A network pharmacology-based approach to understand the mechanism of action of anti-mycobacterial activity of Acacia nilotica: a modelling and experimental study.

The rapid rise in drug-resistant tuberculosis poses a serious threat to public health and demands the discovery of new anti-mycobacterial agents. Medicinal plants are a proven potential source of bioactive compounds; however, identifying those responsible for the putative anti-mycobacterial action still remains a challenging task. In this study, we undertook a systematic network pharmacology approach to identify and evaluate anti-mycobacterial compounds from a traditional plant, Acacia nilotica, as a model system. The protein-protein interaction network revealed 17 key pathways in M. tuberculosis encompassing 40 unique druggable targets that are necessary for its growth and survival. The phytochemicals of A. nilotica were preferentially found to interfere with the cell division and cell wall biogenesis proteins, especially FtsZ and Mur. Notably, the compounds epigallocatechin, ellagic acid, chlorogenic acid, and D-pinitol were found to exhibit a potential polypharmacological effect against multiple proteins. Further, in vitro studies confirmed that the selected candidates, chlorogenic acid, and ellagic acid exhibited potent anti-mycobacterial activity (against M. smegmatis) with specific inhibition of purified M.tb FtsZ enzyme. Taken together, the present study demonstrates that network pharmacology combined with molecular docking can be utilized as an efficient approach to identify potential bioactive phytochemicals from natural products along with their mechanism of action. Hence, the compounds identified in this study can be potential lead candidates for developing novel anti-mycobacterial drugs, while the key proteins identified here can be potential drug targets.

Molecular docking analysis reveals the functional inhibitory effect of Genistein and Quercetin on TMPRSS2: SARS-COV-2 cell entry facilitator spike protein.

BACKGROUND: The Transmembrane Serine Protease 2 (TMPRSS2) of human cell plays a significant role in proteolytic cleavage of SARS-Cov-2 coronavirus spike protein and subsequent priming to the receptor ACE2. Approaching TMPRSS2 as a therapeutic target for the inhibition of SARS-Cov-2 infection is highly promising. Hence, in the present study, we docked the binding efficacy of ten naturally available phyto compounds with known anti-viral potential with TMPRSS2. The aim is to identify the best phyto compound with a high functional affinity towards the active site of the TMPRSS2 with the aid of two different docking software. Molecular Dynamic Simulations were performed to analyse the conformational space of the binding pocket of the target protein with selected molecules. RESULTS: Docking analysis using PyRx version 0.8 along with AutoDockVina reveals that among the screened phyto compounds, Genistein shows the maximum binding affinity towards the hydrophobic substrate-binding site of TMPRSS2 with three hydrogen bonds interaction ( - 7.5 kcal/mol). On the other hand, molecular docking analysis using Schrodinger identified Quercetin as the most potent phyto compound with a maximum binding affinity towards the hydrophilic catalytic site of TMPRSS2 ( - 7.847 kcal/mol) with three hydrogen bonds interaction. The molecular dynamics simulation reveals that the Quercetin-TMPRSS complex is stable until 50 ns and forms stable interaction with the protein ( - 22.37 kcal/mol of MM-PBSA binding free energy). Genistein creates a weak interaction with the loop residues and hence has an unstable binding and exits from the binding pocket. CONCLUSION: The compounds, Quercetin and Genistein, can inhibit the TMPRSS2 guided priming of the spike protein. The compounds could reduce the interaction of the host cell with the type I transmembrane glycoprotein to prevent the entry of the virus. The critical finding is that compared to Genistein, Quercetin exhibits higher binding affinity with the catalytic unit of TMPRSS2 and forms a stable complex with the target. Thus, enhancing our innate immunity by consuming foods rich in Quercetin and Genistein or developing a novel drug in the combination of Quercetin and Genistein could be the brilliant choices to prevent SARS-Cov-2 infection when we consider the present chaos associated with vaccines and anti-viral medicines.

Synthesis of novel spirobibenzopyrans as potent anticancer leads inducing apoptosis in HeLa cells.

Spirobibenzopyrans are an unexplored class of therapeutics. We report the anticancer activity of novel spirobibenzopyrans, synthesized by a one-pot reaction and extensively characterized. Structure of one of the spirobibenzopyran has been determined by the single crystal XRD technique. The in vitro anticancer activity of these derivatives across the NCI 60-cell line panel was evaluated and for the first time their mechanism of action against HeLa cells was probed via cell morphology analysis and cell cycle analysis. They were determined to be apoptosis inducers with cell cycle arrest in G0/G1 and S phase suggesting CDK-4 protein inhibition and the inhibition of DNA replication. The DNA inhibition was studied and confirmed using the alkaline comet assay for the compound CHX-4MO-SAL showing S phase inhibition. Further, conformity with the in silico Lipinski's score signify the potential of spirobibenzopyrans as anticancer leads.

A Mechanistic Review on Medicinal Mushrooms-Derived Bioactive Compounds: Potential Mycotherapy Candidates for Alleviating Neurological Disorders.

According to the World Health Organization, neurological and neurodegenerative diseases are highly debilitating and pose the greatest threats to public health. Diseases of the nervous system are caused by a particular pathological process that negatively affects the central and peripheral nervous systems. These diseases also lead to the loss of neuronal cell function, which causes alterations in the nervous system structure, resulting in the degeneration or death of nerve cells throughout the body. This causes problems with movement (ataxia) and mental dysfunction (dementia), both of which are commonly observed symptoms in Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Medicinal mushrooms are higher fungi with nutraceutical properties and are low in calories and fat. They are also a rich source of nutrients and bioactive compounds such as carbohydrates, proteins, fibers, and vitamins that have been used in the treatment of many ailments. Medicinal mushrooms such as Pleurotus giganteus, Ganoderma lucidium, and Hericium erinaceus are commonly produced worldwide for use as health supplements and medicine. Medicinal mushrooms and their extracts have a large number of bioactive compounds, such as polysaccharide ß-glucan, or polysaccharide-protein complexes, like lectins, lactones, terpenoids, alkaloids, antibiotics, and metal-chelating agents. This review will focus on the role of the medicinal properties of different medicinal mushrooms that contain bioactive compounds with a protective effect against neuronal dysfunction. This information will facilitate the development of drugs against neurodegenerative diseases.

Bilayer nanostructure coated AZ31 magnesium alloy implants: in vivo reconstruction of critical-sized rabbit femoral segmental bone defect.

Healing or reconstruction of critical-sized bone defects is still challenging in orthopaedic practice. In this study, we developed a new approach to control the degradation and improve the bone regeneration of the AZ31 magnesium substrate, fabricated as mesh cage implants. Subsequently, bilayer nanocomposite coating was carried out using polycaprolactone (PCL) and nano-hydroxyapatite (nHA) by dip-coating and electrospinning. Lastly, the healing capacity of the implants was studied in New Zealand White (NZW) rabbit critical-sized femur bone defects. X-ray analysis showed the coated implant group bridged and healed the critical defects 100% during four weeks of post-implantation. Micro-computed tomography (Micro-CT) study showed higher total bone volume (21.10%), trabecular thickness (0.73), and total porosity (85.71%) with bilayer coated implants than uncoated. Our results showed that nanocomposite coated implants controlled the in vivo degradation and improved bioactivity. Hence, the coated implants can be used as a promising bioresorbable implant for critical segmental bone defect repair applications.

Production and investigation of the physico-chemical properties of MEL-A from glycerol and coconut water.

This work reports the production of MEL-A using coconut water as the carbon source. Proximate analysis of coconut water indicated the presence of nutrients necessary for growth of the organism and production of desired metabolite. The amount of MEL produced using coconut water was 3.85 g/L (± 0.35) with 74% of it being MEL-A when compared to 2.58 g/L (± 0.15) with 60% being MEL-A using glycerol, a conventional carbon source. MEL-A from coconut water consisted of 38.1% long-chain saturated fatty acids (C16:0 and C18:0) whereas with glycerol it was 9.6%. The critical micellar concentration of the biosurfactant from coconut water was 2.32 ± 0.21 µM when compared to 4.41 ± 0.25 µM from glycerol. The stability of O/W emulsion was reduced by 50% and 90% after incubation for 8 h in the case of MEL-A from coconut water and glycerol respectively when compared to synthetic surfactant, Tween-20. MEL-A from both the sources exhibited free radical scavenging activity (DPPH assay) in a dose-dependent manner wherein MEL-A from coconut water showed two fold higher activity than the other. The interaction of coconut water MEL-A with DPPC for drug encapsulation applications was also studied. The DSC measurements showed the differences in the interaction of drugs with DPPC/MEL-A liposome. The differences were also observed in the solubility of drugs after encapsulation with DPPC/MEL-A liposome.

Development of a Next-Generation Fluorescent Turn-On Sensor to Simultaneously Detect and Detoxify Mercury in Living Samples.

Strategies for simultaneous detection and detoxification of Hg2+ using a single sensor from biological and environmental samples are limited and have not been realized in living organisms so far. We report a highly selective, small molecule "turn-on" fluorescent sensor, PYDMSA, based on the cationic dye Pyronin Y (PY) and chelating agent meso-2,3-dimercaptosuccinic acid (DMSA) for the simultaneous detection and detoxification of inorganic mercury (Hg2+). After Hg2+ detection, concomitant detoxification was carried out with sufficient efficacy in living samples, which makes the sensor unique. PYDMSA exhibits high selectivity for Hg2+ over other competing metal ions with an experimental detection limit of ∼300 pM in aqueous buffer solution. When PYDMSA reacts with Hg2+, the CS-C9 bond in the sensor gets cleaved. This results in the "turn-on" response of the fluorescence probe with a concomitant release of one equivalent of water-soluble Hg2+-DMSA complex which leads to a synchronous detoxifying effect. The sensor by itself is nontoxic to cells in culture and has been used to monitor the real-time uptake of Hg2+ in live cells and zebrafish larvae. Thus, PYDMSA is a unique sensor which can be used to detect and detoxify mercury at the same time in living samples.

5-Lipoxygenase as a drug target: A review on trends in inhibitors structural design, SAR and mechanism based approach.

The most common inflammatory disease of the airways is asthma among children affecting around 235 million people worldwide. 5-Lipoxygenase (5-LOX) is a crucial enzyme which helps in the conversion of arachidonic acid (AA) to leukotrienes (LTs), the lipid mediators. It is associated with several inflammation related disorders such as asthma, allergy, and atherosclerosis. Therefore, it is considered as a promising target against inflammation and asthma. Currently, the only drug against 5-LOX which is available is Zileuton, while a few inhibitors are in clinical trial stages such as Atreleuton and Setileuton. So, there is a dire requirement in the area of progress of novel 5-LOX inhibitors which necessitates an understanding of their structure activity relationship and mode of action. In this review, novel 5-LOX inhibitors reported so far, their structural design, SAR and developmental strategies along with clinical updates are discussed over the last two decades.

Design, synthesis and identification of novel coumaperine derivatives for inhibition of human 5-LOX: Antioxidant, pseudoperoxidase and docking studies.

5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors especially, natural product based ones, are highly attractive. Coumaperine, a natural product found in white pepper and its derivatives were herein developed as 5-LOX inhibitors. We have synthesized twenty four derivatives, characterized and evaluated their 5-LOX inhibition potential. Coumaperine derivatives substituted with multiple hydroxy and multiple methoxy groups exhibited best 5-LOX inhibition. CP-209, a catechol type dihydroxyl derivative and CP-262-F2, a vicinal trihydroxyl derivative exhibited, 82.7% and 82.5% inhibition of 5-LOX respectively at 20 µM. Their IC50 values are 2.1 ±â€¯0.2 µM and 2.3 ±â€¯0.2 µM respectively, and are comparable to zileuton, IC50 = 1.4 ±â€¯0.2 µM. CP-155, a methylenedioxy derivative (a natural product) and CP-194, a 2,4,6-trimethoxy derivative showed 76.0% and 77.1% inhibition of 5-LOX respectively at 20 µM. Antioxidant study revealed that CP-209 and 262-F2 (at 20 µM) scavenged DPPH radical by 76.8% and 71.3% respectively. On the other hand, CP-155 and 194 showed very poor DPPH radical scavenging activity. Pseudo peroxidase assay confirmed that the mode of action of CP-209 and 262-F2 were by redox process, similar to zileuton, affecting the oxidation state of the metal ion in the enzyme. On the contrary, CP-155 and 194 probably act through some other mechanism which does not involve the disruption of the oxidation state of the metal in the enzyme. Molecular docking of CP-155 and 194 to the active site of 5-LOX and binding energy calculation suggested that they are non-competitive inhibitors. The In-Silico ADME/TOX analysis shows the active compounds (CP-155, 194, 209 and 262-F2) are with good drug likeliness and reduced toxicity compared to existing drug. These studies indicate that there is a great potential for coumaperine derivatives to be developed as anti-inflammatory drug.

Eggshell derived brushite bone cement with minimal inflammatory response and higher osteoconductive potential.

Brushite cements are known for excellent osteoconductive and degradation properties, however, its widespread use is limited due to rapid setting time and poor mechanical properties. The eggshell derived calcium phosphates exhibits improved physical and biological properties due to the presence of biologically relevant ions. In this study, eggshell derived brushite cement (EB) was fabricated using ß-tricalcium phosphate synthesized from eggshells. The presence of trace elements in EB prolonged its setting time. The size of brushite crystals in EB was found to be smaller than the pure brushite cement (PB) leading to increased initial compressive strength and higher in vitro degradation rate. The L6 and MG63 cell lines exhibited good biocompatibility with the cement at the end 72 h. In vivo studies of the cements were performed in rat calvarial defect model. Micro CT analysis showed faster degradation and accelerated bone formation in EB filled defect. Histological studies revealed infiltration of inflammatory cells into the implant site for both the cements till 6th week. However, inflammation was found to be significantly reduced at the 12th week in EB compared to PB leading to complete bone bridge formation. Multi-ion substituted EB seems to be a potential bone substitute material with a reasonable setting time for ease of handling, higher mechanical strength, minimal inflammatory response and higher bone regeneration.

Structural characterization and applications of a novel polysaccharide produced by Azospirillum lipoferum MTCC 2306.

Azospirillum lipoferum MTCC 2306, a free-living nitrogen fixing bacteria, has a doubling time of 1.7 h in MPSS media. At the end of 28 h at a pH of 7 and temperature of 30 °C it produces 1.8 ± 0.013 g/L biomass and 2.1 ± 0.018 g/L of cyclic beta glucan (CßG) in MPSS medium with a yield coefficient (YP/S) of 2.1. This novel polysaccharide is a water-soluble cyclic biopolymer and is generally produced by Rhizobiaceae and predominantly made up of glucose. The CßG has a degree of polymerisation varying between 10 and 13 and has both α- and ß-glycosidic linkages. It is not substituted with any functional groups such as acetates or succinates. Its ability to bind to aniline blue suggests that it can be a potential candidate for being used as carrier in medical imaging as well as in reducing toxicity of textile effluents. It is able to encapsulate rifampicin, a hydrophobic drug and increase its aqueous solubility by 71%. So, CßG appears to have promising applications in the field of drug, food, cosmetic and nutraceutical industries.

Development of Egg Shell Derived Carbonated Apatite Nanocarrier System for Drug Delivery.

Carbonated apatite has a chemical composition quite similar to biological apatite found in native bone. The incorporation of carbonate (CO2-3) ions groups into the apatitic crystal structure can tailor its crystallinity, solubility and biological activity that benefit the bone repair and regeneration. In this study, we report a simple and elegant method of synthesizing carbonated calcium deficient hydroxyapatite (ECCDHA) nanoparticles from egg shell wastes and its efficacy has been compared with synthetic calcium deficient hydroxyapatite (SCDHA) nanoparticles. Egg shell contains about 94% of calcium carbonate. Fourier transform infrared (FT-IR) spectroscopy results confirmed the carbonate substitution in the apatite as B-type and CHNS/O elemental analysis showed 6 wt.% of carbonate content in ECCDHA. Energy dispersive spectroscopy (EDS) analysis confirmed the presence of biologically relevant elements such as magnesium, strontium, fluoride, potassium etc., in ECCDHA inherited from the egg shell. In vitro cell culture studies confirmed that the ECCDHA is cellular compatible and it has enhanced cell adhesion and proliferation of L6 myoblast cells as compared to SCDHA. The potential of ECCDHA suitable for bone drug applications was tested with an antibiotic drug, doxycycline. The results showed higher drug loading and releasing for ECCDHA as compared to SCDHA during the period of study. Based on these results, the ECCDHA may be considered as a potential bone substitute and drug carrier system.

Phytochemicals as multi-target inhibitors of the inflammatory pathway- A modeling and experimental study.

The arachidonic acid pathway consists of several enzymes and targeting them is favored for developing anti-inflammatory drugs. However, till date the current drugs are generally active against a single target, leading to undesirable side-effects. Phytochemicals are known to inhibit multiple targets simultaneously and hence, an attempt is made here to investigate their suitability. A pharmacophore based study is performed with three sets of reported phytochemicals namely, dual 5-LOX/mPGES1, alkaloids and FLAP inhibitors. The analysis indicated that phenylpropanoids (including ferulic acid) and benzoic acids derivatives, and berberine mapped onto these pharmacophores with three hydrophobic centroids and an acceptor feature. 2,4,5-trimethoxy (7) and 3,4-dimethoxy cinnamic acids (8) mapped onto all the three pharmacophores. Experimental studies indicated that berberine inhibited 5-LOX (100 µM) and PGE2 (50 µM) production by 72.2 and 72.0% and ferulic acid by 74.3 and 54.4% respectively. This approach offers a promising theoretical combined with experimental strategy for designing novel molecules against inflammatory enzymes.

Dentin remineralizing ability and enhanced antibacterial activity of strontium and hydroxyl ion co-releasing radiopaque hydroxyapatite cement.

Dental caries is an infection of the mineralized tooth structures that advances when acid secreted by bacterial action on dietary carbohydrates diffuses and dissolves the tooth mineral leading to demineralization. During treatment, clinicians often remove only the superficial infected tooth structures and retain a part of affected carious dentin to prevent excessive dentin loss and pulp exposure. Calcium hydroxide is used to treat the affected dentin because it is alkaline, induces pulp-dentin remineralization and decreases bacterial infection. Presence of strontium ions has also been reported to exhibit anticariogenic activity, and promote enamel and dentin remineralization. The objective of the present study was to develop novel hydroxyapatite cement from tetracalcium phosphate which gradually releases hydroxyl and strontium ions to exhibit antibacterial activity. Its potential to remineralize the dentin sections collected from extracted human molar tooth was studied in detail. The pH of all the experimental cements exhibited a gradual increase to ~10.5 in 10 days with 10% strontium substituted tetracalcium phosphate cement (10SC) showing the highest pH value which was sustained for 6 weeks. 10SC showed better antibacterial property against S. aureus and E. coli at the end of 1 week compared to other cements studied. It also exhibited the highest radiopacity equivalent to 4.8 mm of Al standard. 10SC treated dentin section showed better remineralization ability and highest elastic modulus. We can conclude that the hydroxyl and strontium ions releasing tetracalcium phosphate cement exhibits good antibacterial property, radiopacity and has the potential to encourage dentin remineralization.

Characterization and biological activities of cyclic (1 → 3, 1 → 6)-ß-glucans from Bradyrhizobium japonicum.

OBJECTIVE: To isolate cyclic (1 â†’ 3, 1 â†’ 6)-ß-glucan from Bradyrhizobium japonicum MTCC120, to characterize its structure and to study its biological activities. RESULTS: The degree of polymerization of cyclic (1 â†’ 3, 1 â†’ 6)-ß-glucan varied between 10 and 13 and with substituents acetyl, succinyl and phosphocholine. The cyclic glucans showed bimodal particle size distribution, with hydrodynamic diameters of 1.92 and 231 nm corresponding to monomeric and aggregated cyclic glucans, respectively. SEM and TEM images showed that the glucans formed aggregates of nanorods. The glucans were biocompatible, exhibited good antioxidant activity and had the abilities to bind to Aniline Blue dye to form a fluorescence complex which was concentration dependent. CONCLUSION: The glucans isolated are cyclic and have good antioxidant activities, hence have potential application in food and pharmaceutical industries. Their dye binding ability could be exploited in medical imaging to reduce the cytotoxicity of the dyes.

Attenuated total reflection fourier transform infrared spectroscopy towards disclosing mechanism of bacterial adhesion on thermally stabilized titanium nano-interfaces.

Titanium is widely used as medical implant material and as condenser material in the nuclear industry where its integrity is questioned due to its susceptibility to bacterial adhesion. A systematic investigation on the influence of thermally (50-800 °C) stabilized titanium (TS-Ti) nano oxide towards bacterial adhesion was carried out. The results showed that below 350 °C significant bacterio-phobicity was observed, while above 500 °C significant affinity towards bacterial cells was recorded. Conventional characterization tools such as HR-TEM and XRD did not provide much insight on the changes occurring on the oxide film with heat treatment, however, attenuated total reflection fourier transform infrared spectroscopy (ATR-FTIR) of the surface showed significant changes in the spectral pattern as a function of increasing heat treatment. It was observed that elevated OH, N-H and C=O groups and rutile titania on the TS-Ti oxide films led to higher affinity for bacterial adhesion. On the other hand low temperature TS-Ti nanooxide films (<350 °C) showed high C-H groups and decreased OH groups on their surface, which possibly contributed towards their bacterio-phobicity. The TS-Ti nanooxide film grown at 50 °C was observed to be the most efficient anti-bacterial adhesion interface, while the 800 °C interface was the one showing highest affinity towards bacterial adhesion. This study confirms the successful application of ATR-FTIR technique for nano-oxide film characterization and towards understanding the variations in bacterial interaction of such nano interfaces.

Synergistic growth of Bacillus and Pseudomonas and its degradation potential on pretreated polypropylene.

This study investigated biodegradation of physically pretreated polypropylene (PP) by using two different combinations of microorganisms, namely, Bacillus flexus + Pseudomonas azotoformans(B1) and B. flexus + B. subtilis(B2), for a period of 12 months. The growth rate of (B1) was found to be high throughout the study period, and reached a maximum of 1 × 10(14) colony-forming units (CFU)/mL. At the end of the experiment, the polymers become hydrophilic. Carbonyl indices showed that ultraviolet (UV)-treated polymers started degrading faster than the thermally treated PP. The thermogravimetric analysis also revealed that UV-treated PP exposed to the B. flexus + P. azotoformans combination for 1 year exhibited maximum degradation (22.7%). The gravimetric weight loss method showed 1.95% weight loss followed by 1.45% with B. flexus + B. subtilis. The changes in the carbonyl indices of the polymer through Fourier-transform infrared (FTIR) analysis also support the degradation.

Biocompatible ι-carrageenan-γ-maghemite nanocomposite for biomedical applications - synthesis, characterization and in vitro anticancer efficacy.

BACKGROUND: Carrageenans are naturally occurring hydrophilic, polyanionic polysaccharide bioploymers with wide application in pharmaceutical industries for controlled drug delivery. Magnetic nanoparticles with their exceptional properties enable them to be an ideal candidate for the production of functional nanostructures, thus facilitating them for biomedical applications. The development of novel nanocomposite by coupling the synergistic effects of the sulfated polysaccharide (iota carrageenan) and a magnetic nanoparticle (maghemite) may offer new interesting applications in drug delivery and cancer therapy. The nanocomposite was characterized by ultraviolet-visible spectroscopy, high resolution scanning electron microscopy, dynamic light scattering analysis, Fourier transform infrared spectroscopy and powder XRD to highlight the possible interaction between the two components. Biocompatibility and the anticancer efficacy of the nanocomposite were assayed and analysed in vitro. RESULTS: Results suggested that iota carrageenans have electrostatically entrapped the maghemite nanoparticles in their sulfate groups. Biocompatibility of the nanocomposite (at different concentrations) against normal cell lines (HEK-293 and L6) was confirmed by MTT assay. Hoechst 33342 and 7-AAD staining studies under fluorescent microscopy revealed that the nanocomposite is able to induce appoptosis as the mode of cell death in human colon cancer cell line (HCT116). Cell apoptosis here is induced by following the ROS-mediated mitochondrial pathway, combined with downregulation of the expression levels of mRNA of XIAP and PARP-1 and upregulation of caspase3, Bcl-2 and Bcl-xL. CONCLUSIONS: This novel nanocomposite is biocompatible with potential properties to serve in magnet aided targeted drug delivery and cancer therapy.

Production of acylated homoserine lactone by a novel marine strain of Proteus vulgaris and inhibition of its swarming by phytochemicals.

A marine strain of Proteus vulgaris capable of activating multiple acylated homoserine lactone (AHL)-based reporter cultures was isolated. The cognate signal molecule was characterized as octanoyl homoserine lactone (OHL) and its production was observed to be growth dependent, with maximum production (5.675 µg l(-1)) at 24 h growth. The strain exhibited swarming, but its motility was not affected upon addition of pure OHL or culture supernatant. Phytochemicals such as quercitin and berberine chloride inhibited OHL production and reduced swarming. FliA, the predominantly upregulated protein during swarming, was considered as a possible target for these inhibitors, and docking of the two most active and two least active inhibitors to this protein suggested preferential binding of the former set of compounds. Apart from adding new evidence to AHL production in Proteus vulgaris, active inhibitors shortlisted from this study could help in identifying lead compounds to act against this opportunistic pathogen of the respiratory and gastrointestinal tract.

Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor α, ß, γ subtypes: an in silico approach.

This exhaustive in silico study looks into the molecular interactions of phthalates and their metabolites with human peroxisome proliferator-activated receptor (hPPAR) and retinoid X receptor (hRXR) α, ß and γ subtypes--the nuclear receptor proteins function as transcription factors by regulating the expression of downstream genes. Apart from the much discussed plasticizer bisphenol A, we examined the binding affinities of 15 common diphthalates and their monophthalates, natural (linoleic acid, conjugated linoleic acid) and synthetic (bezafibrate, pioglitazone, GW 50156) ligands with hPPARs. In addition to these phthalates, specific natural (retinoic and phytanic acids) and synthetic (bexarotene, rosiglitazone) ligands were examined with hRXRs. The Maestro, Schrödinger Suite 2012 was used for the molecular docking study. In general, natural ligands of hPPAR showed less binding efficiencies than phthalic acid esters and drugs. The diphthalate di-iso-decyl phthalate showed the highest G score (-9.99) with hPPAR (γ), while its monophthalate (mono-iso-decyl phthalate) showed a comparatively less G score (-9.56). Though the PPAR modulator GW 50156 showed strong affinity with all hPPAR subtypes, its highest G score (-12.43) was with hPPARß. Hazardous di(2-ethylhexyl)phthalate generally showed a greater preference to hRXRs than hPPARs, but its highest G score (-10.87) was with hRXRα; while its monophthalate (Mono(2-ethylhexyl)phthalate) showed a lesser G score (-8.59). The drug bexarotene showed the highest G score (-13.32) with hRXRß. Moreover, bisphenol A showed more affinity towards hRXR. Briefly, this study gives an overview on the preference of phthalic acid esters, natural and synthetic ligands on to hPPAR and hRXR subtypes, which would lead to further in vitro mechanistic as well as in vivo preclinical and clinical studies.