The uncarboxylated form of the osteoblast-specific secreted molecule osteocalcin is a hormone favoring glucose handling and increasing energy expenditure. As a result, the absence of osteocalcin leads to glucose intolerance in mice, while genetically modified mice with an increase in uncarboxylated osteocalcin are protected from type 2 diabetes and obesity. Here, we tested in the mouse the therapeutic potential of intermittent administration of osteocalcin. We found that daily injections of osteocalcin at either 3 or 30 ng/g/day significantly improved glucose tolerance and insulin sensitivity in mice fed a normal diet. This was attributable, in part, to an increase in both β-cell mass and insulin secretion. When mice were fed a high-fat diet (HFD), daily injections of osteocalcin partially restored insulin sensitivity and glucose tolerance. Moreover, mice treated with intermittent osteocalcin injections displayed additional mitochondria in their skeletal muscle, had increased energy expenditure and were protected from diet-induced obesity. Finally, the hepatic steatosis induced by the HFD was completely rescued in mice receiving osteocalcin daily. Overall, these results provide evidence that daily injections of osteocalcin can improve glucose handling and prevent the development of type 2 diabetes.
Thanks to integrative physiology, new relationships between organs and homeostatic functions have emerged. This approach to physiology based on a whole organism approach has allowed the bone field to make fundamental progress. In the last decade, clinical observations and scientific evidences in vivo have uncovered that fat with leptin controls bone mass through brain including a hypothalamic relay and sympathetic nervous system. The finding that energy metabolism affects bone remodelling suggested that in an endocrine perspective, a feedback loop should exist. Beside its classical functions, bone can now be considered as a true endocrine organ secreting osteocalcin, a hormone pharmacologically active on glucose and fat metabolism. Indeed osteocalcin stimulates insulin secretion and β-cell proliferation. Simultaneously, osteocalcin acts on adipocytes to induce Adiponectin which secondarily reduce insulin resistance. This cross regulation between bone and energy metabolism offers novel therapeutic targets in type 2 diabetes and osteoporosis.
An end-tidal carbon dioxide level of 10 mm Hg or less measured 20 minutes after the initiation of advanced cardiac life support accurately predicts death in patients with cardiac arrest associated with electrical activity but no pulse. Cardiopulmonary resuscitation may reasonably be terminated in such patients.
We have investigated olfactory bulb connections in the goldfish by using both horseradish peroxidase applied to olfactory tract lesions and wheat germ agglutinin-conjugated peroxidase administered to the olfactory bulb. The projections from the bulb pass to the brain in two major bundles: the lateral and the medial olfactory tracts. The lateral tract innervates the posterior terminal field in the area dorsalis. The medial tract divides into two rami. The dorsolateral ramus is the most substantial olfactory bundle in the brain and innervates several targets in both the area dorsalis and the area ventralis. The ventromedial ramus appears to innervate targets in the area ventralis exclusively. In addition, fibers of the medial olfactory tract (both rami) innervate the preoptic nucleus as well as targets in the diencephalon and, possibly, in the mesencephalon as well. Olfactory fibers from the dorsolateral and ventro-medial rami cross the midline in the dorsal and ventral olfactory decussations, respectively. Between these two decussations is a dense olfactory plexus which has not previously been reported, and which may serve as a nexus allowing interchange of fibers between the two olfactory rami. The terminal nerve in the goldfish has two parts. The major part of the nerve projects to the ventral nucleus (Vv) and is far more extensive than has previously been reported. A much less substantial component of the terminal nerve projects to the two retinae. There are four large groups of cells in the telencephalon which project to the olfactory bulb. Of these two, the dorsal and the anterolateral groups have not been described in previous studies of the goldfish. We also report weakly labeled bulbopetal cells in the nucleus preglomerulosus and in the locus ceruleus.
1,N6 -Ethenodeoxyadenosine, a DNA adduct generated by exogenous and endogenous sources, severely blocks DNA synthesis and induces miscoding events in human cells. To probe the mechanism for in vivo translesion DNA synthesis across this adduct, in vitro primer extension studies were conducted using newly identified human DNA polymerases (pol) and , which have been shown to catalyze translesion DNA synthesis past several DNA lesions. Steady-state kinetic analyses and analysis of translesion products have revealed that the synthesis is >100-fold more efficient with pol than with pol and that both error-free and error-prone syntheses are observed with these enzymes. The miscoding events include both base substitution and frameshift mutations. These results suggest that both polymerases, particularly pol , may contribute to the translesion DNA synthesis events observed for 1,N 6 -ethenodeoxyadenosine in human cells.In the last few years, several new human DNA polymerases (pols), 1 which are likely to be involved in translesion DNA synthesis (TLS), were discovered. This list includes pol (1), pol (2, 3), pol (4), and pol (5). Pol , pol , and pol are encoded by the hRAD30A, hRAD30B, and DINB1 genes, respectively. These new pols form a Rad30/UmuC/DinB/REV1 superfamily (2, 3, 6). Pol consists of two gene products: hREV3 containing pol activity and hREV7 with an unknown function (5). In general, these pols catalyze TLS more efficiently than previously known pols. They synthesize DNA in a distributive manner and tend to show lower replication fidelity than other pols such as pol ␣, pol , and pol ␦ when unmodified DNA is used as a template (7-10).There are several pieces of evidence for the involvement of human pol and pol in TLS in vivo (5,(11)(12)(13). Although the involvement of human pol or pol has not yet been established in vivo, the Escherichia coli homologue of pol , pol IV, has been shown to play a role in TLS in vivo (14). Pol , which is missing in xeroderma pigmentosum variant cells (13,15), is shown to catalyze efficient TLS across the cis-syn cyclobutane thymine-thymine dimer by inserting two dAMPs opposite the lesion (16). Therefore, the cancer proneness of xeroderma pigmentosum variant patients is thought to be caused by the lack of accurate TLS across this and/or other UV photo products. Pol also catalyzes TLS across other DNA lesions such as cisplatin G-G intrastrand cross-link (16), acetylaminofluorene-dG (16), and 8-oxodeoxyguanosine (17) Based on these findings, we are motivated to study the efficiency and fidelity of TLS catalyzed by these novel pols across 1,N 6 -ethenodeoxyadenosine (⑀dA) to probe the in vivo TLS mechanism. We have shown that ⑀dA is miscoding in simian and human cells by inducing ⑀dA3 T, ⑀dA3 G, and ⑀dA3 C (21, 22). This adduct is produced in animals exposed to vinyl compounds such as the human carcinogen vinyl chloride. Surprisingly, this adduct is also found in unexposed animals and humans with lipid peroxidation products being the suspected source of this adduct (23). Our in vitr...
Brain injury biomarkers may have clinical utility in stratifying injury severity level, predicting adverse secondary events or outcomes, and monitoring the effectiveness of therapeutic interventions. As a biomarker source, serum offers several advantages over cerebrospinal fluid (CSF), including ease of accessibility and reduced risk to the patient. We screened pooled serum samples obtained from 11 severely injured traumatic brain injury (TBI) patients (Glasgow Coma Scale [GCS]
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.