The HPA axis modulates the CNS melanocortin control of liver triacylglyceride metabolism

The central melanocortin system regulates lipid metabolism in peripheral tissues such as white adipose tissue. Alterations in the activity of sympathetic nerves connecting hypothalamic cells expressing melanocortin 3/4 receptors (MC3/4R) with white adipocytes have been shown to partly mediate these effects. Interestingly, hypothalamic neurons producing corticotropin-releasing hormone and thyrotropin-releasing hormone co-express MC4R. Therefore we hypothesized that regulation of hypothalamo-pituitary adrenal (HPA) and hypothalamo-pituitary thyroid (HPT) axes activity by the central melanocortin system could contribute to its control of peripheral lipid metabolism. To test this hypothesis, we chronically infused rats intracerebroventricularly (i.c.v.) either with an MC3/4R antagonist (SHU9119), an MC3/4R agonist (MTII) or saline. Rats had been previously adrenalectomized (ADX) and supplemented daily with 1mg/kg corticosterone (s.c.), thyroidectomized (TDX) and supplemented daily with 10 μg/kgL-thyroxin (s.c.), or sham operated (SO). Blockade of MC3/4R signaling with SHU9119 increased food intake and body mass, irrespective of gland surgery. The increase in body mass was accompanied by higher epididymal white adipose tissue (eWAT) weight and higher mRNA content of lipogenic enzymes in eWAT. SHU9119 infusion increased triglyceride content in the liver of SO and TDX rats, but not in those of ADX rats. Concomitantly, mRNA expression of lipogenic enzymes in liver was increased in SO and TDX, but not in ADX rats. We conclude that the HPA and HPT axes do not play an essential role in mediating central melanocortinergic effects on white adipose tissue and liver lipid metabolism. However, while basal hepatic lipid metabolism does not depend on a functional HPA axis, the induction of hepatic lipogenesis due to central melanocortin system blockade does require a functional HPA axis.     

Primary mediastinal chondrosarcoma with Horner’s syndrome

Chondrosarcomas are uncommon tumors of the mediastinum. Cases reported in the literature are chondrosarcomas originating from osteocartilaginous structures; primary chondrosarcomas that have no anatomical relation with cartilaginous structures are rare. They present with myriad symptoms depending on compression of the adjacent structures; but Horner’s syndrome, as a symptom, has not been described before. We report a rare case of a large primary mediastinal chondrosarcoma that presented with Horner’s syndrome.     

Intervention in acute cerebral ischaemic stroke: a review of the role of pharmacological therapies and intra-arterial mechanical thrombectomy devices

Acute ischaemic stroke (AIS) is the leading cause of death and disability in developed nations. In the past decade pharmacologic and endovascular therapy has been approved for use in treatment of patients presenting with AIS. The time window from symptom onset to be eligible for treatment is narrow, allowing for only a small proportion of these patients to be treated. Currently the established method of treatment is intravenous thrombolytic therapy for patients without contraindication, presenting within the time window of 4.5 h from the onset of symptoms. The improvement in patient outcome with this therapy is poor. This has led to exploration of intra-arterial mechanical thrombectomy devices to both increase the time window and also attempt to improve patient outcome with and without intravenous thrombolytic therapy. Several studies have shown a high rate of vessel recanalisation with endovascular techniques; however, their efficacy and translation to improved patient outcome is not yet established. Advanced imaging techniques may help select patients who would predictably benefit from endovascular intervention. In the light of existing controversies, this review discusses the current evidence for intravenous and intra-arterial thrombolytics, intra-arterial mechanical thrombectomy devices, and intracranial stent placement for treatment of AIS.     

Fibrovascular polyp of the oropharynx

Fibrovascular polyps are benign but rare tumours of the upper digestive tract. In most of the cases reported to date, fibrovascular polyps have originated from the oesophagus or hypopharynx. In 85-90 percent of these reports, the commonest site was adjacent to the cricopharyngeal muscle. We report a very rare case, the third in the English language literature, of a fibrovascular polyp arising from the oropharynx. The patient provided a history of coughing with regurgitation of the polyp, which caused respiratory discomfort that was only relieved by swallowing it. The patient was successfully treated by excision through the peroral route. There was no recurrence in the three years of follow-up. We also discuss the various diagnostic tests available and the pathogenesis and histopathology of such lesions.     

Hydrogen-bonding interactions in T-2 toxin studied using solution and solid-state NMR

The structure of T-2 toxin in the solid-state is limited to X-ray crystallographic studies, which lack sufficient resolution to provide direct evidence for hydrogen-bonding interactions. Furthermore, its solution-structure, despite extensive Nuclear Magnetic Resonance (NMR) studies, has provided little insight into its hydrogen-bonding behavior, thus far. Hydrogen-bonding interactions are often an important part of biological activity. In order to study these interactions, the structure of T-2 toxin was compared in both the solution- and solid-state using NMR Spectroscopy. It was determined that the solution- and solid-state structure differ dramatically, as indicated by differences in their carbon chemical shifts, these observations are further supported by solution proton spectral parameters and exchange behavior. The slow chemical exchange process and cross-relaxation dynamics with water observed between the hydroxyl hydrogen on C-3 and water supports the existence of a preferential hydrogen bonding interaction on the opposite side of the molecule from the epoxide ring, which is known to be essential for trichothecene toxicity. This result implies that these hydrogen-bonding interactions could play an important role in the biological function of T-2 toxin and posits towards a possible interaction for the trichothecene class of toxins and the ribosome. These findings clearly illustrate the importance of utilizing solid-state NMR for the study of biological compounds, and suggest that a more detailed study of this whole class of toxins, namely trichothecenes, should be pursued using this methodology.     

Synthesis, biological evaluation and molecular docking studies of 1,3-benzoxazine derivatives as potential anticancer agents

A series of 6 and/or 8-substituted derivatives of 1,3-benzoxazines, having flavone moiety at 3-position, have been synthesized. For synthesis of the compounds, 6 or/and 8-substituted saliscylaldehydes were reacted with aminoflavone followed by reduction, and CHCl₃/HCHO promoted cyclization to give corresponding aminoflavone precursors which provided the desired 1,3-benzoxazine skeleton. Cytotoxic effects of the synthesized compounds were investigated in vitro against human breast cancer (MCF-7) cell lines. Among the compounds tested, methyl (3f and 6f), methoxy (3h, 3i, and 6h), and chloro (3d) derivatives were found to be most potent with IC₅₀ values of 14.3, 14.9, 17.1, 8.03, 12.1, and 12.03 μM, respectively. Molecular docking studies of most active compounds of the series revealed that they bind to a narrow hydrophobic pocket of the N-terminal chain in the ATP binding site of EGFR.     

Evaluation of genotoxicity of Trois through Ames and in vitro chromosomal aberration tests

Objective

To investigate the mutagenic potential of Trois using the bacterial reverse mutation assay (Ames test) and in vitro chromosomal aberration test.

Methods

The ability of Trois to induce reverse mutations was evaluated in Salmonella typhimurium (TA 98, TA100, TA1535 and TA1537) and Escherichia coli (WP2 uvrA) with and without metabolic activation system (S9 mix) at the dose range of 313 to 5000 µg/plate. Chromosomal aberrations were evaluated in Chinese hamster lung (CHL) cell line at the dose levels of 15, 7.5, 3.7, 1.9 and 0.9 mg/mL in the absence and presence of S9 mix.

Results

There were no increases in the number of revertant colonies at any concentrations of Trois used in the study with and without S9 mix in all tester strains. Trois did not produce any structural aberration in CHL cells in the presence or absence of S9 mix.

Conclusions

Results of this study suggest that Trois is non-mutagenic.     

Impact of Aspergillus fumigatus in allergic airway diseases

ABSTRACT: For decades, fungi have been recognized as associated with asthma and other reactive airway diseases. In contrast to type I-mediated allergies caused by pollen, fungi cause a large number of allergic diseases such as allergic bronchopulmonary mycoses, rhinitis, allergic sinusitis and hypersensitivity pneumonitis. Amongst the fungi, Aspergillus fumigatus is the most prevalent cause of severe pulmonary allergic disease, including allergic bronchopulmonary aspergillosis (ABPA), known to be associated with chronic lung injury and deterioration in pulmonary function in people with chronic asthma and cystic fibrosis (CF). The goal of this review is to discuss new understandings of host-pathogen interactions in the genesis of allergic airway diseases caused by A. fumigatus. Host and pathogen related factors that participate in triggering the inflammatory cycle leading to pulmonary exacerbations in ABPA are discussed.