Authorities of Drug Administration in the United States of America approved about 5000 drugs for use in the therapy or management of several diseases. About two hundred of these drugs have active ...metabolites and the knowledge of their medicinal chemistry is important both in medical practice and pharmaceutical research. This review gives a detailed description of the medicinal chemistry of drugs with active metabolites generated after conjugation. This review focused on glucuronide-, acetyl-, sulphate- and phosphate-conjugation of drugs, converting the drug into an active metabolite. This conversion essentially changed the lipophilicity of the drug.
The immune system is likely to play a key role in the etiology of gliomas. Genetic polymorphisms in the mannose-binding lectin gene, a key activator in the lectin complement pathway, have been ...associated with risk of several cancers.
To examine the role of the lectin complement pathway, we combined data from prospectively collected cohorts with available DNA specimens. Using a nested case-control design, we genotyped 85 single nucleotide polymorphisms (SNPs) in 9 genes in the lectin complement pathway and 3 additional SNPs in MBL2 were tested post hoc). Initial SNPs were selected using tagging SNPs for haplotypes; the second group of SNPs for MBL2 was selected based on functional SNPs related to phenotype. Associations were examined using logistic regression analysis. All statistical tests were two-sided. Nominal p-values are presented and are not corrected for multiple comparisons.
A total of 143 glioma cases and 419 controls were available for this analysis. Statistically significant associations were observed for two SNPs in the mannose-binding lectin 2 (ML2) gene and risk of glioma (rs1982266 and rs1800450, test for trend p = 0.003 and p = 0.04, respectively, using the additive model). One of these SNPs, rs1800450, was associated with a 58% increase in glioma risk among those carrying one or two mutated alleles (odds ratio = 1.58, 95% confidence interval = 0.99-2.54), compared to those homozygous for the wild type allele.
Overall, our findings suggest that MBL may play a role in the etiology of glioma. Future studies are needed to confirm these findings which may be due to chance, and if reproduced, to determine mechanisms that link glioma pathogenesis with the MBL complement pathway.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Substance P (SP) is the most widely distributed neuropeptide in central nervous system (CNS) where it participates in numerous physiological and pathophysiological processes including stress and ...anxiety related behaviors. In line with this notion, brain areas that are thought to be involved in anxiety regulation contains SP and its specific NK1 receptors. SP concentration in different brain regions alters with the exposure of stressful stimulus and affected NK1 receptor binding is observed. SP is released in response to a stressor, which produces anxiogenic effects via activation of hypothalamic-pituitary-adrenal (HPA) axis, resulting in the liberation of cortisol. Moreover, SP is also involved in the activation of the sympathetic nervous system via stimulation of locus coeruleus (LC). This sympathetic surge initiates cortisol discharge by activation of HPA axis, representing the indirect anxiogenic effect of SP. Besides the aforementioned regions, SP also has an impact on other brain regions known to be involved in stress and anxiety mechanisms, including amygdala, lateral septum (LS), periaqueductal gray (PAG), ventromedial nucleus of the hypothalamus (VMH), and bed nucleus of stria terminalis (BNST). Thus, SP acts as an important neuromodulator in various brain regions in stress and anxiety response. Consistent with the above statement, SP makes a robust link in the psychopathology of anxiety disorders. As SP concentration is found elevated in stressed conditions, several studies have reported that the pharmacological antagonism or genetic depletion of NK-1 receptors results in the anxiolytic response making them a suitable therapeutic target for the treatment of stress and anxiety related disorders.
•Anxiety occurs when a person encounters with any stressful situation.•SP is a well-known 11-amino acids neuropeptide of tachykinin family.•SP and its receptors are confined in brain regions involved in anxiety response.•HPA axis is implicated in the modulation of anxiety in response to stressors.
The PI3K/AKT signaling has crucial role in the regulation of numerous physiological functions through activation of downstream effectors and modulation of cell cycle transition, growth and ...proliferation. This pathway participates in the pathogenesis of several human disorders such as heart diseases through regulation of size and survival of cardiomyocytes, angiogenic processes as well as inflammatory responses. Moreover, PI3K/AKT pathway participates in the process of myocardial injury induced by a number of substances such as H
2
O
2
, Mercury, lipopolysaccharides, adriamycin, doxorubicin and epirubicin. In this review, we describe the contribution of this pathway in the pathoetiology of myocardial ischemia/reperfusion injury and myocardial infarction, heart failure, cardiac hypertrophy, cardiomyopathy and toxins-induced cardiac injury.
Genome-wide Linkage Analysis for Severe Obesity in French Caucasians Finds Significant Susceptibility Locus on Chromosome
19q
Christopher G. Bell 1 ,
Michael Benzinou 1 ,
Afshan Siddiq 1 ,
Cécile ...Lecoeur 1 ,
Christian Dina 2 ,
Arnaud Lemainque 3 ,
Karine Clément 4 ,
Arnaud Basdevant 4 ,
Bernard Guy-Grand 4 ,
Charles A. Mein 5 ,
David Meyre 2 and
Philippe Froguel 1 2
1 Hammersmith Genome Centre and Department of Genomic Medicine, Hammersmith Hospital, Imperial College Faculty of Medicine,
London, U.K
2 Centre National de la Recherche Scientifique, UMR 8090, Pasteur Institute, Lille, France
3 Centre National de Genotypage, Evry, France
4 Hôtel-Dieu Hospital, Assistance Publique Hôpitaux de Paris, and INSERM Avenir, Paris, France
5 Bart’s and the London Genome Centre, Queen Mary’s School of Medicine, London, U.K
Address correspondence and reprint requests to Philippe Froguel, Professor of Genomic Medicine, Director of the Hammersmith
Genome Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN, U.K. E-mail: p.froguel{at}imperial.ac.uk and philippe.froguel{at}mail-good.pasteur-lille.fr
Abstract
To ascertain whether distinct chromosomal loci existed that were linked to severe obesity, as well as to utilize the increased
heritability of this excessive phenotype, we performed a genome-wide scan in severely obese French Caucasians. The 109 selected
pedigrees, totaling 447 individuals, required both the proband and a sibling to be severely obese (BMI ≥35 kg/m 2 ), and 84.8% of the nuclear families possessed ≥1 morbidly obese sibling (BMI ≥40). Severe and morbid obesity are still relatively
rare in France, with rates of 2.5 and 0.6%, respectively. The initial genome scan consisted of 395 evenly spaced microsatellite
markers. Six regions were found to have suggestive linkage on 4q, 6cen-q, 17q, and 19q for a BMI ≥35 phenotypic subset, and
5q and 10q for an inclusive BMI ≥27 group. The highest peak on chromosome 19q (logarithm of odds LOD = 3.59) was significant
by genome scan simulation testing ( P = 0.042). These regions then underwent second-stage mapping with an additional set of 42 markers. BMI ≥35 analysis defined
regions on 17q23.3–25.1 and 19q13.33–13.43 with an maximum likelihood score LOD of 3.16 and 3.21, respectively. Subsequent
pooled data analysis with an additional previous population of 66 BMI ≥35 sib-pairs led to a significant LOD score of 3.8
at the 19q locus (empirical P = 0.023). For more moderate obesity and overweight susceptibility loci, BMI ≥27 analysis confirmed suggestive linkage to
chromosome regions 5q14.3–q21.3 (LOD = 2.68) and 10q24.32–26.2 (LOD = 2.47). Plausible positional candidate genes include
NR1H2 and TULP2 .
IBD, identity-by-descent
LOD, logarithm of odds
LXR, liver X receptor
MLS, maximum likelihood score
Footnotes
C.G.B., M.B., A.S., and C.L. contributed equally to the study.
Accepted April 13, 2004.
Received December 18, 2003.
DIABETES
The pods of Radish are known as Raphanus caudatus that belongs to the family Brassicaceae. They are commonly known as Mungra or Sungra in Pakistan, while the common English name for this species is ...Rat-tailed radish. This variety of radish is unique and less tested for pharmacological as well as toxicological potential. In the current research, the ethanol extract of pods was assessed for anti-inflammatory potential in vitro and in vivo. Furthermore the effect of plant on hematological parameters was also investigated. For in vitro study, luminol-enhanced chemiluminescence method was used while in vivo study was carried out via Acetic acid- induced Paw Edema Test in wistar rats. The extract of Raphanus caudatus indicated significant anti-inflammatory effects regarding in vitro assay. Administered tested doses (250mg, 500mg and 1000mg/kg) of plant extract showed significant reduction in rat's paw but highest in vivo anti-inflammatory effect was observed at the dose of 1000mg/kg. Moreover, in the case of hematological study, noticeable elevation of white blood cell count was observed at 500 and 1000 mg/kg. However the number of platelets was reduced in dose dependent manner.
The Cancer Programme of the 100,000 Genomes Project was an initiative to provide whole-genome sequencing (WGS) for patients with cancer, evaluating opportunities for precision cancer care within the ...UK National Healthcare System (NHS). Genomics England, alongside NHS England, analyzed WGS data from 13,880 solid tumors spanning 33 cancer types, integrating genomic data with real-world treatment and outcome data, within a secure Research Environment. Incidence of somatic mutations in genes recommended for standard-of-care testing varied across cancer types. For instance, in glioblastoma multiforme, small variants were present in 94% of cases and copy number aberrations in at least one gene in 58% of cases, while sarcoma demonstrated the highest occurrence of actionable structural variants (13%). Homologous recombination deficiency was identified in 40% of high-grade serous ovarian cancer cases with 30% linked to pathogenic germline variants, highlighting the value of combined somatic and germline analysis. The linkage of WGS and longitudinal life course clinical data allowed the assessment of treatment outcomes for patients stratified according to pangenomic markers. Our findings demonstrate the utility of linking genomic and real-world clinical data to enable survival analysis to identify cancer genes that affect prognosis and advance our understanding of how cancer genomics impacts patient outcomes.
The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair
. In microorganisms, transcription has ...been demonstrated to be mutagenic
; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes
. Here we show that ID4-a cancer insertion-deletion (indel) mutation signature of unknown aetiology
characterized by short (2 to 5 base pair) deletions -is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress
, their activity may also be an important source of mutations in the human genome.
Acetylenic anticancer agents Siddiq, A; Dembitsky, V
Anti-cancer agents in medicinal chemistry
8, Številka:
2
Journal Article
Recenzirano
This review is a comprehensive survey of acetylenic anticancer agents obtained from living organisms. Acetylenic metabolites belong to a class of molecules containing triple bond(s). They are found ...in plants, fungi, microorganisms, and marine invertebrates. Although acetylenes are common as components of terrestrial plants, fungi, and bacteria, it is only within the last 30 years that biologically active polyacetylenes having unusual structural features have been reported from plants, cyanobacteria, algae, invertebrates, and other sources. Naturally occurring aquatic acetylenes are of particular interest since many of them display important biological activities and possess antitumor, antibacterial, antimicrobial, antifungal, phototoxic, HIV inhibitory, and immunosuppressive properties. There is no doubt that they are of great interest, especially for the medicinal chemistry, and/or pharmaceutical industries. This review presents structures and describes cytotoxic activities of more than 300 acetylenic metabolites isolated from living organisms.
The diseases caused by protozoan parasite are responsible for considerable mortality and morbidity, affecting more than 500 million of people in the world. The epidemiological control of protozoan is ...unsatisfactory due to difficulties of vector and reservoir control; while the progress in the development of vaccine tends to be slow and arduous. Currently, the chemotherapy remains essential component of both clinical management and disease control programmer in endemic areas. The drugs in use as anti-protozoan agents were discovered over 50 years and a number of factors limit their utility such as: high cost, poor compliance, drug resistance, low efficacy and poor safety. In the recent years, the searches about the development of new drugs against protozoa parasite have been increased. This special issue of The Open Medicinal Chemistry Journal will present some of developments in this field with the aim to shown the significant advances in the discovery of new anti-protozoan drugs.
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