Phytochemical profiling, antioxidant potential and cytotoxic activity of Sargassum prismaticum extracts: implications for therapeutic applications.

Seaweeds are sources of bioactive compounds with medicinal properties, which make them attractive candidates for natural therapeutic agents. Marine brown algae are known to possess anti-inflammatory, hepatoprotective, anticancer properties, etc. Present study was carried out to identify the phytochemical constituents, antioxidant and cytotoxic activities of Sargassum prismaticum in two different solvents viz., chloroform and methanol. Chloroform was found to be the superior solvent for phenol and flavonoid extraction. Antioxidant activity was determined using DPPH and ABTS assays; however, the methanolic extract demonstrated better antioxidant potential. The highest cell cytotoxicity with an IC50 value of 7.6 ± 0.02 µg/mL was observed in methanolic extract, while the chloroform extract had an IC50 value of 9.6 ± 0.03 µg/mL against U937 cell line. These finding suggest that Sargassum prismaticum possesses potent antioxidant and cytotoxic properties, making it a potential candidate for further study as a novel antioxidant drug source.

Evaluation of antihypertensive activity and molecular docking analysis of Padina boergesenii extract.

INTRODUCTION: Antihypertensive drugs that are chemically synthesized usually tend to initiate different health complications. The quest for bioactive molecules to create novel medicines has focused on Marine resources like seaweeds. These molecules can furnish a positive probability for patients to gain benefits from these natural substances. METHODS: This study aims to identify phytoconstituents present in brown seaweed-Padina boergesenii. Five different solvents were used to prepare extracts and their antioxidant activity as well as antihypertensive activity was evaluated. Phytoconstituents were identified using LC-MS/MS, and subjected to molecular interaction against ACE enzyme. RESULTS: The 70% ethanolic extract exhibited the highest total phenolic content (TPC), significant radical scavenging activity and concentration dependent Angiotensin Converting Enzyme (ACE) inhibition activity. LC-MS/MS analysis confirmed the presence of bioactive compounds from which 7,8 dihydroxycoumarin had the highest affinity against ACE enzyme in molecular docking study. CONCLUSION: These findings advocate that Padina boergesenii can be a potential source for developing novel antihypertensive therapeutic drug(s) and could pave the way for evolving effective and safe remedies from natural resources.

Subcuticular skin closure at cesarean delivery with poliglecaprone-25 vs polyglactin-910: a randomized controlled trial.

BACKGROUND: Cesarean delivery is a commonly performed surgical procedure worldwide. There is limited good-quality evidence regarding subcuticular skin closure with absorbable sutures in transverse incisions after cesarean delivery. OBJECTIVE: This study aimed to compare poliglecaprone-25 (3-0) and polyglactin-910 (4-0) sutures for subcuticular skin closure in Pfannenstiel incisions among women undergoing cesarean delivery. STUDY DESIGN: In this double-blind, single-center, randomized controlled trial among women undergoing cesarean delivery (elective and emergency), 200 women were randomized (Group 1-subcuticular skin closure with poliglecaprone-25 [3-0] vs Group 2-subcuticular skin closure with polyglactin-910 [4-0]). All women received similar preoperative and postoperative care. A sample size of 200 women was selected with the aim of reducing the composite wound complication rate from 15.8% to 3.6% with a power of 0.80 and a 2-tailed α of 0.05. Thus, 90 women were required in each group, but 100 were selected to account for attrition. RESULTS: Composite wound complications (including surgical site infection, hematoma, seroma, need for resuturing or readmission for wound complications) were similar in the 2 groups (Group 1 vs 2: 16 vs 10; P=.293; relative risk, 1.28; 95% confidence interval, 0.91-1.79). Surgical site infection (8 vs 7; P=1.000; relative risk, 1.08; 95% confidence interval, 0.64-1.83), hematoma (1 vs 2; P=.561; relative risk, 0.66; 95% confidence interval, 0.13-3.31), seroma (8 vs 2; P=.052; relative risk, 1.65; 95% confidence interval, 1.17-2.33), need for resuturing (4 vs 3; P=.700; relative risk, 1.15; 95% confidence interval, 0.60-2.22), and need for readmission (4 vs 4; P=1.000) were similar in the 2 groups. Pain score on the visual analog scale at 3 days (3.2±1.0 vs 3.6±1.2) and 6 weeks after operation (1.6±0.8 vs 1.7±0.9;) was significantly lower in Group 1 (P=.023 and P=.033, respectively). There was no difference between observer and patient scar assessment scores measured at 6 weeks after operation (P=.069 and P=.431, respectively). CONCLUSION: Poliglecaprone-25 (3-0) and polyglactin-910 (4-0) subcuticular sutures were comparable regarding composite wound complications (surgical site infection, hematoma, seroma, wound separation or re-suturing, need for readmission) and cosmetic appearance (patient scar assessment score & observer scar assessment score) related to skin closure among women undergoing cesarean delivery through a Pfannenstiel incision in nonobese women (average body mass index, 25).

4-Dimensional printing: exploring current and future capabilities in biomedical and healthcare systems-a Concise review.

4-Dimensional Printing (4DP) is the latest concept in the pharmacy and biomedical segment with enormous potential in dosage from personalization and medication designing, which adopts time as the fourth dimension, giving printed structures the flexibility to modify their morphology. It can be defined as the fabrication in morphology with the help of smart/intelligent materials like polymers that permit the final object to alter its properties, shape, or function in response to external stimuli such as heat, light, pH, and moisture. The applications of 4DP in biomedicines and healthcare are explored with a focus on tissue engineering, artificial organs, drug delivery, pharmaceutical and biomedical field, etc. In the medical treatments and pharmaceutical field 4DP is paving the way with unlimited potential applications; however, its mainstream use in healthcare and medical treatments is highly dependent on future developments and thorough research findings. Therefore, previous innovations with smart materials are likely to act as precursors of 4DP in many industries. This review highlights the most recent applications of 4DP technology and smart materials in biomedical and healthcare fields which can show a better perspective of 4DP applications in the future. However, in view of the existing limitations, major challenges of this technology must be addressed along with some suggestions for future research. We believe that the application of proper regulatory constraints with 4DP technology would pave the way for the next technological revolution in the biomedical and healthcare sectors.

Nyctanthes arbor-tristis alkaloids activates p53 independent cell death receptor and necroptosis pathways in HepG2 cells.

Nyctanthes arbor-tristis is a traditional medicinal plant with potential anti-cancer properties. In this study, crude and alkaloid extracts were prepared from different parts of the plant, and their cytotoxicity was evaluated on four different cancer cell lines. The alkaloid extracts from the leaf and fruit showed promising results, with the HepG2 cell line exhibiting significant cytotoxicity. The promising extracts were further studied for their apoptotic potential using various methods, including DNA fragmentation, TUNEL, Caspase-3 activity, Giemsa, and Hoechst staining. Our results indicated that the fruit extract had the highest apoptotic potential, with clear nuclear condensation, fragmentation, and apoptotic bodies observed. We also investigated the alteration of the Bax/Bcl-2 ratio both at the mRNA and protein levels. Our results showed a significant upregulation of the Bax gene and downregulation of the Bcl-2 gene for the fruit alkaloid extract. This indicates that the phenomenon of cell death expression might be following a p53-independent extrinsic pathway and Bax-activated caspase-independent AIF-mediated necroptosis in the HepG2 cancer cell line. Overall, our findings suggest that Nyctanthes arbor-tristis has potential as a therapeutic option for cancer treatment. The alkaloid extracts from the leaf and fruit may hold promise as a source of bioactive compounds for further development into anti-cancer agents. Further studies are needed to explore the underlying mechanisms of their cytotoxic and apoptotic effects and to evaluate their safety and efficacy in animal models and clinical trials.

Foley catheter (80 vs 60 mL) and misoprostol for labor induction in nulliparous women: a randomized controlled trial.

BACKGROUND: Induction of labor is a common intervention in obstetrics worldwide. Foley catheter is a commonly used mechanical method for labor induction in nulliparous women with an unfavorable cervix at term. We hypothesize that a higher volume of Foley catheter (80 mL vs 60 mL) will shorten the induction-delivery interval for labor induction in nulliparous women at term with an unfavorable cervix with simultaneous use of vaginal misoprostol. OBJECTIVE: This study aimed to evaluate the effect of transcervical Foley catheter (80 mL vs 60 mL) with simultaneous use of vaginal misoprostol on the induction-delivery interval in nulliparous women at term with an unfavorable cervix for induction of labor. STUDY DESIGN: In this double-blind, single-center, randomized controlled trial, nulliparous women with a term singleton gestation with unfavorable cervix were randomized to either group 1 (Foley catheter [80 mL] simultaneously with vaginal misoprostol 25 µg every 4h) or group 2 (Foley catheter [60 mL] with vaginal misoprostol 25 µg every 4h). The primary outcome was induction-delivery interval. Secondary outcomes were duration of the latent phase of labor, number of doses of vaginal misoprostol required, mode of delivery, as well as maternal and neonatal morbidity. Analyses were based on the intention-to-treat method. A sample size of 100 women per group (N=200) was selected. RESULTS: Between September 2021 to September 2022, 200 nulliparous women at term with an unfavorable cervix were randomized to labor induction with either FC (80 mL vs 60 mL) and vaginal misoprostol. Induction delivery interval (in minutes) was statistically significantly shorter in Foley catheter (80 mL) (median [interquartile range], 604 [524-719] vs 846 [596-990]; [P<.001]). Median time to labor onset (in minutes) (240 [120-300] vs 360 [180-600]; P<.001) was also shorter in group 1 (80 mL). The number of doses of misoprostol required for labor induction was statistically significantly less than with 80 mL (mean±standard deviation, 1.4±0.7 vs 2.4±1.3; P<.001). There was no statistically significant difference in the mode of delivery (vaginal delivery: 69 vs 80; odds ratio, 0.55 [1.1-0.3]; P=.104 and cesarean delivery: 29 vs 17; odds ratio, 0.99 [0.9-1.1]; P=.063, respectively). The relative risk of delivery within 12 hours with 80 mL was 2.4 [95% confidence interval, 1.68-3.43], P<.001. Maternal and neonatal morbidity were similar across the 2 groups. CONCLUSION: FC (80 mL) simultaneously with vaginal misoprostol significantly shortens the induction-delivery interval (P<.001) in nulliparous women at term with an unfavorable cervix, as compared with Foley catheter 60 mL and vaginal misoprostol.

A randomized controlled trial comparing combined medical and mechanical method for early mid-trimester abortion (13-20 weeks).

OBJECTIVE: To examine the combined effect of a medical and mechanical method on induction-to-abortion interval (IAI) in women undergoing early mid-trimester abortion (MTA) (13-20 weeks of pregnancy). METHODS: A randomized controlled trial was conducted among women undergoing MTA. Primary outcome was IAI. At enrollment, 60 women were randomized (group 1: medical method alone [mifepristone 200 mg, then 48 h later vaginal misoprostol 400 µg every 4 h] versus group 2: combined medical and mechanical method [transcervical Foley catheter inflated with 60 ml of normal saline]). Demographic and clinical data were collected at enrollment and abortion. RESULTS: Women in group 2 had statistically significantly shorter IAI (mean ± standard deviation: 347 ± 130 min vs. 640 ± 242 min, for group 2 and group 1, respectively; P < 0.001). All the women in group 2 had complete abortion within 12 h, compared with 19 (63%) in group 1 (P < 0.001). Median number of doses of vaginal misoprostol (400 µg every 4 h) required in group 1 was 4 (interquartile range [IQR] 3-5) versus 1 (IQR 1-3) in group 2 (P < 0.001). Statistically significantly fewer women required additional oxytocin (group 1 vs. group 2; 4 vs. zero, respectively, P = 0.038). All women in the study had complete abortion. There was no significant difference with respect to maternal complications. CONCLUSION: A combined medical and mechanical method significantly shortens the IAI (P < 0.001) in women undergoing early MTA (13-20 weeks of pregnancy). TRIAL REGISTRATION: Clinical Trial Registry of India www.ctri.nic.in CTRI/2020/12/030077 (date; 28-12-2020).

Conformational dynamics promotes disordered regions from function-dispensable to essential in evolved site-specific DNA recombinases.

Protein intrinsically disordered regions (IDRs) play pivotal roles in molecular recognition and regulatory processes through structural disorder-to-order transitions. To understand and exploit the distinctive functional implications of IDRs and to unravel the underlying molecular mechanisms, structural disorder-to-function relationships need to be deciphered. The DNA site-specific recombinase system Cre/loxP represents an attractive model to investigate functional molecular mechanisms of IDRs. Cre contains a functionally dispensable disordered N-terminal tail, which becomes indispensable in the evolved Tre/loxLTR recombinase system. The difficulty to experimentally obtain structural information about this tail has so far precluded any mechanistic study on its involvement in DNA recombination. Here, we use in vitro and in silico evolution data, conformational dynamics, AI-based folding simulations, thermodynamic stability calculations, mutagenesis and DNA recombination assays to investigate how evolution and the dynamic behavior of this IDR may determine distinct functional properties. Our studies suggest that partial conformational order in the N-terminal tail of Tre recombinase and its packing to a conserved hydrophobic surface on the protein provide thermodynamic stability. Based on our results, we propose a link between protein stability and function, offering new plausible atom-detailed mechanistic insights into disorder-function relationships. Our work highlights the potential of N-terminal tails to be exploited for regulation of the activity of Cre-like tyrosine-type SSRs, which merits future investigations and could be of relevance in future rational engineering for their use in biotechnology and genomic medicine.

Simultaneous use of high-volume Foley catheter (60 ml) and misoprostol for labor induction in nulliparous women: A randomized controlled trial.

OBJECTIVE: To examine the simultaneous effect of high-volume Foley catheter (HVFC) (60 ml) and vaginal misoprostol on labor induction in nulliparous women. METHODS: A randomized, double-blind, controlled trial was conducted among nulliparous post-date (>40 weeks) pregnant women between June and December 2019. At enrollment 100 women were randomized into each group (either HVFC and vaginal misoprostol or low-volume Foley catheter [LVFC] [30 ml] and vaginal misoprostol), for labor induction. Demographic and clinical data were collected at enrollment and delivery. RESULTS: Women in the HVFC group had statistically significantly shorter induction to delivery interval (median 860 min, interquartile range [IQR] 840-940 min vs. 1160 min, IQR 1080-1320 min, P < 0.001) and duration of labor (median 615 min, IQR 600-680 min vs. 750, IQR 692.5-800 min, P < 0.001). Mode of vaginal delivery (n = 94 vs. n = 78, P = 0.002), number of doses of misoprostol required (median 2, IQR 1-2 vs. 2, IQR 1-3), and need of oxytocin augmentation (n = 22 vs. n = 39, P = 0.014 and P < 0.001), was significantly better in the HVFC group. However, there was no significant difference with respect to other maternal or neonatal outcomes. CONCLUSION: Simultaneous use of HVFC and vaginal misoprostol for labor induction significantly shortens the induction to delivery interval and duration of labor in nulliparous women. TRIAL REGISTRATION: Clinical Trial Registry of India CTRI/2019/05/019394 (http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=31554&EncHid=&userName=Foley%20catheter).

Genome-wide identification and functional prediction of salt- stress related long non-coding RNAs (lncRNAs) in chickpea (Cicer arietinum L.).

LncRNAs (long noncoding RNAs) are 200 bp length crucial RNA molecules, lacking coding potential and having important roles in regulating gene expression, particularly in response to abiotic stresses. In this study, we identified salt stress-induced lncRNAs in chickpea roots and predicted their intricate regulatory roles. A total of 3452 novel lncRNAs were identified to be distributed across all 08 chickpea chromosomes. On comparing salt-tolerant (ICCV 10, JG 11) and salt-sensitive cultivars (DCP 92-3, Pusa 256), 4446 differentially expressed lncRNAs were detected under various salt  treatments. We predicted 3373 lncRNAs to be regulating their target genes in cis regulating manner and 80 unique lncRNAs were observed as interacting with 136 different miRNAs, as eTMs (endogenous target mimic) targets of miRNAs and implicated them in the regulatory network of salt stress response. Functional analysis of these lncRNA revealed their association in targeting salt stress response-related genes like potassium transporter, transporter family genes, serine/threonine-protein kinase, aquaporins like TIP1-2, PIP2-5 and transcription factors like, AP2, NAC, bZIP, ERF, MYB and WRKY. Furthermore, about 614 lncRNA-SSRs (simple sequence repeats) were identified as a new generation of molecular markers with higher efficiency and specificity in chickpea. Overall, these findings will pave the understanding of comprehensive functional role of potential lncRNAs, which can help in providing insight into the molecular mechanism of salt tolerance in chickpea. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-021-01093-0.

Identification of steroidal saponins from Tribulus terrestris and their in silico docking studies.

Tribulus terrestris is known to possess many pharmacological properties, most notably its anticancer activities, owing to its rich steroidal saponin contents. Even though many reports are available elucidating the anticancer potential of the herb, we, for the very first time have attempted to isolate and identified the active compound present in seed crude saponin extract and confers its in silico docking ability with various cellular targets proteins. High performance thin layer chromatography confirms the presence of active saponins in leaf and seed saponin extracts which were further fractionated by silica gel column chromatography. Fractions collected were assessed for cytotoxicity on human breast cancer cells. High resolution liquid chromatography and mass spectroscopy was employ to identify the active components present in fraction with highest cytotoxicity. Intriguingly, Nautigenin type of steriodal saponin was identified to present in the active fraction of seed extract (SF11) and the identified compound was further analyzed for its in silico docking interaction using PyRx AutodockVina. Docking studies revealed the high binding affinity of Nuatigenin at significant sites with apoptotic proteins Bcl-2, Bax, caspase-3, caspase-8, p53 and apoptosis inducing factor along with cell surface receptors estrogen receptor, projesterone receptor, epidermal growth factor receptor, and human epidermal growth factor receptor-2. Thus, the conclusions were drawn that saponin fraction of Tribulus terrestis possesses active compounds having anticancer property and specifically, Nuatigenin saponin can be considered as an important therapeutic drug for the breast cancer treatment.

Evaluation of novobiocin and telmisartan for anti-CHIKV activity.

Chikungunya has re-emerged as an epidemic with global distribution and high morbidity, necessitating the need for effective therapeutics. We utilized already approved drugs with a good safety profile used in other diseases for their new property of anti-chikungunya activity. It provides a base for a fast and efficient approach to bring a novel therapy from bench to bedside by the process of drug-repositioning. We utilized an in-silico drug screening with FDA approved molecule library to identify inhibitors of the chikungunya nsP2 protease, a multifunctional and essential non-structural protein required for virus replication. Telmisartan, an anti-hypertension drug, and the antibiotic novobiocin emerged among top hits on the screen. Further, SPR experiments revealed strong in-vitro binding of telmisartan and novobiocin to nsP2 protein. Additionally, small angle x-ray scattering suggested binding of molecules to nsP2 and post-binding compaction and retention of monomeric state in the protein-inhibitor complex. Protease activity measurement revealed that both compounds inhibited nsP2 protease activity with IC50 values in the low micromolar range. More importantly, plaque formation assays could show the effectiveness of these drugs in suppressing virus propagation in host cells. We propose novobiocin and telmisartan as potential inhibitors of chikungunya replication. Further research is required to establish the molecules as antivirals of clinical relevance against chikungunya.

Nearest-neighbor amino acids of specificity-determining residues influence the activity of engineered Cre-type recombinases.

The tyrosine-type site-specific DNA recombinase Cre recombines its target site, loxP, with high activity and specificity without cross-recombining the target sites of highly related recombinases. Understanding how Cre achieves this precision is key to be able to rationally engineer site-specific recombinases (SSRs) for genome editing applications. Previous work has revealed key residues for target site selectivity in the Cre/loxP and the related Dre/rox recombinase systems. However, enzymes in which these residues were changed to the respective counterpart only showed weak activity on the foreign target site. Here, we use molecular modeling and dynamics simulation techniques to comprehensively explore the mechanisms by which these residues determine target recognition in the context of their flanking regions in the protein-DNA interface, and we establish a structure-based rationale for the design of improved recombination activities. Our theoretical models reveal that nearest-neighbors to the specificity-determining residues are important players for enhancing SSR activity on the foreign target site. Based on the established rationale, we design new Cre variants with improved rox recombination activities, which we validate experimentally. Our work provides new insights into the target recognition mechanisms of Cre-like recombinases and represents an important step towards the rational design of SSRs for applied genome engineering.

Improving the binding affinity estimations of protein-ligand complexes using machine-learning facilitated force field method.

Scoring functions are routinely deployed in structure-based drug design to quantify the potential for protein-ligand (PL) complex formation. Here, we present a new scoring function Bappl+ that is designed to predict the binding affinities of non-metallo and metallo PL complexes. Bappl+ outperforms other state-of-the-art scoring functions, achieving a high Pearson correlation coefficient of up to ~ 0.76 with low standard deviations. The biggest contributors to the increased performance are the use of a machine-learning model and the enlarged training dataset. We have also evaluated the performance of Bappl+ on target-specific proteins, which highlighted the limitations of our function and provides a way for further improvements. We believe that Bappl+ methodology could prove valuable in ranking candidate molecules against a target metallo or non-metallo protein by reliably predicting their binding affinities, thus helping in the drug discovery process.

An insight into the anticancer mechanism of Tribulus terrestris extracts on human breast cancer cells.

Tribulus terrestris (TT), a herb belonging to Zygophyllaceae family is widely used due to its medicinal properties. This study was undertaken to elucidate the anticancer mechanism of TT on MCF-7 breast cancer cells. Cytotoxic effect of the herb was assessed by 3-(4,5-diethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptotic potential was assessed through DNA fragmentation, TUNEL and caspase 3 activity assays. Expressions of genes regulating the apoptotic pathway were examined by RT-PCR and expression of proteins was analyzed by immunocytochemistry. The result of MTT assay revealed that methanolic and saponin extracts from leaves and seeds of TT were cytotoxic to MCF-7 cells. Cytotoxicity studies on peripheral blood mononuclear cells (PBMC) proved that TT extracts were non-toxic to non-malignant cells. Treatment of human breast cancer MCF-7 cells with seed and leaf methanol and saponin extracts of TT resulted in fragmentation of DNA and induction of apoptosis. This was evident by agarose gel electrophoresis of DNA and TUNNEL assay. The extracts of TT also caused a significant increase in caspase 3 activity in MCF-7 cells. TT extracts caused an induction of intrinsic apoptotic pathway which was evident by the upregulation in the expression of Bax and p53 genes and downregulation in the expression of Bcl-2. FADD, AIF and caspase 8 genes were also upregulated indicating the possible induction of extrinsic apoptotic pathway. Therefore, our results suggest that the Tribulus terrestris (TT) extracts may exert their anticancer activity by both extrinsic and intrinsic apoptotic pathways.

Effect of Tribulus terrestris saponins on proliferation of adipose-derived mesenchymal stem cells.

Adipose-derived mesenchymal stem cells (ASCs) transplantation has shown great promise for treating various diseases; however, poor viability of transplanted ASCs because of oxidative stress has limited its therapeutic efficiency. Plant saponins are recently been reported to have antioxidant activity tested in various cancer cell lines. This study was designed to investigate the protective effects of Tribulus terrestris saponins (TTS) on the proliferation of ASCs. The cytotoxic activity of hydrogen peroxide (H2 O2 ) was determined by treating ASCs with 100, 200, 300, 400, and 500 µM H2 O2 for 2 hours. ASCs were treated with 6.25, 12.5, 25, 50, and 100 µg/mL concentrations of TTS for the proliferative experiment. To check the protective effect of TTS, experiments were designed in two ways. In one set, ASCs were pretreated with different concentrations of TTS for 2 hours and then apoptosis was induced by treating them with 400 µM H2 O2 for next 2 hours, while in other set, ASCs were first treated with 400 µM H2 O2 for 2 hours and subsequently with different concentrations of TTS for 24 hours. The vitality and proliferation potential of cells were detected by 3-(4,5-Dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The result of the current study shows that in response to stress-induced by H2 O2 at concentration of 400 µM, ASCs underwent growth arrest and cell viability was reduced to half while treatment with TTS before and after H2 O2 exposure significantly prevents premature apoptosis. The findings suggest that saponins may act as an effective protective agent against oxidative stress-induced ASCs apoptosis.

Nonsteroidal estrogen receptor isoform-selective biphenyls.

Estrogen receptor (ER) has been a therapeutic target to treat ER-positive breast cancer, most notably by agents known as selective estrogen receptor modulators (SERMs). However, resistance and severe adverse effects of known drugs gave impetus to the search for newer agents with better therapeutic profile. ERα and ERß are two isoforms sharing 56% identity and having different physiological functions and expressions in various tissues. Only two residues differ in the active sites of the two isoforms motivating us to design isoform-selective ligands. Guided by computational docking and molecular dynamics simulations, we have designed, synthesized, and tested, substituted biphenyl-2,6-diethanones and their derivatives as potential agents targeting ERα. Four of the molecules synthesized exhibited preferential cytotoxicity in ERα+ cell line (MCF-7) compared to ERß+ cell line (MDA-MB-231). Molecular dynamics (MD) in combination with molecular mechanics-generalized Born surface area (MM-GBSA) methods could account for binding selectivity. Further cotreatment and E-screen studies with known ER ligands-estradiol (E2 ) and tamoxifen (Tam)-indicated isoform-selective anti-estrogenicity in ERα+ cell line which might be ER-mediated. ERα siRNA silencing experiments further confirmed the ER selective nature of ligands.

Hydralazine vs nifedipine for acute hypertensive emergency in pregnancy: a randomized controlled trial.

BACKGROUND: There is a paucity of good quality evidence regarding the best therapeutic option for acute control of blood pressure during acute hypertensive emergency of pregnancy. OBJECTIVE: We sought to compare the efficacy of intravenously administered hydralazine and oral nifedipine for acute blood pressure control in acute hypertensive emergency of pregnancy. STUDY DESIGN: In this double-blind, randomized, controlled trial, pregnant women (≥24 weeks period of gestation) with sustained increase in systolic blood pressure of ≥160 mm Hg or diastolic blood pressure of ≥110 mm Hg were randomized to receive intravenous hydralazine injection in doses of 5, 10, 10, and 10 mg and a placebo tablet or oral nifedipine (10 mg tablet up to 4 doses) and intravenous saline injection every 20 minutes until the target blood pressure of 150 mm Hg systolic and ≤100 mm Hg diastolic was achieved. Crossover treatment was administered if the initial treatment failed. The primary outcome of the study was time necessary to achieve target blood pressure. The secondary outcomes were the number of dosages required, adverse maternal and neonatal effects, and perinatal outcome. RESULTS: From December 2014 through September 2015, we enrolled 60 patients. The median time to achieve target blood pressure was 40 minutes in both groups (intravenous hydralazine and oral nifedipine) (interquartile interval 5 and 40 minutes, respectively, P = .809). The median dose requirement in both groups was 2 (intravenous hydralazine and oral nifedipine) (interquartile range 1 and 2 doses, respectively, P = .625). Intravenous hydralazine was associated with statistically significantly higher occurrence of vomiting (9/30 vs 2/30, respectively, P = .042). No serious adverse maternal or perinatal side effects were witnessed in either group. CONCLUSION: Both intravenous hydralazine and oral nifedipine are equally effective in lowering of blood pressure in acute hypertensive emergency of pregnancy.

Mifepristone vs balloon catheter for labor induction in previous cesarean: a randomized controlled trial.

OBJECTIVE: To compare oral mifepristone (400 mg) with trans-cervical balloon catheter for induction of labor (IOL) in post date women with previous one cesarean section (CS). METHODS: In this randomized trial, post date pregnant women (gestation 40 weeks 5 days), with previous one low segment CS (no previous vaginal delivery) were induced either with oral mifepristone (400 mg) or balloon catheter [Foley's catheter (16 Fr); bulb filled with 30 ml normal saline]. They were re-assessed 24 and 48 h later. If at any time Bishop Score was >6; amniotomy was done, followed by oxytocin infusion. Primary outcome of the study was labor onset after first manoeuvre. Secondary outcomes were cervical ripening, need of oxytocin, vaginal delivery and CS, in two groups. RESULTS: From June 2012 to September 2015, we enrolled 107 women. Out of these, 57 received oral tablet mifepristone (400 mg) and 50 were inserted with balloon catheter. Labor onset after first manoeuvre was statistically significantly more in mifepristone group (37/57 vs. 13/50, respectively; p value 0.000). Bishop Score after 24 h was better in balloon catheter (p value 0.000). More women with balloon catheter required oxytocin for IOL (37/50 vs. 20/57, respectively; p value 0.000) along with higher dose [840 (320) mU vs 560 (120) mU, respectively, p value 0.000]. Failure of induction was statistically significantly higher in balloon catheter group (8 out of 50 vs. 2 out of 57, respectively, p value 0.043). There was no statistically significant difference in normal delivery or CS in either group (p value 0.242 and 0.331, respectively). CONCLUSION: Oral mifepristone (400 mg) is associated with statistically significantly higher incidence of labor onset in post date pregnant women with previous one CS, as compared to balloon catheter. Both methods are primarily for cervical ripening and oxytocin should not be delayed in the absence of onset of labor. CLINICAL TRIAL REGISTRATION: Clinical Trials Registry-India, www.ctri.nic.in , CTRI/2012/05/003634.

A DNA intercalation methodology for an efficient prediction of ligand binding pose and energetics.

MOTIVATION: Drug intercalation is an important strategy for DNA inhibition which is often employed in cancer chemotherapy. Despite its high significance, the field is characterized by limited success in identification of novel intercalator molecules and lack of automated and dedicated drug-DNA intercalation methodology. RESULTS: We report here a novel intercalation methodology (christened ' Intercalate' ) for predicting both the structures and energetics of DNA-intercalator complexes, covering the processes of DNA unwinding and (non-covalent) binding. Given a DNA sequence and intercalation site information, Intercalate generates the 3D structure of DNA, creates the intercalation site, performs docking at the intercalation site and evaluates DNA-intercalator binding energy in an automated way. The structures and energetics of the DNA-intercalator complexes produced by Intercalate methodology are seen to be in good agreement with experiment. The dedicated attempt made in developing a drug-DNA intercalation methodology (compatible with its mechanism) with high accuracy should prove useful in the discovery of potential intercalators for their use as anticancers, antibacterials or antivirals. AVAILABILITY AND IMPLEMENTATION: http://www.scfbio-iitd.res.in/intercalate/. CONTACT: anjali@scfbio-iitd.res.in or bjayaram@chemistry.iitd.ac.in. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.