Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signal transduction mechanism in the regulation of high mobility group box protein 1 (HMGB1) has not yet been well elucidated. Our data showed for the first time that Janus kinase-signal transduction and activator of transcription (JAK/STAT) pathway played a major role in the regulation of expression and inflammatory effect of HMGB1. The study was carried out in the following sequence. Firstly, the role of JAK/STAT pathway in the regulation of expression of HMGB1 was examined. After stimulation with 75 ng/mL LPS in vitro, significant increases in HMGB1 expression and prompt activation of JAK/STAT pathway were demonstrated in cultured macrophages. On the other hand, administration of AG490 (specific inhibitor for JAK2), fludarabine (specific inhibitor for STAT1) or rapamycin (specific inhibitor for STAT3) markedly suppressed HMGB1 expression. Secondly, the role of JAK/STAT pathway in the regulation of TNF-alpha expression induced by HMGB1 was examined. When macrophages were stimulated with 10 microg/mL HMGB1 in vitro, significant increases in TNF-alpha expression and prompt activation of JAK/STAT pathway were demonstrated, whereas inhibitors of JAK/STAT pathway significantly suppressed TNF-alpha expression. Taken together, our data strongly indicated that expression and inflammatory effect of HMGB1 could be mediated by JAK/STAT pathway and suggested a possible clinical strategy to control an inflammatory effect of HMGB1 in sepsis.
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PMID:Role of Janus kinase/signal transducer and activator of transcription pathway in regulation of expression and inflammation-promoting activity of high mobility group box protein 1 in rat peritoneal macrophages. 1717 81

Mucosal repair is a complex event that immediately follows acute injury induced by ischemia and noxious luminal contents such as bile. In the small intestine, villous contraction is the initial phase of repair and is initiated by myofibroblasts that reside immediately beneath the epithelial basement membrane. Subsequent events include crawling of healthy epithelium adjacent to the wound, referred to as restitution. This is a highly regulated event involving signaling via basement membrane integrins by molecules such as focal adhesion kinase and growth factors. Interestingly, however, ex vivo studies of mammalian small intestine have revealed the importance of closure of the interepithelial tight junctions and the paracellular space. The critical role of tight junction closure is underscored by the prominent contribution of the paracellular space to measures of barrier function such as transepithelial electrical resistance. Additional roles are played by subepithelial cell populations, including neutrophils, related to their role in innate immunity. The net result of reparative mechanisms is remarkably rapid closure of mucosal wounds in mammalian tissues to prevent the onset of sepsis.
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PMID:Restoration of barrier function in injured intestinal mucosa. 1742 41

A 30-year-old HIV-infected intravenous drug user presented with sepsis, acute renal failure, oedema, proteinuria and iron deficiency anaemia. After extensive investigation, a diagnosis of reactive systemic AA (amyloid, serum amyloid A protein) amyloidosis was made on the basis of renal, gastric and duodenal biopsies.
Int J STD AIDS 2007 May
PMID:Renal and gastrointestinal amyloidosis in an HIV-infected injection drug user. 1752 3

Kaposi's sarcoma (KS) usually presents with typical skin lesions. We report two cases that presented with illnesses suggesting major sepsis, but were found to have disseminated KS at postmortem with little in the way of cutaneous involvement.
Int J STD AIDS 2007 Nov
PMID:Septic illness and Kaposi's sarcoma. 1800 17

Endothelial cells control the passage of plasma constituents and circulating cells from blood to the underlying tissues. This specialized function is lost or impaired in several pathological conditions - including inflammation, sepsis, ischemia and diabetes - which leads to severe, and sometimes fatal, organ dysfunction. Endothelial permeability is regulated in part by the dynamic opening and closure of cell-cell adherens junctions (AJs). In endothelial cells, AJs are largely composed of vascular endothelial cadherin (VE-cadherin), an endothelium-specific member of the cadherin family of adhesion proteins that binds, via its cytoplasmic domain, to several protein partners, including p120, beta-catenin and plakoglobin. Endogenous pathways that increase vascular permeability affect the function and organization of VE-cadherin and other proteins at AJs in diverse ways. For instance, several factors, including vascular endothelial growth factor (VEGF), induce the tyrosine phosphorylation of VE-cadherin, which accompanies an increase in vascular permeability and leukocyte diapedesis; in addition, the internalization and cleavage of VE-cadherin can cause AJs to be dismantled. From the knowledge of how AJ organization can be modulated, it is possible to formulate several pharmacological strategies to control the barrier function of the endothelium. We discuss the possible use of inhibitors of SRC and other kinases, of agents that increase cAMP levels, and of inhibitors of lytic enzymes as pharmacological tools for decreasing endothelial permeability.
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PMID:The role of adherens junctions and VE-cadherin in the control of vascular permeability. 1856 24

Tigecycline belong to glycylcycline antibiotics. This new group of antibiotics was derived from lipophilic tetracyclines but differs from them by higher effectivity, lower affinity to bacterial resistance mechanisms, and very long half-time. Tigecycline is registered for treatment two groups of infections: skin and soft tissue infections and complicated intra-abdominal infections. Nevertheless, its therapeutic use probably can be enlarged to pneumonia, STD, infections caused by multi-resistant Helicobacter pylori, subacute and chronic infections associated with biofilm formation, and serious infections caused by intracellular pathogens (serious brucellosis, Q-fever, rickettsial infections). By contrast, tigecycline seems not appropriate for treatment sepsis and similar acute life-threatening bacterial diseases.
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PMID:[Tigecycline: Its position between other antibiotics, features, clinical usage]. 1939 24

Respiratory failure is a major cause of mortality during septic shock and is due in part to decreased ventilatory muscle contraction. Ventilatory muscles have high energy demands; fatty acid (FA) oxidation is an important source of ATP. FA oxidation is regulated by nuclear hormone receptors; studies have shown that the expression of these receptors is decreased in liver, heart, and kidney during sepsis. Here, we demonstrate that lipopolysaccharide (LPS) decreases FA oxidation and the expression of lipoprotein lipase (LPL), FA transport protein 1 (FATP-1), CD36, carnitine palmitoyltransferase beta, medium chain acyl-CoA dehydrogenase (MCAD), and acyl-CoA synthetase, key proteins required for FA uptake and oxidation, in the diaphragm. LPS also decreased mRNA levels of PPARalpha and beta/delta, RXRalpha, beta, and gamma, thyroid hormone receptor alpha and beta, and estrogen related receptor alpha (ERRalpha) and their coactivators PGC-1alpha, PGC-1beta, SRC1, SRC2, Lipin 1, and CBP. Zymosan resulted in similar changes in the diaphragm. Finally, in PPARalpha deficient mice, baseline CPT-1beta and FATP-1 levels were markedly decreased and were not further reduced by LPS suggesting that a decrease in the PPARalpha signaling pathway plays an important role in inducing some of these changes. The decrease in FA oxidation in the diaphragm may be detrimental, leading to decreased diaphragm contraction and an increased risk of respiratory failure during sepsis.
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PMID:Infection decreases fatty acid oxidation and nuclear hormone receptors in the diaphragm. 1944 62

We previously reported that a combination of beta-glucan and indomethacin (IND), a non-steroidal anti-inflammatory drug, was lethal to mice. This lethality was strongly related to translocation of enterobacterial flora to various organs and the development of a systemic inflammation. In this study, we examined expression of microsomal cytochrome P450 (CYP), a drug-metabolizing enzyme mostly found in the liver. Normal ICR mice and endotoxin-low responder C3H/HeJ mice were employed to assess effects of endotoxin on impairment of CYP. In the ICR mice, CYP3A11 expression was decreased by beta-glucan or IND. In the early stage of beta-glucan + IND-treatment, 3A11 expression decreased more significantly; when shock was induced, CYP was dramatically decreased. 3A11 expression was also decreased in C3H/HeJ mice, but the effect was milder. In contrast, in both strains, CYP2E1 expression did not vary due to beta-glucan or IND, but decreased during sepsis. To clarify the molecular mechanisms of induced sepsis in C3H/HeJ mice, the reactivity of other pathogen-associated molecular patterns (PAMPs) was assessed. Those studies showed cooperative effects between Pam(3)CSK(4) (Pam(3)) and CpG ODN (CpG-oligodeoxynucleotide) on the induction of IL-6 synthesis by C3H/HeJ spleen cells. The findings here suggest that the beta-glucan + IND combination influenced hepatic cytochrome P450 expression, particularly in the late stage of sepsis. The results also indicate that this change may be associated with not only endotoxin but other PAMPs as well, and could be affected by the integrity of a host's drug metabolism function.
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PMID:Effect of SPG/indomethacin treatment on sepsis, interleukin-6 production, and expression of hepatic cytochrome P450 isoforms in differing strains of mice. 1951 62

With improved survival, more AIDS patients, especially heavy smokers and alcohol abusers, may be confronted with laryngeal squamous cell carcinoma. Since curative treatment may require aggressive combined therapy, these patients, often suffering from immunosupression and poor general condition, present unique therapeutic challenges. The objective of the study was to describe treatment dilemmas. This case report presents a detailed description of an AIDS patient with carcinoma of the larynx. A patient with T3N0M0 laryngeal carcinoma and AIDS underwent tracheotomy and biopsy, followed by severe neck and pulmonary infection. After convalescence, radiotherapy was administered, with no evidence of a disease during a 3.5-year follow-up. During his remaining life, the patient developed severe psychoaffective disorder, his immune state deteriorated until he demised from sepsis. In conclusion, patients with HIV infection, especially having a history of tobacco or alcohol abuse, should be carefully examined for head and neck carcinoma that is likely to be more aggressive. Following surgery, AIDS patients may have worse wound healing and a greater tendency to contract infections. Radiotherapy and especially chemotherapy may cause life-threatening complications. Although early detection may increase survival, curative treatment should involve many disciplines and extra caution.
Int J STD AIDS 2009 Aug
PMID:Laryngeal cancer in acquired immunodeficiency syndrome. 1962 96

Sepsis, a leading cause of death in hospitalized patients, is characterized by lethal systemic inflammatory responses. JAK2 is an essential tyrosine kinase modulating immune responses. However, the implications of JAK2 in infectious disorders remain undetermined. Here, we report that JAK2 inhibitors rescue animals from polymicrobial sepsis in a clinically relevant time frame. JAK2 inhibition with AG490 prevents NF-kappaB activation, modulates macrophage activation, and restrains the production of inflammatory cytokines. The inhibition of JAK2 blunted TNF production in both macrophages and splenocytes in a concentration-dependent manner. JAK2 inhibition specifically prevents LPS-induced STAT3 tyrosine phosphorylation without affecting serine phosphorylation in macrophages. JAK2 inhibitor prevents the activation of the canonical p65RelA/p50NF-kappaB1 pathway but not the other NF-kappaB proteins. In vivo, JAK2 inhibition restrains serum TNF levels by modulating TNF production in the lung and the spleen and protects mice from lethal endotoxemia in a concentration-dependent manner. AG490 also inhibits extracellular release of HMGB1 from macrophages and prevents an increase in serum HMGB1 levels during sepsis. JAK2 inhibition started at 24 h after the onset of sepsis rescued the mice from polymicrobial sepsis. Our study is the first experimental evidence that JAK2 inhibitors may provide a pharmacological advantage for the treatment of sepsis in a clinically relevant time frame.
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PMID:JAK2 inhibition prevents innate immune responses and rescues animals from sepsis. 2039 90


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