Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesis of GSH from glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes, gamma-glutamylcysteine synthetase and GSH synthetase. Compelling evidence shows that GSH synthesis is regulated primarily by gamma-glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.
 ...
PMID:Glutathione metabolism and its implications for health. 1498 35

The use of the recreational drug crystal methamphetamine among younger homosexual men is expanding, and with it, unsafe sex behaviors that increase the transmission of human immunodeficiency virus (HIV). This article reviews available literature on the medical and psychiatric morbidities associated with methamphetamine abuse in HIV-infected patients. Medical complications include hypertension, hyperthermia, rhabdoymyolysis, and stroke. One fatal case of ingestion of methamphetamine with HIV medication has been documented. Two fatal cases of ingestion of HIV medication with the amphetamine analogue n-methyl-3,4 methylenedioxymethamphetamine (MDMA, or "ecstasy") have also been reported. Some molecular researchers suggest that dopaminergic systems are vulnerable to the combined neurotoxicity of HIV infection and methamphetamine. Population surveys indicate high rates of HIV infection among methamphetamine abusers and high rates of unprotected anal intercourse during drug intoxication. Intoxication can sometimes produce paranoia, auditory hallucinations, and, occasionally, violent behavior. Amphetamine withdrawal commonly results in symptoms of depression. Methamphetamine is a new challenge related to treatment and prevention of HIV infection.
 ...
PMID:Crystal methamphetamine, its analogues, and HIV infection: medical and psychiatric aspects of a new epidemic. 1499 36

Herpes zoster (HZ) results from recrudescence of varicella zoster virus latent since primary infection (varicella). The overall incidence of HZ is approximately 3/1000 of the population per year rising to 10/1000 per year by 80 years of age. Approximately 50% of individuals reaching 90 years of age will have had HZ. In approximately 6%, a second attack may occur (usually several decades after the first). Patients with HZ can transmit the virus to a non-immune individual causing varicella. HZ is not contracted from individuals with varicella or HZ. Reduced cell-mediated immunity to HZ occurs with ageing, explaining the increased incidence in the elderly and from other causes such as tumours, HIV and immunosuppressant drugs. Diagnosis is usually clinical from typical unilateral dermatomal pain and rash. Prodromal symptoms, pain, itching and malaise, are common. The most common complication of HZ is postherpetic neuralgia (PHN), defined as significant pain or dysaesthesia present >or= 3 months after HZ. PHN results from damage and secondary changes within components of the nervous system subserving pain. Some motor deficit is common; severe and long-lasting paresis may rarely accompany HZ. More than 5% of elderly patients have PHN at 1 year after acute HZ. Predictors of PHN are, greater age, acute pain and rash severity, prodromal pain, the presence of virus in peripheral blood as well as adverse psychosocial factors. Therapy for acute HZ is intended to reduce acute pain, hasten rash healing and reduce the risk of PHN and other complications. Antiviral drugs are close to achieving these aims but do not entirely remove risk of PHN. Oral steroids show no protective effect against PHN. Adequate analgesia during the acute phase may require strong opioid drugs. Nerve blocks and tricyclic antidepressants (TCAs) may reduce the risk of PHN although firm evidence is lacking. PHN requires thorough evaluation and development of a management strategy for each individual patient. Initial therapy is with TCAs (e.g., nortriptyline) or the anticonvulsant gabapentin. Topical lidocaine patches frequently reduce allodynia. Strong opioids are sometimes required. Topical capsaicin cream is beneficial for a small proportion of patients but is poorly tolerated. NMDA antagonists have not proved beneficial with the exception of ketamine. Transcutaneous Electrical Nerve Stimulation (TENS) may be effective in some cases. HZ is a common condition. Severe complications such as stroke, encephalitis and myelitis are relatively rare whereas sight threatening complications of ophthalmic HZ are more common. PHN is common, distressing and often intractable. Good management improves outcome.
 ...
PMID:Management of herpes zoster (shingles) and postherpetic neuralgia. 1501 24

This review presents an overview of the highlights of major concepts involving the anatomical routes for the transport of macromolecules and the transmigration of cellular elements across the blood-brain barrier (BBB) during inflammation. The particular focus will include inflammatory leukocytes, neoplastic cells and pathogenic microorganisms including specific types of viruses, bacteria and yeasts. The experimental animal models presented here have been employed successfully by the authors in several independent experiments during the past twenty-five years for investigations of pathologic alterations of the BBB after a variety of experimentally induced injuries and inflammatory conditions in mammalian and non-mammalian animal species. The initial descriptions of endothelial cell (EC) vesicles or caveolae serving as mini-transporters of fluid substances essentially served as a springboard for many subsequent discoveries during the past half century related to mechanisms of uptake of materials into ECs and whether or not pinocytosis is related to the transport of these materials across EC barriers under normal physiologic conditions and after tissue injury. In the mid-1970's, the authors of this review independently applied morphologic techniques (transmission electron microscopy-TEM), in conjunction with the plant protein tracer horseradish peroxidase (HRP) to investigate macromolecular transport structures that increased after the brain and spinal cord had been subjected to a variety of injuries. Based on morphologic evidence from these studies of BBB injury, the authors elaborated a unique EC system of modified caveolae that purportedly fused together forming transendothelial cell channels, and later similar EC profiles defined as vesiculo-canalicular or vesiculo-tubular structures (VTS, Lossinsky, et al., 1999). These EC structures were observed in association with increased BBB permeability of tracers including exogenously injected HRP, normally excluded from the intercellular milieu of the CNS. Subsequent studies of non-BBB-type tumor ECs determined that the EC VTS and other vesicular structures were defined by others as vesiculo-vacuolar organelles (VVOs, Kohn et al., 1992; Dvorak et al., 1996). Collectively, these structures appear to represent a type of anatomical gateway to the CNS likely serving as conduits. However, these CNS conduits become patent only in damaged ECs for the passage of macromolecules, and purportedly for inflammatory and neoplastic cells as well (Lossinsky et al., 1999). In this review, we focus attention on the similarities and differences between caveolae, fused racemic vesicular bundles, endothelial tubules and channels (VTS and the VVOs) that are manifest in normal, non-BBB-type blood vessels, and in the BBB after injury. This review will present evidence that the previous studies by the authors and other researchers established a framework for subsequent transmission (TEM), scanning (SEM) and high-voltage electron microscopic (HVEM) investigations concerning ultrastructural, ultracytochemical and immunoultra-structural alterations of the cerebral ECs and the mechanisms of the BBB transport that occurs after CNS injury. This review is not intended to include all of the many observations that might be included in a general historical overview of the development of the EC channel hypothesis, but it will discuss several of the major contributions. We have attempted to present some of the structural evidence that supports our early contributions and those made by other investigators by highlighting major features of these EC structures that are manifest in the injured BBB. We have focused on currently established concepts and principles related to mechanisms for the transendothelial transport of macromolecules after CNS injury and also offer a critical appraisal of some of this literature. Finally, we describe more recent concepts of transBBB avenues for viruses, including HIV-1, bacterial and mycotic organisms, as well as inflammatory and neoplastic cell adhesion and migration across the injured mammalian BBB. Data from studies of EC-related adhesion molecules, both from the literature and from the author's experimental results and observations made in other laboratories, as well as from personal communications underscore the importance of the adhesion molecules in facilitating the movement of leukocytic, neoplastic cell and human pathogens across the BBB during inflammatory and neoplastic events. Exciting, ongoing clinical trials are addressing possible therapeutic intervention in neuroinflammatory diseases, including multiple sclerosis, by blocking certain glycoprotein adhesion molecules before cells have the ability to adhere to the ECs and migrate across the BBB. Approaches whereby inflammation may be reduced or arrested using anti-adhesion molecules, by restructuring EC cytoskeletal, filamentous proteins, as well as remodeling cholesterol components of the modified VTS are discussed in the context of developing future therapies for BBB injury and inflammation. Understanding new concepts about the mechanism(s) by which inflammatory cells and a variety of pathogenic microorganisms are transported across the BBB can be expected to advance our understanding of fundamental disease processes. Taken together, the literature and the author's experiences during the past quarter of a century, will hopefully provide new clues related to the mechanisms of transendothelial cell adhesion and emigration across the injured BBB, issues that have been receiving considerable attention in the clinical arena. Learning how to chemically modulate the opening and/or closure of EC VTS and VVO structural pathways, or junctional complexes prior to cellular or microorganism adhesion and breaching the BBB presents challenging new questions in modern medicine. Future studies will be critically important for the development of therapeutic intervention in several human afflictions including traumatic brain and spinal cord injuries, stroke, cancer, multiple sclerosis and conditions where the immune system may be compromised including HIV infection, infantile and adult meningitis.
 ...
PMID:Structural pathways for macromolecular and cellular transport across the blood-brain barrier during inflammatory conditions. Review. 1502 15

chlamdAs with other organ systems, the vulnerability of the nervous system to infectious agents increases with aging. Several different infectious agents can cause neurodegenerative conditions, with prominent examples being human immunodeficiency virus (HIV-1) dementia and prion disorders. Such infections of the central nervous system (CNS) typically have a relatively long incubation period and a chronic progressive course, and are therefore increasing in frequency as more people live longer. Infectious agents may enter the central nervous system in infected migratory macrophages, by transcytosis across blood-brain barrier cells or by intraneuronal transfer from peripheral nerves. Synapses and lipid rafts are important sites at which infectious agents may enter neurons and/or exert their cytotoxic effects. Recent findings suggest the possibility that infectious agents may increase the risk of common age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and stroke. While scenarios can be envisioned whereby viruses such as Chlamydia pneumoniae, herpes simplex and influenza promote damage to neurons during aging, there is no conclusive evidence for a major role of these pathogens in neurodegenerative disorders. In the case of stroke, blood vessels may be adversely affected by bacteria or viruses resulting in atherosclerosis.
 ...
PMID:Infectious agents and age-related neurodegenerative disorders. 1516 5

Excessive activation of calpains (calcium-activated neutral proteases) is observed following spinal cord contusion injury, traumatic brain injury, stroke, and in neurodegenerative disorders including Alzheimer's disease. Calpain inhibition represents an attractive therapeutic target, but current calpain inhibitors possess relatively weak potency, poor specificity, and in many cases, limited cellular and blood-brain barrier permeability. We developed novel calpain inhibitors consisting of the endogenous inhibitor, calpastatin or its inhibitory domain I, fused to the protein transduction domain of the HIV trans-activator (Tat) protein (Tat(47-57)). The Tat-calpastatin fusion proteins were potent calpain inhibitors in a cell-free activity assay, but did not inhibit cellular calpain activity in primary rat cortical neurons when applied exogenously at concentrations up to 5 microM. The fusion proteins were able to transduce neurons, but were localized within endosome-like structures. A similar endosomal uptake was observed for Tat-GFP. Together, the results suggest that endosomal uptake of the Tat-calpastatin prevents its interaction with calpain in other cellular compartments. Endosomal uptake of proteins fused to the Tat protein transduction domain severely limits the applications of this methodology.
 ...
PMID:Tat-calpastatin fusion proteins transduce primary rat cortical neurons but do not inhibit cellular calpain activity. 1519 12

The blood-brain barrier (BBB) is a diffusion barrier, which impedes influx of most compounds from blood to brain. Three cellular elements of the brain microvasculature compose the BBB-endothelial cells, astrocyte end-feet, and pericytes (PCs). Tight junctions (TJs), present between the cerebral endothelial cells, form a diffusion barrier, which selectively excludes most blood-borne substances from entering the brain. Astrocytic end-feet tightly ensheath the vessel wall and appear to be critical for the induction and maintenance of the TJ barrier, but astrocytes are not believed to have a barrier function in the mammalian brain. Dysfunction of the BBB, for example, impairment of the TJ seal, complicates a number of neurologic diseases including stroke and neuroinflammatory disorders. We review here the recent developments in our understanding of the BBB and the role of the BBB dysfunction in CNS disease. We have focused on intraventricular hemorrhage (IVH) in premature infants, which may involve dysfunction of the TJ seal as well as immaturity of the BBB in the germinal matrix (GM). A paucity of TJs or PCs, coupled with incomplete coverage of blood vessels by astrocyte end-feet, may account for the fragility of blood vessels in the GM of premature infants. Finally, this review describes the pathogenesis of increased BBB permeability in hypoxia-ischemia and inflammatory mechanisms involving the BBB in septic encephalopathy, HIV-induced dementia, multiple sclerosis, and Alzheimer disease.
 ...
PMID:The blood-brain barrier: an overview: structure, regulation, and clinical implications. 1520 56

L-Glutamate serves as a major excitatory neurotransmitter in the mammalian central nervous system (CNS) and is stored in synaptic vesicles by an uptake system that is dependent on the proton electrochemical gradient (VGLUTs). Following its exocytotic release, glutamate activates fast-acting, excitatory ionotropic receptors and slower-acting metabotropic receptors to mediate neurotransmission. Na+-dependent glutamate transporters (EAATs) located on the plasma membrane of neurons and glial cells rapidly terminate the action of glutamate and maintain its extracellular concentration below excitotoxic levels. Thus far, five Na+-dependent glutamate transporters (EAATs 1-5) and three vesicular glutamate transporters (VGLUTs 1-3) have been identified. Examination of EAATs and VGLUTs in brain preparations and by heterologous expression of the various cloned subtypes shows these two transporter families differ in many of their functional properties including substrate specificity and ion requirements. Alterations in the function and/or expression of these carriers have been implicated in a range of psychiatric and neurological disorders. EAATs have been implicated in cerebral stroke, epilepsy, Alzheimer's disease, HIV-associated dementia, Huntington's disease, amyotrophic lateral sclerosis (ALS) and malignant glioma, while VGLUTs have been implicated in schizophrenia. To examine the physiological role of glutamate transporters in more detail, several classes of transportable and non-transportable inhibitors have been developed, many of which are derivatives of the natural amino acids, aspartate and glutamate. This review summarizes the development of these indispensable pharmacological tools, which have been critical to our understanding of normal and abnormal synaptic transmission.
 ...
PMID:Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. 1521 Mar 7

Acetaminophen is a widely used antipyretic analgesic, reducing fever caused by bacterial and viral infections and by clinical trauma such as cancer or stroke. In rare cases in humans, e.g., in febrile children or HIV or stroke patients, acetaminophen causes hypothermia while therapeutic blood levels of the drug are maintained. In C57/BL6 mice, acetaminophen caused hypothermia that was dose related and maximum (>2 degrees C below normal) with a dose of 300 mg/kg. The reduction and recovery of body temperature was paralleled by a fall of >90% and a subsequent rise of prostaglandin (PG)E(2) concentrations in the brain. In cyclooxygenase (COX)-2(-/-) mice, acetaminophen (300 mg/kg) produced hypothermia accompanied by a reduction in brain PGE(2) levels, whereas in COX-1(-/-) mice, the hypothermia to this dose of acetaminophen was attenuated. The brains of COX-1(-/-) mice had approximately 70% lower levels of PGE(2) than those of WT animals, and these levels were not reduced further by acetaminophen. The putative selective COX-3 inhibitors antipyrine and aminopyrine also reduced basal body temperature and brain PGE(2) levels in normal mice. We propose that acetaminophen is a selective inhibitor of a COX-1 variant and this enzyme is involved in the continual synthesis of PGE(2) that maintains a normal body temperature. Thus, acetaminophen reduces basal body temperature below normal in mice most likely by inhibiting COX-3.
 ...
PMID:Acetaminophen-induced hypothermia in mice is mediated by a prostaglandin endoperoxide synthase 1 gene-derived protein. 1526 79

Neurological dysfunction as the first manifestation of AIDS has been found in 10 to 20% of symptomatic human immunodeficiency virus infections. However, stroke has rarely been reported in AIDS patients. The most common causes of cerebral infarction in AIDS are central nervous system infections: toxoplasmosis, cryptococcal meningitis and tuberculosis. Potential vascular mechanisms for cerebral infarction and transient neurological deficits among AIDS patients include deposition of antigen-antibody complexes with vasculitis and infarction, and a direct toxic effect of a viral antigen or infectious agent on vascular endothelium. The role of cryptococcal meningitis in vasculopathy is still not clear. We report a case of cerebral infarction in an HIV-infected patient, with cryptococcal meningitis as the first manifestation of AIDS.
 ...
PMID:Cerebral infarction related to cryptococcal meningitis in an HIV-infected patient: case report and literature review. 1536 96


<< Previous 1 2 3 4 5 6 7 8 9 10