Prevention of hair graying by factors that promote the growth and differentiation of melanocytes

Epidermal melanocyte precursors migrate into developing hair follicles to form the melanocyte stem cell system required to supply pigmented melanocytes necessary for hair pigmentation in repetitive hair cycles. Hair graying is caused by irreversible defects in the self‐renewal and/or development of follicular melanocyte stem cells in the hair follicles. To investigate the mechanism(s) of hair graying during the normal aging process, we established a hair graying model in mice by repeatedly plucking or shaving trunk hairs. We repeatedly plucked or shaved trunk hairs to induce and accelerate the hair graying and counted the gray hairs. By using this functional model of hair graying in mice, we assessed the effects of genes known to affect melanocyte development, such as Kitl, hepatocyte growth factor (HGF) and endotheline 3 (ET3). After increasing the total numbers of cumulative hair cycles by plucking or shaving, we observed a significant increase in the gray hair of C57BL/6 mice. Kitl expression in the skin was the most effective for preventing hair graying and a significant effect was also confirmed for HGF and ET3 expression. The repeated hair plucking or shaving led to hair graying without any genetic lesion. Kitl is a more effective factor for prevention of hair graying than HGF or ET3. Our simple model of hair graying may provide a basic tool for screening the molecules or reagents preventing the progression of hair graying.     

The biphasic effect of extracellular glucose concentration on carbachol‐induced fluid secretion from mouse submandibular glands

Cholinergic agonists evoke elevations of the cytoplasmic free‐calcium concentration ([Ca²⁺]_i) to stimulate fluid secretion in salivary glands. Salivary flow rates are significantly reduced in diabetic patients. However, it remains elusive how salivary secretion is impaired in diabetes. Here, we used an ex vivo submandibular gland perfusion technique to characterize the dependency of salivary flow rates on extracellular glucose concentration and activities of glucose transporters expressed in the glands. The cholinergic agonist carbachol (CCh) induced sustained fluid secretion, the rates of which were modulated by the extracellular glucose concentration in a biphasic manner. Both lowering the extracellular glucose concentration to less than 2.5 mM and elevating it to higher than 5 mM resulted in decreased CCh‐induced fluid secretion. The CCh‐induced salivary flow was suppressed by phlorizin, an inhibitor of the sodium–glucose cotransporter 1 (SGLT1) located basolaterally in submandibular acinar cells, which is altered at the protein expression level in diabetic animal models. Our data suggest that SGLT1‐mediated glucose uptake in acinar cells is required to maintain the fluid secretion by sustaining Cl^? secretion in real‐time. High extracellular glucose levels may suppress the CCh‐induced secretion of salivary fluid by altering the activities of ion channels and transporters downstream of [Ca²⁺]_i signals.     

The effect of an elemental diet on oral mucositis of esophageal cancer patients treated with DCF chemotherapy: a multi-center prospective feasibility study (EPOC study)

Purpose

Oral mucositis (OM) is one of the most uncomfortable adverse events experienced by cancer patients undergoing chemotherapy. Previous reports have revealed that the oral administration of an elemental diet (ED) may prevent OM. However, the incidence of OM has not been accurately determined by specialized diagnostic methods and the effects of an ED on OM remain unclear. We investigated the dose that could feasibly be administered and its effects with regard to the suppression of OM in esophageal cancer patients undergoing chemotherapy.

Methods

We performed a prospective multi-center feasibility study of the administration of an ED (160 g/day) with 2 cycles of docetaxel/cisplatin/5-FU (DCF) chemotherapy. We assessed compliance to the ED for 49 days and the incidence of OM according to the amount of the ED that was orally administered. The incidence of OM was graded by a dental specialist who was experienced in dental oncology using a central OM review system.

Results

Fourteen of 20 patients (70%) were able to complete the orally administered ED (160 g/day) during the course of chemotherapy. Three patients (15%) could not take the ED orally for 9, 14, and 21 days, respectively, while 1 patient (5%) took the ED orally at an average dose of 80 g/day for 35 days. The remaining 2 patients (10%) could not take the 80 g/day dose for 11 and 12 days, respectively. The incidence of grade?≥?2 OM in the ED completion group (15.4%, 2 of 13 patients) was significantly lower than that in the non-completion group (66.7%, 4 of 6 patients) (p?=?0.046).

Conclusions

An ED might be a one of the test treatment to reduce the incidence of OM in esophageal cancer patients treated with DCF and should be evaluated in further randomized study.

Clinical trial

The date of submission: Dec 08th, 2017.

     

A case of coexisting malignant carcinoid tumor and adenocarcinoma in the papilla of Vater

A 47-year-old Japanese woman in whom obstructive jaundice had already been diagnosed, was found to have a dome-shaped elevated tumor approximately 3 cm in diameter located in the area very close to the papilla of Vater on endoscopical and radiographical investigations. Histopathologically, the resected tumor was composed mainly of solid nests of atypical argyrophilic cells, and partially of an area of well differentiated tubular adenocarcinoma, showing mutual transition in the mucosal layer. Both immunohistochemical and ultrastructural analyses confirmed the difference in character of tumor cells between these two areas: neuroendocrine cell carcinoma and tubular adenocarcinoma of common type in the intestine. To the best of our knowledge, this is only the third case reported to be a coexisting malignant carcinoid tumor and adenocarcinoma arising in the periampullary region.     

Effects of phospholipase A2 inhibitors on Ca2+ oscillations in pancreatic acinar cells

High-affinity cholecystokinin (CCK) receptors were reported to be coupled with phospholipase A2 (PLA2)-arachidonic acid (AA) pathways to mediate Ca2+ oscillations and amylase secretion in rat pancreatic acinar cells. To investigate which types of PLA2 were involved in PLA2-AA pathways, the effects of specific inhibitors for type II and type IV PLA2 on Ca2+ oscillations and amylase secretion were studied in isolated rat pancreatic acini. An inhibitor of type IV (cytosolic) PLA2, AACOCF3 inhibited Ca2+ oscillations elicited by CCK-8 (30 pM) and JMV-180 (100 nM). AACOCF3 inhibited amylase secretion stimulated by JMV-180 and low concentrations of CCK-8 (< or =30 pM). On the other hand, an inhibitor of type II (secretory, nonpancreatic) PLA2 had no effects on Ca2+ oscillations and amylase secretion stimulated by CCK-8 and JMV-180. These results suggest that high-affinity CCK receptors are coupled to cytosolic PLA2 to mediate Ca2+ oscillations and amylase secretion in rat pancreatic acinar cells.     

Primary non-Hodgkin’s lymphoma of the gallbladder diagnosed by laparoscopic cholecystectomy

Primary lymphoma of the gallbladder is an exceedingly rare disease. We experienced an asymptomatic case of primary non-Hodgkin’s lymphoma of the gallbladder in a 55-year-old woman in whom laparoscopic cholecystectomy made a definite diagnosis. Abdominal computed tomography revealed a 4-cm gallbladder tumor with markedly enlarged lymph nodes in the retropancreatic area. Despite the marked involvement of lymph nodes, serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were not elevated. The discrepancy between the imaging findings and the patient’s mild clinical presentation led us to suspect that the tumor was a lymphoma. We examined serum markers of lymphoma, revealing slight elevations of interleukin (IL)-2 receptor and thymidine kinase. Laparoscopic cholecystectomy for a total biopsy was performed successfully, and the results of intraoperative frozen-section examination led us to have a high suspicion of malignant lymphoma. The final diagnosis was large diffuse B-cell lymphoma of the gallbladder with a positive CD20 antibody reaction. The patient received postoperative chemotherapy with R-CHOP (rituximab, 500 mg; cyclophosphamide, 1000 mg; adriamycin, 68 mg; vincristine, 1.9 mg; and prednisone, 80 mg) starting on postoperative day 12. She achieved complete remission and is still in complete remission 3 years and 2 months after the cholecystectomy. In conclusion, gallbladder lymphoma should be added to the differential diagnosis of gallbladder tumors, especially when the imaging findings and clinical presentation are not consistent with typical signs of gallbladder carcinoma, and laparoscopic cholecystectomy is helpful for the confirmation of suspicious cases.     

Adrenergic regulation of clock gene expression in mouse liver

A main oscillator in the suprachiasmatic nucleus (SCN) conveys circadian information to the peripheral clock systems for the regulation of fundamental physiological functions. Although polysynaptic autonomic neural pathways between the SCN and the liver were observed in rats, whether activation of the sympathetic nervous system entrains clock gene expression in the liver has yet to be understood. To assess sympathetic innervation from the SCN to liver tissue, we investigated whether injection of adrenaline/noradrenaline (epinephrine/norepinephrine) or sympathetic nerve stimulation could induce mPer gene expression in mouse liver. Acute administration of adrenaline or noradrenaline increased mPer1 but not mPer2 expression in the liver of mice in vivo and in hepatic slices in vitro. Electrical stimulation of the sympathetic nerves or adrenaline injection caused an elevation of bioluminescence in the liver area of transgenic mice carrying mPer1 promoter-luciferase. Under a light-dark cycle, destruction of the SCN flattened the daily rhythms of not only mPer1, mPer2, and mBmal1 genes but also noradrenaline content in the liver. Daily injection of adrenaline, administered at a fixed time for 6 days, recovered oscillations of mPer2 and mBmal1 gene expression in the liver of mice with SCN lesion on day 7. Sympathetic nerve denervation by 6-hydroxydopamine flattened the daily rhythm of mPer1 and mPer2 gene expression. Thus, on the basis of the present results, activation of the sympathetic nerves through noradrenaline and/or adrenaline release was a factor controlling the peripheral clock.