Adenosine 5'-monophosphate activated protein kinase (AMPK) is a master sensor of cellular energy status that plays a key role in the regulation of whole-body energy homeostasis. AMPK is a serine/threonine kinase that is activated by upstream kinases LKB1, CaMKK?, and Tak1, among others. AMPK exists as ??? trimeric complexes that are allosterically regulated by AMP, ADP, and ATP. Dysregulation of AMPK has been implicated in a number of metabolic diseases including type 2 diabetes mellitus and obesity. Recent studies have associated roles of AMPK with the development of cancer and neurological disorders, making it a potential therapeutic target to treat human diseases. This review focuses on the structure and function of AMPK, its role in human diseases, and its direct substrates and provides a brief synopsis of key AMPK modulators and their relevance in human diseases.
West Nile Virus (WNV) is an arthropod-borne flavivirus, which causes flu-like illness and is sporadically associated with encephalitis. Transmission to humans occurs following a bite from an infected mosquito, which acquires the virus after feeding on dead birds. WNV meningoencephalitis is a rare infection with a neuroinvasive disease occurring in less than 1% of the cases, with varied presentations including aseptic meningitis, meningoencephalitis, and acute flaccid paralysis. Chorioretinitis is the most common eye finding in this infection, while other ocular manifestations have been rarely reported in the literature. We present the first case report of WNV meningoencephalitis, with rare ocular manifestations of acute hemorrhagic conjunctivitis, bilateral subconjunctival hemorrhages, and nystagmus. The rare ocular findings of acute hemorrhagic conjunctivitis, bilateral subconjunctival hemorrhages, and nystagmus diagnosed in our case can guide clinicians toward early diagnosis of WNV meningoencephalitis, while serologic testing is still pending.
Sternal cleft is a rare anomaly and has been variously managed by using either autogenous tissue or synthetic materials for bony reconstruction. We report the reconstruction of sternal cleft in a 15-month-old child with a single-piece outer-table cranial bone graft that was harvested by splitting in situ. The reconstructed sternum was covered with bilateral pectoralis major advancement muscle flaps.
Heme-regulated inhibitor kinase (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2?) kinase, plays critical roles in cell proliferation, differentiation, and adaptation to cytoplasmic stress. HRI is also a critical modifier of hemoglobin disorders such as ?-thalassemia. We previously identified N,N-diarylureas as potent activators of HRI suitable for studying the biology of this important kinase. To expand the repertoire of chemotypes that activate HRI, we screened a ?1900 member N,N-disubstituted urea library in the surrogate eIF2? phosphorylation assay, identifying N-aryl,N-cyclohexylphenoxyurea as a promising scaffold. We validated hit compounds as a bona fide HRI activators in secondary assays and explored the contributions of substitutions on the N-aryl and N-cyclohexylphenoxy groups to their activity by studying focused libraries of complementing analogues. We tested these N-aryl,N-cyclohexylphenoxyureas in the surrogate eIF2? phosphorylation and cell proliferation assays, demonstrating significantly improved bioactivities and specificities. We consider these compounds to represent lead candidates for the development of potent and specific HRI activators.
We reported previously that insect acetylcholinesterases (AChEs) could be selectively and irreversibly inhibited by methanethiosulfonates presumably through conjugation to an insect-specific cysteine in these enzymes. However, no direct proof for the conjugation has been published to date, and doubts remain about whether such cysteine-targeting inhibitors have desirable kinetic properties for insecticide use. Here we report mass spectrometric proof of the conjugation and new chemicals that irreversibly inhibited African malaria mosquito AChE with bimolecular inhibition rate constants (k(inact)/K(I)) of 3,604-458,597 M(-1)sec(-1) but spared human AChE. In comparison, the insecticide paraoxon irreversibly inhibited mosquito and human AChEs with k(inact)/K(I) values of 1,915 and 1,507 M(-1)sec(-1), respectively, under the same assay conditions. These results further support our hypothesis that the insect-specific AChE cysteine is a unique and unexplored target to develop new insecticides with reduced insecticide resistance and low toxicity to mammals, fish, and birds for the control of mosquito-borne diseases.
Intrapericardial teratomas are rare after infancy. An accurate diagnosis can only be made with a high index of suspicion. Most of the time, a mediastinal teratoma ruptures/perforates the pericardial cavity, thus causing either pericardial effusion or life-threatening tamponade. These factors emphasize the importance of an early surgical excision even for extrapericardial locations. This report presents the case of a 16-year-old girl with intrapericardial teratoma who presented with cardiac tamponade which is a rare complication of this rare tumor with only eight cases reported so far beyond infancy. This patient presented with recurrent tamponade, and underwent multiple procedures of pericardiocentesis and developed pyopericardium and polyserositis. This intrapericardial teratoma was not detected by imaging modalities.
New insecticides are urgently needed because resistance to current insecticides allows resurgence of disease-transmitting mosquitoes while concerns for human toxicity from current compounds are growing. We previously reported the finding of a free cysteine (Cys) residue at the entrance of the active site of acetylcholinesterase (AChE) in some insects but not in mammals, birds, and fish. These insects have two AChE genes (AP and AO), and only AP-AChE carries the Cys residue. Most of these insects are disease vectors such as the African malaria mosquito (Anopheles gambiae sensu stricto) or crop pests such as aphids. Recently we reported a Cys-targeting small molecule that irreversibly inhibited all AChE activity extracted from aphids while an identical exposure caused no effect on the human AChE. Full inhibition of AChE in aphids indicates that AP-AChE contributes most of the enzymatic activity and suggests that the Cys residue might serve as a target for developing better aphicides. It is therefore worth investigating whether the Cys-targeting strategy is applicable to mosquitocides. Herein, we report that, under conditions that spare the human AChE, a methanethiosulfonate-containing molecule at 6 microM irreversibly inhibited 95% of the AChE activity extracted from An. gambiae s. str. and >80% of the activity from the yellow fever mosquito (Aedes aegypti L.) or the northern house mosquito (Culex pipiens L.) that is a vector of St. Louis encephalitis. This type of inhibition is fast ( approximately 30 min) and due to conjugation of the inhibitor to the active-site Cys of mosquito AP-AChE, according to our observed reactivation of the methanethiosulfonate-inhibited AChE by 2-mercaptoethanol. We also note that our sulfhydryl agents partially and irreversibly inhibited the human AChE after prolonged exposure (>4 hr). This slow inhibition is due to partial enzyme denaturation by the inhibitor and/or micelles of the inhibitor, according to our studies using atomic force microscopy, circular dichroism spectroscopy, X-ray crystallography, time-resolved fluorescence spectroscopy, and liquid chromatography triple quadrupole mass spectrometry. These results support our view that the mosquito-specific Cys is a viable target for developing new mosquitocides to control disease vectors and to alleviate resistance problems with reduced toxicity toward non-target species.
Huntingtons disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion mutation in the coding region of a novel gene. The mechanism of HD is unknown. Most data suggest that polyglutamine-mediated aggregation associated with expression of mutant huntingtin protein (mhtt) contributes to the pathology. However, recent studies have identified early cellular dysfunctions that preclude aggregate formation. Suppression of aggregation is accepted as one of the markers of successful therapeutic approaches. Previously, we demonstrated that tricyclic pyrone (TP) compounds efficiently inhibited formation of amyloid-beta (Abeta) aggregates in cell and mouse models representing Alzheimers Disease (AD). In the present study, we aimed to determine whether TP compounds could prevent aggregation and restore early cellular defects in primary embryonic striatal neurons from animal model representing HD.
In this retrospective study, we compared the initial presentation of patients who were eventually diagnosed with either benign fasciculations (BF) or amyotrophic lateral sclerosis (ALS). We found a significantly higher number of patients with BF reporting a past history of psychiatric symptoms, life stressors, and concurrent psychosomatic symptoms. There was no difference between the two groups in patient report of current anxiety or depression symptoms. These findings support our hypothesis that BF are a manifestation of psychological distress due to somatization and that reviewing psychosocial history is important when patients are being evaluated for fasciculations. Patients seeking medical attention for fasciculations and who do not report a history of underlying psychiatric or psychosomatic disorders should be followed closely as fasciculations have been reported to be a presenting feature of ALS.
Small beta-amyloid (Abeta) 1-42 aggregates are toxic to neurons and may be the primary toxic species in Alzheimers disease (AD). Methods to reduce the level of Abeta, prevent Abeta aggregation, and eliminate existing Abeta aggregates have been proposed for treatment of AD. A tricyclic pyrone named CP2 is found to prevent cell death associated with Abeta oligomers. We studied the possible mechanisms of neuroprotection by CP2. Surface plasmon resonance spectroscopy shows a direct binding of CP2 with Abeta42 oligomer. Circular dichroism spectroscopy reveals monomeric Abeta42 peptide remains as a random coil/alpha-helix structure in the presence of CP2 over 48 h. Atomic force microscopy studies show CP2 exhibits similar ability to inhibit Abeta42 aggregation as that of Congo red and curcumin. Atomic force microscopy closed-fluid cell study demonstrates that CP2 disaggregates Abeta42 oligomers and protofibrils. CP2 also blocks Abeta fibrillations using a protein quantification method. Treatment of 5x familial Alzheimers disease mice, a robust Abeta42-producing animal model of AD, with a 2-week course of CP2 resulted in 40% and 50% decreases in non-fibrillar and fibrillar Abeta species, respectively. Our results suggest that CP2 might be beneficial to AD patients by preventing Abeta aggregation and disaggregating existing Abeta oligomers and protofibrils.
The SbetaC gene is conditionally expressed a 99-residue carboxy terminal fragment, C99, of amyloid precursor protein in MC65 cells and causes cell death. Consequently, MC65 cell line was used to identify inhibitors of toxicity related to intracellular amyloid beta (Abeta) oligomers. Compounds that reduce the level of Abeta peptides, prevent Abeta aggregation, or eliminate existing Abeta aggregates may be used in the treatment of Alzheimers disease (AD). Previously, we found that a tricyclic pyrone (TP) molecule, compound 1, prevents MC65 cell death and inhibits Abeta aggregation. Hence various TPs containing heterocycle at C7 side chain and a nitrogen at position 2 or 5 were synthesized and their MC65 cell protective activities evaluated. TPs containing N3-adenine moiety such as compounds 1 and 11 are most active with EC(50) values of 0.31 and 0.35 microM, respectively. EC(50) values of tricyclic N5-analog, pyranoisoquinolinone 13, and N2-analog, pyranopyridinone 20, are 2.49 and 1.25 microM, respectively, despite the lack of adenine moiety. Further investigation of tricyclic N2- and N5-analogs is warranted.
Left ventricle (LV) pseudoaneurysm is a late mechanical complication of myocardial infarction. A giant LV pseudoaneurysm is a rare presentation. We report a case of giant LV pseudoaneurysm in a post-MI patient who presented with gross congestive heart failure. The patient had a successful surgical repair of the aneurysm and had a favorable 3-mo outcome. The imaging modality and surgical treatment of the pseudoaneurysm are discussed.
We report an unusual face selective reduction of the exocyclic double bond in the ?-methylene-?-butyrolactone motif of spiro-oxindole systems. The spiro-oxindoles were assembled by an indium metal mediated Barbier-type reaction followed by an acid catalyzed lactonization.
Left ventricular (LV) pseudoaneurysm is a late mechanical complication of myocardial infarction (MI). A giant LV pseudoaneurysm is a rare presentation. We report a case of a giant LV pseudoaneurysm in a post MI patient, who presented with hemoptysis. Hemoptysis is a rare clinical presentation of LV pseudoaneurysm. The patient had successful surgical repair of the aneurysm and had a favorable outcome in 9 mo follow-up. The imaging modalities and surgical treatment of a pseudoaneurysm is discussed.
Isaacs syndrome is a rare disease resulting from hyperexcitability of peripheral nerves causing continuous muscle fiber activity characterized by muscle twitching and stiffness at rest and delayed muscle relaxation after voluntary contraction. Our objective was to discuss the relationship of Isaacs syndrome to paraneoplastic syndromes as reported in the available literature and in 3 patients evaluated at our academic medical center.
Severe mitral annular calcification (MAC) is frequently seen in patients with advanced age and chronic kidney disease, but it is rare in rheumatic heart disease (RHD). We hereby report a case of 45-year-old female with chronic RHD, who had severe MAC and mitral regurgitation. Fluoroscopy revealed a "crown"-like severe calcification of the mitral annulus. Autopsy of the heart revealed a calcified posterior mitral annulus, fused commissures, and calcified nodules at the atrial aspect of the mitral valve.
Flaviviruses are small, enveloped RNA viruses which cause a variety of diseases into animals and man. Despite the existence of licensed vaccines, yellow fever, Japanese encephalitis and tick-borne encephalitis also claim many thousands of victims each year across their vast endemic areas. A number of studies have already revealed that the non-structural NS3 serine protease is required for the maturation of the viral polyprotein and thus is a promising target for the development of antiviral inhibitors. Hence, the 3D structure of NS3 protein was modeled using homology modeling by MODELLER 9v7. Validation of the constructed NS3 protein models were done by PROCHECK, VERYFY3D and through ProSA calculations. Ligands for the catalytic triad (H51, D75, and S135) were designed using LIGBUILDER. The NS3 proteins catalytic triad was explored to find out the interactions pattern for inhibitor binding using molecular docking methodology using AUTODOCK Vina. The interactions of complex NS3protein-ligand conformations, including hydrogen bonds and the bond lengths were analyzed using Accelrys DS Visualizer software. Hence, from this observation, the novel molecule designed was observed to be the best ligand against the NS3 protein of flavivirus. This molecule may prove to be a potential identity in modulating disease manifestation for all the selected flavivirus members.
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