Anticancer phytochemical analogs 37: synthesis, characterization, molecular docking and cytotoxicity of novel plumbagin hydrazones against breast cancer cells.

We have synthesized, structurally characterized and examined cytotoxicity of novel plumbagin hydrazones against estrogen and progesterone receptor positive (ER+/PR+) MCF-7 and triple negative MDA-MB-231 breast cancer cell lines in order to evaluate the potential of these novel phytochemical analogs. Compounds were docked into the protein cavity of p50-subunit of NF-κB protein revealing better fit and better binding energies than the parent plumbagin compound. This was also reflected in their superior cytotoxicities which were found to be mediated by inhibition of NF-κB expression. These compounds can provide a starting point for the development of novel drug molecules against triple negative breast cancers.

In vitro callus induction and estimation of plumbagin content from Plumbago auriculata Lam.

The medicinal plant Plumbago contains a very potent secondary metabolite, plumbagin having many therapeutic properties. Callus culture was induced using explants, leaf, stem and shoot apex, from P. auriculata. Murashige and Skoog media fortified with various growth hormones like NAA, IAA, IBA and 2, 4-D individually and in various combinations were checked for callus induction. Among the growth hormones used, 1 mg/L 2, 4-D showed best callusing. The hormonal combinations of 1 mg/L IAA and 1.5 mg/L NAA in the media exhibited best callus induction using stem internode as an explant. Plumbagin content from root, stem, leaf and callus was analyzed by using thin layer chromatographic technique. The callus derived from stem showed comparable plumbagin content to the in vivo plant parts. Quantitative spectrophotometric analysis of plumbagin from plant samples and callus indicated that plumbagin content was maximum in roots which was followed by callus, stem and leaf samples respectively. Generation of in vitro sources for p!umbagin, for therapeutic applications will serve as a continuous supply and will contribute to preserve the natural plant recourses.

Inclusion complex of novel curcumin analogue CDF and ß-cyclodextrin (1:2) and its enhanced in vivo anticancer activity against pancreatic cancer.

PURPOSE: Several formulations have been proposed to improve the systemic delivery of novel cancer therapeutic compounds, including cyclodextrin derivatives. We aimed to synthesize and characterize of CDF-ß-cyclodextrin inclusion complex (1:2) (CDFCD). METHODS: The compound was characterized by Fourier transform infrared, differential scanning calorimetry, powder X-ray diffraction studies, H1 & C13 NMR studies and scanning electron microscopic analysis. Its activity was tested against multiple cancer cell lines, and in vivo bioavailability was checked. RESULTS: CDF-ß-cyclodextrin was found to lower IC(50) value by half when tested against multiple cancer cell lines. It preferentially accumulated in the pancreas, where levels of CDF-ß-cyclodextrin in mice were 10 times higher than in serum, following intravenous administration of an aqueous CDF-ß-cyclodextrin preparation. CONCLUSIONS: Novel curcumin analog CDF preferentially accumulates in the pancreas, leading to its potent anticancer activity against pancreatic cancer cells. Synthesis of such CDF-ß-cyclodextrin self-assembly is an effective strategy to enhance its bioavailability and tissue distribution, warranting further evaluation for CDF delivery in clinical settings for treatment of human malignancies.

Synthesis, characterization, molecular docking and cytotoxic activity of novel plumbagin hydrazones against breast cancer cells.

Novel plumbagin hydrazonates were prepared, structurally characterized and evaluated for anti-proliferative activity against estrogen receptor-positive MCF-7 and triple negative MDA-MB-231 and MDA-MB-468 breast cancer cell lines which exhibited superior inhibitory activity than parent plumbagin compound. Molecular docking studies indicated that hydroxyl groups on plumbagin and hydrazonate side chain favor additional hydrogen bonding interactions with amino acid residues in p50-subunit of NF-κB protein and these compounds inhibited NF-κB expression which may be responsible for the enhanced anti-proliferative activity. These compounds were found to be more effective against triple negative breast cancer cells and might serve as a starting point for building future strategies against triple negative breast cancers which are known for their increased drug resistance and poor prognosis of breast cancer patients.

Fluorinated 2'-hydroxychalcones as garcinol analogs with enhanced antioxidant and anticancer activities.

Chalcones are involved in the synthesis of flavonoids and are themselves known to exhibit multiple pharmacological properties. However, compared to other structurally similar phytochemicals like garcinol and curcumin, the therapeutic use of chalcones is limited because of their lower bioavailability and rapid metabolic clearance from biological system. In the present work, we have attempted to overcome these limitations in case of 2'-hydroxychalcones through bioisosteric substitution of fluoro groups in place of phenolic hydroxyls. The fluorinated chalcones were found to be more potent antioxidant and anti-proliferative compounds than their hydroxyl counterparts indicating the influence of metabolically stable C-F bonds towards bioavailability. The difluoro derivatives were found to be most effective against human pancreatic BxPC-3 cancer cells which possess up-regulated COX-2 expression and also showed activity against human breast cancer BT-20 cells with triple negative phenotype, suggesting that these compounds will have broader application in the future.

Evaluation of magnesium as an adjuvant to ropivacaine-induced axillary brachial plexus block: A prospective, randomised, double-blind study.

BACKGROUND AND AIMS: Axillary brachial plexus block is commonly performed for surgeries on the hand and forearm. However, there are very few studies on the use of magnesium sulphate in axillary brachial plexus block and, hence, the study was designed to evaluate magnesium as an adjuvant to ropivacaine-induced axillary block with respect to onset and duration of sensorimotor block and postoperative analgesia. METHODS: Sixty patients of the American Society of Anesthesiologists (ASA) physical status I and II, undergoing surgeries on the hand and forearm were randomly recruited to receive ultrasound-guided axillary block with either 150 mg magnesium sulphate or 1 mL normal saline added to 0.5% ropivacaine. The primary outcome measure was to compare block characteristics including postoperative analgesia and the secondary outcome was to compare the use of rescue analgesia and the side-effect profile. Data were statistically analysed using Statistical Package for Social Sciences (SPSS version 21.0). Categorical variables were compared using the Chi-square test or Fisher's exact probability test; continuous variables compared using unpaired t-test or Mann-Whitney U test. RESULTS: Onset of sensory (9.93 ± 1.31 vs 8.83 ± 1.12 min) as well as motor block (13.37 ± 1.63 vs 11.57 ± 1.30 min) was significantly hastened with addition of magnesium to ropivacaine (p < 0.001) and so was the duration (sensory 386.60 ± 18.26 vs 526.37 ± 27.43, motor 323.73 ± 15.17 vs 436.97 ± 18.99 min) (p < 0.001) and postoperative analgesia (425 ± 21.39 vs 572.83 ± 32.04 min) (p < 0.001) which reflected in decreased requirement of rescue analgesic and total postoperative analgesic dosage. CONCLUSIONS: Magnesium is an effective and safe adjuvant to local anaesthetics and improves all characteristics of axillary brachial plexus block along with postoperative analgesia.

Lignocaine Versus Ropivacaine Infiltration for Postpartum Perineal Pain.

BACKGROUND: Millions of women worldwide undergo postpartum perineal repair under local infiltration. Inadequate postpartum pain management can negatively impact a mother's physical and psychological recovery. AIMS: To study and compare the analgesic effect and maternal satisfaction with lignocaine versus ropivacaine infiltration for postpartum perineal pain relief. MATERIALS AND METHODS: After clearance from the Institutional Ethics Committee, a double-blind prospective randomized study carried out on 100 parturients of aged 18-40 years who had spontaneous vaginal delivery, comparing 1% lignocaine and 0.75% ropivacaine infiltration for the repair of selective episiotomy or perineal injury. Time of the first analgesic (TFA) demand, maternal satisfaction at 24 h, and visual analog scale (VAS) pain score were studied. STATISTICAL ANALYSIS: Chi-square test and Student's t-test were used and P < 0.05 was considered as significant. RESULTS: VAS pain score was significantly lower at 2 and 4 h in ropivacaine group versus lignocaine group (P < 0.0001). Significantly, longer TFA (10.2 ± 1.54 vs. 2.20 ± 0.44 h, P < 0.0001) and higher percentage of maternal satisfaction (86% vs. 44%) were observed in ropivacaine as compared to lignocaine group (P < 0.0001). CONCLUSIONS: Prolonged analgesia and higher rate of maternal satisfaction were found when ropivacaine infiltration was used for perineal repair as compared to lignocaine.

The Analgesic Efficacy of Dexamethasone Added to Ropivacaine in Transversus Abdominis Plane Block for Transabdominal Hysterectomy under Subarachnoid Block.

BACKGROUND AND AIMS: Ultrasound-guided transversus abdominis plane (TAP) block has been proven as a safe and effective analgesic technique for several lower abdominal surgeries. Various adjuvants have been used to intensify the quality and prolong the local anesthetic effect. We evaluated the analgesic efficacy of dexamethasone addition to ropivacaine in TAP block following open abdominal hysterectomy. MATERIALS AND METHODS: After clearance from the Institutional Ethics Committee, a double-blind, prospective, randomized study was carried out on sixty patients aged 40-60 years posted for elective open abdominal hysterectomy comparing bilateral TAP block using 20 ml of 0.5% ropivacaine + 1 ml of 0.9% saline (control Group R) or 20 ml of 0.5% ropivacaine + 4 mg dexamethasone (Group RD). The aim of our study was to observe postoperative pain score (visual analog scale [VAS]), time for first analgesic (TFA) demand, total analgesic consumption, and incidence of nausea or vomiting. STATISTICAL ANALYSIS: Chi-square test and Student's t-test were used, and P < 0.05 was considered as statistically significant. RESULTS: Postoperative VAS pain scores were significantly lower at 4, 6, and 12 h in Group RD as compared to Group R (P < 0.05). Significantly longer TFA (13.2 ± 7.6 vs. 7.1 ± 4.6 h, P < 0.001) with lesser tramadol requirement in first 24 h (50.2 ± 34 vs. 94 ± 35 mg, P < 0.001) were observed in Group RD as compared to Group R. Incidence of nausea or vomiting was statistically insignificant between the groups (P > 0.05). CONCLUSIONS: Addition of dexamethasone to ropivacaine TAP block prolonged the postoperative analgesia and reduced analgesic requirement following abdominal hysterectomy.

Vitamin B12 deficiency and hyperhomocysteinemia in rural and urban Indians.

BACKGROUND: Low vitamin B12 concentration in South Asian Indians is common, but the exact prevalence is not known. AIM: To investigate prevalence and associations of low vitamin B12 concentration and hyperhomocysteinemia in rural and urban Indian men living in and around Pune, Maharashtra. METHOD: We studied 441 middle-aged men (149 rural, 142 slum and 150 urban middle-class residents, mean age 39 y). Data on lifestyle, socio-economic status, nutrition and medical history were obtained. Circulating concentrations of vitamin B12, folate, ferritin, total homocysteine (tHcy), and haematological indices, and cardiovascular risk variables were measured. RESULTS: Median plasma B12 concentration was low (110 pmol/L): Overall, 67% of men had low vitamin B12 concentration (<150 pmol/L) and 58% had hyperhomocysteinemia (>15 micromol/L). Of the urban middle class, 81% had low vitamin B12 concentration and 79% had hyperhomocysteinemia. Low vitamin B12 concentration contributed 28% to the risk of hyperhomocysteinemia (population attributable risk) while low red cell folate contributed 2%. Vegetarians had 4.4 times (95% CI 2.1, 9.4) higher risk of low vitamin B12 concentrations and 3.0 times (95% CI 1.4, 6.5) higher risk of hyperhomocysteinemia compared to those who ate non-vegetarian foods frequently. Urban middle-class residence was an additional independent risk factor of hyperhomocysteinemia (odds ratio 7.6 (95% CI 2.5, 22.6), compared to rural men). Low vitamin B12 concentration was related to lower blood haemoglobin concentration and higher mean corpuscular volume, but macrocytic anemia was rare. CONCLUSION: Low vitamin B12 concentration and hyperhomocysteinemia are common in Indian men, particularly in vegetarians and urban middle class residents. Further studies are needed to confirm these findings in other parts of India.

Perspectives on chemopreventive and therapeutic potential of curcumin analogs in medicinal chemistry.

Curcumin is a natural polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over past 50 years has indicated that this polyphenol is highly pleiotropic molecule capable of preventing and treating various cancers. The anticancer potential of Curcumin is severely affected by its limited systemic and target tissue bioavailability and rapid metabolism. In the present review article, we provide a summarized account of different drug delivery systems employed for tackling the problem of cucumin's bioavailability such as liposomes, phospholipid complexes and nanoparticles. Concomitantly we have reviewed the large volume of literature reports describing structural modifications of Curcumin and the anticancer potential of its analogs. Some of the difluorocurcumin analogs allowing longer circulation times and preferential accumulation in the pancreas seem to offer promising leads for conducting first in-depth animal studies and subsequently clinical trials for the use of these analogs for prevention of tumor progression and/or treatments of human malignancies.

Oral vitamin B12 supplementation reduces plasma total homocysteine concentration in women in India.

People in India have a high prevalence of low vitamin B12 status and high plasma total homocysteine (tHcy) concentrations. In a proof of principle trial, we studied the effect of oral vitamin B12 (500 microg) and/or 100 g cooked green leafy vegetables (GLV) every alternate day in a 2x2 factorial design over a 6-week period. Forty-two non-pregnant vegetarian women (age 20-50 years) were randomly allocated to four study groups. Clinical measurements were made at the beginning and at the end of the study, and blood samples were collected before, and 2 and 6 weeks after commencement of intervention. Forty women completed the trial. Twenty-six women had low vitamin B12 status (<150 pmol/L) and 24 had hyperhomocysteinemia (>15 micromol/L). GLV supplementation did not alter plasma folate or tHcy. Vitamin B12 supplementation increased plasma vitamin B12 concentration (125 to 215 pmol/L, p <0.05) and reduced tHcy concentration (18.0 to 13.0 micromol/L, p <0.05) within first 2 weeks, both of which remained stable for the next 4 weeks. Plasma vitamin B12 and tHcy concentrations did not change in those who did not receive vitamin B12, and there was no change in plasma folate concentration in any of the groups. Blood haemoglobin concentration increased marginally within first two weeks in those women who received vitamin B12 (by 3 g/L, p <0.05) and the number of women with macrocytosis decreased from 2 to zero. There was no change in vibration sensory threshold during the period of the study. High-dose per oral vitamin B12 supplementation significantly reduced plasma tHcy within 2 weeks but did not achieve normal plasma tHcy concentration even after 6 weeks. People in India have a high prevalence of low vitamin B12 status and high plasma total homocysteine (tHcy) concentrations.

Maternal total homocysteine concentration and neonatal size in India.

The smallness of Indian babies is ascribed to small maternal size and their chronic under nutrition. Micronutrient nutrition of the mother may be particularly important. We investigated the relationship between maternal circulating concentrations of total homocysteine (tHcy), vitamin B12 and folate and offspring size at birth. Mothers of full term small for gestation age babies (SGA, gestation and sex specific birth weight <10th centile, N = 30) and mothers of appropriate for gestational age babies (AGA, >10th centile, N = 50) were compared for their body size, plasma tHcy, vitamin B12 and red cell folate concentration at 28 week gestation. Mothers of SGA babies were lighter and shorter than those of AGA babies (P <0.05, both) and had higher plasma tHcy concentration (P<0.01). Total homocysteine concentrations were inversely related to plasma vitamin B12 and red cell folate concentrations (r = approximately -0.5, P <0.01, both). Seventy percent of the women had a low vitamin B12 status (plasma vitamin B12 <150 pmol/L) but none were folate deficient (red cell folate <283 nmol/L). Higher maternal plasma tHcy concentration was significantly associated with lower offspring birth weight (r = -0.28, P<0.05 adjusting for maternal height, weight, gestation at delivery and the baby's gender), this effect was reduced by adjustment for red cell folate concentration. We conclude that maternal vitamin B12 deficiency reflected in plasma tHcy concentration contributes to small size of Indian babies.