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Gut hormone analogues and skeletal health in diabetes and obesity: Evidence from preclinical models.Peptides Jul 2024Diabetes mellitus and obesity are rapidly growing worldwide. Aside from metabolic disturbances, these two disorders also affect bone with a higher prevalence of bone... (Review)
Review
Diabetes mellitus and obesity are rapidly growing worldwide. Aside from metabolic disturbances, these two disorders also affect bone with a higher prevalence of bone fractures. In the last decade, a growing body of evidence suggested that several gut hormones, including ghrelin, gastrin, glucose-dependent insulinotropic polypeptide (GIP), glucagon, and glucagon-like peptide-1 and 2 (GLP-1 and GLP-2, respectively) may affect bone physiology. Several gut hormone analogues have been developed for the treatment of type 2 diabetes and obesity, and could represent a new alternative in the therapeutic arsenal against bone fragility. In the present review, a summary of the physiological roles of these gut hormones and their analogues is presented at the cellular level but also in several preclinical models of bone fragility disorders including type 2 diabetes mellitus, especially on bone mineral density, microarchitecture and bone material properties. The present review also summarizes the impact of GLP-1 receptor agonists approved for the treatment of type 2 diabetes mellitus and the more recent dual or triple analogue on bone physiology and strength.
Topics: Humans; Obesity; Diabetes Mellitus, Type 2; Animals; Gastrointestinal Hormones; Bone Density; Bone and Bones; Glucagon-Like Peptide 1; Gastric Inhibitory Polypeptide
PubMed: 38657908
DOI: 10.1016/j.peptides.2024.171228 -
Yakugaku Zasshi : Journal of the... Feb 2002Our studies on creation of functional organic compounds and their applications, have focused on three areas, namely, (A) organic chemical studies on VD (vitamin D)... (Review)
Review
Our studies on creation of functional organic compounds and their applications, have focused on three areas, namely, (A) organic chemical studies on VD (vitamin D) analogues, (B) studies on solitary wasp venoms, and (C) studies on functional building blocks for organic synthesis. In the first area, several novel and important vitamin D analogues were synthesized and biologically evaluated, and their high VDR (vitamin D receptor) binding affinities were discussed on the basis of conformational analysis and docking study by Molecular Mechanics Calculation to the LBD (ligand binding domain) of VDR: These compounds include 24,24-difluoro-1 alpha,25-dihydroxy-VD3 (2) (an antimetabolism agent, the first VD analogue having higher potency than the natural hormone (1)), 2 alpha-methyl-1 alpha,25-dihydroxy-VD3 (42b) (the first A-ring-modified VD analogue exhibiting stronger VDR affinity than 1) and its 20-epimer (43b) (a VD analogue having a highest HL-60 cell differentiation inducing activity with a relatively low calcemic effect), and 2 alpha-(omega-hydroxypropyl)-1 alpha,25-dihydroxy-VD3 (exceptionally high calcemic effect). In the second area, we isolated and determined the structure of pompilidotoxins (76, 77), novel peptide neurotoxins in solitary wasp venoms. In the third area, we created furan-fused 3-sulfolene, 4H, 6H-thieno [3,4-c]-furan 5,5-dioxide and pyrrole-fused 3-sulfolene (96), 3,5-dihydro-1H-thieno[3,4-c] pyrrole 2,2-dioxide (125), and studied their inter- and intramolecular Diels-Alder reactions.
Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Chemistry, Organic; Cyclic S-Oxides; Neurotoxins; Organic Chemistry Phenomena; Receptors, Calcitriol; Structure-Activity Relationship; Vitamin D; Wasp Venoms
PubMed: 11857955
DOI: 10.1248/yakushi.122.127 -
Journal of Experimental Child Psychology Oct 2022Prior research presents a mixed picture regarding the circumstances under which children transfer learning of problem solutions from fantastical stories to real-world...
Prior research presents a mixed picture regarding the circumstances under which children transfer learning of problem solutions from fantastical stories to real-world problems. Two experiments examined 3- to 5-year-old children's transfer of learning from fantastical storybooks that systematically varied in the fantastical abilities of storybook characters. In both experiments, participants heard stories about a character solving physical problems, and then participants attempted to solve analogous real-world problems. In Experiment 1, children heard stories that varied the fantastical abilities and practices of the protagonist; characters either did or did not have the ability to violate physical laws and did or did not use magic to help in solving a problem. Children were more likely to transfer problem solutions from the stories in which characters were presented as having the ability to violate real-world physical laws. In Experiment 2, the fantastical abilities of the characters varied by whether the characters were described as real, as pretend but living in a world where no physical laws could be violated, as pretend and living in a world where some physical laws could be violated, or as pretend and living in a world where many physical laws could be violated. Other than varying the characters' abilities, all characters used realistic solutions to solve the problem. Again, transfer was higher for children who heard about characters with the ability to violate real-world laws. The findings suggest that fantastical stories in which characters have the ability to do impossible things but use realistic solutions to problems can be effective in teaching children how to solve physical problems.
Topics: Child Development; Child, Preschool; Fantasy; Humans; Transfer, Psychology
PubMed: 35679778
DOI: 10.1016/j.jecp.2022.105474 -
Molecules (Basel, Switzerland) Nov 2018Nucleoside antibiotics are uridine-derived natural products that inhibit the bacterial membrane protein MraY. MraY is a key enzyme in the membrane-associated...
Nucleoside antibiotics are uridine-derived natural products that inhibit the bacterial membrane protein MraY. MraY is a key enzyme in the membrane-associated intracellular stages of peptidoglycan biosynthesis and therefore considered to be a promising, yet unexploited target for novel antibacterial agents. Muraymycins are one subclass of such naturally occurring MraY inhibitors. As part of structure-activity relationship (SAR) studies on muraymycins and their analogues, we now report on novel derivatives with different attachment of one characteristic structural motif, i.e., the aminoribose moiety normally linked to the muraymycin glycyluridine core unit. Based on considerations derived from an X-ray co-crystal structure, we designed and synthesised muraymycin analogues having the aminoribose attached (via a linker) to either the glycyluridine amino group or to the uracil nucleobase. Reference compounds bearing the non-aminoribosylated linker units were also prepared. It was found that the novel aminoribosylated analogues were inactive as MraY inhibitors in vitro, but that the glycyluridine-modified reference compound retained most of the inhibitory potency relative to the unmodified parent muraymycin analogue. These results point to 6'alkylated muraymycin analogues as a potential novel variation of the muraymycin scaffold for future SAR optimisation.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Nucleosides; Reference Standards; Ribose; Staphylococcus aureus; Structure-Activity Relationship; Transferases; Transferases (Other Substituted Phosphate Groups)
PubMed: 30486316
DOI: 10.3390/molecules23123085 -
Annals of Oncology : Official Journal... May 2002Somatostatin (SST) analogues represent a novel approach for the treatment of certain cancers. The objective of this article is to summarise the current knowledge on SST... (Review)
Review
BACKGROUND
Somatostatin (SST) analogues represent a novel approach for the treatment of certain cancers. The objective of this article is to summarise the current knowledge on SST analogues in the treatment of cancer patients.
METHODS
Computerised (Medline) and manual searches were performed to identify publications on clinical trials published in the English-speaking literature between 1966 and 2000. Information abstracted included patients' pre-treatment status, histology, SST receptor (SSTR) evaluation, type of SST analogue, application schedule and dose, duration of treatment, side-effects, response criteria applied (i.e. WHO response criteria, biochemical criteria or symptomatic investigations) and survival.
RESULTS
Our search disclosed 22 case reports, five phase 1 and 47 phase II trials, and eight randomised clinical trials using SST analogues (octreotide, lanreotide and vapreotide) as antineoplastic agents. With regard to the phase II trials, conflicting results have been demonstrated in almost all tumour entities investigated. The few randomised studies published so far have shown an impact on survival in patients with hepatocellular cancer, while the effect attributed to treatment in patients with gastrointestinal adenocarcinomas might well have been due to an exceptionally short survival in the control group. There appears to be evidence that SST analogues are able to enhance the therapeutic effects of hormonal intervention in patients with breast cancer, prostate cancer and probably pancreatic cancer. Interpretation of the findings, however, is complicated by the fact that patients were heavily pre-treated in some studies and response criteria have not been uniformly applied. In addition, most studies have not been designed to distinguish between receptor-mediated (direct) and indirect effects of SST analogues in tumour patients.
CONCLUSIONS
According to the results obtained so far, there can be no doubt about the wide therapeutic index and the high efficacy of SST analogues in the symptomatic management of neuroendocrine tumours. Apart from these indications, the data do not justify recommendation of SST analogues as antineoplastic agents outside of clinical trials, as the optimal dose and schedule of application for antineoplastic activity has not been defined for currently used agents. Carefully designed clinical trials including investigation of SSTR status before treatment, evaluation of an indirect mechanism of SST analogues, and assessment of optimal combination of hormone therapy and chemotherapy with SST analogues are clearly needed in the near future.
Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Neoplasms; Octreotide; Peptides, Cyclic; Randomized Controlled Trials as Topic; Sensitivity and Specificity; Somatostatin; Survival Analysis; Treatment Outcome
PubMed: 12075733
DOI: 10.1093/annonc/mdf142 -
Antiviral Research Feb 2019This is the second of two invited articles reviewing the development of nucleoside analogue antiviral drugs, written for a target audience of virologists and other... (Review)
Review
This is the second of two invited articles reviewing the development of nucleoside analogue antiviral drugs, written for a target audience of virologists and other non-chemists, as well as chemists who may not be familiar with the field. As with the first paper, rather than providing a chronological account, we have chosen to examine particular examples of structural modifications made to nucleoside analogues that have proven fruitful as various antiviral, anticancer, and other therapeutics. The first review covered the more common, and in most cases, single modifications to the sugar and base moieties of the nucleoside scaffold. This paper focuses on more recent developments, especially nucleoside analogues that contain more than one modification to the nucleoside scaffold. We hope that these two articles will provide an informative historical perspective of some of the successfully designed analogues, as well as many candidate compounds that encountered obstacles.
Topics: Antiviral Agents; Chemistry Techniques, Synthetic; Clinical Trials as Topic; Drug Development; Humans; Molecular Structure; Nucleosides; Prodrugs
PubMed: 30529089
DOI: 10.1016/j.antiviral.2018.11.016 -
Journal of the American Chemical Society Feb 2017Proteorhodopsin (PR) and Gloeobacter rhodopsin (GR) are retinal-based light-driven proton pumps that absorb visible light (maxima at 520-540 nm). Shifting the action...
Proteorhodopsin (PR) and Gloeobacter rhodopsin (GR) are retinal-based light-driven proton pumps that absorb visible light (maxima at 520-540 nm). Shifting the action spectra of these proton pumps beyond 700 nm would generate new prospects in optogenetics, membrane sensor technology, and complementation of oxygenic phototrophy. We therefore investigated the effect of red-shifting analogues of retinal, combined with red-shifting mutations, on the spectral properties and pump activity of the resulting pigments. We investigated a variety of analogues, including many novel ones. One of the novel analogues we tested, 3-methylamino-16-nor-1,2,3,4-didehydroretinal (MMAR), produced exciting results. This analogue red-shifted all of the rhodopsin variants tested, accompanied by a strong broadening of the absorbance band, tailing out to 850-950 nm. In particular, MMAR showed a strong synergistic effect with the PR-D212N,F234S double mutant, inducing an astonishing 200 nm red shift in the absorbance maximum. To our knowledge, this is by far the largest red shift reported for any retinal protein. Very importantly, all MMAR-containing holoproteins are the first rhodopsins retaining significant pump activity under near-infrared illumination (730 nm light-emitting diode). Such MMAR-based rhodopsin variants present very promising opportunities for further synthetic biology modification and for a variety of biotechnological and biophysical applications.
Topics: Infrared Rays; Molecular Structure; Proton Pumps; Retinaldehyde
PubMed: 28094925
DOI: 10.1021/jacs.6b11366 -
Journal of Hepatology Aug 2010Chronic hepatitis B patients are at increased risk for hepatocellular carcinoma (HCC). The effect of medium-term nucleos(t)ide analogue therapy on HCC incidence is... (Review)
Review
BACKGROUND & AIMS
Chronic hepatitis B patients are at increased risk for hepatocellular carcinoma (HCC). The effect of medium-term nucleos(t)ide analogue therapy on HCC incidence is unclear; therefore, we systematically reviewed all the data on HCC incidence from studies in chronic hepatitis B patients treated with nucleos(t)ide analogues.
METHODS
We performed a literature search to identify studies with chronic hepatitis B patients treated with nucleos(t)ide analogues for> or = 24 months.
RESULTS
Twenty-one studies including 3881 treated and 534 untreated patients met our inclusion criteria. HCC was diagnosed in 2.8% and 6.4% of treated and untreated patients, respectively, during a 46 (32-108) month period (p=0.003), in 10.8% and 0.5% of nucleos(t)ide naive patients with and without cirrhosis (p<0.001) and in 17.6% and 0% of lamivudine resistance patients with and without cirrhosis (p<0.001). HCC developed less frequently in nucleos(t)ide naive patients compared to those without virological remission (2.3% vs 7.5%, p<0.001), but there was no difference between lamivudine resistance patients with or without virological response to rescue therapy (5.9% vs 8.8%, p=0.466).
CONCLUSIONS
Chronic hepatitis B patients receiving medium-term nucleos(t)ide analogue therapy had a significantly lower incidence of HCC compared to untreated patients but treatment does not completely eliminate the risk of HCC. Among the treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC.
Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Cytosine; Female; Hepatitis B, Chronic; Humans; Incidence; Lamivudine; Liver Neoplasms; Male; Middle Aged; Nucleosides; Risk Factors
PubMed: 20483498
DOI: 10.1016/j.jhep.2010.02.035 -
The Journal of Biological Chemistry Sep 1975A number of cytokinin analogs containing modifications in the heterocyclic moiety were prepared. These compounds were tested for activity as cytokinins and...
A number of cytokinin analogs containing modifications in the heterocyclic moiety were prepared. These compounds were tested for activity as cytokinins and anticytokinins in the tabacco bioassay and the results were used to determine whether any position(s) of the heterocyclic nucleus of cytokinins may require derivatization as part of an over-all "activation" process. 3-substituted 4-alkylaminopyrazolo [3,4-d]pyrimidines and 4-alkylaminopyrrolo[2,3-d]pyrimidines, for example, have (substituted) carbon rather than nitrogen atoms at positions 3 and 5, respectively (analogous to position 7 in purines) and would be predicted to be metabolically stable at these positions. The finding that these compounds had cytokinin activity suggested that modification at the metabolically stable positions. The finding that these compounds had cytokinin activity suggested that modification at the metabolically stable position, and by extension at position 7 in cytokinin analogues which are purines, is not a prerequisite for the expression of cytokinin activity. Similar consideration of other heterocyclic analogs which have cytokinin activity suggests that the active form of a cytokinin can be the exogenous compound itself. Certain structural analogs of cytokinins were found to inhibit the growth of tobacco callus promoted by 6-(3-methyl-2-butenylamino)purine. These compounds were studied as potential cytokinin antagonists, i.e. having activity analogous to the 7-alkylamino-3-methylpyrazolo[4,3-d]pyrimidines (Hecht, S. M., 2068-2610; Skoog, F., Schmitz, R.Y., Hecht, S.M., and Bock, R. M. (1973) Phytochemistry 12, 25-37). The activity of these compounds is discussed and criteria are proposed to distinguish between those species which are specific anticytokinins and those which otherwise inhibit growth.
Topics: Biological Assay; Cytokinins; Plant Growth Regulators; Plants; Plants, Toxic; Structure-Activity Relationship; Nicotiana
PubMed: 1165244
DOI: No ID Found -
International Journal of Clinical... Nov 2009Basal insulin and premix insulin are commonly prescribed first-line insulin therapies for patients failing to maintain glycaemic control on oral therapy. When control on...
BACKGROUND
Basal insulin and premix insulin are commonly prescribed first-line insulin therapies for patients failing to maintain glycaemic control on oral therapy. When control on these insulins starts to drift, premix analogues, such as biphasic insulin aspart 30/70 (BIAsp 30), are a simple and effective tool for intensification as they can be injected up to three-times daily (TID). However, at present, international recommendations for intensification of insulin therapy using premix analogues are limited and specific guidance on dosing is not available for many scenarios.
METHODS
In October 2008, an international expert panel met to review the current guidelines for insulin intensification with BIAsp 30 in patients with type 2 diabetes, with the aim of developing practical guidance for general and specialist practitioners.
RESULTS
Simple treatment algorithms have been developed for (i) patients on basal insulin (human or analogue) once daily or twice daily (BID) who need intensification to BIAsp 30 BID, and (ii) patients on BIAsp 30 once daily or BID who can be intensified to BIAsp 30 BID or TID. As well as these algorithms, specific guidance has been provided on dose transfer (from basal insulin to BIAsp 30), dose split (when intensifying from once daily to BID), and combination oral therapies. In addition, a guide to dose titration is included.
CONCLUSIONS
The guidelines presented here should enable general or specialist practitioners to use BIAsp 30 to intensify the insulin therapy of patients failing on basal insulin or BIAsp 30 once or twice daily.
Topics: Algorithms; Biphasic Insulins; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Aspart; Insulin, Isophane; Treatment Failure
PubMed: 19780866
DOI: 10.1111/j.1742-1241.2009.02192.x