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Biomedical subjects

M V Kumar

Publications and source records attributed to M V Kumar.

At least 19 recordsLinked to original sources
PubMed2001

Differential expression of members of the tumor necrosis factor alpha-related apoptosis-inducing ligand pathway in prostate cancer cells.

Androgen ablation therapy induces apoptosis only in androgen-sensitive prostate cancer cells; therefore, other cytotoxic drugs are being used to induce apoptosis in androgen-refractory cells. Mifepristone, an antiprogestin used individually or together with the antiestrogen Tamoxifen, has been recommended for induction of cell death and treatment of several hormonal cancers. However, little is known about the mechanism of action of these drugs in prostate cancer. Therefore, we investigated the effect of Mifepristone on the tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL) pathway, a newly identified and very effective member of tumor necrosis factor-alpha family. Mifepristone and Tamoxifen induced significant expression of death receptors in prostate cancer cells in vitro and in xenografts. However, Mifepristone in combination with Tamoxifen did not increase prostate cancer cell death compared with their individual values. The involvement of the TRAIL pathway was further confirmed by the activation of caspase-8 in Mifepristone-treated cells. This was followed by truncation of Bid, confirming that Mifepristone activates the TRAIL pathway. This knowledge is being used to design a combination treatment of TRAIL and Mifepristone to induce significant apoptosis in prostate cancer cells.

Animals↗
PubMed2000

Hypocholesterolemic effect of anhydrous milk fat ghee is mediated by increasing the secretion of biliary lipids.

The anhydrous milk fat ghee is one of the important sources of fat in the Indian diet. Our earlier studies showed that rats fed diets containing greater than 2.5 wt% of ghee had lower levels of serum cholesterol compared with rats fed diets containing groundnut oil. To evaluate the mechanism of the hypocholesterolemic effect of ghee, male Wistar rats were fed a diet containing 2.5 or 5.0 wt% ghee for a period of 8 weeks. The diets were made isocaloric with groundnut oil. Both native and ghee heated at 120 degrees C containing oxidized lipids were included in the diet. The ghee in the diet did not affect the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity in the liver microsomes, but it significantly increased biliary excretion of cholesterol, bile acids, uronic acid, and phospholipids. The rats fed ghee had lower levels of cholesterol esters in the serum as well as in the intestinal mucosa. Both native and oxidized ghee influenced cholesterol metabolism. These results indicate that supplementation of diets with ghee lipids would increase the excretion of bile constituents and lower serum cholesterol levels.

Journal Article↗
PubMed2000

Uncoupling proteins 2 and 3 with age: regulation by fasting and beta3-adrenergic agonist treatment.

In rodents, adaptive thermogenesis in brown adipose tissue (BAT) serves both to regulate body mass after hyperphagia and to conserve energy during food deprivation. In addition to uncoupling protein 1 (UCP1), UCP3 and possibly UCP2 may have a role in energy homeostasis in BAT. We examined basal levels of UCP2 and UCP3 mRNA with age and regulation of UCP1, UCP2, and UCP3 mRNA by two conditions known to modulate energy homeostasis: fasting and beta3-adrenergic agonists. UCP1, UCP2, and UCP3 mRNA levels were unchanged between 3, 24, and 31 months of age in BAT, and UCP2 and UCP3 mRNA levels were unchanged between 6 and 24 months of age in retroperitoneal white adipose tissue (RTWAT). Following a 2-day fast, there were sizable reductions in BAT UCP1 and UCP3 mRNA, but these decreases with fasting were significantly less in the older compared with the young rats. Fasting had no effect on UCP2 mRNA levels at any age. The beta3-adrenergic agonist, CL316,243, increased BAT UCP1 and UCP3 mRNA equally in both young and old rats. The beta3-adrenergic agonist did not increase UCP2 mRNA in BAT but did increase expression in RTWAT of both young and old rats. In summary, these data indicate that the expression of the three uncoupling proteins is unchanged with age. Although the upregulation of these uncoupling proteins by beta3-adrenergic agonist treatment is maintained with age, the downregulation by fasting is diminished with age. The parallel regulation of UCP1 and UCP3 expression in BAT suggests that UCP3, like UCP1, may have a role in energy homeostasis in BAT. The diminished downregulation of UCP1 and UCP3 expression in BAT by fasting suggests that energy conservation in response to food deprivation is impaired with age, and this may contribute to an inability of older animals to maintain body mass during periods when food is limited.

Adipose Tissue, Brown↗
PubMed2000

Modulation of uncoupling protein 2 and uncoupling protein 3: regulation by denervation, leptin and retinoic acid treatment.

We recently reported that the leptin-induced increase in uncoupling protein 1 (UCP1) mRNA in brown adipose tissue (BAT) is prevented by the denervation of BAT. We also reported that retinoic acid (RA) increases UCP1 mRNA in BAT. To extend these finding to UCP2 and UCP3 in BAT, we examined UCP2 and UCP3 mRNA after unilateral denervation of BAT, as well as after leptin, beta(3)-adrenergic agonist, RA, and glucocorticoid administration to rats. UCP3 mRNA was 20% less in the denervated compared with the intact BAT, whereas UCP2 mRNA was unchanged with denervation. The beta(3)-adrenergic agonist, CGP-12177 (0.75 mg/kg), increased UPC3 mRNA by 40% in the innervated and by 85% in the denervated BAT. Leptin (0.9 mg/day for 3 days) increased both UCP2 and UCP3 mRNA by 30% in the innervated and, surprisingly, in the denervated BAT. RA (7.5 mg/kg) increased UCP1 mRNA but decreased UCP2 and UCP3 mRNA by 50%, whereas methylprednisolone (65 mg/kg, two doses 24 h apart) suppressed all three uncoupling proteins by greater than 60%. The present findings indicate that: sympathetic innervation is necessary to maintain basal levels of UCP3 mRNA; beta(3)-adrenergic agonist stimulation induces UCP3 mRNA; leptin induces UCP2 and UCP3 mRNA and this induction is not dependent on sympathetic innervation; RA increases UCP1 but decreases UCP2 and UCP3 mRNA; and methylprednisolone suppresses UCP1, UCP2, and UCP3 mRNA equally. These data suggest that there are distinct patterns of regulation between UCP1, UCP2, and UCP3, and there may be at least two modes by which leptin could modulate thermogenesis in BAT; first, by increasing sympathetic stimulation of BAT and induction of UCP1 mRNA and, secondly, by increasing UCP2 and UCP3 mRNA by a mechanism independent of sympathetic stimulation.

Adipose Tissue, Brown↗
PubMed1999

Effect of dietary ghee--the anhydrous milk fat, on blood and liver lipids in rats.

Dairy products are important sources of dietary fat in India. Anhydrous milk fat, viz., ghee, is consumed as such in the diet and also is used for frying the dishes. Ghee contains high levels of saturated fatty acids and cholesterol, which are considered risk factors for cardiovascular diseases. In the present study, ghee, at levels ranging from 0.25 to 10%, was included in a nutritionally balanced AIN-76 diet fed to Wistar rats for a period of 8 weeks. The serum lipid profiles of these animals showed a dose dependent decrease in total cholesterol, low density lipoproteins and very low density lipoproteins cholesterol, and triglyceride levels when ghee was present at levels greater than 2.5% in the diet. Liver cholesterol and triglycerides also were decreased in these animals. When ghee was included as a sole source of fat at a 10% level, polyunsaturated fatty acids in the serum and liver lipids were reduced significantly. Similar results were observed when ghee was subjected to a higher temperature (120 degrees C) to generate cholesterol oxidation products and fed to the animals. Although cholesterol oxidation products were not accumulated in serum, significant amounts were accumulated in liver only when ghee was fed as a sole source of fat at a 10% level. This study revealed that the consumption of ghee up to a 10% level in the diet altered blood lipid profiles in such a manner as not to elevate the risk factors for cardiovascular diseases.

Journal Article↗
PubMed1999

Heterotopic ossification in non-traumatic myelopathies.

Heterotopic ossification (HO) is an important complication of spinal cord and brain injuries but is rarely reported among patients with non-traumatic myelopathies. In a prospective study on medical problems seven (6.04%) among the 114 subjects with non-traumatic myelopathies had heterotopic ossification. All of them had involvement of hip joints. The co-morbid conditions were: urinary tract infection, seven; spasticity, three; pressure sores, five; and deep venous thrombosis, one. The initial diagnosis was often other than heterotopic ossification. Erythrocyte sedimentation rate and serum alkaline phosphatase levels were elevated in all subjects. Following rest and non-steroidal anti-inflammatory drugs, the range of motion improved in two patients. Heterotopic ossification can occur in patients with non-traumatic myelopathies and has risk factors and clinical features similar to patients with traumatic spinal cord injury. A high index of suspicion about this complication is necessary for early diagnosis and prompt intervention.

Adolescent↗
PubMed1999

Balanitis xerotica obliterans complicating hypospadias repair.

We review the literature and report a series of eight cases of balanitis xerotica obliterans (BXO) developing in patients following primary hypospadias repair. The ages of these patients ranged from 8 to 25 years with BXO developing from 1 to 16 years postoperatively. Six patients were treated by excision of the BXO tissue and two-stage urethroplasties with full-thickness grafts. Three of these patients had further recurrence of BXO and had re-do urethroplasty using a combination of bladder and buccal mucosa. The last two patients in this series had re-do urethroplasty using bladder mucosa only and bladder-buccal mucosa technique, respectively, as first choice for BXO complicating their hypospadias repair.

Adolescent↗
PubMed1999

Lower abdominal wall reconstruction using the anterior thigh fasciocutaneous flap.

Full thickness defects of the lower abdominal wall are uncommon. They can occur in congenital abdominal wall defects, acute trauma and following resection of soft tissue tumours. In reconstruction of defects not amenable to primary closure, three problems need to be addressed: (i) the fascial layer needs to be reconstructed; (ii) stable and sensate skin coverage is needed as the lower abdominal waistline area is subject to pressure; (iii) it is desirable to restore the contour of the abdominal wall. We present a case with a large area of radiation dermatitis and recurrence of a malignant ovarian tumour in the lower abdominal wall. After en bloc resection the 25 x 6 cm lower abdominal defect was reconstructed with a sensate anterior thigh fasciocutaneous flap. The vascular supply was reliable and the outcome was good. The reasons for using this fasciocutaneous flap in preference to the other options are discussed.

Abdominal Muscles↗
PubMed1999

Dietary vitamin A supplementation in rats: suppression of leptin and induction of UCP1 mRNA.

All-trans-retinoic acid (RA), an active metabolite of vitamin A, induces the gene expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) and suppresses leptin gene expression in white adipose tissue (WAT) when given as an acute dose. These contrasting effects of RA leave in doubt the overall effect of chronic RA or vitamin A supplementation on energy homeostasis. To investigate the effects of dietary vitamin A supplementation on leptin and UCP1 gene expression, rats were fed either a normal diet (2.6 retinol/kg diet) or a vitamin A-supplemented diet (129 mg retinol/kg diet) for 8 weeks, and adiposity, serum leptin levels, leptin mRNA levels in perirenal WAT, UCP1 and UCP2 mRNA levels in BAT, and beta3-adrenergic receptor mRNA levels in BAT and WAT were examined. Rats on both diets gained a similar amount of weight, but there was a small 9% decrease in the adiposity index in the vitamin A-supplemented rats. Dietary vitamin A supplementation increased UCP1 gene expression in BAT by 31%, but suppressed leptin gene expression by 44% and serum leptin levels by 65%. UCP2 and beta3-adrenergic receptor gene expression in BAT and perirenal WAT were unchanged by the vitamin A diet. These data suggest that dietary vitamin A has a role in regulating energy homeostasis by enhancing UCP1 gene expression and decreasing serum leptin levels.

Adipose Tissue↗
PubMed1999

Beta3-adrenergic regulation of leptin, food intake, and adiposity is impaired with age.

With age, there are increases in adiposity, leptin mRNA in white adipose tissue (WAT), and serum leptin levels in rats. Beta3-adrenergic agonists are anti-obesity agents in rodents, and activation of beta3-adrenergic receptors (beta3AR) mediates an acute decrease in food consumption, increased thermogenesis in brown adipose tissue (BAT), increased lipolysis in WAT, and suppression of leptin gene expression and serum leptin levels. Because beta3AR signal transduction is impaired with age in BAT and WAT, beta3AR-mediated regulation of leptin, feeding behavior, and adiposity may also be impaired with age. To test this hypothesis, we infused young (6 month) and old (24 month) F344 x BN rats with the beta3AR agonist CL316,243 (1 mg kg(-1) day(-1)) using osmotic minipumps for 7 days. Food intake, body mass, adiposity, and serum leptin, as well as leptin, uncoupling protein 1 (UCP1), and lipoprotein lipase (LPL) mRNA in BAT or WAT were determined. In young rats, CL316,243 infusion reduced body mass and adiposity, suppressed serum leptin and leptin mRNA levels in WAT, induced UCP1 in WAT, and increased UCP1 and LPL mRNA levels in BAT. Moreover, treatment with CL316,243 was associated with a marked but transient suppression of food intake. Most of the responses elicited in the old rats with CL316,243 treatment were qualitatively similar to those in the young rats, but blunted in magnitude. Beta3AR activation of adenylyl cyclase was also reduced in the aged rats. These data suggest that, although CL316,243 is an effective agent in aged rats, the maximum responses are reduced, suggesting that the impaired beta3AR signal transduction with age is a major determining factor in the reduced effectiveness of CL316,243 in older rats.

Adipose Tissue↗
PubMed1999

Preceding infection as a risk factor of stroke in the young.

INTRODUCTION: The cause of stroke in the young remains unknown in 20-50% of the patients. Infections preceding stroke have been recently recognised to be an independent risk factor of stroke. MATERIAL AND METHODS: Sixty consecutive patients aged 40 years or less presenting with ischaemic completed stroke are taken up for the study. Patients with neurological deficit of less than 24 hours, evidence of haemorrhage on CT scan, infection occurring after the onset of stroke were excluded. Controls consisted of age and sex matched persons residing in the same area. Both the groups were enquired about preceding fever and infections and were examined for evidence of infections. Serum was examined for antibodies against measles, herpes simplex, and Japanese B encephalitis viruses. Cultures were put up from appropriate samples and CSF examined in patients only. RESULTS: Evidence of infection was noted in 26 (43.3%) of patients and 6 controls (p < 0.001). History of fever was elicited in 23 patients and 3 controls while 15 patients were febrile on examination at admission. Signs of local infection was observed in 14 patients and one control. The commonest site of infection was respiratory tract. Cultures were positive in 11 patients, commonest being beta haemolytic streptococci in six from throat. Conventional risk factors were identical in both groups of patients with and without evidence of preceding infection. Smoking and alcoholism were significantly higher in patients with preceding infection. CONCLUSION: Preceding infection is an important risk factor of stroke in the young. Smoking and alcoholism are more frequent in patients with preceding infection. Whether they predispose the individual for infection or infection increases the stroke risk in them needs to be examined.

Adult↗
PubMed1998

Expression of early growth response genes in human prostate cancer.

Early growth-response (EGR) genes are nuclear transcription factors that are implicated in regulating cell proliferation. Because these genes show divergent expression in various human tumors, we sought to determine their expression in nonmalignant and malignant prostate tissues. Total RNA extracted from prostate tissues was probed with EGR-1, EGR-2, and EGR-alpha cDNA for Northern blots and digoxigenin-labeled cRNA for in situ hybridization. Both Northern blot and in situ hybridization analyses demonstrated increased EGR-1, but not EGR-2 or EGR-alpha expression, in malignant prostate tissue as compared with weak expression in nonmalignant tissue. EGR-1 mRNA was quantified in 96 prostate specimens (86 adenocarcinomas representing different Gleason scores and 10 benign tissues showing no histological manifestation of benign prostatic hypertrophy) using in situ hybridization with an 35S-labeled cRNA probe. EGR-1 mRNA was expressed at significantly higher levels in cancer than in normal prostate (P < 0.001). In cancer with Gleason scores 8-10, the expression of EGR-1 was higher compared with those of lower Gleason scores (P < 0.005). Immunohistochemical staining showed predominately basal cell nuclear EGR-1 protein in prostatic acini. Nuclear staining was weak in nonmalignant tissues, more intense in moderately differentiated carcinoma, and most intense in poorly differentiated carcinoma. These results show that EGR-1 is overexpressed in prostate cancer and suggest a role for EGR-1 in prostate cancer growth.

Adenocarcinoma↗
PubMed1998

Transcriptional regulation of the steroid receptor genes.

Steroid hormones, via their binding to specific receptors, are involved in the development, differentiation, and physiological response of cells to diverse stimuli. Activation by hormonal ligands induces conformational change in the receptor, enabling interaction with the target genes. The steroid receptor superfamily includes androgen, glucocorticoid, mineralocorticoid, progesterone, estrogen, thyroid, vitamin D, retinoic acid, and orphan receptors. This review will focus on the classic steroid receptors, i.e., the androgen, glucocorticoid, progesterone, and estrogen receptors, with emphasis on their transcriptional regulation. Readers are directed to several authoritative reviews for further details of steroid receptors (1-11).

Animals↗
PubMed1998

Differential effects of retinoic acid on uncoupling protein-1 and leptin gene expression.

All-trans-retinoic acid (RA), one of the active metabolites of vitamin A, can increase the expression of uncoupling protein-1 (UCP1) gene. To determine whether RA stimulates brown adipose tissue (BAT) thermogenesis and modulates leptin gene expression in vivo, 6-month-old, vitamin-A sufficient, F344 x BN rats were administered a single dose of RA (7.5 mg/kg, i.p.) or the beta 3-adrenergic receptor (beta 3AR) specific agonist, CGP 12177 (0.75 mg/kg). Levels of UCP1 mRNA in BAT and leptin mRNA in perirenal white adipose tissue (WAT) were examined 5 h after treatment. mRNA levels of lipoprotein lipase (LPL) were also examined in BAT and perirenal WAT. Administration of CGP 12177 caused the expected increase in UCP1 mRNA levels. RA treatment also significantly increased UCP1 mRNA levels but to a lesser extent than CGP 12177. In contrast, there was no acute effect of RA on whole body oxygen consumption, one measure of BAT thermogenesis. Both CGP 12177 and RA treatment decreased levels of leptin mRNA to a similar extent. RA treatment had no effect on mRNA levels of LPL in BAT or perirenal WAT. There were no changes in total DNA content, total protein content, or in the levels of beta-actin mRNA in either BAT or perirenal WAT upon administration of RA or CGP 12177. Thus, the acute effects of RA paralleled the effects of the beta 3AR specific agonist, CGP 12177, on UCP1 and leptin gene expression. This involvement of RA in positive regulation of UCP1 mRNA and negative regulation of leptin mRNA suggests a contrasting role for RA in energy homeostasis.

Adipose Tissue↗
PubMed1998

Inhibitory effect of Garcinia kola on lipid peroxidation in rat liver homogenate.

Garcinia kola, (a herb grown in Nigeria; calorific value 358.54 k.cal/100 g) inhibited in vitro lipid peroxidation of rat liver homogenate in a dose dependent manner. The inhibitory activity of G.kola was not affected by heating (100 degrees C/10 min). The antioxidant component of G.kola was soluble in aqueous and ethanolic media. The active component(s) in G. kola responsible for its inhibitory activity on lipid peroxidation is tentatively identified as isoflavones.

Animals↗
PubMed1996

LY191704 inhibits type I steroid 5 alpha-reductase in human scalp.

Conversion of testosterone to dihydrotestosterone (DHT) has been demonstrated to be catalyzed by two isoforms of steroid 5 alpha-reductase, designated types I and II. Although several classes of steroid-based inhibitors of the type II isoform have been identified, these agents have not demonstrated highly selective pharmacological activity against human type I 5 alpha-reductase. LY191704 is representative of a series of nonsteroidal agents that have potent [apparent inhibitory constant (Ki) = 11.3 nM] inhibitory activity in human scalp skin homogenates (pH 7.5), a source of type I 5 alpha-reductase. [3H]-DHT production in the presence and absence of LY191704 is consistent with a noncompetitive mode of inhibition. In human prostatic homogenates (pH 5.5), a source of type II 5 alpha-reductase, LY191704 is virtually inactive as an inhibitor [concentration of inhibitor producing 50% inhibition of enzymatic activity (IC50) > 1,000 nM] of [3H]-DHT formation. LY191704 does not inhibit the type I or type II isoforms of rat 5 alpha-reductase, nor does the compound compete for binding to the murine androgen receptor expressed in SF9 cells using a baculo virus expression system. The benzoquinolinones, as exemplified by LY191704, possess exquisite pharmacological selectivity and provide a tool to understand the role of human type I 5 alpha-reductase in normal and pathophysiological states. These agents may also find clinical utility in treating androgen-dependent dermatological conditions.

5-alpha Reductase Inhibitors↗
PubMed1995

Isolation of cDNAs that are differentially expressed between androgen-dependent and androgen-independent prostate carcinoma cells using differential display PCR.

In the development of prostate cancer there is an important transition from androgen-dependent growth (which can be treated) to androgen-independent growth (which is beyond medical control). This transition is probably accompanied by genetic changes, resulting in the activation of oncogenes or the inactivation of tumor suppressor genes. In the present manuscript, the isolation of genes that may be involved in advanced, androgen-independent prostate cancer growth is described. Using differential display PCR, 13 cDNAs were isolated representing genes that are differentially expressed between the androgen-dependent prostate carcinoma cell line LN-CaP and the androgen-independent prostate carcinoma cell lines PC-3 and DU 145. These clones were divided into four groups: androgen-responsive genes (TL5, TL25, TL32, and TL35); genes with a marked decreased expression in one of the prostate cancer cell lines (TL27); genes with a marked, increased expression in one or more of the prostate cancer cell lines (TL4, TL16, TL21, and TL22); and genes with minor (but repeatable) changes in expression between prostate cancer cell lines (TL7, TL15, TL18, and TL33). The 13 genes were analyzed for their sequence information, tissue specificity, and androgen responsiveness in order to identify genes of interest. In summary, differential display PCR appears to provide an attractive alternative to existing molecular techniques to screen for differentially expressed genes in prostate cancer cells.

Androgens↗