Central and peripheral molecular targets for antiobesity pharmacotherapy.

Obesity has emerged as one of the principal worldwide health concerns of the modern era, and there exists a tremendous unmet clinical need for safe and effective therapies to combat this global pandemic. The prevalence of obesity and its associated comorbidities, including cardiovascular and metabolic diseases, has focused the attention of those in drug discovery and development on generating effective modalities for the treatment and prevention of obesity. Early efforts in the field of obesity pharmacotherapy centered on the development of agents with indeterminate mechanisms of action. This led to treatment paradigms characterized by significant off-target effects. In the past two decades, new insights have been made into the physiologic regulation of energy balance and the subordinate central and peripheral circuits coordinating appetite, metabolism, and lipogenesis. These studies have revealed previously unrecognized molecular targets for controlling appetite and managing weight from which has emerged a new wave of targeted pharmacotherapies to prevent and control obesity.

GCC signaling in colorectal cancer: Is colorectal cancer a paracrine deficiency syndrome?

Guanylyl cyclase C (GCC) is the receptor expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin that coordinate mucosal homeostasis and its silencing contributes to intestinal transformation. It orchestrates proliferative and metabolic circuits by limiting the cell cycle and programming metabolic transitions central to regeneration along the crypt-villus axis. Mice deficient in GCC are more susceptible to colon cancer induced by germline mutations or carcinogens. Moreover, guanylin and uroguanylin are the most commonly lost gene products in colon cancer. The role of GCC as a tumor suppressor and the universal loss of its hormones in transformation suggest a paradigm in which colorectal cancer is a disease of paracrine hormone insufficiency. Indeed, GCC signaling reverses the tumorigenic phenotype of human colon cancer cells by regulating proliferation and metabolism. These data suggest a pathophysiological hypothesis in which GCC is a tumor suppressor coordinating proliferative homeostasis whose silencing through hormone loss initiates transformation. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral hormone replacement therapy employing GCC ligands.

Generation of a transcription map of a 1 Mbase region containing the HFE gene (6p22).

A transcription map was generated of a 1 Mb interval including the HFE gene on 6p22. Thirty-seven unique cDNA fragments were characterised following their retrieval from hybridisation of immobilised YACs to primary pools of cDNAs prepared from RNA of foetal brain, human liver, foetal human liver, placenta, and CaCo2 cell line. All cDNA fragments were positioned on the physical map on the basis of presence in aligned and overlapping YACs and cosmid clones of the region. The isolated cDNAs together with established or published sequence tagged sites (STSs) and markers provided sufficient landmark density to cover approximately 90% of the 1 Mb interval with cosmid clones. The precise localisation of two known genes (NPT1 and RING finger protein) was established. A minimum of 14 additional transcription units has also been integrated. Twenty-eight cDNA fragments showed no similarity with known sequences, but 20 of these detected discrete mRNAs upon northern analysis. Their characterisation is still under investigation. Eleven new polymorphisms were also identified and localised, and the HFE genomic structure was better defined. This integrated transcription map considerably extends a recently published map of the HFE region. It will be useful for the identification of genetic defects mapping to this region and for providing template resources for genomic sequencing.

Cloning of a new gene (FB19) within HLA class I region.

A novel gene (named FB19) has been identified within the HLA class I region at human chromosome 6p21.3. A 4.5-kb cDNA containing a 2820-bp open reading frame for a predicted protein of 940 aa was identified. No homology with known gene was detected at the DNA level, while the predicted protein is characterized by a glycine-rich region followed by a domain of 35 residues that shows high homology with the CAT56 gene, another gene of MHC class I. A 4. 5-kb transcript was detected in several tissues and cell lines, clearly indicating a wide distribution of expression. Once its function is defined, it could be possible to investigate the relationship between the FB19 gene and the several diseases already mapped within the HLA class I region.

Mutation analysis of the HLA-H gene in Italian hemochromatosis patients.

Hemochromatosis (HH) is an inborn error of iron metabolism, frequent among Caucasians, characterized by progressive iron loading that, if untreated, causes high morbidity and death. HLA-H, a putative HH gene, has recently been isolated. The large majority of patients so far studied are homozygous for a single mutation, which results in a cysteine-to-tyrosine substitution at amino acid 282 of the protein. A second, less frequent, variant, His63Asp, has an undefined role in the pathogenesis of the disease. Here we report that the Cys282Tyr change accounts for 69% of HH chromosomes in a series of 75 unrelated Italian patients who fulfilled well-defined criteria for HH diagnosis. Sixty-four percent of patients were Cys282Tyr homozygous, 10% were heterozygous, and 21% carried the normal allele. The same mutation was rare in normal controls. The His63Asp variant was less frequent but had a similar frequency among affected and normal chromosomes. Subjects without two copies of the Cys282Tyr change were both isolated patients and individuals from families with a 6p-linked disease. Mutation analysis of the HLA-H gene, carried out by RNA-SSCP in the latter patients, did not reveal any significant nucleotide abnormality in coding sequences and intron-exon boundaries. The absence of mutations in HLA-H gene was confirmed in three cases by direct sequencing. Major deletions or rearrangements of the gene were excluded by Southern blotting. The existence of patients with clinical and histological features of HH, but without mutations in HLA-H gene, suggests that in Italy the disease is more heterogeneous than reported in northern Europe.

Aesthetic preference and lateral dominance.

Aesthetic preferences for photographs with the main focal content either to the left or right of the photograph's center were examined in right- and left-handed subjects. Verbal responses or manual responses were required. In one experiment with 261 introductory psychology student-subjects, left-handers more often preferred photographs with the more important part on the left ("left-geared") than did right-handers. Exp. 2, involving 84 right-handed student subjects, showed that left-geared photographs presented on the left side were preferred more often than left-geared photographs presented on the right side, and left-geared photographs presented on the left side were more often chosen when a left-handed manual response was required. Interactions between handedness, position of the stimulus, language hemisphere, and response mode make it extremely difficult to ascertain whether the right hemisphere is really more involved in aesthetic decisions.

Appearance of sex hormone receptors in frog (Rana esculenta) tadpole skin during metamorphosis.

In tadpole skin of Rana esculenta, a specific testosterone receptor was detected during the climax in both males and females. The Kass ranged between 1 and 2.79 x 10(9)M-1.