Ligation; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Models, Biological; Molecular Targeted Therapy; Naphthoquinones; Phosphotyrosine; Punctures; RAW 264.7 Cells; Sepsis; STAT3 Transcription Factor; Sulfonamides; Suppression, Genetic; Survival Analysis; Thromboplastin; Toll-Like Receptor 4

Sepsis is characterized by a dysregulated immune response to infection characterized by an early hyperinflammatory and oxidative response followed by a subsequent immunosuppression phase. Although there have been some advances in the treatment of sepsis, mortality rates remain high, urging for the search of new therapies.

Topics: Animals; Anti-Inflammatory Agents; Chemoprevention; Cytokines; Disease Models, Animal; Immunosuppression Therapy; Inflammation; Inflammation Mediators; Male; Mice; Naphthoquinones; Oxidative Stress; Sepsis; Survival Rate

Topics: Animals; Anti-Bacterial Agents; Boraginaceae; Drug Synergism; Mice; Microbial Sensitivity Tests; Naphthoquinones; Pentanoic Acids; Peritonitis; Sepsis; Staphylococcal Infections; Staphylococcus aureus

Sepsis is an inevitable stage of bacterial invasion characterized by the deregulated inflammatory response, resulting in multiorgan dysfunction syndrome. Acute liver injury is a common and serious complication in patients with severe sepsis. The most of conventional antibiotics in managing sepsis are effective, but they are accompanied by undesirable side effects. Therefore, the ongoing study aimed to evaluate the efficacy of echinochrome (Ech) pigment isolated from sea urchins on sepsis-induced liver damage using cecal ligation and puncture (CLP) model.. Male albino rats were randomly divided into three groups: sham group, CLP-induced sepsis, and septic rats treated with Ech. The estimation of liver function markers and oxidative status were analyzed.. The results demonstrated that Ech administration significantly improved liver function, as indicated by the decreased liver enzyme activities such as alanine transaminase, gamma-glutamyl transferase, lactate dehydrogenase, aspartate transaminase, and alkaline phosphatase, as well as the increase of albumin content. Moreover, Ech could counteract the hepatic oxidative stress induced by CLP via a marked increment in glutathione content and antioxidant enzyme activities (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-s-transferase), as well as downregulation of malondialdehyde, nitric oxide, and hydrogen peroxide formation. In addition, the Ech treatment repaired, to some extent, the abnormal architecture of hepatic tissues induced by polymicrobial infection.. In conclusion, Ech could be used as a potential alternative antiseptic remedy via oxidative damage attenuation.

Topics: Animals; Liver Diseases; Liver Function Tests; Male; Naphthoquinones; Oxidative Stress; Paracentrotus; Pigments, Biological; Protective Agents; Quinones; Random Allocation; Rats; Rats, Wistar; Sepsis; Treatment Outcome

Sepsis, severe sepsis and septic shock are the main cause of mortality in non-cardiac intensive care units. Immunometabolism has been linked to sepsis; however, the precise mechanism by which metabolic reprogramming regulates the inflammatory response is unclear. Here we show that aerobic glycolysis contributes to sepsis by modulating inflammasome activation in macrophages. PKM2-mediated glycolysis promotes inflammasome activation by modulating EIF2AK2 phosphorylation in macrophages. Pharmacological and genetic inhibition of PKM2 or EIF2AK2 attenuates NLRP3 and AIM2 inflammasomes activation, and consequently suppresses the release of IL-1β, IL-18 and HMGB1 by macrophages. Pharmacological inhibition of the PKM2-EIF2AK2 pathway protects mice from lethal endotoxemia and polymicrobial sepsis. Moreover, conditional knockout of PKM2 in myeloid cells protects mice from septic death induced by NLRP3 and AIM2 inflammasome activation. These findings define an important role of PKM2 in immunometabolism and guide future development of therapeutic strategies to treat sepsis.

Topics: Animals; Carrier Proteins; Coinfection; Disease Models, Animal; DNA-Binding Proteins; eIF-2 Kinase; Female; Glycolysis; HMGB1 Protein; Humans; Inflammasomes; Interleukin-18; Interleukin-1beta; Macrophages; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Knockout; Myeloid Cells; Naphthoquinones; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphorylation; Pyruvate Kinase; Sepsis; Signal Transduction; Thyroid Hormone-Binding Proteins; Thyroid Hormones

beta-Lapachone, a 1,2-naphthoquinone, is a novel chemotherapeutic agent. It has been shown to be capable of suppressing inducible nitric oxide synthase expression and function in rat alveolar macrophages. The authors further performed experiments to examine the molecular mechanism of beta-lapachone on LPS-induced responses in rat alveolar macrophages and to evaluate its in vivo antiinflammatory effect. A significant increase in nitrite production and inducible nitric oxide synthase expression was elicited in macrophages treated with LPS that was inhibited by coincubation with beta-lapachone. beta-Lapachone could also inhibit the production of tumor necrosis factor-alpha induced by LPS. LPS induces protein tyrosine phosphorylation and nuclear factor-kappaB binding activity by gel mobility shift assay in macrophages. These events were significantly inhibited by beta-lapachone. Furthermore, beta-lapachone in vivo protected against the induction of lung edema, lung-inducible nitric oxide synthase protein expression and nuclear factor-kappaB activation, lethality, and increased plasma nitrite and serum tumor necrosis factor-alpha levels induced by LPS. These results indicate that beta-lapachone suppresses inducible nitric oxide synthase induction and tumor necrosis factor-alpha production mediated by the inhibition of protein tyrosine phosphorylation and nuclear factor-kappaB activation caused by LPS. This results in a beneficial effect in an animal model of sepsis.

Topics: Animals; Anti-Infective Agents; Cells, Cultured; Disease Models, Animal; Drug Evaluation, Preclinical; Endotoxins; Inflammation; Lipopolysaccharides; Macrophage Activation; Macrophages, Alveolar; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Naphthoquinones; NF-kappa B; Nitric Oxide Synthase; Phosphorylation; Pulmonary Edema; Rats; Sepsis; Signal Transduction; Tumor Necrosis Factor-alpha