Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase belonging to the family of cyclin-dependent kinases. In addition to maintaining the neuronal architecture, CDK5 plays an important role in the regulation of synaptic plasticity, neurotransmitter release, neuron migration and neurite outgrowth. Although various reports have shown links between neurodegeneration and deregulation of cyclin-dependent kinases, the specific role of CDK5 inhibition in causing neuroprotection in cases of neuronal insult or in neurodegenerative diseases is not wellunderstood. This article discusses current evidence for the involvement of CDK5 deregulation in neurodegenerative disorders and neurodegeneration associated with stroke through various mechanisms. These include upregulation of cyclin D1 and overactivation of CDK5 mediated neuronal cell death pathways, aberrant hyperphosphorylation of human tau proteins and/or neurofilament proteins, formation of neurofibrillary lesions, excitotoxicity, cytoskeletal disruption, motor neuron death (due to abnormally high levels of CDK5/p25) and colchicine- induced apoptosis in cerebellar granule neurons. A better understanding of the role of CDK5 inhibition in neuroprotective mechanisms will help scientists and researchers to develop selective, safe and efficacious pharmacological inhibitors of CDK5 for therapeutic use against human neurodegenerative disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis and neuronal loss associated with stroke. Keywords: CDK5 inhibitors, neuroprotection, neurodegeneration, β-amyloid, Alzheimer's disease, tau hyperphosphorylation, ischemic stroke, synaptic, excitotoxicity, amyotrophic lateral sclerosis.
4015 Suberoylanilide hydroxamic acid (SAHA) is an orally administered histone deacetylase inhibitor in advanced clinical trials. Oral SAHA has single agent antitumor activity in a variety of refractory solid tumors and hematologic malignancies at dosages associated with reversible constitutional symptoms. We sought to characterize the metabolism and pharmacokinetics of SAHA so as to understand better the clearance of SAHA, and the relationship of systemic exposure to toxicity and activity. When SAHA was incubated with mouse, rat, dog, and human liver microsomes 77%, 79%, 92%, and 83%, respectively, of the drug remained intact after 60 minutes. To survey for potential metabolites in vitro, SAHA was incubated with S9 fractions from rat, dog, monkey, and human livers. SAHA glucuronide (the predominant metabolite), SAHA amide, SAHA acid, SAHA acid glucuronide, methylated SAHA, and hydroxylated SAHA were detected by LC-MS in the incubations. Sera from rats, dogs, and humans administered oral SAHA were also analyzed by LC-MS. SAHA, SAHA glucuronide, SAHA succinate, SAHA amide, SAHA acid, SAHA adipic acid, and acetanilide were detected. The in vivo metabolite profiles were similar in these species, with SAHA glucuronide and SAHA succinate being the major metabolites. The substantial levels of the succinate detected in vivo but not in S9 fractions in vitro suggests that it arose by successive β-oxidations in mitochondria. None of the metabolites detected in sera inhibited histone deacetylase or cell proliferation in vitro. SAHA glucuronide was the only metabolite detected in dog bile. In rat, dog, and human urine, various hydroxylated metabolites as well as conjugates of acetanilide were observed in addition to all of the serum metabolites. Toxicokinetics of SAHA, SAHA glucuronide, and SAHA succinate in serum were obtained on Days 1 and 28 in rat and dog oral toxicology studies. The pharmacokinetics of SAHA and SAHA succinate were comparable in male and female rats over doses ranging from 20 to 150 mg/kg/day and did not appear to change with repeated dosing. The pharmacokinetics of SAHA glucuronide showed that female rats had a greater exposure than males at the 50 and 150 mg/kg/day doses. Serum concentrations of these 3 analytes increased in a linear but less than dose proportional manner between 20 and 150 mg/kg/day. The serum AUC0-6 hr for SAHA in the high-dose rats approximated the AUC0-t in human plasma following a 400 mg oral dose. Pharmacokinetic parameters in dogs were highly variable, but showed a dose-dependent trend and accumulation of all 3 analytes. In summary, metabolite profiles in serum were similar in rats, dogs, and humans. The main metabolic clearance pathways appear to be direct glucuronidation of the hydroxamate, and hydrolysis followed by successive β-oxidations to generate SAHA succinate.
Cryptosporidium is one of the most common causes of diarrhea in calves worldwide, and the risk factors contributing to its control and prevention are extensively studied. This epidemiological study was conducted in an unstable breeding environment. Ninety-six (96) calves suffering from diarrhea were studied from five regions in northwestern Syria. The goal of this study was to assess the prevalence of cryptosporidium in fecal samples and to measure the expected risk and regression for assumed risk factors that may cause diarrhea in calves up to 60 days old. Fecal samples were tested using direct ELISA. The results showed 9.1% (1/11) cases in the western Aleppo countryside, 21.1% (4/19) in the eastern Idlib countryside, 13.6% (3/22) in the Northern Idlib countryside, 2.9% (1/35) in the Jisr Al-Shughur countryside, while no positive case was recorded in the western countryside. This is the first study conducted in the region showing the incidence, regression, and risk rates, and it accentuates the need for a broader study on the effect of certain drugs used in the treatment of diarrhea and its consequences. Keywords: newborn calves, diarrhea, multiscreen ELISA, Cryptosporidium
Chemotherapeutic delivery by oral route in cancer patients has the potential to create "hospitalization free chemotherapy" which is a vision of oncologists, formulation scientists and patients. Such a therapeutic approach will improve patients' compliance, ease the burden of the patients' caregivers and significantly reduce the cost of treatment. In current clinical practice, chemotherapy carried out by intravenous injection or infusion leads to undesired side-effects such as plasma concentrations crossing the maximum safe concentration, rapid body clearance and lower bioavailability. Despite the presence of challenges such as poor aqueous solubility and stability of drugs and the presence of biological barriers like multidrug efflux transporter in the GI tract, oral cancer chemotherapy has the potential to surmount those obstacles. Lipid nanoparticles (LNPs) such as solid lipid nanoparticle, nanostructured lipid carriers, nano lipid–drug conjugates, mixed micelles, liposomes and nanoemulsions have shown some promising results for use in oral anticancer drug delivery through nanotechnological approach. LNPs demonstrate enhanced oral bioavailability owing to their ability to inhibit first pass metabolism via lymphatic absorption by chylomicron-linked and/or M-cell uptake. LNPs reduce the inter- and intrasubject pharmacokinetics variability of administrated drugs. Moreover, certain classes of phospholipids and surfactants used in the formulations of LNPs can suppress the P-glycoprotein efflux system. Here, we shall be discussing the biopharmaceutical challenges in oral cancer chemotherapy and how the LNPs may provide solutions to such challenges. The effect of GI tract environment on LNPs and pharmacokinetics shall also be discussed. Keywords: Cancer, lipid nanoparticles, metabolism, multidrug efflux transporter, nano lipid–drug conjugates, nanostructured lipid carriers, oral chemotherapy, solid lipid nanoparticle.
Recent evidence has indicated that type 2 diabetes mellitus (T2DM) increases the risk of developing Alzheimer’s disease (AD). Therefore, it is crucial to investigate the potential common processes that could explain this relation between AD and T2DM. In the recent decades, an abundance of evidence has emerged demonstrating that chronic inflammatory processes may be the major factors contributing to the development and progression of T2DM and AD. In this article, we have discussed the molecular underpinnings of inflammatory process that contribute to the pathogenesis of T2DM and AD and how they are linked to these two diseases. In depth understanding of the inflammatory mechanisms through which AD and T2DM are associated to each other may help the researchers to develop novel and more effective strategies to treat together AD and T2DM. Several treatment options have been identified which spurn the inflammatory processes and discourage the production of inflammatory mediators, thereby preventing or slowing down the onset of T2DM and AD.
The emerging data suggest that type 2 diabetes mellitus (T2DM) can contribute significantly to the onset or progression of Alzheimer's disease (AD) either directly or as a cofactor. Various in vitro and in vivo animal and human clinical studies have provided evidence that T2DM is a major risk factor in the pathology of AD and the two diseases share common biological mechanisms at the molecular level. The biological mechanisms that are common in the pathology of both T2DM and AD include insulin resistance, impaired glucose metabolism, β-amyloid formation, oxidative stress, and the presence of advanced glycation end products. With better understanding of the degree of association between AD and T2DM and the underlying molecular mechanisms explaining this relationship, it is hoped that researchers will be able to develop effective therapeutic interventions to treat or control T2DM and, as a consequence, delay the onset or progression of AD.
Adenosine-Monophosphate-Activated protein kinase (AMPK) is a conserved kinase that plays an important role in maintaining the homeostasis of cells. AMPK activation has a positive impact on treatment of diseases such as diabetes, obesity and cancer as well. This observation led to the development of AMPK activators. Certain naturally occurring compounds have also been known to activate AMPK.In this study, we retrieved the AMPK activators that include chemical drugs, xenobiotics and natural compounds and analyzed their interactions with AMPK via docking studies. Using this ligand dataset, a pharmacophore model was generated based upon ligand-based pharmacophore modeling strategy. The generated pharmacophore model was used to screen a library of ZINC database. The new hits which share the properties of our pharmacophore model were further analyzed via docking studies.This study led to the identification of new chemical compounds which has the potential to activate AMPK. Even some of the screened hits showed better binding energies as compared to that of the ligand dataset used thus having the potential to activate AMPK more efficiently. The promising hits obtained after virtual screening of ZINC database were also checked against the Lipinski's rule of five.Compound 7 out of the 10 compounds showed best binding energies even more efficient than the ligand dataset itself.
The activities of several tricyclic heteroaryl isothiazolones (HITZs) against an assortment of gram-positive and gram-negative clinical isolates were assessed. These compounds target bacterial DNA replication and were found to possess broad-spectrum activities especially against gram-positive strains, including antibiotic-resistant staphylococci and streptococci. These included methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-nonsusceptible staphylococci, and quinolone-resistant strains. The HITZs were more active than the comparator antimicrobials in most cases. For gram-negative bacteria, the tested compounds were less active against members of the family Enterobacteriaceae but showed exceptional potencies against Haemophilus influenzae, Moraxella catarrhalis, and Neisseria spp. Good activity against several anaerobes, as well as Legionella pneumophila and Mycoplasma pneumoniae, was also observed. Excellent bactericidal activity against staphylococci was observed in time-kill assays, with an approximately 3-log drop in the numbers of CFU/ml occurring after 4 h of exposure to compound. Postantibiotic effects (PAEs) of 2.0 and 1.7 h for methicillin-susceptible S. aureus and MRSA strains, respectively, were observed, and these were similar to those seen with moxifloxacin at 10x MIC. In vivo efficacy was demonstrated in murine infections by using sepsis and thigh infection models. The 50% protective doses were
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