Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melatonin, or N-acetyl-5-methoxytryptamine, is a compound derived from tryptophan that is found in all organisms from unicells to vertebrates. This indoleamine may act as a protective agent in disease conditions such as Parkinson's, Alzheimer's, aging, sepsis and other disorders including ischemia/reperfusion. In addition, melatonin has been proposed as a drug for the treatment of cancer. These disorders have in common a dysfunction of the apoptotic program. Thus, while defects which reduce apoptotic processes can exaggerate cancer, neurodegenerative disorders and ischemic conditions are made worse by enhanced apoptosis. The mechanism by which melatonin controls cell death is not entirely known. Recently, mitochondria, which are implicated in the intrinsic pathway of apoptosis, have been identified as a target for melatonin actions. It is known that melatonin scavenges oxygen and nitrogen-based reactants generated in mitochondria. This limits the loss of the intramitochondrial glutathione and lowers mitochondrial protein damage, improving electron transport chain (ETC) activity and reducing mtDNA damage. Melatonin also increases the activity of the complex I and complex IV of the ETC, thereby improving mitochondrial respiration and increasing ATP synthesis under normal and stressful conditions. These effects reflect the ability of melatonin to reduce the harmful reduction in the mitochondrial membrane potential that may trigger mitochondrial transition pore (MTP) opening and the apoptotic cascade. In addition, a reported direct action of melatonin in the control of currents through the MTP opens a new perspective in the understanding of the regulation of apoptotic cell death by the indoleamine.
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PMID:Melatonin mitigates mitochondrial malfunction. 1561 31

Liposomes have been investigated as drug carriers since first discovered in the 1960s. However, the first-generation, so-called classic liposomes found relatively limited therapeutic utility. Nonetheless, the advent in the 1980s of the second-generation sterically stabilized liposomes (SSL) that evade uptake by the host's reticuloendothelial system greatly enhanced their utility as drug carriers because of their prolonged circulation half-life and passive targeting to injured and cancerous tissues. Over the past decade, our work focused on exploiting the bioactivity of vasoactive intestinal peptide (VIP), a ubiquitous 28-amino acid, amphipathic and pleiotropic mammalian neuropeptide, as a drug. To this end, the peptide expresses distinct and unique innate bioactivity that could be harnessed to treat several human diseases that represent unmet medical needs, such as pulmonary hypertension, stroke, Alzheimer's disease, sepsis, female sexual arousal dysfunction, acute lung injury, and arthritis. Unfortunately, the bioactive effects of VIP last only a few minutes due to its rapid degradation and inactivation by enzymes, catalytic antibodies, and spontaneous hydrolysis in biological fluids. Hence, our goal was to develop and test stable, long-acting formulations of VIP using both classic and SSL as platform technologies. We found that spontaneous association of VIP with phospholipid bilayers leads to a transition in the conformation of the peptide from random coil in an aqueous environment to alpha-helix, the preferred conformation for ligand-receptor interactions, in the presence of lipids. This process, in turn, protects VIP from degradation and inactivation and amplifies its bioactivity in vivo. Importantly, we discovered that the film rehydration and extrusion technique is the most suitable to passively load VIP onto SSL at room temperature and yields the most consistent results. Collectively, these attributes indicate that VIP on SSL represents a suitable formulation that could be tested in human disease.
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PMID:Liposomal vasoactive intestinal peptide. 1572 92

This paper will review our recent data relevant to the antioxidant effects of N-acetylserotonin (NAS), the immediate precursor of melatonin, the pineal gland indole. Mechanisms of the antioxidant effects of NAS might involve interaction with melatonin type 3 receptors and nonreceptor mechanisms such as stimulation of glutathione peroxidase, an antioxidant enzyme; inhibition of lipid peroxidation; suppression of phospholipase A2 activation; attenuation of tumor necrosis factor-alpha production; prevention of pathological opening of the mitochondrial permeability transition pores; and inhibition of sepiapterin reductase, the key enzyme of biosynthesis of tetrahydrobiopterin, the essential cofactor of nitric oxide synthase. NAS actions on some of these enzymes might be receptor-mediated. Protective effects of NAS against oxidative damage are independent from the effect of melatonin and, depending on the model, are 5 to 20 times stronger than that of melatonin. Antioxidant effect of NAS might underpin its cognition-enhancing, antiaging, antidepressant, antihypertensive, and antitumor effects. NAS and its derivatives might be useful in protection against oxidative stress-related disorders (cell death, mutagenesis, aging) and diseases (sepsis, cancer, postischemic trauma, Alzheimer's disease, parkinsonism).
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PMID:Antioxidant effects of N-acetylserotonin: possible mechanisms and clinical implications. 1617 40

Dementia is one of the major causes of dependency after stroke. The prevalence of poststroke dementia (PSD)-defined as any dementia occurring after stroke-is likely to increase in the future. In community-based studies, the prevalence of PSD in stroke survivors is about 30% and the incidence of new onset dementia after stroke increases from 7% after 1 year 48% after 25 years. Having a stroke doubles the risk of dementia. Patient-related variables associated with an increased risk of PSD are increasing age, low education level, dependency before stroke, prestroke cognitive decline without dementia, diabetes mellitus, atrial fibrillation, myocardial infarction, epileptic seizures, sepsis, cardiac arrhythmias, congestive heart failure, silent cerebral infarcts, global and medial-temporal-lobe atrophy, and white-matter changes. Stroke-related variables associated with an increased risk of PSD are stroke severity, cause, location, and recurrence. PSD might be the result of vascular lesions, Alzheimer pathology, white-matter changes, or combinations of these. The cause of PSD differs among studies in relation to the mean age of patients, ethnicity, criteria used, and time after stroke. In developed countries, the proportion of patients with presumed Alzheimer's disease among those with PSD is between 19% and 61%. Patients with PSD have high mortality rates and are likely to be functionally impaired. These patients should be treated according to the current guidelines for stroke prevention.
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PMID:Poststroke dementia. 1623 82

Undesired activation of the complement system, a part of the immune system, is a major pathogenic factor contributing to various diseases, such as ischemia-reperfusion injury, sepsis, asthma, allergic reactions, rheumatoid arthritis, Alzheimer's disease, myasthenia, multiple sclerosis and others. The history of the development of complement system inhibitors, preventing its destructive action on the body, represents the evolution of the main methods of drug design. This review illustrates the main approaches of drug design, ranging from screening and modification of natural products to structure-based ligand design, on the basis of complement inhibitors' creation. The current status of the field of complement inhibitors is also discussed.
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PMID:Drug design using the example of the complement system inhibitors' development. 1625 76

Since its identification a third of a century ago, the high-mobility group box-1 (HMGB1) protein has been linked to varied diverse cellular processes, including release from necrotic cells and secretion by activated macrophages engulfing apoptotic cells. Initially described as solely chromatin-associated, HMGB1 was additionally discovered in the cytoplasm of several types of cultured mammalian cells 6 years later. In addition to its intracellular role, HMGB1 has been identified extracellularly as a putative leaderless cytokine and differentiation factor. In the years since its discovery, HMGB1 has also been implicated in disease states, including Alzheimer's, sepsis, ischemia-reperfusion, arthritis, and cancer. In cancer, overexpression of HMGB1, particularly in conjunction with its receptor for advanced glycation end products, has been associated with the proliferation and metastasis of many tumor types, including breast, colon, melanoma, and others. This review focuses on current knowledge and speculation on the role of HMGB1 in the development of cancer, metastasis, and potential targets for therapy.
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PMID:Masquerader: high mobility group box-1 and cancer. 1750 81

The cytokines interleukin-1 (IL-1alpha and IL-1beta) and the tumor necrosis factor-alpha (TNF-alpha) both play a major role in the initiation and regulation of inflammation and immunity responses. Polymorphisms within the gene sequences of these cytokines IL-1 and TNF-alpha have been proposed to play an important role in the pathogenesis of certain diseases. Affecting nearly every organ, various diseases, including some cancers, are described to be associated with an increased level of IL-1 and TNF-alpha proteins, for example, solid tumors, hematologic malignancies, malignant histiocytosis, autoimmune disorders, Alzheimer's disease, Parkinson's disease, sepsis, and rheumatoid arthritis. Regarding genetic backgrounds and pathways, numerous canine diseases show close similarities to their human counterparts. As a genetic model, the dog could be used to unravel the genetic mechanisms, for example, in particular the predispositions, the development, and progression of cancer and metabolic diseases. The identity comparison of gene and protein sequences of different species could be used to elucidate the structure and function of the genes and proteins by identifying the evolutionary conserved regions and domains. Herein we analyzed in detail the mRNA and protein structures and identities of the present known mammalian (human, canine, murine, rat, ovine, equine, feline, porcine, and bovine) TNF-alpha, IL-1alpha, and IL-1beta mRNAs and proteins. Additionally, based on the canine genome sequence, we derived in silico the complete mRNA structures of the IL-1alpha and IL-1beta mRNAs.
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PMID:Comparison of the human and canine cytokines IL-1(alpha/beta) and TNF-alpha to orthologous other mammalians. 1757 84

Complete Center for Disease Control death certificate records and Centers for Medicare and Medicaid Services 100% Standard Analytic File for hospice claims for 2002 were used to describe the whole population of hospice users and nonusers in the United States. The overall hospice utilization rate for persons 65 years and older was 28.6%. Hospice utilization varied by cause of death, and was highest for individuals with malignancies (65%), kidney disease and nephritis (55%), and Alzheimer's disease (41%). Hospice utilization was lowest for conditions leading to rapid or unexpected death, such as accidents and suicide (0%), influenza and pneumonia (3%), and sepsis (6%). Considerable geographic differences in hospice utilization existed, with hospice use higher in the South and the Southwest and lower in the Midwest and the Northeast. State-specific usage rates ranged from 8% in Alaska to 49% in Arizona. Our findings highlight opportunities for the hospice industry to provide more care, opportunities defined by diagnostic and geographic axes.
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PMID:Geographic variation in hospice use in the United States in 2002. 1759 May 66

Procalcitonin (PCT) is an established marker for severe systemic bacterial infection and sepsis in blood. Here we measured PCT by immunoassay in CSF and matched serum/plasma samples of controls and patients with different primary dementia disorders and acute neuroinflammation. PCT in CSF was significantly increased in patients with probable Alzheimer's disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and acute neuroinflammation (encephalitis, meningitis) compared to non-demented controls. In contrast, PCT levels in matched plasma samples were normal in dementia groups, but elevated in meningitis/encephalitis. Our results indicate a central production of PCT and suggest PCT as a valuable marker candidate for the monitoring of dementia and acute neuroinflammation.
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PMID:Procalcitonin is elevated in the cerebrospinal fluid of patients with dementia and acute neuroinflammation. 1769 9

Statins are pluripotent agents exhibiting multiple non-lipid-lowering actions. Besides their established role in the management of hypercholesterolemia, statins may also have beneficial actions in other pathological conditions, namely: a) osteoporosis and osteoporosis-related bone fractures, b) cancer, c) solid organ transplantation, d) cerebrovascular events (transient ischemic attack and stroke episodes), e) various neurological disorders, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis, f) cardiac arrhythmias and heart failure, g) renal diseases, h) rheumatoid arthritis, i) autoimmune diseases, j) sepsis, and k) allergic asthma. We reviewed the literature searching for studies that support or oppose the use of statins in each proposed indication. In some of these emerging indications, a role for statin treatment is more firmly set; for others, current evidence is more controversial. Future trials may reveal more convincing evidence that will make statin use necessary in the therapeutic management of several diseases.
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PMID:Emerging indications for statins: a pluripotent family of agents with several potential applications. 1822 Jul 99


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