Ghrelin regulates insulin release and glycemia: physiological role and therapeutic potential

Insulin release from pancreatic islet beta-cells is stimulated by glucose. Glucose-induced insulin release is potentiated or suppressed by hormones and neural substances. Ghrelin, a novel acylated 28-amino acid peptide isolated from stomach, is the endogenous ligand for the growth hormone (GH) secretagogue-receptor (GHS-R). Circulating ghrelin is produced predominantly in stomach. Ghrelin is a potent stimulator of GH release and feeding as well as exhibiting positive cardiovascular effects. In relation to the glucose metabolism, initial studies indicated that low plasma ghrelin levels are associated with elevated fasting insulin levels, insulin resistance, and obesity. It has recently been demonstrated that ghrelin suppresses glucose-induced insulin release via G alpha(i2) subtype of GTP-binding proteins and delayed outward K(+) (Kv) channels, representing a novel signaling mechanism, and that the ghrelin originating from islets regulates insulin release and thereby glycemia. Furthermore, elimination of ghrelin enhances insulin release to prevent or ameliorate glucose intolerance in high-fat diet fed mice and ob/ob mice. This review focuses on the physiological roles of ghrelin in regulating insulin release and glycemia, the insulinostatic mechanisms of ghrelin in islet beta-cells, and the potential of ghrelin-GHS-R system as the therapeutic target to treat type 2 diabetes.     

Targeting oncogenic interleukin‐7 receptor signalling with N‐acetylcysteine in T cell acute lymphoblastic leukaemia

Activating mutations of the interleukin‐7 receptor (IL7R) occur in approximately 10% of patients with T cell acute lymphoblastic leukaemia (T‐ALL). Most mutations generate a cysteine at the transmembrane domain leading to receptor homodimerization through disulfide bond formation and ligand‐independent activation of STAT5. We hypothesized that the reducing agent N‐acetylcysteine (NAC), a well‐tolerated drug used widely in clinical practice to treat acetaminophen overdose, would reduce disulfide bond formation, and inhibit mutant IL7R‐mediated oncogenic signalling. We found that treatment with NAC disrupted IL7R homodimerization in IL7R‐mutant DND‐41 cells as assessed by non‐reducing Western blot, as well as in a luciferase complementation assay. NAC led to STAT5 dephosphorylation and cell apoptosis at clinically achievable concentrations in DND‐41 cells, and Ba/F3 cells transformed by an IL7R‐mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of STAT5. Despite using doses lower than those tolerated in humans, NAC treatment significantly inhibited the progression of human DND‐41 cells engrafted in immunodeficient mice. Thus, targeting leukaemogenic IL7R homodimerization with NAC offers a potentially effective and feasible therapeutic strategy that warrants testing in patients with T‐ALL.     

Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD

The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) on CKD. Oral administration of lubiprostone (500 µg/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresis–mass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment.     

A father and son with Turcot's syndrome: Evidence for autosomal dominant inheritance

Typical Turcot's syndrome is characterized by the association of a brain glioma together with multiple colonic polyposis, in which the number of polypoid lesions is small and the association of colonic cancer occurs at a younger age than in familial adenomatous polyposis. We describe a family in which both the father and his son presented with typical Turcot's syndrome without parental consanguinity. This is the first report of a family that is considered to follow an autosomal dominant inheritance. After reviewing 25 documented cases in which the average age of death was 20.3 years old, it was learned that the major cause of death was brain tumor (76 percent) and the minor cause was colon cancer (16 percent). Patients were very young and, therefore, unlikely to have produced a child before their death. These facts seem to support the theory that Turcot's syndrome is an autosomal dominant disorder.     

Hepatic Circulation and Hepatic Oxygen Consumption in Alcoholic and Nonalcoholic Fatty Liver

The purpose of this study was to determine the differences in hepatic circulation and oxygen consumption in two groups: those with nonalcoholic obesity-related fatty live and those with alcoholic fatty liver. Although the histological degree of fatty infiltration was equal in the two groups, the delta Er569-650, as an index of the regional liver blood flow estimated by spectrophotometric method, was significantly lower in alcoholic fatty liver than in nonalcoholic fatty liver, and the in vivo hepatic oxygen consumption (VO2), also determined by hepatic reflectance spectrophotometry during peritoneoscopy, tended to be lower in alcoholic fatty liver than in nonalcoholic fatty liver. The oxygen saturation of hemoglobin in local liver blood (SO2) was, however, significantly higher in alcoholic fatty liver than in nonalcoholic fatty liver. These results suggest that an increase in oxygen extraction to maintain oxygen consumption, which was indicated by the lowering of the SO2, was not found in alcoholic fatty liver, in spite of a reduction of oxygen supply to the liver. It is concluded that the impairment of hepatic circulation and hepatic oxygen consumption was more serious in alcoholic fatty liver than in nonalcoholic fatty liver, possibly contributing to a different prognosis for the two forms of fatty liver.     

Combined pure red cell aplasia and autoimmune hemolytic anemia in systemic lupus erythematosus with anti-erythropoietin autoantibodies

A 42-year-old woman with systemic lupus erythematosus was admitted to our hospital because of severe anemia. Her bone marrow was almost normocellular and erythroblasts were nearly absent. Laboratory data showed elevated levels of lactate dehydrogenase and positive findings on Coombs' tests. On the basis of these findings, her anemia was diagnosed as the overlap of pure red cell aplasia with autoimmune hemolytic anemia. Radioimmunoprecipitation assay revealed that her serum was positive for anti-erythropoietin antibodies before therapy. Furthermore, the autoantibodies inhibited proliferation of an erythropoietin-dependent cell line in a dose-dependent manner. Immunosuppressive treatment improved the anemia accompanied with disappearance of the autoantibodies.     

Gastrobiliary motility is not coordinated in patients with non-ulcer dyspepsia of normal gastric emptying time: simultaneous sonographic study

BACKGROUND: Disorders of the motor function of the upper gastrointestinal tract have been implicated in the pathogenesis of non-ulcer dyspepsia. Approximately 50% of patients with abdominal symptoms (without ulcer) have normal gastric emptying. Apart from gastric emptying, other mechanisms are very important in the etiology of non-ulcer dyspepsia. METHODS: Gastric emptying and gallbladder motility were simultaneously investigated in 16 patients with non-ulcer dyspepsia and in 15 healthy controls. Fasting blood samples were taken, and pepsinogen levels were assayed. RESULTS: Gastric emptying time, fasting antral diameter, and post-prandial antral diameter were not significantly different between the patients with non-ulcer dyspepsia and the controls. Fasting gallbladder volume, the time required to reach minimal gallbladder residual volume, minimal gallbladder residual volume, and the serum levels of pepsinogen were not significantly different. Simple linear regression was used to summarize the relationship between gastric emptying time and time required to reach minimal gallbladder residual volume. In the controls, the gastric emptying time and time required to reach minimal gallbladder residual volume were linearly related. However, in the patients with non-ulcer dyspepsia, they were not related. CONCLUSIONS: These observations suggest that disturbance of coordination between gastric emptying and gallbladder emptying is a cause of the symptoms of non-ulcer dyspepsia.     

Apoptosis and p53 expression in chondrocytes relate to degeneration in articular cartilage of immobilized knee joints

OBJECTIVE: We have reported that articular cartilage showed early stage degeneration at 7 and 14 days after immobilization, moderate degeneration at 28 days, and severe degeneration at 42 days in rabbits. To test whether apoptosis occurs in association with p53 expression in chondrocytes during the process of articular cartilage degeneration, we investigated the degree of cartilage degeneration, the frequency of apoptotic cells, and the levels of p53 mRNA in rabbits and mice after knee immobilization. METHODS: Right knees of male Japanese white rabbits were immobilized in full extension with fiberglass casts for up to 42 days. Similarly, right knees of male p53 wild-type [p53 (+/+)] and p53 null [p53 (-/-)] mice were immobilized in full extension with bandage tape for up to 84 days. Apoptotic cells were confirmed by TUNEL staining on the sections of knee joints. Total RNA of articular chondrocytes obtained from Day 0 or immobilized knees was analyzed semiquantitatively by RT-PCR using specific primers for p53. RESULTS: Articular cartilage degenerated after immobilization of p53 (+/+) mouse knees, but not after immobilization of p53 (-/-) knees. Apoptotic cells were observed in articular cartilage in the femur and tibia of rabbits and p53 (+/+) mice after immobilization. However, only a few apoptotic cells were observed at the same sites in p53 (-/-) mice. In RT-PCR analysis, the levels of p53 mRNA obtained from immobilized groups were significantly higher than those of Day 0 groups in rabbit and p53 (+/+) mouse knees. CONCLUSION: Apoptosis and p53 expression in chondrocytes relate to degeneration in articular cartilage of immobilized knee joints.