In our studies of Na+-glucose cotransporter (SGLT) inhibitors as antidiabetic agents, a series of novel 4‘-dehydroxyphlorizin derivatives substituted on the B ring was prepared and their effects on ...urinary glucose excretion were evaluated in rats. Introduction of only a small alkyl group at the 4‘-position increased the activity, and 3-(benzobfuran-5-yl)-2‘,6‘-dihydroxy-4‘-methylpropiophenone 2‘-O-β-d-glucopyranoside (4) showed the most potent effect. To overcome hydrolysis of compound 4 by β-glucosidase in the digestive tract, the OH groups on the glucose moiety of compound 4 were modified. Three prodrugs (5, 42, and 55) were more potent than the parent compound 4 by oral administration, and finally 3-(benzobfuran-5-yl)-2‘,6‘-dihydroxy-4‘-methylpropiophenone 2‘-O-(6-O-methoxycarbonyl-β-d-glucopyranoside) (5) was selected as a new promising candidate. Compound 5 was metabolized mainly by liver esterase to the active form (4), which was about 10 times more potent than 5 in inhibiting SGLT. In oral glucose tolerance test in db/db mice, compound 5 dose-dependently suppressed the elevation of glucose levels. Single administration of 5 reduced hyperglycemia concurrently with increase of glucose excretion into urine in diabetic KK-Ay mice. Furthermore, compound 5 suppressed the elevation of blood glucose levels but did not lower it below the normal level even in fasted conditions in KK-Ay mice. Additionally, long-term treatment with 5 dose-dependently reduced hyperglycemia and HbA1c in KK-Ay mice. These pharmacological data strongly suggest that compound 5 has a therapeutic potential in the treatment of NIDDM.
In July 2022, a workshop and exhibition on SDG Goal 13 “Climate Change” was held in the East Annex. Students and students from integrated schools participated in the activities, using the “open ...space” created by KeMCo as a learning space for lectures, making things, viewing real objects, and reflecting on the experience. All of these activities included activities to give form to their own sensibilities through dialogue and co-speaking.It is said that it is future generations that will face the problem of climate change. In order to tackle this problem, sustainable education for future generations is essential. By sharing the “question” that is the challenge, creative activities will be conducted to find the answer that has no “right” answer. This is the kind of learning practiced in “vacant lots. Even in these activities, the dialogue and co-speaking among the multi-generational participants provided insights for a shift in values.This paper reports an example of how the “vacant land” created by KeMCo became an educational environment for creating and practicing sustainable learning.
Using Japanese firms that went public during the period 1998–2006, we find that independent venture capitalist-backed IPO firms are significantly younger and smaller than IPO companies backed by ...venture capital firms that are subsidiaries of financial institutions. IPOs backed by independent venture capitalists also tend to use less reputable underwriters and go public on stock exchanges with less strict listing requirements due to their immaturity. Young and small IPO companies experience significantly greater underpricing and poorer long-term operating performance. Taken all together, independent venture capitalists make lower quality companies go public than finance-affiliated venture capitalists.
► Independent venture capitalists make immature firms go public. ► Independent venture capitalist-backed IPO firms choose less reputable underwriters. ► Independent venture capitalists make firms list on exchanges with loose requirements. ► These firms experience large underpricing and poor long-term performance. ► Finance-affiliated venture capitalists prohibit immature firms from going public.
Axonal regeneration across end-to-side neurorrhaphy has recently been reported; however, neither the mechanism by which collateral sprouting from intact axons is elicited, nor the origin of the ...regenerating axons are known. There has even been controversy over the presence of collateral axonal sprouting from intact axons altogether. This reported experimental study was designed to clarify these questions. A rat sciatic nerve model was used. To avoid any mechanical damage to the donor nerve during the procedure, a Y-shaped silicone chamber was employed instead of direct suture. Axonal regeneration from the intact tibial nerve across the gap into the peroneal nerve was assessed using a retrograde neurotracer and immunohistochemical staining. Axonal regeneration across the gap was observed in 66 percent of the animals. The neurotracer evaluation clearly showed that all regenerating axons were sensory axons from the dorsal root ganglia. The authors concluded that Schwann cells from the distal wallerian degeneration of nerve segments did elicit collateral axonal sprouting from intact sensory axons, but not from motor axons in end-to-side neurorrhaphy. Invasion of the Schwann cells into the epineurial layer was the crucial step for the initiation of collateral axonal sprouting from the intact axons.
T-1095, a derivative of phlorizin, is an orally active inhibitor of Na+ -glucose cotransporter (SGLT). We investigated the acute antihyperglycemic effect of T-1095 in streptozotocin-induced diabetic ...rats (STZ rats). T-1095 and its metabolite T-1095A inhibited the SGLT activity in brush border membranes prepared from kidneys of both normal and STZ rats, but the latter agent was approximately 10 times more potent than the former. Single oral administration of T-1095 (30-100 mg/kg) dose-dependently induced glycosuria in normal rats. The fed glucose levels in STZ rats were dose-dependently suppressed by single oral administration of T-1095 (3-100 mg/kg), whereas there was only marginal hypoglycemic effect in normal rats. Since there was no effect on blood glucose in nephrectomized STZ rats, inhibition of renal glucose reabsorption rather than intestinal glucose absorption mainly contributes to the antihyperglycemic effect of T-1095. In conclusion, T-1095 is the first orally active agent which has an acute antihyperglycemic action in the absence of endogeneous insulin secretion with a low risk of hypoglycemia and has therapeutic potential for treatment of diabetes mellitus.
Based on our new concept that inhibitors of the Na(+)-glucose cotransporter (SGLT) would be useful as antidiabetics, 4'-dehydroxyphlorizin derivatives 1a--f were designed, synthesized, and examined ...for various pharmacological properties related to antidiabetic activity. In normal rats, 1a, e and phlorizin showed a strong SGLT-inhibitory effect and significantly increased urinary glucose on intraperitoneal administration at 10 mg/kg, though only 1a resulted in excretion of large quantities of urinary glucose on oral administration at 100 mg/kg. Compounds 1a, e, and phlorizin markedly inhibited glucose uptake in the small intestine during enteric perfusion in normal rats. Compound 1a had a significant reducing effect on blood glucose in the glucose tolerance test in mice when administered orally and also lowered blood glucose in streptozotocin-induced diabetic rats. The aglycons 2a, e of 1a, e, and 1a showed weak inhibitory effects on the facilitated glucose transporter-1 (GLUT-1) in human erythrocytes, while phloretin had a strong inhibitory effect on GLUT-1. Compound 1a caused no apparent renal damage in rats when administered orally at 1 g/kg for 4 successive weeks. Thus, 1a was considered to be a promising candidate as a lead compound for antidiabetics of a new type, and was selected for further pharmacological evaluation.
A novel series of 4'-dehydroxyphlorizin derivatives was synthesized and the effects of these compounds on urinary glucose excretion were evaluated in rats. There was a strict structural requirement ...for activity. Introduction of a small substituent or a flat ring at the 3- and/or the 4-position on the A ring was permissible, but any change at the bridge part between the A and B rings or in the sugar moiety resulted in complete loss of activity. The 6'-OH group on the B ring was also necessary, and even small structural modifications of the 6'-OH group reduced the activity considerably. Among the compounds synthesizez, the 5-benzofuryl derivative 25 was the most potent and was selected as a new lead for further structure-activity relationship investigations.
The therapeutic effects of an orally active inhibitor of Na+‐glucose cotransporter (SGLT), T‐1095 (a derivative of phlorizin; 3‐(benzobfuran‐5‐yl)‐2′,6′‐dihydroxy‐4′‐methylpropiophenone ...2′‐O‐(6‐O‐methoxycarbonyl‐β‐D‐glycopyranoside)) were examined in C57BL/KsJ‐db/db (db/db) mice, a genetic animal model of obese type 2 diabetes.
The higher renal SGLT activity in db/db mice than normoglycaemic C57BL/KsJ‐db/+m (db/+m) mice may support the rationale for using an SGLT inhibitor in the treatment regimen for type 2 diabetes. Both T‐1095 and its metabolite, T‐1095A, which had approximately 10 times more potency, effectively inhibited renal SGLT activity of these mice in vitro.
Single oral administration of T‐1095 (10, 30, 100 mg kg−1, p.o.) to db/db mice caused a dose‐dependent reduction in blood glucose levels and a concomitant increase in glucose excretion into urine. In contrast, T‐1095 only slightly affected blood glucose levels in db/+m mice.
Chronic administration of T‐1095 (0.1% w w−1 pellet chow, for 12 weeks) decreased blood glucose and haemoglobin A1C levels, and improved glucose intolerance in db/db mice. The age‐related decrease in plasma insulin levels was markedly inhibited and there was a 2.5 fold increase of insulin content in the pancreas of T‐1095‐treated db/db mice. Food consumption was not changed, while impaired body weight gain was ameliorated by T‐1095 treatment.
Both the development of albuminuria and the expansion of glomerular mesangial area in db/db mice were significantly suppressed by chronic T‐1095 treatment, indicating the prevention of the progression of diabetic nephropathy.
These results demonstrate that the SGLT inhibitor T‐1095 is able to improve the metabolic abnormalities and inhibit the development of diabetic complications in db/db mice. Thus, T‐1095 can be used for therapy of type 2 diabetic patients.
British Journal of Pharmacology (2001) 132, 578–586; doi:10.1038/sj.bjp.0703829
T-1095A and T-1095 are synthetic agents derived from phlorizin, a specific inhibitor of Na+-glucose cotransporters (SGLTs). Unlike phlorizin, T-1095 is absorbed into the circulation via oral ...administration, is metabolized to the active form, T-1095A, and suppresses the activity of SGLTs in the kidney. Orally administered T-1095 increases urinary glucose excretion in diabetic animals, thereby decreasing blood glucose levels. Indeed, the postprandial hyperglycemia after a meal load was shown to be suppressed by this compound in streptozotocin (STZ)-induced diabetic rats. With long-term T-1095 treatment, both blood glucose and HbA1c levels were reduced in STZ-induced diabetic rats and yellow KK mice. In addition, there was amelioration of abnormal carbohydrate metabolism, i.e., hyperinsulinemia and hypertriglyceridemia, and of the development of microalbuminuria, in yellow KK mice. Thus, T-1095 may be a useful antidiabetic drug, providing a novel therapeutic approach for diabetes.
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