Current Issue : July - September Volume : 2014 Issue Number : 3 Articles : 6 Articles
Background: Plumbagin is the major active constituent in several plants including Plumbago indica Linn. (root).\nThis compound has been shown to exhibit a wide spectrum of biological and pharmacological activities. The\npresent study aimed to evaluate the in vitro and in vivo antimalarial activity of plumbagin including its acute\nand subacute toxicity in mice.\nMethods: In vitro antimalarial activity of plumbagin against K1 and 3D7 Plasmodium falciparum clones were\nassessed using SYBR Green I based assay. In vivo antimalarial activity was investigated in Plasmodium bergheiinfected\nmouse model (a 4-day suppressive test).\nResults: Plumbagin exhibited promising antimalarial activity with in vitro IC50 (concentration that inhibits parasite\ngrowth to 50%) against 3D7 chloroquine-sensitive P. falciparum and K1 chloroquine-resistant P. falciparum clones\nof 580 (270ââ?¬â??640) and 370 (270ââ?¬â??490) nM, respectively. Toxicity testing indicated relatively low toxicity at the dose\nlevels up to 100 (single oral dose) and 25 (daily doses for 14 days) mg/kg body weight for acute and subacute\ntoxicity, respectively. Chloroquine exhibited the most potent antimalarial activity in mice infected with P. berghei\nANKA strain with respect to its activity on the reduction of parasitaemia on day 4 and the prolongation of\nsurvival time.\nConclusions: Plumbagin at the dose of 25 mg/kg body weight given for 4 days was safe and produced weak\nantimalarial activity. Chemical derivatization of the parent compound or preparation of modified formulation is\nrequired to improve its systemic bioavailability...
Disseminated intravascular coagulation (DIC) has a common pathogenesis in terms of persistent widespread\nactivation of coagulation in the presence of underlying disease, but the degree of fibrinolytic activation often differs\nby DIC type. DIC with suppressed fibrinolysis is a DIC type usually seen in sepsis. Coagulation activation is severe,\nbut fibrinolytic activation is mild. DIC with enhanced fibrinolysis is a DIC type usually seen in acute promyelocytic\nleukemia (APL). Both coagulation activation and fibrinolytic activation are severe. DIC with balanced fibrinolysis is a\nDIC type usually seen in solid tumors, with an intermediate pathogenesis between the above two types. In animal\nDIC models, lipopolysaccharide (LPS)-induced models are similar to suppressed-fibrinolytic-type DIC, whereas tissue\nfactor (TF)-induced models are similar to enhanced fibrinolytic/balanced fibrinolytic DIC. Appropriate diagnosis and\ntreatment may also differ depending on the DIC type....
Liver fibrosis is defined as excessive extracellular matrix deposition and is based on complex interactions between\nmatrix-producing hepatic stellate cells and an abundance of liver-resident and infiltrating cells. Investigation of\nthese processes requires in vitro and in vivo experimental work in animals. However, the use of animals in\ntranslational research will be increasingly challenged, at least in countries of the European Union, because of the\nadoption of new animal welfare rules in 2013. These rules will create an urgent need for optimized standard\noperating procedures regarding animal experimentation and improved international communication in the liver\nfibrosis community. This review gives an update on current animal models, techniques and underlying\npathomechanisms with the aim of fostering a critical discussion of the limitations and potential of up-to-date\nanimal experimentation. We discuss potential complications in experimental liver fibrosis and provide examples of\nhow the findings of studies in which these models are used can be translated to human disease and therapy. In\nthis review, we want to motivate the international community to design more standardized animal models which\nmight help to address the legally requested replacement, refinement and reduction of animals in fibrosis research....
Background: The anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited\nefficacy. Therefore, we synthesized phospho-aspirin (PA-2; MDC-22), a novel derivative of aspirin, and evaluated its\nchemotherapeutic and chemopreventive efficacy in preclinical models of triple negative breast cancer (TNBC).\nMethods: Efficacy of PA-2 was evaluated in human breast cancer cells in vitro, and in orthotopic and subcutaneous\nTNBC xenografts in nude mice. Mechanistic studies were also carried out to elucidate the mechanism of action of\nPA-2.\nResults: PA-2 inhibited the growth of TNBC cells in vitro more potently than aspirin. Treatment of established\nsubcutaneous TNBC xenografts (MDA-MB-231 and BT-20) with PA-2 induced a strong growth inhibitory effect,\nresulting in tumor stasis (79% and 90% inhibition, respectively). PA-2, but not aspirin, significantly prevented\nthe development of orthotopic MDA-MB-231 xenografts (62% inhibition). Mechanistically, PA-2: 1) inhibited the\nactivation of epidermal growth factor receptor (EGFR) and suppressed its downstream signaling cascades,\nincluding PI3K/AKT/mTOR and STAT3; 2) induced acetylation of p53 at multiple lysine residues and enhanced\nits DNA binding activity, leading to cell cycle arrest; and 3) induced oxidative stress by suppressing the\nthioredoxin system, consequently inhibiting the activation of the redox sensitive transcription factor NF-?B.\nThese molecular alterations were observed in vitro and in vivo, demonstrating their relevance to the anticancer\neffect of PA-2.\nConclusions: Our findings demonstrate that PA-2 possesses potent chemotherapeutic efficacy against TNBC,\nand is also effective in its chemoprevention, warranting further evaluation as an anticancer agent....
Background: Given the large medical burden of polycystic kidney disease (PKD) and recent clinical trial failures,\nthere is a need for novel, safe and effective treatments for the disorder.\nMethods: In PCK rat and PKD2(ws25/w183) mouse models, entanercept was administered once every three days at 5\nor 10 mg/kg, once daily. Mozavaptan was administered as a pilot control, provided continuously via milled chow at\n0.1%. Animals were assessed for measures of pharmacodynamic response, and improvements in measures of\npolycystic kidney disease.\nResults: Entanercept treatment modulated inflammatory markers, but provided limited therapeutic benefit in\nmultiple animal models of established polycystic kidney disease. Kidney weight, cyst burden and renal function\nmarkers remained unchanged following administration of etanercept at various dose levels and multiple treatment\ndurations.\nConclusions: While it remains possible that TNF-a inhibition may be effective in truly preventative settings, our\nobservations suggest this pathway is less likely to exhibit therapeutic or disease-modifying efficacy following the\nstandard clinical diagnosis of disease....
Despite the success of postexposure prophylaxis (PEP) of the newborn in preventing mother-to-child transmission of hepatitis\nB virus), in non-US clinical trials, administering hepatitis B immune globulin (HBIG) to mothers at the end of pregnancy (in\naddition to passive-active PEP of the newborn) only partially improved outcomes. That is, a significant percentage of newborns\nbecame infected during their first year of life. We used a relevant animal model for human IgG transplacental transfer to study\ndose, time and subclass dependence ofHBVneutralizing antibody (nAb) maternal, and fetal levels at the end of pregnancy. Pregnant\nguinea pigs received 50 or 100 IU/kg HBIGIV 2ââ?¬â??5 days before delivery. Human total IgG, IgG subclasses, and nAb in mothers and\ntheir litters were measured.In vitro analyses of guinea pig Fc neonatal receptor binding to HBIGIV, as well as to all human IgG\nsubclasses, were also performed. Our study showed that nAb transferred transplacentally from the pregnant guinea pigs to their\nlitters; no transfer occurred during parturition.The amount of the transferred nAb was dose and time dependent.Thus, selection\nof an efficacious dose in the clinic is important: microdosing may be underdosing, particularly in cases of high viraemia....
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