Medicinal plants of India with anti-diabetic potential.

Acetylcholine (ACh), the major parasympathetic neurotransmitter, is released by intrapancreatic nerve endings during the preabsorptive and absorptive phases of feeding. In beta-cells, ACh binds to muscarinic M(3) receptors and exerts complex effects, which culminate in an increase of glucose (nutrient)-induced insulin secretion. Activation of PLC generates diacylglycerol. Activation of PLA(2) produces arachidonic acid and lysophosphatidylcholine. These phospholipid-derived messengers, particularly diacylglycerol, activate PKC, thereby increasing the efficiency of free cytosolic Ca(2+) concentration ([Ca(2+)](c)) on exocytosis of insulin granules. IP3, also produced by PLC, causes a rapid elevation of [Ca(2+)](c) by mobilizing Ca(2+) from the endoplasmic reticulum; the resulting fall in Ca(2+) in the organelle produces a small capacitative Ca(2+) entry. ACh also depolarizes the plasma membrane of beta-cells by a Na(+)- dependent mechanism. When the plasma membrane is already depolarized by secretagogues such as glucose, this additional depolarization induces a sustained increase in [Ca(2+)](c). Surprisingly, ACh can also inhibit voltage-dependent Ca(2+) channels and stimulate Ca(2+) efflux when [Ca(2+)](c) is elevated. However, under physiological conditions, the net effect of ACh on [Ca(2+)](c) is always positive. The insulinotropic effect of ACh results from two mechanisms: one involves a rise in [Ca(2+)](c) and the other involves a marked, PKC-mediated increase in the efficiency of Ca(2+) on exocytosis. The paper also discusses the mechanisms explaining the glucose dependence of the effects of ACh on insulin release.

Mechanisms and Physiological Significance of the Cholinergic Control of Pancreatic β-Cell Function

Summary: Infection of humans with the nematode worm parasite Anisakis simplex was first described in the 1960s in association with the consumption of raw or undercooked fish During the 1990s it was realized that even the ingestion of dead worms in food fish can cause severe hypersensitivity reactions, that these may be more prevalent than infection itself, and that this outcome could be associated with food preparations previously considered safe Not only may allergic symptoms arise from infection by the parasites (“gastroallergic anisakiasis”), but true anaphylactic reactions can also occur following exposure to allergens from dead worms by food-borne, airborne, or skin contact routes This review discusses A simplex pathogenesis in humans, covering immune hypersensitivity reactions both in the context of a living infection and in terms of exposure to its allergens by other routes Over the last 20 years, several studies have concentrated on A simplex antigen characterization and innate as well as adaptive immune response to this parasite Molecular characterization of Anisakis allergens and isolation of their encoding cDNAs is now an active field of research that should provide improved diagnostic tools in addition to tools with which to enhance our understanding of pathogenesis and controversial aspects of A simplex allergy We also discuss the potential relevance of parasite products such as allergens, proteinases, and proteinase inhibitors and the activation of basophils, eosinophils, and mast cells in the induction of A simplex-related immune hypersensitivity states induced by exposure to the parasite, dead or alive

Anisakis simplex: from Obscure Infectious Worm to Inducer of Immune Hypersensitivity

The aim of this study was to determine whether tumor necrosis factor-alpha (TNFalpha) and receptors for TNFalpha are expressed in the exocrine pancreas, and whether pancreatic acinar cells release and respond to TNFalpha. Reverse transcription PCR, immunoprecipitation, and Western blot analysis demonstrated the presence of TNFalpha and 55- and 75-kD TNFalpha receptors in pancreas from control rats, rats with experimental pancreatitis induced by supramaximal doses of cerulein, and in isolated pancreatic acini. Immunohistochemistry showed TNFalpha presence in pancreatic acinar cells. ELISA and bioassay measurements of TNFalpha indicated its release from pancreatic acinar cells during incubation in primary culture. Acinar cells responded to TNFalpha. TNFalpha potentiated NF-kappaB translocation into the nucleus and stimulated apoptosis in isolated acini while not affecting LDH release. In vivo studies demonstrated that neutralization of TNFalpha with an antibody produced a mild improvement in the parameters of cerulein-induced pancreatitis. However, TNFalpha neutralization greatly inhibited apoptosis in a modification of the cerulein model of pancreatitis which is associated with a high percentage of apoptotic cell death. The results indicate that pancreatic acinar cells produce, release, and respond to TNFalpha. This cytokine regulates apoptosis in both isolated pancreatic acini and experimental pancreatitis.

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Pancreatic acinar cells produce, release, and respond to tumor necrosis factor-alpha : role in regulating cell death and pancreatitis

Type 2 diabetes has become a global epidemic. Modern medicines, despite offering a variety of effective treatment options, can have several adverse effects. Ayurveda, a science that uses herbal medicines extensively, originated in India. Of considerable interest is the adoption of Ayurveda by the mainstream medical system in some European countries (e.g., Hungary), emphasizing this modality is increasing worldwide recognition. From ancient times, some of these herbal preparations have been used in the treatment of diabetes. This paper reviews the accumulated literature for 10 Indian herbs that have antidiabetic activity and that have been scientifically tested. Few of these herbs, such as Momordica charantia, Pterocarpus marsupium, and Trigonella foenum greacum, have been reported to be beneficial for treating type 2 diabetes. Mechanisms such as the stimulating or regenerating effect on beta cells or extrapancreatic effects are proposed for the hypoglycemic action of these herbs.

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Role of selected Indian plants in management of type 2 diabetes: a review.

We examined the biological and histologic characteristics of a new experimental model of acute necrotizing pancreatitis induced by excessive doses of arginine in rats. Rats were given a single intraperitoneal injection of 500 mg/100 g body weight of L-arginine. At 12-24 hr after the arginine injection, serum levels of amylase, lipase, and anionic trypsin(ogen) reached respective peak values 2, 5, and 20 times those of control rats without arginine and returned to control levels after 24-48 hr. The contents of pancreatic protein, DNA, and digestive enzymes were markedly reduced after the arginine injection and reached their nadirs at 72 hr. After 14 days these levels were almost normal. Histologic examination revealed a number of small vesicles within acinar cells at 6 hr, which were identified as markedly swollen mitochondria by the electron microscope. Other intracellular organelles and nuclei also showed degenerative changes. At 12 hr interstitial edema appeared, and acinar cell necrosis was seen after 24 hr. The extent and severity of necrotic changes of pancreatic exocrine tissue with inflammatory cell infiltration were maximal at 72 hr. At seven days, pancreatic acinar cells began to regenerate, and pancreatic architecture appeared almost normal after 14 days. The present study has demonstrated that the administration of excessive doses of arginine induces a new, noninvasive experimental model of acute necrotizing pancreatitis.

New model of acute necrotizing pancreatitis induced by excessive doses of arginine in rats.

We studied the histologic and biochemical alterations in experimental acute pancreatitis induced by supramaximal caerulein stimulation in rats. All rats received 4 subcutaneous injections of various doses of caerulein (5–50 μg/kg body weight) at hourly intervals over 3 h, and 9 h after the first injection all animals were killed. Subcutaneous injections of 20 μg/kg body weight of caerulein induced a significant increase in serum amylase activity and histologic evidence of acute interstitial pancreatitis similar to those observed with the 50 μg/kg body weight dosage of caerulein. Therefore, a total of 4 subcutaneous injections of 20 μg/kg body weight of caerulein was chosen to study the time-course of structural and biochemical alterations in caerulein-induced acute pancreatitis. Serum amylase activity reached a maximal value of 10-fold increase over the basal values at 6 h, and then decreased gradually to normal values at 18 h after the first injection. Remarkable interstitial edema and cytoplasmic vacuoles in acinar cells were the earliest histologic alterations. Cellular infiltration was prominent at 9–12 h after the first injection. Although these histologic changes almost completely disappeared after 24 h, the reduction in the number of zymogen granules was still detectable by electron microscopic examination even after 7 days. DNA content in the pancreas showed no significant changes following the induction of acute pancreatitis, whereas a moderate to marked reduction in enzyme content persisted after 7 days. Within 14 days after the initiation of the injections, both structural and biochemical changes had completely disappeared. *** DIRECT SUPPORT *** A00DX035 00005

Histologic and biochemical alterations in experimental acute pancreatitis induced by supramaximal caerulein stimulation

Anisakiasis is a disease which occurs following eating raw fish infected with anisakis larvae. Many cases have been reported from Japan and from other countries with increasing opportunities of eating raw fish such as “sushi” and “sashimi.” We have reviewed 28 patients with acute gastric anisakiasis during the last 10 years from November 1984 to October 1994. This disease has rarely been detected in persons over 60 years of age and in patients with gastric surgery. Therefore it is postulated that gastric acid secretion influences the activities of anisakis larvae. An alkaline gastric pH could interfere with the toxicity of anisakis larvae.

Acute gastric anisakiasis: 28 cases during the last 10 years.

Effect of Gymnema sylvestre, R.Br. on glucose homeostasis in rats

We evaluated the effects of a new cholecystokinin (CCK) receptor antagonist, loxiglumide, in a model of mild pancreatitis induced by repeated injections of cerulein and in a severe necrotizing form of pancreatitis induced by retrograde ductal injection of sodium taurocholate (NaTc) in rats. A single subcutaneous injection or oral administration of 50 mg/kg of body weight of loxiglumide almost completely reduced the increases of serum amylase activity and pancreatic wet weight, and caused histologic improvements of the cerulein-induced acute pancreatitis when given 30 min before the first cerulein injection. Loxiglumide was also effective in reducing the elevated serum amylase activity, pancreatic wet weight, and histologic alterations even when administered after the induction of acute pancreatitis. However, loxiglumide offered no apparent beneficial effects when given 30 min before and 3 h after the induction of acute pancreatitis by NaTc as determined by changes in serum amylase activity, pancreatic wet weight, and histology. These results do not necessarily suggest that CCK is not important in the pathogenesis of pancreatitis, but do suggest that the sole blockade of peripheral CCK receptors is ineffective against NaTc-induced severe necrotizing pancreatitis.

Masatoshi Fujii

Papers

New model of acute necrotizing pancreatitis induced by excessive doses of arginine in rats.

Histologic and biochemical alterations in experimental acute pancreatitis induced by supramaximal caerulein stimulation

Acute gastric anisakiasis: 28 cases during the last 10 years.

Effect of Gymnema sylvestre, R.Br. on glucose homeostasis in rats

Effect of a new cholecystokinin receptor antagonist loxiglumide on acute pancreatitis in two experimental animal models.