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Search for other papers by T. P. SINGH in
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Search for other papers by A. K. SINGH in
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Effects of clomiphene citrate, cyclofenil and prostaglandins (PGE1 and PGF2α) on ovarian 32P uptake, on gonadotrophin levels in the pituitary gland and blood serum and on a gonadotrophin releasing hormone-like (GnRH-like) substance in the hypothalamus were investigated in Heteropneustes fossilis. These drugs were very effective in increasing the serum level of gonadotrophin with a subsequent increase in ovarian 32P uptake in sham-hypophysectomized recipients. All the drugs except cyclofenil failed to stimulate 32P incorporation by the ovary in hypophysectomized fish. Clomiphene citrate and cyclofenil also induced a significant increase in the GnRH-like factor in the hypothalamus of H. fossilis. Such a response was not obtained in fish treated with PGE1 and PGF2α. It seems likely that the action of clomiphene is routed through the hypothalamo-pituitary-ovarian axis and that of prostaglandins directly through the pituitary-ovarian axis. The action of cyclofenil is bimodal; one effect like that of clomiphene and the other direct upon the ovary probably by increasing its sensitivity to the available gonadotrophin.
Search for other papers by D. V. SINGH in
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Search for other papers by H. A. BERN in
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SUMMARY
Intact female BALB/cCrgl mice, 3–4 weeks old, were pretreated with oestrogen and progesterone for 9 days. Whole mammary glands from these mice were cultivated for 5 days in a synthetic medium supplemented with aldosterone (A), prolactin (MH) and insulin (I), with and without thyroxine (T4) at concentrations ranging from 0·01 to 5 μg./ml.
A medium containing 1 μg. A +5 μg.MH +5 μg.I/ml. was generally optimal for lobulo-alveolar development. Addition of thyroxine to this combination resulted in a decrease in development which was highly significant at higher concentrations. However, when cultures were maintained in media containing suboptimal or low amounts of prolactin (1 μg. A + 3 μg. MH +5 μg. I/ml. and 1 μg. A + 1 μg. MH +5 μg. I/ml., respectively), the results indicate two possible effects of thyroxine: lower amounts of thyroxine had synergistic effects, whereas greater amounts had antagonistic effects on lobulo-alveolar development.
Search for other papers by Aijaz A John in
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Search for other papers by Ravi Prakash in
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Search for other papers by Divya Singh in
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miRNAs have appeared as critical controllers of gene expression at post-transcriptional level either by degrading RNA transcripts or repressing translation. It is evident from the ever-growing scientific literature that miRNAs play a significant role in osteoblast commitment and differentiation. Here, we report that overexpression of miR-487b-3p leads to inhibition of osteoblastic differentiation. Using in silico approaches, Nrarp was found to be the direct target of miR-487b-3p, which was further validated by luciferase 3′ UTR reporter assay. Nrarp inhibits Notch-1 signaling and promotes Wnt signaling by stabilization of LEF-1. Role of miR-487b-3p in regulating canonical Wnt and Notch signaling was determined by western blotting. Protein levels of Nrarp, RUNX-2, Lef1 and β catenin were reduced in osteoblasts cells transfected with miR-487b-3p, whereas protein levels of Notch1, Hes1 and P-β catenin were upregulated when osteoblast cells were transfected with miR-487b-3p. These outcomes were reversed after treating cells with anti-miR-487b-3p. Further silencing of miR-487b-3p in neonatal Balb/c mice attenuated all the inhibitory actions of miR-487b-3p on osteoblast differentiation. Importantly, in vivo action of anti-miR-487b-3p to ovariectomized osteopenic BALB/c mice steered to significant enhancement in trabecular bone microarchitecture. Furthermore, the bio-mechanical properties of isolated femurs were enhanced in anti-miR-487b-3p-treated mice. Overall, miR-487b-3p negatively regulates osteogenesis by suppressing Nrarp expression, which in turn, suppresses Runx-2 and Wnt signaling, both of which play a pivotal action in osteoblast differentiation.
Search for other papers by R Singh in
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Search for other papers by G Upadhyay in
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Search for other papers by S Kumar in
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Search for other papers by A Kapoor in
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Search for other papers by MM Godbole in
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Thyroid hormone (TH) deficiency results in delayed proliferation and migration of cerebellar granule cells. Although extensive cell loss during the development of the cerebellum under hypothyroid conditions is known, its nature and its mechanism are poorly understood. Bcl-2 family gene expression is known to determine the fate of cells to undergo apoptosis. We evaluated the effect of hypothyroidism on Bcl-2 family gene expression in the developing rat cerebellum. Electrophoresis and Western blotting were used to analyze DNA fragmentation and expression of DNA fragmentation factor (DFF-45), Bcl-2, Bcl-xL and Bax genes respectively. In the hypothyroid condition, extensive DNA fragmentation and enhanced cleavage of DFF-45 were seen throughout development (postnatal day 0 to day 24) and adulthood whereas they were absent in the euthyroid state. The anti-apoptotic genes Bcl-2 and Bcl-xL were down-regulated and the pro-apoptotic gene Bax was expressed at higher levels compared with the euthyroid state. These results suggest that normal levels of TH prevent cerebellar apoptosis to a large extent, whereas hypothyroidism not only increases the extent but also the duration of apoptosis by down-regulating the anti-apoptotic genes and maintaining a high level of the pro-apoptotic gene Bax.
Search for other papers by B. A. Crawford in
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Search for other papers by J. Singh in
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Search for other papers by D. J. Handelsman in
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ABSTRACT
This study aimed at determining the relationship of sex steroids, particularly in the perinatal period, to the pubertal insulin-like growth factor-I (IGF-I) surge in male mice. We used hypogonadal (hpg) mice, which have a major deletion in the gonadotrophin-releasing hormone (GnRH) gene, in order to have a model lacking all GnRH-induced gonadotrophin and sex steroid secretion throughout pre- and postnatal life. Cross-sectional data on body weights and weights of testes, seminal vesicles, kidneys, liver and spleen from 9 to 77 days of age were obtained in male hpg, heterozygous (Hz) and homozygous normal (N/N) littermates (n = 75–78/group). These data did not reveal any difference between Hz and N/N mice. Hpg mice had decreased body weights which by 70–77 days of age were approximately 18% less than normal controls. Testes and seminal vesicles of hpg mice did not demonstrate any significant postnatal growth. Relative to body weight, kidney weights were also markedly reduced in hpg mice (P<0·0001), deviating significantly from normal by 28–35 days of age, reflecting the impact of androgen deficiency on a non-reproductive organ. From the cross-sectional data it was concluded that puberty commenced soon after weaning (21 days) in the male and that maturity was achieved within 4–5 weeks. Longitudinal study showed that, compared with normal controls, untreated hpg mice had an exaggerated pubertal IGF-I surge (P<0·005) which peaked in mid-puberty. This, together with their reduced body weights (P<0·05), were normalized by treatment from 21 to 70 days of age with two 1 cm s.c. implants of testosterone (n=6) or dihydrotestosterone (n=7). There was no difference in IGF-I levels or in weights of testes, seminal vesicles, kidney, liver or spleen between testosterone and dihydrotestosterone treatments (P>0·05). Prolonged high levels of androgen also restored testicular and seminal vesicle weights to 40% of phenotypically normal controls, while kidney, liver and spleen weights were also significantly increased. The pubertal IGF-I surge in mice does not, therefore, require androgens in either the pre- or postnatal periods, and it is exaggerated in androgen-deficient male mice and dampened to normal regardless of aromatization.
Journal of Endocrinology (1993) 139, 57–65
Division of Parasitology, Central Drug Research Institute, Lucknow, India
Search for other papers by A Makker in
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Division of Parasitology, Central Drug Research Institute, Lucknow, India
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Division of Parasitology, Central Drug Research Institute, Lucknow, India
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Division of Parasitology, Central Drug Research Institute, Lucknow, India
Search for other papers by M M Singh in
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The role of the antioxidant defense system during endometrial receptivity, a phenomenon crucial for implantation and decidualization, and the effect of ormeloxifene, a selective estrogen receptor modulator, were investigated in the guinea pig, a laboratory mammalian species with interstitial implantation and a long functional luteal phase during each estrous cycle. A sharp rise in the activity of superoxide dismutase (SOD) in both antimesometrial (AM) and mesometrial segments and peroxidase in the AM segment of the uterus was observed on the day of maximal endometrial receptivity. Pretreatment with ormeloxifene resulted in loss of endometrial responsiveness, as evidenced by inhibition of trauma-induced decidualization and the activity of ornithine decarboxylase, a marker of tissue growth and repair. This was associated with a decrease in SOD and estradiol dehydrogenase activities, with corresponding increases in estrone dehydrogenase activity and stimulation of uterine luminal epithelial cell height and a distension of the uterine and glandular lumen. A decrease in peroxidase activity was observed only in the AM segment of the uterus on the imminent day of maximal endometrial receptivity. No effect on peripheral plasma progesterone concentration or surface ultrastructure was evident. These findings demonstrate that SOD plays an important role, with peroxidase having a supplementary role, in the first line of defense against superoxide anion radicals during the period of maximal endometrial receptivity in the guinea pig. Inhibition of endometrial receptivity and decidualization by ormeloxifene administered during the pre-receptive phase appears to be due to a depressed antioxidant defense system via dysregulation of redox-sensitive signaling, resulting in altered cellular toxicity due to increased superoxide radicals, and might contribute to the contraceptive action of ormeloxifene. This might be related to its estrogen antagonistic activity and/or decreased bioavailability of estradiol at a cellular level due to its increased metabolism to biologically less-active estrone via activation of estradiol-17 beta-hydroxysteroid dehydrogenase and suppression of estrone-17 beta-hydroxysteroid dehydrogenase.
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Search for other papers by A. Purohit in
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Search for other papers by M.J. Reed in
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ABSTRACT
The interleukin-6 soluble receptor (IL-6sR) may regulate the ability of IL-6 to stimulate oestrogen synthesis in breast cancer cells and breast tumours. Significant aromatase activity was detectable in IL-6 stimulated fibroblasts derived from subcutaneous adipose tissue, but the combination of IL-6sR plus IL-6 resulted in a marked 21-fold stimulation of aromatase activity. To examine the control of IL-6sR release, the effects of oestradiol, 4-hydroxytamoxifen (4-OHT), dexamethasone, TPA, TNFα or IL-6 on this process was examined using MCF-7 breast cancer cells. Oestradiol, TNFα and dexamethasone all markedly increased IL-6sR release. While 4-OHT had a small stimulatory effect on IL-6sR release, it blocked the ability of oestradiol to increase IL-6sR release. Significant concentrations of IL-6sR were also detected in conditioned medium collected from lymphocytes and macrophages and in cytosols prepared from normal and malignant breast tissues. These results indicate that IL-6sR may have an important role in potentiating the effect of IL-6 on oestrogen synthesis in breast cancer cells. The abilities of oestradiol or tamoxifen to potentiate or inhibit the IL-6 stimulation of oestrogen synthesis in breast cancer cells may result from their effects on IL-6sR release.
Search for other papers by A. Singh in
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Search for other papers by D. Hamilton-Fairley in
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Search for other papers by R. Koistinen in
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Search for other papers by M. Seppälä in
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Search for other papers by M.J. Reed in
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ABSTRACT
Dietary factors are known to modulate concentrations of sex hormone-binding globulin (SHBG). In the present study we have investigated the possibility that insulin like growth factor-type I (IGF-I) may be an additional regulator of SHBG using cultured human hepatoma cells which secrete SHBG. The inhibitory effect of insulin on SHBG secretion by these cells was confirmed but, in addition, IGF-I was shown to inhibit SHBG secretion by about 40% at a concentration of 100 nmol/l. A similar degree of inhibition was achieved using insulin at a concentration of 10 umol/l. Insulin, but not IGF-I, was also found to inhibit the secretion of a low molecular weight IGF-binding protein (IBP-I), which is also secreted by hepatoma cells. It is concluded that IGF-I is an additional regulator of SHBG secretion by these cells and that it may be involved in regulating SHBG secretion in vivo in response to dietary factors.
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Search for other papers by Kritika Singh in
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Search for other papers by Eric P Skaar in
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Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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Search for other papers by Richard M O’Brien in
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SLC30A8 encodes the zinc transporter ZnT8. SLC30A8 haploinsufficiency protects against type 2 diabetes (T2D), suggesting that ZnT8 inhibitors may prevent T2D. We show here that, while adult chow fed Slc30a8 haploinsufficient and knockout (KO) mice have normal glucose tolerance, they are protected against diet-induced obesity (DIO), resulting in improved glucose tolerance. We hypothesize that this protection against DIO may represent one mechanism whereby SLC30A8 haploinsufficiency protects against T2D in humans and that, while SLC30A8 is predominantly expressed in pancreatic islet beta cells, this may involve a role for ZnT8 in extra-pancreatic tissues. Consistent with this latter concept we show in humans, using electronic health record-derived phenotype analyses, that the ‘C’ allele of the non-synonymous rs13266634 SNP, which confers a gain of ZnT8 function, is associated not only with increased T2D risk and blood glucose, but also with increased risk for hemolytic anemia and decreased mean corpuscular hemoglobin (MCH). In Slc30a8 KO mice, MCH was unchanged but reticulocytes, platelets and lymphocytes were elevated. Both young and adult Slc30a8 KO mice exhibit a delayed rise in insulin after glucose injection, but only the former exhibit increased basal insulin clearance and impaired glucose tolerance. Young Slc30a8 KO mice also exhibit elevated pancreatic G6pc2 gene expression, potentially mediated by decreased islet zinc levels. These data indicate that the absence of ZnT8 results in a transient impairment in some aspects of metabolism during development. These observations in humans and mice suggest the potential for negative effects associated with T2D prevention using ZnT8 inhibitors.
