Current Issue : January - March Volume : 2012 Issue Number : 1 Articles : 9 Articles
Cell surface receptors have been shown to be the sites of disease infectivity in living organisms in two previous studies. The cell surface receptors were shown to have two reactive heads or terminals with one head being half the size and shape of the other head. A new study reported here involved a comparism of the effects of acid and alkaline herbal extracts on Candida albicans infected cell surface receptors at human cutaneous Candida infection sites. The effects of three acid herbal extracts on cutaneous Candida albicans infection were compared with those of three alkaline herbal extracts. The three alkaline herbal extracts were the extract of Azadirachta indica leaves; the extract of Vernonia amygdalina leaves and the pulp of ripe Carica papaya (pawpaw) fruit. The three acid herbal extracts were the extract of Aniseed (ugugo) [a tiny Central African moderately hot spice] seeds; the juice of Gambeya albida (family sapotaceae) fruit (a local Nigerian fruit that has a high content of ascorbic acid); and the extract of curry leaves.The mode of data collection was the observation and photographing of the effects of the acid and alkaline herbal extracts on cutaneous Candida albicans infection sites. The results of the study showed that candida albicans tissues infected the human skin by attaching themselves to cell surface receptors of skin epithelial cells.They also showed that the cell surface receptor on the human skin to which the ‘root’ (centromere) of a candida colony attached itself had two receptive ends, to which an infective organism attached itself (and to which an anti-infective agent also attached to eliminate the infective agent). These two ends consisted of an excitatory or ‘muscarinic’ end which was stimulated by the acidic herbal extracts and an inhibitory or ‘adrenergic’ end to which the alkaline herbal extract molecules attached themselves to produce inhibitory effects on the stimulatory effects of the attached candida tissues. The excitatory (stimulatory) harsh stinging actions of the acid heral extracts were interpreted as contractile or muscarinic-like action. The cell surface receptor head to which the acid herbal extracts attached to exercise the muscarinic action to eliminate attached Candida tissues was termed a muscarinic receptor site. From the structure of muscarine (that contains 2 indole ring structures), the muscarinic receptor site was infered to be to be an indole ring structure and the inhibitory or ‘adrenergic ‘end to be a benzene ring structure. Since the two heads of the cell surface receptor lie side by side, a placement of an indole ring to the right of a benzene ring produced the 5-hydroxytryptamine nucleus structure. Conclusions: The study therefore concludes that the cell surface receptor to which the roots of candida albicans attached themselves in the human skin is the 5- hydroxytryptamine receptor. This means that under the normal body functioning situation, 5-hydroxytryptamine was the endogenous body substance that guarded cell surface receptors against the attachment and habitation of the Candida albicans infective organisms. The findings of this study have therefore established 5-hydroxytrptamine (5-HT or Serotonin) as the endogenous mediator of the human body’s defence and cell surface receptors to which candida albicans (and by implication , all infective organisms and antigens / toxins) attached themselves to infect and damage the body) as the receptors of 5-hydroxytryptamine. Since body defence is a part of normal physiological body functioning (as the mediator of the body’s defence also ensures that the body is working normally at all times), 5-hydroxytryptamine is therefore through the findings of this study also the endogenous mediator of all normal human body (physiological) functioning. This means that 5-hydroxytryptamine (5-HT or Serotonin) mediates all activities of normal human body functioning. The conclusions of this study about 5-HT as the endogenous mediator of...
While advanced melanoma remains one of the most challenging cancers, recent developments in our understanding of the molecular drivers of this disease have uncovered exciting opportunities to guide personalized therapeutic decisions. Genetic analyses of melanoma have uncovered several key molecular pathways that are involved in disease onset and progression, as well as prognosis. These advances now make it possible to create a ââ?¬Å?Molecular Disease Modelââ?¬Â (MDM) for melanoma that classifies individual tumors into molecular subtypes (in contrast to traditional histological subtypes), with proposed treatment guidelines for each subtype including specific assays, drugs, and clinical trials. This paper describes such a Melanoma Molecular Disease Model reflecting the latest scientific, clinical, and technological advances....
An antipsychotic are the drug substances used to manage psychosis. Psychosis means abnormal condition of the mind which involves a \"loss of contact with reality\". Schizophrenia is a psychotic disorder with impairment of reality testing, thinking, speech, emotions. Approximately 4.75 million individuals suffer from schizophrenia in the United States. Antipsychotic action of drug or compound has not been predicted by pharmacological tests but has been found in clinical trials by serendipity. Several in vitro methods and in vivo model were developed to measure the receptor blockade by antipsychotics. In vitro methods are describe as follows: (1). D1 receptor assay: [3h]-sch 23390 binding to rat striatal homogenates: It helps to find the class of compound and also about selectivity for the D1 receptor. (2) D2 receptor assay: [3h]-spiroperidol binding: measure drug binding affinities for D2 receptor and their molar potencies in antagonism of apomorphine- or amphetamine-induced stereotypy. Several other in vitro methods are used to measure binding affinities for receptor present in the brain tissues, anatomical locations of receptors, side effect or adverse effect. In vivo studies are performed to study the behavioral changes that occur after drug administration, mechanism of action and side effect of a drug substance. For behavioral studies following models are widely used catalepsy in rodents, Pole climb avoidance in rats, Foot -shock induced aggression. For dosing and mechanism of action drug substance side effect, adverse effect studies following models are majorly used like Amphetamine group toxicity, Inhibition of amphetamine stereotypy in rats....
Background\r\nBCR-ABL kinase domain (KD) mutation is the major mechanism contributing to suboptimal response to tyrosine kinase inhibitors (TKI) in BCR-ABL-positive chronic myeloid leukemia (CML) patients. T315I mutation, as one of the most frequent KD mutations, has been shown to be strongly associated with TKI resistance and subsequent therapeutic failure. A simple and sensitive method is thus required to detect T315I mutation at the earliest stage.\r\nMethods\r\nA single-tube allele specific-polymerase chain reaction (AS-PCR) method was developed to detect T315I mutation in a mixture of normal and mutant alleles of varying dilutions. Denaturing high performance liquid chromatography (DHPLC) and direct sequencing were performed as a comparison to AS-PCR.\r\nResults\r\nT315I mutant bands were observed in the mixtures containing as low as 0.5-1% of mutant alleles by AS-PCR. The detection sensitivity of DHPLC was around 1.5-3% dilution whereas sequencing analysis was unable to detect below 6.25% dilution.\r\nConclusion\r\nA single-tube AS-PCR is a rapid and sensitive screening method for T315I mutation. Detection of the most resistant leukemic clone in CML patients undergoing TKI therapy should be feasible with this simple and inexpensive method....
The matrix metalloproteinases (MMPs) are zinc dependent endopeptidases which cleave extracellular matrix (ECM) constituents, as well as non-matrix proteins. (MMPs) are also known as matrixins, hydrolyze components of the extracellular matrix. The members of this family contain a signal peptide, a propeptide and a catalytic domain. The catalytic domain contains two zinc ions and at least one calcium ion coordinated to various residues. All MMPs, with the exception matrilysin, have a hemopexin/vitronectin-like domain that is connected to the catalytic domain by a hinge or linker region. The hemopexin-like domain influences tissue inhibitor of metalloproteinases (TIMP) binding , membrane activation, and some proteolytic activities These proteinases play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration. Currently 23 MMP genes have been identified in humans, and most are multi domain proteins. This review describes the members of the matrixin family and discusses substrate specificity, domain structure, functions, regulation of matrixin activity by tissue inhibitors of metalloproteinases, and their pathophysiological implication....
The epidermal growth factor receptor 2 (HER2) is a tyrosine kinase overexpressed in nearly 20% to 25% of invasive breast cancers. Trastuzumab is a humanized monoclonal antibody that targets HER2. The majority of patients with metastatic breast cancer initially respond to trastuzumab, however, within 1 year of treatment disease progresses. Several molecular mechanisms have been described as contributing to the development of trastuzumab resistance. They could be grouped as impaired access of trastuzumab to HER2, upregulation of HER2 downstream signaling pathways, signaling of alternative pathways, and impaired immune antitumor mechanisms. However, since many of them have overlapping effects, it would be of great clinical impact to identify the principal signaling pathways involved in drug resistance. Significant efforts are being applied to find other therapeutic modalities besides trastuzumab treatment to be used alone or in combination with current modalities....
Short-acting b2-adrenergic receptor agonists are commonly used bronchodilators for symptom relief in asthmatics. The aim of this study was to test whether genetic variants in PDE4D gene, a key regulator of b2-adrenoceptor-induced cAMP turnover in airway smooth muscle cells, affect the response to short-acting b2-agonists. Bronchodilator responsiveness was assessed in 133 asthmatic children by % change in baseline forced expiratory volume in one second (FEV1) after administration of albuterol. The analyses were performed in patients with airway obstruction (FEV1/FVC ratio below 90%, ?? = 9 3). FEV1??% change adjusted for baseline FEV1 values was significantly different between genotypes of rs1544791 G/A polymorphism (?? = 0 . 0 0 6) and -1345 C/T (rs1504982) promoter variation (?? = 0 . 0 3). The association remained significant with inclusion of age, sex, atopy, and controller medication into multivariate model (?? = 0 . 0 0 4 and ?? = 0 . 0 2, resp.). Our work identifies new genetic variants implicated in modulation of asthma treatment, one of them (rs1544791) previously associated with asthma phenotype....
First line chemotherapeutics for brain tumors (malignant gliomas) are alkylating agents such as temozolomide and nimustine. Despite growing knowledge of how these agents work, patients suffering from this malignancy still face a dismal prognosis. Alkylating agents target DNA, forming the killing lesion O6-alkylguanine, which is converted into DNA double-strand breaks (DSBs) that trigger apoptosis. Here we assessed whether inhibiting repair of DSBs by homologous recombination (HR) or non-homologous end joining (NHEJ) is a reasonable strategy for sensitizing glioma cells to alkylating agents. For down-regulation of HR in glioma cells, we used an interference RNA (iRNA) approach targeting Rad51 and BRCA2, and for NHEJ we employed the DNA-PK inhibitor NU7026. We also assessed whether inhibition of poly(ADP)ribosyltransferase (PARP) by olaparib would enhance the killing effect. The data show that knockdown of Rad51 or BRCA2 greatly sensitizes cells to DSBs and the induction of cell death following temozolomide and nimustine (ACNU). It did not sensitize to ionizing radiation (IR). The expression of O6-methylguanine-DNA methyltransferase (MGMT) abolished all these effects, indicating that O6-alkylguanine induced by these drugs is the primary lesion responsible for the formation of DSBs and increased sensitivity of glioma cells following knockdown of Rad51 and BRCA2. Inhibition of DNA-PK only slightly sensitized to temozolomide whereas a significant effect was observed with IR. A triple strategy including siRNA and the PARP inhibitor olaparib further improved the killing effect of temozolomide. The data provides evidence that down-regulation of Rad51 or BRCA2 is a reasonable strategy for sensitizing glioma cells to killing by O6-alkylating anti-cancer drugs. The data also provide proof of principle that a triple strategy involving down-regulation of HR, PARP inhibition and MGMT depletion may greatly enhance the therapeutic effect of temozolomide....
Orally ingested Vernonia amygdalina (VA) aqueous leaf extract and orally ingested VA leaf powder have been shown in previous studies to produce a quieting or calming effect on the activities of the whole human body. Since a quietened state of the human body is only a few steps away from a sleeping state, the present study investigated the potentials of sleep production by aqueous VA leaf extract and ingested VA leaf powder. VA leaf infusion was prepared was prepared and taken for 2 weeks. A preparation of VA leaf extract was made in combination with ground ripe carica papaya pulp or ripe Carica papaya leaves [fallen yellow or brown leaves] and also taken for 2 weeks. The body being still (sitting, standing or lying) after the intake of the combined VA and Carica papaya extract caused the VA / Carica papaya extract combination to produce natural sleep which refreshed the brain and the whole body of the subject. Staying still after an intake of the pure (unmixed) VA extract did not produce sleep. The sleep produced by the aqueous VA leaf extract / Carica papaya extract combination was calm ‘smooth sailing’ natural sleep which was not dotted by alarming dreams. These results showed that VA leaf extract produces sleep that resembles natural sleep in the presence of ripe pawpaw fruit or leaf extract and generalized low energy working level of the body (basal muscular activity in the whole body).The findings of the study enable the author to conclude that oral aqueous VA leaf extract and VA leaf powder have natural sleep producing properties and that the presence of Vitamin A and very low energy muscular activity in the whole body are necessary for sleep mediation by a substance. The study also concludes that the peaceful sound sleep which aqueous VA leaf extract produced which was devoid of wild type (fearful) dreams was protective of the human brain as it provided extended rest for the brain. Thus oral aqueous VA leaf extract mediated sleep has brain protective properties...
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