Longer Fasting After Rybelsus Administration Contributes Higher Efficacy

Recent pharmacological topic for diabetes includes clinical application of Glucagon-like peptide 1 receptor agonists (GLP-1 RAs). Among them, oral semaglutide (Rybelsus) has been developed as the first oral form of GLP-1RA by useful application of sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Semaglutide concentration in the blood was compared when fasting time period after Rybelsus administration would be 15, 30, 60 and 120 minutes. As a result, the concentration ratio after 4 hours was 1.00, 1.67, 2.60 and 3.06, respectively. Authors have experienced a diabetic case of remarkable efficacy as HbA1c -1.4% and weight -5kg, who kept 3-4 hours fasting after Rybelsus intake

Transport of dopamine and levodopa and their interaction in COS-7 cells heterologously expressing monoamine neurotransmitter transporters and in monoaminergic cell lines PC12 and SK-N-SH

The present study investigated the effects of levodopa, a precursor of dopamine (DA) therapeutically used for the treatment of Parkinson's disease, on DA transport in the two different systems, COS-7 cells heterologously expressing rat monoamine transporter cDNA and in monoaminergic cell lines PC12 and SK-N-SH. Levodopa enhanced uptake of [3H]DA and [3H]norepinephrine (NE) but not [3H]serotonin in the transfected COS-7 cells in a concentration-dependent manner. On the other hand, in PC12 and SK-N-SH cells where NET is functionally expressed, levodopa enhanced [3H]DA and [3H]NE uptake at low concentrations and inhibited the uptake at higher concentrations. The effects of levodopa on catecholamine transporters in the opposite direction suggest a different mechanism at the intra- and extracellular sites in a levodopa transport-dependent and independent manner

Mechanisms of pain sensitization and the treatments

Hyperalgesia and allodynia, major symptoms of neuropathic pain can results after nerve injury or chronic inflammation. Trigeminal neuropathic pain resulting from alterations in peripheral and central noxious transmission systems often produced after nerve injury by pulpectomy or tooth-extraction or from temporomandibular joint inflammation. Neuropathic also occurs in some disease state, diabetic peripheral neuropathy, post-herpetic neuropathy and trigeminal neuralgia. Allodynia is characterized by long lasting pain evoked by essentially non-painful stimuli such as just light touch and tolerance to medication with conventional analgesics.Neuropathic pain is probably not a result of a single pathological mechanism, but the final product of an altered peripheral and central processing. Recent advances in pain research revealed that many factors derived from neurons and also non-neuronal neighboring residents participate in the initiation, development and maintenance. Among them, lipid mediators such as prostaglandins, lysophosphatidic acid and platelet-activating factor are recently found to play conspicuous roles for development of allodynia and hyperalgesia in spinal cord. Further advance by using cellular biological and molecular techniques would dig into the mechanisms underlying neuropathic pain and illustrate the new strategy and target candidate for drug development.There are also needs for tools and methods to assess neuropathic pain, common guidelines on classification, diagnosis and management, and evidence-based approach to the treatment of neuropathic pain

Essential Role of the Small GTPase Ran in Postnatal Pancreatic Islet Development

The small GTPase Ran orchestrates pleiotropic cellular responses of nucleo-cytoplasmic shuttling, mitosis and subcellular trafficking, but whether deregulation of these pathways contributes to disease pathogenesis has remained elusive. Here, we generated transgenic mice expressing wild type (WT) Ran, loss-of-function Ran T24N mutant or constitutively active Ran G19V mutant in pancreatic islet β cells under the control of the rat insulin promoter. Embryonic pancreas and islet development, including emergence of insulin+ β cells, was indistinguishable in control or transgenic mice. However, by one month after birth, transgenic mice expressing any of the three Ran variants exhibited overt diabetes, with hyperglycemia, reduced insulin production, and nearly complete loss of islet number and islet mass, in vivo. Deregulated Ran signaling in transgenic mice, adenoviral over-expression of WT or mutant Ran in isolated islets, or short hairpin RNA (shRNA) silencing of endogenous Ran in model insulinoma INS-1 cells, all resulted in decreased expression of the pancreatic and duodenal homeobox transcription factor, PDX-1, and reduced β cell proliferation, in vivo. These data demonstrate that a finely-tuned balance of Ran GTPase signaling is essential for postnatal pancreatic islet development and glucose homeostasis, in vivo

YM155 Induces EGFR Suppression in Pancreatic Cancer Cells

YM155, which inhibits the anti-apoptotic protein survivin, is known to exert anti-tumor effects in various cancers, including prostate and lung cancer. However, there are few reports describing the inhibitory effect of YM155 on human pancreatic cancers that highly express survivin. Here, we tested the effects of YM155 on a variety of cancer cell lines, including pancreatic cancer cells. We found that YM155 exerts an anti-proliferative effect in pancreatic cancer cells, inducing cell death through suppression of XIAP (X-linked inhibitor of apoptosis) as well as survivin without affecting the anti-apoptotic proteins Bcl-xL or Mcl-1. YM155 also inhibited tumor growth in vivo, reducing the size of pancreatic cancer cell line MIAPaCa-2 xenografts by 77.1% on day 31. Western blot analyses further showed that YM155 downregulated phosphoinoside 3-kinase (PI3K) expression and reduced the levels of phosphorylated (activated) extracellular signal-regulated kinase (ERK) and STAT3 (signal transducer and activator of transcription 3) in PANC-1 cells. Interestingly, we also found that YM155 downregulated the epidermal growth factor receptor (EGFR) in various cancer cell lines and induced the EGFR phosphorylation and ubiquitination of EGFR in PANC-1 cells. YM155 also modestly promoted the ubiquitination of survivin and XIAP. Therefore, YM155 acts through modulation of EGFR and survivin expression to subsequently reduce survival. We suggest that YM155 has potential as a therapeutic agent in the treatment of pancreatic cancer

Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells

Cimetidine has been shown to have beneficial effects in colorectal cancer patients. In this study, a total of 64 colorectal cancer patients who received curative operation were examined for the effects of cimetidine treatment on survival and recurrence. The cimetidine group was given 800 mg day−1 of cimetidine orally together with 200 mg day−1 of 5-fluorouracil, while the control group received 5-fluorouracil alone. The treatment was initiated 2 weeks after the operation and terminated after 1 year. Robust beneficial effects of cimetidine were noted: the 10-year survival rate of the cimetidine group was 84.6% whereas that of control group was 49.8% (P<0.0001). According to our previous observations that cimetidine blocked the expression of E-selectin on vascular endothelium and inhibited the adhesion of cancer cells to the endothelium, we have further stratified the patients according to the expression levels of sialyl Lewis antigens X (sLx) and A (sLa). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sLx and sLa antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sLx, of tumours was 95.5%, whereas that of control group was 35.1% (P=0.0001). In contrast, in the group of patients with no or low levels CSLEX staining, cimetidine did not show significant beneficial effect (the 10-year survival rate of the cimetidine group was 70.0% and that of control group was 85.7% (P=n.s.)). These results clearly indicate that cimetidine treatment dramatically improved survival in colorectal cancer patients with tumour cells expressing high levels of sLx and sLa