The effects of vitamin D on osteoblast mineralization are well documented. Reports of the effects of vitamin D on osteoclasts, however, are conflicting, showing both inhibition and stimulation. Finding that resorbing ...The effects of vitamin D on osteoblast mineralization are well documented. Reports of the effects of vitamin D on osteoclasts, however, are conflicting, showing both inhibition and stimulation. Finding that resorbing osteoclasts in human bone express vitamin D receptor （VDR）, we examined their response to different concentrations of 25-hydroxy vitamin D3 [25（OH）D3] （100 or 500 nmol·L^-1） and 1,25-dihydroxy vitamin D3 [1,25（OH）2D3] （0.1 or 0.5 nmol·L^-1） metabolites in cell cultures. Specifically, CD14＋ monocytes were cultured in charcoal-stripped serum in the presence of receptor activator of nuclear factor kappa-B ligand （RANKL） and macrophage colony-stimulating factor （M-CSF）. Tartrate-resistant acid phosphatase （TRAP） histochemical staining assays and dentine resorption analysis were used to identify the size and number of osteoclast cells, number of nuclei per cell and resorption activity. The expression of VDR was detected in human bone tissue （ex vivo） by immunohistochemistry and in vitro cell cultures by western blotting. Quantitative reverse transcription-PCR （qRT-PCR） was used to determine the level of expression of vitamin D-related genes in response to vitamin D metabolites. VDR-related genes during osteoclastogenesis, shown by qRT-PCR, was stimulated in response to 500 nmol·L^-1 of 25（OH）D3 and 0.1-0.5 nmol·L^-1 of 1,25（OH）2D3, upregulating cytochrome P450 family 27 subfamily B member I （CYP27B1） and cytochrome P450 family 24 subfamily A member I （CYP24A1）. Osteoclast fusion transcripts transmembrane 7 subfamily member 4 （tm7sf4） and nuclear factor of activated T-cell cytoplasmic 1 （nfatcl） where downregulated in response to vitamin D metabolites. Osteoclast number and resorption activity were also increased. Both 25（OH）D3 and 1,25（OH）2D3 reduced osteoclast size and number when co-treated with RANKL and M-CSF. The evidence for VDR expression in resorbing osteoclasts in vivo and low-dose effects of 1,25（OH）2D3 on osteoclasts in vitro may therefore provide insight into the effects of clinical vitamin D treatments, further providing a counterpoint to the high-dose effects reported from in vitro experiments.展开更多
AIM: To investigate dose-dependent effects of N-methylD-aspartate(NMDA) on retinal and optic nerve morphology in rats.METHODS: Sprague Dawley rats, 180-250 g in weight were divided into four groups. Groups 1, 2, 3 and...AIM: To investigate dose-dependent effects of N-methylD-aspartate(NMDA) on retinal and optic nerve morphology in rats.METHODS: Sprague Dawley rats, 180-250 g in weight were divided into four groups. Groups 1, 2, 3 and 4 were intravitreally administered with vehicle and NMDA at the doses 80, 160 and 320 nmol respectively. Seven days after injection, rats were euthanized, and their eyes were taken for optic nerve toluidine blue and retinal hematoxylin and eosin stainings. The TUNEL assay was done for detecting apoptotic cells.RESULTS: All groups treated with NMDA showed significantly reduced ganglion cell layer(GCL) thickness within inner retina, as compared to control group. Group NMDA 160 nmol showed a significantly greater GCL thickness than the group NMDA 320 nmol. Administration of NMDA also resulted in a dose-dependent decrease in the number of nuclei both per 100 μm GCL length and per 100 μm2 of GCL. Intravitreal NMDA injection caused dosedependent damage to the optic nerve. The degeneration of nerve fibres with increased clearing of cytoplasm was observed more prominently as the NMDA dose increased. In accordance with the results of retinal morphometry analysis and optic nerve grading, TUNEL staining demonstrated NMDA-induced excitotoxic retinal injury in a dose-dependent manner.CONCLUSION: Our results demonstrate dose-dependent effects of NMDA on retinal and optic nerve morphology in rats that may be attributed to differences in the severity of excitotoxicity and oxidative stress. Our results also suggest that care should be taken while making dose selections experimentally so that the choice might best uphold study objectives.展开更多
Sex differences on the effect of dose-dependent capsaicinoids on lipid metabolism were studied in rats. 24 rats of each sex were administered orally 0 mg/kg, 2.5 mg/kg, 5 mg/kg or 7.5 mg/kg capsaicinoids daily for 28 ...Sex differences on the effect of dose-dependent capsaicinoids on lipid metabolism were studied in rats. 24 rats of each sex were administered orally 0 mg/kg, 2.5 mg/kg, 5 mg/kg or 7.5 mg/kg capsaicinoids daily for 28 days. In male rats, body weight gained, and the levels of total lipids, total cholesterol and triglycerides in the liver were significantly decreased as the dose of capsaicinoids increased. On the other hand, plasma total cholesterol (TC), triglycerides (TG), HDL- and LDL-cholesterol concentration and liver weight were not affected by capsaicinoids. While in female rats, plasma TC, TG, HDL-C and LDL-C concentration, liver total lipids, TC and TG concentration were significantly decreased as the dose of capsaicinoids increased. The mRNA level of hepatic TRPV1, ileac ASBT and IBABP were increased as the dose of capsaicinoids increased in all rats groups. The mRNA level of hepatic HMG-CoA reductase, CYP7A1 and FXR were significantly decreased in female rats groups. These results show that the hypocholesterolemic effect of capsaicinoids in dose-dependent manner in rats was mediated by inhibited synthesis of endogenous cholesterol, female rats were more sensitive than male rats on hypolipidemic effect of capsaicinoids.展开更多
The purpose of this research was to investigate the manner of deaths in Marion County, throughout the years of 2018 to 2021 to see if there were any correlative increases in homicide, suicide, natural, accidental, or ...The purpose of this research was to investigate the manner of deaths in Marion County, throughout the years of 2018 to 2021 to see if there were any correlative increases in homicide, suicide, natural, accidental, or drug overdose related deaths. We surveyed the incidence of all deaths that occurred from 2018 through 2021 which came through the Marion County Coroner’s Office, Indiana. The data was then divided into two halves. According to the data, the leading manner of death in the first half and second half was accidental. This study revealed a total of 8732 cases: 3817 of them were observed to be accidental, 3092 natural, 956 homicide, 689 suicide, and 178 were undetermined. There were initially 318 drug overdose related deaths in 2018 and they increased to 2163 by 2021. In 2018, the number of deaths due to fentanyl related overdoses increased from 195 to 799 in 2021. This research will contribute to the forensic science field by providing information about the manner of death and fentanyl trends in Marion County over the last four years.展开更多
基金financial support from Orthopaedic Research UK (P 470)Arthritis Research UK (grant 20299 and Oxford EOTC)
文摘The effects of vitamin D on osteoblast mineralization are well documented. Reports of the effects of vitamin D on osteoclasts, however, are conflicting, showing both inhibition and stimulation. Finding that resorbing osteoclasts in human bone express vitamin D receptor （VDR）, we examined their response to different concentrations of 25-hydroxy vitamin D3 [25（OH）D3] （100 or 500 nmol·L^-1） and 1,25-dihydroxy vitamin D3 [1,25（OH）2D3] （0.1 or 0.5 nmol·L^-1） metabolites in cell cultures. Specifically, CD14＋ monocytes were cultured in charcoal-stripped serum in the presence of receptor activator of nuclear factor kappa-B ligand （RANKL） and macrophage colony-stimulating factor （M-CSF）. Tartrate-resistant acid phosphatase （TRAP） histochemical staining assays and dentine resorption analysis were used to identify the size and number of osteoclast cells, number of nuclei per cell and resorption activity. The expression of VDR was detected in human bone tissue （ex vivo） by immunohistochemistry and in vitro cell cultures by western blotting. Quantitative reverse transcription-PCR （qRT-PCR） was used to determine the level of expression of vitamin D-related genes in response to vitamin D metabolites. VDR-related genes during osteoclastogenesis, shown by qRT-PCR, was stimulated in response to 500 nmol·L^-1 of 25（OH）D3 and 0.1-0.5 nmol·L^-1 of 1,25（OH）2D3, upregulating cytochrome P450 family 27 subfamily B member I （CYP27B1） and cytochrome P450 family 24 subfamily A member I （CYP24A1）. Osteoclast fusion transcripts transmembrane 7 subfamily member 4 （tm7sf4） and nuclear factor of activated T-cell cytoplasmic 1 （nfatcl） where downregulated in response to vitamin D metabolites. Osteoclast number and resorption activity were also increased. Both 25（OH）D3 and 1,25（OH）2D3 reduced osteoclast size and number when co-treated with RANKL and M-CSF. The evidence for VDR expression in resorbing osteoclasts in vivo and low-dose effects of 1,25（OH）2D3 on osteoclasts in vitro may therefore provide insight into the effects of clinical vitamin D treatments, further providing a counterpoint to the high-dose effects reported from in vitro experiments.
基金Supported by Universiti Teknologi MARA [No.600-IRMI/MYRA5/3/BESTARI (004/2017) No.600IRMI/DANA5/3/LESTARI (0076/2016) No.600-IRMI/ My RA5/3/LESTARI (0088/2016)]
文摘AIM: To investigate dose-dependent effects of N-methylD-aspartate(NMDA) on retinal and optic nerve morphology in rats.METHODS: Sprague Dawley rats, 180-250 g in weight were divided into four groups. Groups 1, 2, 3 and 4 were intravitreally administered with vehicle and NMDA at the doses 80, 160 and 320 nmol respectively. Seven days after injection, rats were euthanized, and their eyes were taken for optic nerve toluidine blue and retinal hematoxylin and eosin stainings. The TUNEL assay was done for detecting apoptotic cells.RESULTS: All groups treated with NMDA showed significantly reduced ganglion cell layer(GCL) thickness within inner retina, as compared to control group. Group NMDA 160 nmol showed a significantly greater GCL thickness than the group NMDA 320 nmol. Administration of NMDA also resulted in a dose-dependent decrease in the number of nuclei both per 100 μm GCL length and per 100 μm2 of GCL. Intravitreal NMDA injection caused dosedependent damage to the optic nerve. The degeneration of nerve fibres with increased clearing of cytoplasm was observed more prominently as the NMDA dose increased. In accordance with the results of retinal morphometry analysis and optic nerve grading, TUNEL staining demonstrated NMDA-induced excitotoxic retinal injury in a dose-dependent manner.CONCLUSION: Our results demonstrate dose-dependent effects of NMDA on retinal and optic nerve morphology in rats that may be attributed to differences in the severity of excitotoxicity and oxidative stress. Our results also suggest that care should be taken while making dose selections experimentally so that the choice might best uphold study objectives.
文摘Sex differences on the effect of dose-dependent capsaicinoids on lipid metabolism were studied in rats. 24 rats of each sex were administered orally 0 mg/kg, 2.5 mg/kg, 5 mg/kg or 7.5 mg/kg capsaicinoids daily for 28 days. In male rats, body weight gained, and the levels of total lipids, total cholesterol and triglycerides in the liver were significantly decreased as the dose of capsaicinoids increased. On the other hand, plasma total cholesterol (TC), triglycerides (TG), HDL- and LDL-cholesterol concentration and liver weight were not affected by capsaicinoids. While in female rats, plasma TC, TG, HDL-C and LDL-C concentration, liver total lipids, TC and TG concentration were significantly decreased as the dose of capsaicinoids increased. The mRNA level of hepatic TRPV1, ileac ASBT and IBABP were increased as the dose of capsaicinoids increased in all rats groups. The mRNA level of hepatic HMG-CoA reductase, CYP7A1 and FXR were significantly decreased in female rats groups. These results show that the hypocholesterolemic effect of capsaicinoids in dose-dependent manner in rats was mediated by inhibited synthesis of endogenous cholesterol, female rats were more sensitive than male rats on hypolipidemic effect of capsaicinoids.
文摘The purpose of this research was to investigate the manner of deaths in Marion County, throughout the years of 2018 to 2021 to see if there were any correlative increases in homicide, suicide, natural, accidental, or drug overdose related deaths. We surveyed the incidence of all deaths that occurred from 2018 through 2021 which came through the Marion County Coroner’s Office, Indiana. The data was then divided into two halves. According to the data, the leading manner of death in the first half and second half was accidental. This study revealed a total of 8732 cases: 3817 of them were observed to be accidental, 3092 natural, 956 homicide, 689 suicide, and 178 were undetermined. There were initially 318 drug overdose related deaths in 2018 and they increased to 2163 by 2021. In 2018, the number of deaths due to fentanyl related overdoses increased from 195 to 799 in 2021. This research will contribute to the forensic science field by providing information about the manner of death and fentanyl trends in Marion County over the last four years.
