1:1 hetero-assembly of 2-aminopyrimidine and (+)-camphoric acid
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Journal Article↗
Biomedical subjects
R Mukherjee
Publications and source records attributed to R Mukherjee.
Self-assembly of 2-pivaloyl-6-chloropterin
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Journal Article↗
A selective peroxisome proliferator-activated receptor-gamma (PPARgamma) modulator blocks adipocyte differentiation but stimulates glucose uptake in 3T3-L1 adipocytes.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists such as the thiazolidinediones are insulin sensitizers used in the treatment of type 2 diabetes. These compounds induce adipogenesis in cell culture models and increase weight gain in rodents and humans. We have identified a novel PPARgamma ligand, LG100641, that does not activate PPARgamma but selectively and competitively blocks thiazolidinedione-induced PPARgamma activation and adipocyte conversion. It also antagonizes target gene activation as well as repression in agonist-treated 3T3-L1 adipocytes. This novel PPARgamma antagonist does not block adipocyte differentiation induced by a ligand for the retinoid X receptor (RXR), the heterodimeric partner for PPARgamma, or by a differentiation cocktail containing insulin, dexamethasone, and 1-methyl-3-isobutylxanthine. Surprisingly, LG100641, like the PPARgamma agonist rosiglitazone, increases glucose uptake in 3T3-L1 adipocytes. Such selective PPARgamma antagonists may help determine whether insulin sensitization by thiazolidinediones is mediated solely through PPARgamma activation, and whether there are PPARgamma-ligand-independent pathways for adipocyte differentiation. If selective PPARgamma modulators block adipogenesis in vivo, they may prevent obesity, lower insulin resistance, and delay the onset of type 2 diabetes.
1-Methyl-3-isobutylxanthine↗
Enhancement of the transformed shape phenotype by microtubule inhibitors and reversal by an inhibitor combination.
Differences between transformed cells and their normal counterparts were defined by analyzing the cells' three-dimensional distribution of mass. Variables called factors, which explained the covariance of the real variables, were extracted from the data. We found that factors #4 (sharp, tapering projections) and #12 (rounding up), corresponded to G-protein functions. Then, the signature-type mass distribution of transformed cells was defined by factor values. Agents that caused signature-type mimicry could quantitatively shift factor values, for example, those affecting endocytic processing disproportionately reduced values of #4. Signature-type reversal was also observed and may be valuable in predicting the efficacy of chemotherapeutic agents.
Animals↗
Mycobacterium w vaccine, a useful adjuvant to multidrug therapy in multibacillary leprosy: a report on hospital based immunotherapeutic clinical trials with a follow-up of 1-7 years after treatment.
A vaccine based on autoclaved Mycobacterium w was administered, in addition to standard multidrug therapy (MDT), to 156 bacteriologically positive, lepromin negative multibacillary leprosy patients compared to a well matched control group of 145 patients with a similar type of disease who received a placebo injection in addition to MDT. The MDT was given for a minimum period of 2 years and continued until skin smear negativity, while the vaccine was given at 3-month intervals up to a maximum of eight doses. The fall in clinical scores and bacteriological indices was significantly more rapid in vaccinated patients, from 6 months onward until years 2 or 3 of therapy. However, no difference was observed in the fall in bacteriological index in the two groups from year 4 onwards. The number of LL and BL patients released from therapy (RFT) following attainment of skin smear negativity, after 24-29 months of treatment was 84/133 (63.1%) in vaccinated and 30/120 (25.0%) in the placebo group; the difference was highly statistically significant (P < 0.0001). In all, 90.2% patients (146/162) converted from lepromin negativity to positivity in the vaccine group, as against 37.9% (56/148) in the placebo group. The average duration of lepromin positivity maintained following eight doses of vaccine administered over 2 years was 3.016 years in the vaccine and 0.920 years in the placebo group. Histological upgrading after 2 years of treatment in the LL type was observed in 34/84 (40.5%) cases in the vaccine and 5/85 (5.9%) cases in the placebo group, the difference being statistically significant (P < 0.001). The incidence of type 1 reactions was significantly higher (30.5%) in the vaccine group than (19.7%) in the placebo group (P = 0.0413); the difference was mainly observed in LL type (P = 0.009). The incidence of type 2 reactions was similar (31.8 and 34.6%) in vaccine and placebo groups. The vaccine did not precipitate neuritis or impairments over and above that encountered with MDT alone. After 5 years of follow-up following RFT, no incidence of bacteriological or clinical relapses was observed in both groups.
Bacterial Vaccines↗
Reactional states and neuritis in multibacillary leprosy patients following MDT with/without immunotherapy with Mycobacterium w antileprosy vaccine.
A vaccine based on autoclaved Mycobacterium w was administered, in addition to standard multidrug therapy (MDT), to 157 untreated, bacteriologically positive, lepromin negative multibacillary leprosy patients, supported by a well matched control group of 147 patients with similar type of disease, who received a placebo injection in addition to MDT. The MDT was given for a minimum period of 2 years and continued until skin smear negativity, while the vaccine/placebo was given at 3-monthly intervals up to a maximum of eight doses. The incidence of type 2 reaction and neuritis during treatment and follow-up showed no statistically significant difference in the vaccine and placebo groups. The incidence of type 1 reaction (mild in most cases), however, was higher in the vaccine group (P = 0.041, relative risk ratio 1.79), considering LL, BL and BB leprosy types together, and considerably higher (P = 0.009) in LL type, probably because of confounding due to higher number of patients with previous history of reaction in this group. The occurrence of reactions and neuritis in terms of single or multiple episodes was similar in the vaccine and placebo groups. The association of neuritis and reactions, as well as their timing of occurrence (during MDT or follow-up), was also similar in the two groups, with more than 90% of occurrences taking place during MDT. The incidence of reversal reaction was significantly higher among the males in the vaccine group (34.5% versus 8.3%, P = 0.019). Patients with high initial BI (4.1-6.0) showed higher incidence of reactions (70.3%) as compared to those with medium (2.1-4.0) and low (0.3-2.0) BI where the reactions were observed with a frequency of 56.1% and 38.8%, respectively. However, unlike reactions, neuritis incidence did not seem to be affected by initial BI to the same extent in the vaccine group, with frequencies of 35.3%, 36.3% and 25.9% in the three mentioned BI ranges. Overall, the vaccine did not precipitate reactional states and neuritis over and above that observed with MDT alone.
Bacterial Vaccines↗
Induction of lepromin positivity and immunoprophylaxis in household contacts of multibacillary leprosy patients: a pilot study with a candidate vaccine, Mycobacterium w.
We screened 487 household contacts of multibacillary (MB) patients for evidence of disease and their lepromin status. From the 444 results available, 302 (68.02%) were lepromin positive and 142 (31.98%) were lepromin negative on initial testing. The initial lepromin status as assessed in the group of 54 contacts having disease at the outset showed 24 out of 46 (52.2%) to be lepromin positive and 22 of 46 (47.8%) to be lepromin negative. In the same group, among 24 lepromin positives, 22 (91.7%) had paucibacillary (PB) and 2 (8.3%) had multibacillary (MB) disease; among the lepromin negatives, 12 (54.5%) had PB and 10 (45.5%) had MB disease. Out of 72 initially lepromin-negative contacts administered Mycobacterium w vaccine and followed up, the cumulative percentages show that 53 (73.6%) converted to positivity after a single dose, 10 (87.5%) after a second dose and 67 (93.1%) after the third dose. The incidence of new cases with leprosy was 8 out of 231 (3.46%) among lepromin-positive contacts and 5 out of 93 (5.38%) among lepromin-negative contacts administered Mycobacterium w vaccine. Among 231 lepromin-positive contacts, the new cases occurred in those with a 1+ and 2+ lepromin response only, and no case occurred among 51 contacts with a 3+ lepromin response. The incidence among lepromin-positive contacts in this study (3.46%) was similar to the observations in two other studies: 3.2% by Dharmendra, et al. and 6.9% by Chaudhary, et al. However, the incidence among lepromin-negative contacts administered Mycobacterium w vaccine was significantly lower than that observed among lepromin-negative contacts not administered any vaccination in the other two studies (14.1% by Dharmendra, et al. and 29.0% by Chaudhary, et al.). To conclude, although a study of small sample size, the preliminary evaluation indicates that administration of Mycobacterium w vaccine seems to have the potential to reduce the incidence of leprosy among household contacts of leprosy patients. More explicit results about the vaccine will be available from the ongoing field trials in Kanpur Dehat in the near future.
Bacterial Vaccines↗
Effects of growth hormone supplementation on left ventricular morphology and myocyte function with the development of congestive heart failure.
BACKGROUND: Release of growth hormone (GH), putatively through alterations in insulin growth factor-1 (IGF-1) levels, has been implicated to influence left ventricular (LV) myocardial structure and function. The objective of this study was to determine contributory mechanisms by which GH supplementation may influence LV function with the development of congestive heart failure (CHF). METHODS AND RESULTS: Pigs were assigned to the following groups: (1) chronic pacing at 240 bpm for 3 weeks (n = 10), (2) chronic pacing and GH supplementation (200 microg x kg(-1) x d(-1), n = 10), and (3) controls (n = 8). GH treatment increased IGF-1 plasma levels by nearly 2.5-fold throughout the pacing protocol. In the untreated pacing CHF group, LV fractional shortening was reduced and peak wall stress increased. In the pacing CHF and GH groups, LV fractional shortening was higher and LV wall stress lower than untreated CHF values. Steady-state myocyte velocity of shortening was reduced with pacing CHF and was unchanged from CHF values with GH treatment. In the presence of 25 nmol/L isoproterenol, the change in myocyte shortening velocity was reduced in the untreated CHF group and increased in the GH-treated group. LV sarcoplasmic reticulum Ca(2+)-ATPase abundance was reduced with pacing CHF but was normalized with GH treatment. CONCLUSIONS: Short-term GH supplementation improved LV pump function in pacing CHF as a result of favorable effects on LV remodeling and contractile processes. Thus, GH supplementation may serve as a novel therapeutic modality in developing CHF.
Animals↗
Matrix metalloproteinase inhibition during the development of congestive heart failure : effects on left ventricular dimensions and function.
The development of congestive heart failure (CHF) is associated with left ventricle (LV) dilation and myocardial remodeling. The matrix metalloproteinases (MMPs) play a significant role in extracellular remodeling, and recent studies have demonstrated increased MMP expression and activity with CHF. Whether increased MMP activity directly contributes to the LV remodeling with CHF remains unknown. Accordingly, this study examined the effects of chronic MMP inhibition (MMPi) on LV size and function during the progression of CHF. Pigs were assigned to the following groups: (1) CHF, rapid pacing for 3 weeks at 240 bpm (n=12); (2) CHF/MMPi, rapid pacing and concomitant MMPi (PD166793, 20 mg/kg per day [n=10]), and (3) control (n=11). With pacing CHF, LV fractional shortening was reduced (19+/-1 versus 45+/-1%), and end-diastolic dimension increased (5.67+/-0.11 versus 3.55+/-0.05 cm), compared with baseline values (P<0.05). In the CHF/MMPi group, LV endocardial shortening increased (25+/-2%) and the end-diastolic dimension was reduced (4.92+/-0.17 cm) compared with CHF-only values (P<0.05). LV midwall shortening was reduced to a comparable degree in the CHF-only and CHF/MMPi groups. LV peak wall stress increased 3-fold with pacing CHF compared with controls and was significantly reduced in the CHF/MMPi group. LV myocardial stiffness was unchanged with CHF but was increased in the CHF/MMPi group. LV myocyte length was increased with pacing CHF compared with controls (180+/-3 versus 125+/-4 microm, P<0.05) and was reduced in the CHF/MMPi group (169+/-4 microm, P<0.05). Basal-state myocyte shortening velocity was reduced with pacing CHF compared with controls (33+/-2 versus 66+/-1 microm/s, P<0.05) and was unchanged in the CHF/MMPi group (31+/-2 microm/s). Using an ex vivo assay system, myocardial MMP activity was increased with pacing CHF and was reduced with chronic MMPi. In summary, concomitant MMPi with developing CHF limited LV dilation and reduced wall stress. These results suggest that increased myocardial MMP activity contributes to LV myocardial remodeling in developing CHF.
Animals↗
Amlodipine therapy in congestive heart failure: hemodynamic and neurohormonal effects at rest and after treadmill exercise.
This study examined the acute effects of amlodipine treatment on left ventricular pump function, systemic hemodynamics, neurohormonal status, and regional blood flow distribution in an animal model of congestive heart failure (CHF), both at rest and with treadmill exercise. A total of 14 pigs were studied under control conditions and after the development of pacing-induced CHF (240 beats per minute, 3 weeks, n = 7) or with CHF and acute amlodipine treatment for the last 3 days of pacing (1.5 mg/kg per day, n = 7). Under resting conditions, left ventricular stroke volume (mL) was reduced with CHF compared with the normal state (15+/-2 vs. 31+/-1, p<0.05) and increased with amlodipine treatment (23+/-4, p<0.05). At rest, systemic vascular resistance increased with CHF compared with the normal state (3,078+/-295 vs. 2,131+/-120 dyne x s cm(-5), p<0.05) and was reduced after amlodipine treatment (2,472+/-355 dyne x s cm(-5), p<0.05). With exercise, left ventricular stroke volume remained lower and systemic vascular resistance higher in the CHF group, but was normalized with amlodipine treatment. With exercise, left ventricular myocardial blood flow increased from resting values, but was reduced from the normal state with CHF (normal: 1.69+/-0.12 to 7.62+/-0.74 mL/min per gram vs. CHF: 1.26+/-0.12 to 4.77+/-0.45 mL/min per gram, both p<0.05) and was normalized with acute amlodipine treatment (1.99+/-0.35 to 6.29+/-1.23 mL/min per gram). Resting plasma norepinephrine was increased by >5-fold in the CHF group at rest and was not affected by amlodipine treatment. However, with exercise, amlodipine treatment blunted the increase in plasma norepinephrine by >50% when compared with untreated CHF values. Resting plasma endothelin levels increased with CHF compared with the normal state (10.9+/-0.9 vs. 2.8+/-0.4 fmol/mL, p<0.05) and was reduced with amlodipine treatment (7.5+/-1.5 fmol/mL, p<0.5). In other vascular beds, acute amlodipine treatment with CHF improved pulmonary and renal blood flow both at rest and with exercise; however, there were no effects observed on skeletal muscle blood flow. With the development of CHF, acute amlodipine treatment does not negatively influence left ventricular pump function, but rather may provide favorable hemodynamic and neurohormonal effects.
Amlodipine↗
Antiproliferative and GH-inhibitory activity of chimeric peptides consisting of GHRP-6 and somatostatin.
Chimeric peptides consisting of growth hormone releasing peptide (GHRP-6) linked to somatostatin (6-11) via an amide bond to provide the effector parts of both the peptides were synthesized. The anti-proliferative, cytotoxic, and GH-inhibitory activities of these chimeric peptides were determined in vitro in the rat pituitary adenoma cell line GH3. One of the chimeric peptides, GSD, exhibited significantly greater (p < 0.001) anti-neoplastic and GH-inhibitory activity, as compared to RC-160. The hybrid peptides displayed high affinity binding to somatostatin receptors on GH3 cells. The bioactivity of GSD was found to be mediated by the stimulation of tyrosine phosphatase, involving a cGMP-dependent pathway, through pertussis toxin-sensitive G-proteins. Such potent GH-inhibitory chimeric peptides may be of potential importance in the therapy of acromegaly, as well as provide novel tools to study the regulation of GH secretion by GHRP and somatostatin.
Animals↗
Cytotoxic constituents from the roots of Tovomita brevistaminea.
Two known xanthones, trapezifolixanthone and manglexanthone were isolated as cytotoxic constituents from the CHCl3 extract of the roots of Tovomita brevistaminea by bioassay-guided fractionation using the KB cell line. In addition, a new compound, tovophenone C, and two known compounds, tovophenones A and B which are benzophenones, were found to be inactive constituents in this investigation. The structure of the new isolate was determined by detailed analysis of spectroscopic parameters including its 1D and 2D NMR spectroscopy data.
Antineoplastic Agents, Phytogenic↗
The monoterpene alkaloid cantleyine from Strychnos trinervis root and its spasmolytic properties.
Cantleyine, a monoterpene alkaloid isolated from the root bark of Strychnos trinervis, was submitted to a broad spectrum pharmacological screening, in which the principal effect observed was a nonspecific relaxation of isolated smooth muscles. Cantleyine relaxed (IC50 2.1 x 10(-4) M) the guinea-pig trachea, pre-contracted by carbachol and antagonized in a nonspecific manner; carbachol (IC50 2.1 x 10(-4) M) and histamine (IC50 1.4 x 10(-4) M) induced contractions in the guinea-pig ileum; and phenylephrine (IC50 3.8 x 10(-4) M) responses in the rat aorta. Cantleyine antagonized (pD'2, 3.82) cumulative concentration response curves to histamine in the ileum in a noncompetitive, reversible (slope, 4.84) and concentration dependent manner. The tonic contractions induced by histamine and KCl were also inhibited in a concentration-dependent and reversible manner (IC50 7.2 x 10(-5) and 1.8 x 10(-4) M, respectively), suggesting that cantleyine should be acting on voltage-dependent Ca2+ channels. This hypothesis was confirmed by the observation that cantleyine inhibited (pD'2, 3.35), in a concentration dependent manner, the CaCl2 induced contraction in depolarizing medium. These results suggest that cantleyine produces nonspecific spasmolytic effects in smooth muscle and that in guinea-pig ileum this effect is, in part, due to the inhibition of Ca+2 influx through voltage-dependent Ca2+ channels.
Alkaloids↗
New biphenyl compounds with DNA strand-scission activity from Clusia paralicola.
Three new biphenyl derivatives, clusiparalicolines A (1), B (2), and C (3), were isolated from the roots of Clusia paralicola by bioassay-directed fractionation using the DNA strand-scission and the KB human cancer cell line cytotoxicity assays. Compounds 1 and 2 were found to be active in the DNA strand-scission assay, whereas all three compounds exhibited modest cytotoxicity against the KB cell line. The structures of 1-3 were elucidated by spectroscopic methods including 1D and 2D NMR techniques.
Antineoplastic Agents, Phytogenic↗
Lipophilization of somatostatin analog RC-160 improves its bioactivity and stability.
PURPOSE: Acromegaly is a symptomatically disabling condition, resulting from a growth hormone (GH) secreting pituitary tumor. The somatostatin analog RC- 160 is known to potently inhibit hypersecretion of GH, from pituitary adenomas. However, the therapeutic potential of RC-160, is limited by its short serum half life. To overcome this limitation, fatty acids with carbon chain lengths ranging from 4 to 18 were conjugated to RC-160. METHODS: The GH-inhibitory activity of these lipopeptides, as well as their binding profile to somatostatin receptors, on the rat pituitary adenoma cell line GH3 was studied in vitro. The relative stability of lipophilized RC-160 towards degradation by crude papaya protease was also determined. RESULTS: The long chain lipopeptides, like myristoyl-RC-160 (carbon chain length = 14) were found to exhibit greater receptor affinity and GH-inhibitory activity, as compared to their counterparts of lower chain lengths. However, the receptor affinity and GH-inhibitory activity of stearoyl-RC-160 (carbon chain length = 18), was found to lower than RC-160 and its lipophilized derivatives. Unlike RC-160, the myristoylated derivative was found to have significantly greater resistance to protease and serum degradation (p < 0.01). CONCLUSIONS: Lipophilization of RC-160 with long chain fatty acids improves its stability and GH-inhibitory activity. The activity of lipophilized RC-160 seems to increase with increasing hydrophobicity of the lipopeptide, and reaches a maxima at myristoyl-RC-160 for GH3. Hence, optimizing the hydrophobicity should be an important consideration governing the design and synthesis of bioactive lipopeptides.
Adenoma↗
Angiotensin-converting enzyme and matrix metalloproteinase inhibition with developing heart failure: comparative effects on left ventricular function and geometry.
The progression of congestive heart failure (CHF) is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) contribute to tissue remodeling and therefore MMP inhibition may serve as a useful therapeutic target in CHF. Angiotensin converting enzyme (ACE) inhibition favorably affects LV myocardial remodeling in CHF. This study examined the effects of specific MMP inhibition, ACE inhibition, and combined treatment on LV systolic and diastolic function in a model of CHF. Pigs were randomly assigned to five groups: 1) rapid atrial pacing (240 beats/min) for 3 weeks (n = 8); 2) ACE inhibition (fosinopril, 2.5 mg/kg b.i.d. orally) and rapid pacing (n = 8); 3) MMP inhibition (PD166793 2 mg/kg/day p.o.) and rapid pacing (n = 8); 4) combined ACE and MMP inhibition (2.5 mg/kg b.i.d. and 2 mg/kg/day, respectively) and rapid pacing (n = 8); and 5) controls (n = 9). LV peak wall stress increased by 2-fold with rapid pacing and was reduced in all treatment groups. LV fractional shortening fell by nearly 2-fold with rapid pacing and increased in all treatment groups. The circumferential fiber shortening-systolic stress relation was reduced with rapid pacing and increased in the ACE inhibition and combination groups. LV myocardial stiffness constant was unchanged in the rapid pacing group, increased nearly 2-fold in the MMP inhibition group, and was normalized in the ACE inhibition and combination treatment groups. Increased MMP activation contributes to the LV dilation and increased wall stress with pacing CHF and a contributory downstream mechanism of ACE inhibition is an effect on MMP activity.
Angiotensin-Converting Enzyme Inhibitors↗
Disabilities in multibacillary leprosy following multidrug therapy with and without immunotherapy with Mycobacterium w antileprosy vaccine.
A vaccine based on autoclaved Mycobacterium w was administered, in addition to standard multidrug therapy (MDT), to 157 bacteriologically positive, lepromin-negative, multibacillary leprosy patients supported by a well-matched control group of 147 patients with similar type of disease who received a placebo injection in addition to MDT. The MDT was given for a minimum period of 2 years and continued until skin-smear negativity, while the vaccine/placebo was given at 3-month intervals up to a maximum of 8 doses in the initial 2 years. The overall incidence of type 1 and type 2 reactions and neuritis during treatment and follow up was nearly equal in the patients in the vaccine and placebo groups; the differences were not statistically significant. The occurrence of disabilities, such as anesthesia, trophic ulcers, claw hand and grade 3 deformities, were not different statistically in the vaccine and placebo groups, an observation valid both for deformities present at induction and for those which developed during the course of therapy and surveillance. A statistically significant difference was observed in the recovery of newly developed trophic ulcers; recovery was quicker in the vaccine group. The recovery rate for motor deformities was marginally higher in the vaccine group, although not significant (p = 0.068) statistically. There was a statistically significant reduction in the incidence of grade 3 deformities following MDT with and without immunotherapy. To conclude, the addition of vaccine to MDT did not precipitate neuritis or deformities over and above that encountered with MDT alone, although it did accelerate bacteriological clearance, histopathological upgrading, conversion to lepromin positivity, and clinical improvement.
Anti-Inflammatory Agents, Non-Steroidal↗
Induction of lepromin positivity following immuno-chemotherapy with Mycobacterium w vaccine and multidrug therapy and its impact on bacteriological clearance in multibacillary leprosy: report on a hospital-based clinical trial with the candidate antileprosy vaccine.
A vaccine based on autoclaved Mycobacterium w was administered, in addition to standard multidrug therapy (MDT), to 157 bacteriologically positive, lepromin-negative, multibacillary (LL, BL and BB) leprosy patients. The vaccinees were supported by a well-matched control group of 147 patients with similar type of disease who received a placebo injection in addition to MDT. The MDT was given for a minimum period of 2 years and continued until skin-smear negativity, while the vaccine was given at 3-month intervals up to a maximum of 8 doses. The lepromin response evaluated in terms of percentage of subjects converting to positivity status, measurement in millimeters, and duration of lepromin positivity sustained, reflected a statistically significant better outcome in the vaccine group patients (especially LL and BL leprosy) in comparison to those in the placebo group. The data indicate that lepromin-positivity status seems to have an impact on accelerating the bacteriological clearance, as is evident by the statistically significant accelerated decline in the BI of those patients who converted to lepromin positivity as compared to those remaining lepromin negative throughout therapy and post-therapy follow up. To conclude, the addition of the Mycobacterium w vaccine to standard MDT induces a lepromin response of a statistically significant higher magnitude than that observed with MDT alone.
Bacterial Vaccines↗