Sharmila Fagoonee

Heme scavenging and the other facets of hemopexin.

Hemopexin is an acute-phase plasma glycoprotein, produced mainly by the liver and released into plasma, where it binds heme with high affinity. Other sites of hemopexin synthesis are the nervous system, skeletal muscle, retina, and kidney. The only known receptor for the heme-hemopexin complex is the scavenger receptor, LDL receptor-related protein (LRP)1, which is expressed in most cell types, thus indicating multiple sites of heme-hemopexin complex recovery. The better-characterized function of hemopexin is heme scavenging at the systemic level, consisting of the transport of heme to the liver, where it is catabolyzed or used for the synthesis of hemoproteins or exported to bile canaliculi. This is important both in physiologic heme management for heme-iron recycling and in pathologic conditions associated with intravascular hemolysis to prevent the prooxidant and proinflammatory effects of heme. Other than scavenging heme, the heme-hemopexin complex has been shown to be able to activate signaling pathways, thus promoting cell survival, and to modulate gene expression. In this review, the importance of heme scavenging by hemopexin, as well as the other emerging functions of this protein, are discussed.

Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice

Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. Only acylated ghrelin (AG), but not the unacylated form (UnAG), can bind GHSR-1a; however, UnAG and AG share several GHSR-1a-independent biological activities. Here we investigated whether UnAG and AG could protect against skeletal muscle atrophy in a GHSR-1a-independent manner. We found that both AG and UnAG inhibited dexamethasone-induced skeletal muscle atrophy and atrogene expression through PI3Kβ-, mTORC2-, and p38-mediated pathways in myotubes. Upregulation of circulating UnAG in mice impaired skeletal muscle atrophy induced by either fasting or denervation without stimulating muscle hypertrophy and GHSR-1a-mediated activation of the GH/IGF-1 axis. In Ghsr-deficient mice, both AG and UnAG induced phosphorylation of Akt in skeletal muscle and impaired fasting-induced atrophy. These results demonstrate that AG and UnAG act on a common, unidentified receptor to block skeletal muscle atrophy in a GH-independent manner.

Functional antagonism between Sall4 and Plzf defines germline progenitors.

Transcription factors required for formation of embryonic tissues often maintain their expression in adult stem cell populations, but whether their function remains equivalent is not clear. Here we demonstrate critical and distinct roles for Sall4 in development of embryonic germ cells and differentiation of postnatal spermatogonial progenitor cells (SPCs). In differentiating SPCs, Sall4 levels transiently increase and Sall4 physically interacts with Plzf, a transcription factor exclusively required for adult stem cell maintenance. Mechanistically, Sall4 sequesters Plzf to noncognate chromatin domains to induce expression of Kit, a target of Plzf-mediated repression required for differentiation. Plzf in turn antagonizes Sall4 function by displacing Sall4 from cognate chromatin to induce Sall1 expression. Taken together, these data suggest that transcription factors required for embryonic tissue development postnatally take on distinct roles through interaction with opposing factors, which hence define properties of the adult stem cell compartment.

Endoscopic mucosal resection for early colorectal neoplasia: pathologic basis, procedures, and outcomes.

Open access endoscopy and screening programs enable detection and removal of an increased number of colon polyps in the early stages of neoplastic transformation. Unfortunately, polyps larger than 3 cm, involving more than one-third of circumference or two haustral folds, or with a flat/depressed morphology are more challenging to remove with standard polypectomy techniques. Endoscopic mucosal resection potentiates the removal, in a minimally invasive way, of certain colonic lesions that would otherwise require surgical or ablative treatment. Because the plane of resection during endoscopic mucosal resection is typically the middle to deep submucosal layer, compared with standard polypectomy, which normally provides resection at a mucosal level, endoscopic mucosal resection offers the advantage of providing en bloc resection specimens for histopathologic analysis. Indications to perform endoscopic mucosal resection are adenoma and small, well-differentiated carcinoma, confined to the mucosa or with minimal invasion to submucosa, and without any invasion to lymphatic channels or vessels. The most frequently reported major complications, such as perforation (0-5%) and bleeding (0.5-6%), may be controlled by endoscopic methods and rarely require surgical treatment. Follow-up postendoscopic mucosal resection is essential because of the risk of neoplastic recurrence.

The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation

Feline leukemia virus subgroup C receptor 1 (FLVCR1) is a cell membrane heme exporter that maintains the balance between heme levels and globin synthesis in erythroid precursors. It was previously shown that Flvcr1-null mice died in utero due to a failure of erythropoiesis. Here, we identify Flvcr1b, a mitochondrial Flvcr1 isoform that promotes heme efflux into the cytoplasm. Flvcr1b overexpression promoted heme synthesis and in vitro erythroid differentiation, whereas silencing of Flvcr1b caused mitochondrial heme accumulation and termination of erythroid differentiation. Furthermore, mice lacking the plasma membrane isoform (Flvcr1a) but expressing Flvcr1b had normal erythropoiesis, but exhibited hemorrhages, edema, and skeletal abnormalities. Thus, FLVCR1b regulates erythropoiesis by controlling mitochondrial heme efflux, whereas FLVCR1a expression is required to prevent hemorrhages and edema. The aberrant expression of Flvcr1 isoforms may play a role in the pathogenesis of disorders characterized by an imbalance between heme and globin synthesis.

Plasma Protein Haptoglobin Modulates Renal Iron Loading

Haptoglobin is the plasma protein with the highest binding affinity for hemoglobin. The strength of hemoglobin binding and the existence of a specific receptor for the haptoglobin-hemoglobin complex in the monocyte/macrophage system clearly suggest that haptoglobin may have a crucial role in heme-iron recovery. We used haptoglobin-null mice to evaluate the impact of haptoglobin gene inactivation on iron metabolism. Haptoglobin deficiency led to increased deposition of hemoglobin in proximal tubules of the kidney instead of the liver and the spleen as occurred in wild-type mice. This difference in organ distribution of hemoglobin in haptoglobin-deficient mice resulted in abnormal iron deposits in proximal tubules during aging. Moreover, iron also accumulated in proximal tubules after renal ischemia-reperfusion injury or after an acute plasma heme-protein overload caused by muscle injury, without affecting morphological and functional parameters of renal damage. These data demonstrate that haptoglobin crucially prevents glomerular filtration of hemoglobin and, consequently, renal iron loading during aging and following acute plasma heme-protein overload.

Helicobacters and Extragastric Diseases

For two decades, Helicobacter pylori has been considered as the culprit in many extragastric manifestations. However, for several of these supposed associations the hypothesis of an etiological role has not yet been fully investigated. This may be due to a series of factors linked to the epidemiological features of the studies and to the diseases investigated. This review attempts to highlight the main reported associations of H. pylori with extragastric manifestations during the last year. The most convincing data arise in the field of idiopathic thrombocytopenic purpura (ITP) and sideropenic anemia. Long‐term follow‐up studies have shown that 50% of subjects with ITP maintain a hematological response after H. pylori eradication. There is also growing evidence of the role of H. pylori in other diseases, including ischemic heart disease even though results are not conclusive.

Haemopexin affects iron distribution and ferritin expression in mouse brain

Haemopexin (Hx) is an acute phase plasma glycoprotein, mainly produced by the liver and released into plasma where it binds heme with high affinity and delivers it to the liver. This system provides protection against free heme‐mediated oxidative stress, limits access by pathogens to heme and contributes to iron homeostasis by recycling heme iron. Hx protein has been found in the sciatic nerve, skeletal muscle, retina, brain and cerebrospinal fluid (CSF). Recently, a comparative proteomic analysis has shown an increase of Hx in CSF from patients with Alzheimer’s disease, thus suggesting its involvement in heme detoxification in brain. Here, we report that Hx is synthesised in brain by the ventricular ependymal cells. To verify whether Hx is involved in heme scavenging in brain, and consequently, in the control of iron level, iron deposits and ferritin expression were analysed in cerebral regions known for iron accumulation. We show a twofold increase in the number of iron‐loaded oligodendrocytes in the basal ganglia and thalamus of Hx‐null mice compared to wild‐type controls. Interestingly, there was no increase in H‐ and L‐ferritin expression in these regions. This condition is common to several human neurological disorders such as Alzheimer’s disease and Parkinson’s disease in which iron loading is not associated with an adequate increase in ferritin expression. However, a strong reduction in the number of ferritin‐positive cells was observed in the cerebral cortex of Hx‐null animals. Consistent with increased iron deposits and inadequate ferritin expression, malondialdehyde level and Cu–Zn superoxide dismutase‐1 expression were higher in the brain of Hx‐null mice than in that of wild‐type controls. These data demonstrate that Hx plays an important role in controlling iron distribution within brain, thus suggesting its involvement in iron‐related neurodegenerative diseases.

Antiglycan antibodies as serological markers in the differential diagnosis of inflammatory bowel disease

Background: The objective of the study was to evaluate the diagnostic accuracy of recently developed antiglycan serological tests in clinical practice for the diagnosis of Crohns disease. Methods: This study was a cohort analysis of both clinical and biochemical parameters of patients with diagnosed inflammatory bowel disease compared with those in a control population. Antiglycan antibodies were determined using commercially available enzyme immunoassays. The setting was the outpatient unit of the gastroenterology department of a large, tertiary‐care referral academic hospital. Participants were 214 consecutive patients, enrolled over a 5‐month period, including 116 with Crohns disease and 53 with ulcerative colitis, as well as 45 with other gastrointestinal diseases and 51 healthy controls. Results: Anti–Saccharomyces cerevisiae antibodies showed the best performance (54% sensitivity and 88%–95% specificity for Crohns disease). Among patients with negative anti‐Saccharomyces antibodies, 19 (34%) had high titers of at least another tested antiglycan antibody. Anti‐Saccharomyces and anti‐laminaribioside antibodies were associated with disease involving the small bowel and with penetrating or stricturing phenotype. Anti‐laminaribioside was significantly higher in patients with a familial history of inflammatory bowel disease. Conclusions: The new proposed serological markers are significantly associated with Crohns disease, with low sensitivity but good specificity. About one third of anti‐Saccharomyces‐negative patients may be positive for at least 1 of those markers. Antiglycan antibodies appear to be associated with characteristic localization and phenotype of the disease.

Helicobacter pylori and Coronary Heart Disease: Which Directions for Future Studies?

Classical risk factors explain the pathogenesis of coronary heart disease (CHD) in only a proportion of cases; therefore, the need to investigate the possible role of “new” agents has incited intense research. Since 1994, a number of studies regarding the possible involvement of Helicobacter pylori (H. pylori) have been published with conflicting results. Establishing a causal link between this infection and CHD would be of major public health importance, since the eradication of the bacterium is easy and much less expensive than long-term treatment of the other risk factors. The main cause of this discordance was the vast heterogeneity of such studies: sufficiently powerful design was found only in few investigations, CHD was defined with a low degree of homogeneity, biases were obvious in the control groups, thus giving room for large variation in the adjustment of potential confounding factors. The present paper attempts to highlight the future directions towards which research should be headed in this area to establish a causal role of H. pylori infection in the pathogenesis of CHD. Future research should take three directions: 1) prospective population-based studies in which the incidence or the recurrence of CHD be evaluated in correlation with H. pylori status, 2) intervention trials, focusing separately on the chronic and acute phases of coronary heart disease and, 3) studies of physiopathology (both in the animal model and humans) to understand the potential biological plausibility.