Inhibition Of Biosynthesis Research Articles

Caffeic acid phenethyl ester analogues as selective inhibitors of 12-lipoxygenase product biosynthesis in human platelets.

The inflammatory response is an essential process for the host defence against pathogens. Lipid mediators are important in coordinating the pro-inflammatory and pro-resolution phases of the inflammatory process. However, unregulated production of these mediators has been associated with chronic inflammatory diseases such as arthritis, asthma, cardiovascular diseases, and several types of cancer. Therefore, it is not surprising that enzymes implicated in the production of these lipid mediators have been targeted for potential therapeutic approaches. Amongst these inflammatory molecules, the 12-hydroxyeicosatetraenoic acid (12(S)-HETE) is abundantly produced in several diseases and is primarily biosynthesized via the platelet's 12-lipoxygenase (12-LO) pathway. To this day, very few compounds selectively inhibit the 12-LO pathway, and most importantly, none are currently used in the clinical settings. In this study, we investigated a series of polyphenol analogues of natural polyphenols that inhibit the 12-LO pathway in human platelets without affecting other normal functions of the cell. Using an ex vivo approach, we found one compound that selectively inhibited the 12-LO pathway, with IC50 values as low as 0.11µM, with minimal inhibition of other lipoxygenase or cyclooxygenase pathways. More importantly, our data show that none of the compounds tested induced significant off-target effects on either the platelet's activation or its viability. In the continuous search for specific and better inhibitors targeting the regulation of inflammation, we characterized two novel inhibitors of the 12-LO pathway that could be promising for subsequent in vivo studies.

The effects of daptomycin on cell wall biosynthesis in Enterococcal faecalis

Daptomycin is a cyclic lipodepsipeptide antibiotic reserved for the treatment of serious infections by multidrug-resistant Gram-positive pathogens. Its mode of action is considered to be multifaceted, encompassing the targeting and depolarization of bacterial cell membranes, alongside the inhibition of cell wall biosynthesis. To characterize the daptomycin mode of action, 15N cross-polarization at magic-angle spinning NMR measurements were performed on intact whole cells of Staphylococcus aureus grown in the presence of a sub-inhibitory concentration of daptomycin in a chemically defined media containing l-[ϵ-15N]Lys. Daptomycin-treated cells showed a reduction in the lysyl-ε-amide intensity that was consistent with cell wall thinning. However, the reduced lysyl-ε-amine intensity at 10 ppm indicated that the daptomycin-treated cells did not accumulate in Park’s nucleotide, the cytoplasmic peptidoglycan (PG) precursor. Consequently, daptomycin did not inhibit the transglycosylation step of PG biosynthesis. To further elucidate the daptomycin mode of action, the PG composition of daptomycin-susceptible Enterococcus faecalis grown in the presence of daptomycin was analyzed using liquid chromatography-mass spectrometry. Sixty-nine muropeptide ions correspond to PG with varying degrees of modifications including crosslinking, acetylation, alanylation, and 1,6-anhydrous ring formation at MurNAc were quantified. Analysis showed that the cell walls of daptomycin-treated E. faecalis had a significant reduction in PG crosslinking which was accompanied by an increase in lytic transglycosylase activities and a decrease in PG-stem modifications by the carboxypeptidases. The changes in PG composition suggest that daptomycin inhibits cell wall biosynthesis by impeding the incorporation of nascent PG into the cell walls by transpeptidases and maturation by carboxypeptidases. As a result, the newly formed cell walls become highly susceptible to degradation by the autolysins, resulting in thinning of the cell wall.

Angelica archangelica essential oil loaded chitosan nanoemulsion as edible coating for preservation of table grape fruit against Botrytis cinerea contamination and storage quality deterioration

The present study deals with the encapsulation of Angelica archangelica essential oil into chitosan nanoemulsion (AAEO-NE) and evaluation of its effectiveness as novel coating agent with innovative controlled release delivery system for protection of table grape (Vitis vinifera L.) fruit against Botrytis cinerea contamination, and quality deterioration over 30 d of storage (25 ± 2 °C, Relative humidity 85%). The AAEO-NE was characterized through dynamic light scattering (DLS), scanning electron microscopy (SEM), and atomic force microscopy (AFM). The mean particle size was tended to increase from 53.69 to 98.63 nm, while ζ-potential was decreased from + 32.3 to + 23.5 mV. Fourier transform infrared spectroscopy (FTIR), and X-ray diffractometry (XRD) analyses suggested intermolecular interaction followed by effective encompassment of AAEO into chitosan nanomatrix. In vitro release study confirmed the biphasic and controlled delivery of AAEO, essentially required for its long term effectiveness in view of maintaining postharvest quality of the treated fruit. The antifungal efficacy of unencapsulated AAEO against B. cinerea was found as 5.5 g L−1, and noticed to be enhanced (2.5 g L−1) after encapsulation into chitosan nanoemulsion. The inhibition of ergosterol biosynthesis followed by subsequent enhancement of ions leakage after treatment of B. cinerea cells with AAEO-NE suggested plasma membrane as major site of antifungal activity. During in vivo investigation, AAEO-NE coating inhibited the contamination of B. cinerea and maintained the quality attributes like weight, titrable acidity, total soluble solids, phenolic content, and pH of table grape fruit. Additionally, the preservation of enzymatic antioxidants, reduced respiration rate, and better sensory qualities of coated table grape fruit recommend the functional potentiality of chitosan as biocompatible wall matrix to encapsulate AAEO and application as novel nano-green smart coating based fungitoxicant and shelf-life enhancer in fruit and agricultural industries.

THE INFLUENCE OF MEDICINAL AND AROMATIC PLANTS EXTRACTS ON THE ANTIFUNGAL EFFECT OF FLUCONAZOLE REGARDING C. ALBICANS AND C. TROPICALIS ISOLATED FROM PATIENTS WITH DENTURE STOMATITS

Candida albicans is one of the most common and virulent representatives of Candida fungi which causes fungal lesions of the mucous membranes predominantly in people with compromised immune system. Candida resistance to classical antifungals such as polyenes, azoles, allylamines is a serious practical problem. Imidazole and triazole are the most commonly used antifungal agents for candidiasis today. Their mechanism of action lies in the inhibition of ergosterol biosynthesis which is indispensable for maintaining the structural integrity of fungal cell membranes. Activation of elimination systems is often associated with changes in the structure of fungal membranes, leading to a decrease in the supply of azoles into the fungal cell Screening of antifungal activity and synergism of antifungal activity of 166 aqueous-ethanol plant extracts with Fluconazole in relation to 2 clinical strains of Candida fungi (C.) (C. albicans and C. tropicalis) with different mechanisms of azole resistance isolated from patients with prosthetic stomatitis was conducted by means of agar diffusion method. The expressed direct antifungal activity of extracts of Calendula officinalis L. inflorescences, flowers of Limonium platyphyllum Lincz., flowers of Grataegus monogyna Jacq., roots of Potentilla repens L., the grass of Melilotus albus Medik, leaves of Peucedanum ruthenicum Bieb, leaves of Rhus coriaria L. and aerial part of Polythridum commune Hedw was determined in reference to the tested strains. Synergism of antifungal action with 1/4, 1/8 and 1/32 of Fluconazole MIC (minimal inhibiting concentration) in relation to both test strains of yeast-like Candida fungi was demonstrated by the flowers of Calendula officinalis L, aerial part of Melilotus albus Medik. The main purpose of the screening was to discriminate extracts in order to select those that would be promising for further testing by a more accurate сheckerboard titration method. The efflux mechanism of resistance to triazoles (in C. tropicalis test strain) is more susceptible to modification by biologically active compounds of medicinal plants. Regarding C. albicans test strain which combines the efflux mechanism of resistance with mutation(s) of ergosterol biosynthesis enzymes, the modifying effect of plant extracts is much less frequent and less pronounced. Therefore, it may be assumed that mutations of ergosterol biosynthesis enzymes provide high stability of the phenotypic manifestation of Candida azole resistance. Should that be the case, determining the azole resistance mechanism of Candida clinical isolates may be important for clinical practice. Combination therapy is more beneficial than monotherapy because it may provide more effective destruction or suppression of pathogens. The combined action of synergistic agents is quite easy to achieve in case of localized superficial lesions (which occur on the mucous membranes of the prosthetic bed in candidal prosthetic stomatitis): for example, using a systemic antifungal agent and a topical agent that contains a modifier of resistance of plant origin fungi. Synergistic interactions will increase the therapeutic efficacy of drugs, reduce the likelihood of resistance occurrence or further development, and will reduce dose-related toxicity.

A role of splenic heme biosynthesis pathway in the persistent prophylactic actions of arketamine in lipopolysaccharide-treated mice

Relapse is common in remitted patients with major depressive disorder (MDD). Arketamine, an (R)-enantiomer of ketamine, has persistent prophylactic actions in an inflammatory model of depression. However, the precise mechanisms underlying these prophylactic actions remain unknown. Given the role of the brain–spleen axis in depression, we sought to identify splenic molecular targets that play a role in the prophylactic actions of arketamine. Lipopolysaccharide (LPS) (1.0 mg/kg) was administered 6 days after a single injection of arketamine (10 mg/kg) or saline. RNA-sequencing analysis found altered expression in the heme biosynthesis II pathway. Quantitative RT-PCR revealed that pretreatment with arketamine blocked increased expression of genes involved in the heme biosynthesis II pathway in LPS-treated mice, namely, 5-aminolevulinase synthase 2 (Alas2), ferrochelatase (Fech), hydroxymethylbilane synthase (Hmbs). Interestingly, there were positive correlations between the expression of these genes and spleen weight or plasma levels of pro-inflammatory cytokines. We also found higher expression of ALAS2 and FECH in the spleen from MDD patients. Pretreatment with a key intermediate precursor of heme, 5-aminolaevulinic acid (300 mg/kg/day for 3 days), caused splenomegaly, higher plasma levels of pro-inflammatory cytokines, and depression-like behavior in low-dose LPS (0.1 mg/kg)-treated mice. Interestingly, pretreatment with a heme biosynthesis inhibitor, succinyl acetone (120 mg/kg/day for 3 days), had prophylactic effects in LPS (1.0 mg/kg)-treated mice. These data suggest a novel role for the heme biosynthesis II pathway in the spleen for inflammation-related depression. Therefore, the heme biosynthesis pathway could be a new target for the prevention of relapse in MDD patients.

Methyl jasmonate‐dependent hydrogen sulfide mediates melatonin‐induced aphid resistance of watermelon

AbstractAs one of the most destructive pests, aphids cause significant damage on various agricultural and horticultural crops. Recently, melatonin has been shown to enhance plant resistance to aphids; however, the underlying mechanisms remain unclear. In this study, our results showed that melatonin, MeJA, and H2S enhanced aphid resistance of watermelon in a dose‐dependent manner, accompanied by increases in the defense‐related enzyme activities and lignin accumulation. On the plants pretreated with 100 μM melatonin, 100 μM MeJA, and 50 μM NaHS, the numbers of aphids were 86.0%, 59.6%, and 47.9% lower than that on control plants, respectively, after aphid infestation for 7 days. Melatonin application induced MeJA and H2S accumulation in response to aphid infestation, while inhibition of MeJA and H2S accumulation attenuated or abolished melatonin‐induced defense response and aphid resistance, suggestive of the involvement of MeJA and H2S in melatonin‐induced aphid resistance. MeJA also increased H2S accumulation, but inhibition of MeJA biosynthesis prevented melatonin‐enhanced H2S accumulation, suggesting that MeJA mediates melatonin‐induced H2S accumulation. Furthermore, inhibition of H2S production attenuated MeJA‐induced defense response and aphid resistance. Taken together, the current study reveals a novel mechanism in which MeJA‐dependent H2S signaling is involved in melatonin‐induced defense response and subsequent aphid resistance. The increasing concern to minimize the use of pesticides and to switch onto sustainable and natural control strategies indicates the great exploitation of such a mechanism in combating aphids.

Molecular pharmacology of coenzyme Q10 in the context of treatment of hyperlipidemic conditions

Background. Therapy of hyperlipidemia with synthetic statin drugs is characterized by a number of side effects. In particular, statin-dependent myopathy occurs as a result of statin inhibition of biosynthesis of cofactor coenzyme Q10 (CoQ10), which plays a central role in the electron transport chains during adenosine triphosphate (ATP) synthesis in mitochondria.Objective: systematic analysis of scientific publications on CoQ10 pharmacology with an emphasis on its effect on the lipid profile.Material and methods. The analysis included 16,788 articles found by “coenzyme Q10 OR ubiquinone" query in the PubMed/MEDLINE biomedical publications database. Topological and metric big data analysis methods were used developed in the scientific school of Academician of the Russian Academy of Sciences Yu.I. Zhuravlev.Results. A much wider range of CoQ10 pharmacological effects was established than simply supporting ATP biosynthesis. Coenzyme Q10 exhibits pronounced lipid-lowering, anti-asthenic, and anti-inflammatory effects and can be successfully used in the treatment of asthenic conditions, cardiovascular pathology (including hyperlipidemia and statin-induced myopathy), carbohydrate metabolism disorders (insulin resistance), and diverse neurological diseases. CoQ10 supplements reduce mortality by 50% in patients with cardiovascular diseases, improve glycemic control in insulin resistance, kidney function, and are useful in the treatment of migraine and neurodegenerative pathologies (Parkinson's disease, etc.).Conclusion. Experimental data and evidence base indicate the potential of using CoQ10 in patients with hyperlipidemia and other cardiovascular system diseases.

PLX4032 resistance of patient-derived melanoma cells: crucial role of oxidative metabolism.

Malignant melanoma is the most lethal form of skin cancer which shows BRAF mutation in 50% of patients. In this context, the identification of BRAFV600E mutation led to the development of specific inhibitors like PLX4032. Nevertheless, although its initial success, its clinical efficacy is reduced after six-months of therapy leading to cancer relapse due to the onset of drug resistance. Therefore, investigating the mechanisms underlying PLX4032 resistance is fundamental to improve therapy efficacy. In this context, several models of PLX4032 resistance have been developed, but the discrepancy between in vitro and in vivo results often limits their clinical translation. The herein reported model has been realized by treating with PLX4032, for six months, patient-derived BRAF-mutated melanoma cells in order to obtain a reliable model of acquired PLX4032 resistance that could be predictive of patient's treatment responses. Metabolic analyses were performed by evaluating glucose consumption, ATP synthesis, oxygen consumption rate, P/O ratio, ATP/AMP ratio, lactate release, lactate dehydrogenase activity, NAD+/NADH ratio and pyruvate dehydrogenase activity in parental and drug resistant melanoma cells. The intracellular oxidative state was analyzed in terms of reactive oxygen species production, glutathione levels and NADPH/NADP+ ratio. In addition, a principal component analysis was conducted in order to identify the variables responsible for the acquisition of targeted therapy resistance. Collectively, our results demonstrate, for the first time in patient-derived melanoma cells, that the rewiring of oxidative phosphorylation and the maintenance of pyruvate dehydrogenase activity and of high glutathione levels contribute to trigger the onset of PLX4032 resistance. Therefore, it is possible to hypothesize that inhibitors of glutathione biosynthesis and/or pyruvate dehydrogenase activity could be used in combination with PLX4032 to overcome drug resistance of BRAF-mutated melanoma patients. However, the identification of new adjuvant targets related to drug-induced metabolic reprogramming could be crucial to counteract the failure of targeted therapy in metastatic melanoma.

Streptomyces tetracycline’s computational behavior against polyketide synthase of aflatoxigenic fungi

produces a variety of bioactive compounds that prevent fungal growth, including aflatoxins. Aflatoxigenic fungi ( and ) are being researched concerning spp. and can prevent the spread of aflatoxins-producing fungi. Aflatoxin-degrading enzymes, which can convert poisonous aflatoxins into less dangerous compounds, are also produced by spp. The processes through which these microorganisms can be used to reduce aflatoxins in food and agricultural systems are still the subject of active research. To evaluate the novelty of tetracycline against the biosynthesis of aflatoxin in aflatoxigenic fungi via computational approach. In this study, we performed molecular docking of polyketide synthase (Pks-A), an enzyme that initiates aflatoxin biosynthesis using tetracycline, using the online SeamDock server. Our results showed that tetracycline had a strong affinity for Pks-A in the binding pocket. The binding energy of tetracycline was -12.7 kcal/mol, indicating a strong binding affinity between the two molecules. Furthermore, the binding site was located in the active site, which is a conserved region in Pks-A and is essential for catalysing the formation of aflatoxin. The results of our docking study suggest that tetracycline may be an effective inhibitor of aflatoxin biosynthesis.

Art2 mediates selective endocytosis of methionine transporters during adaptation to sphingolipid depletion.

Accumulating evidence in several model organisms indicates that reduced sphingolipid biosynthesis promotes longevity, although underlying mechanisms remain unclear. In yeast, sphingolipid depletion induces a state resembling amino acid restriction, which we hypothesized may be due to altered stability of amino acid transporters at the plasma membrane. To test this, we measured surface abundance for a diverse panel of membrane proteins in the presence of myriocin, a sphingolipid biosynthesis inhibitor. Unexpectedly, we found that surface levels of most proteins examined were either unaffected or increased during myriocin treatment, consistent with an observed decrease in bulk endocytosis. In contrast, sphingolipid depletion triggered selective endocytosis of the methionine transporter Mup1. Unlike methionine-induced Mup1 endocytosis, myriocin triggers Mup1 endocytosis that requires the Rsp5 adaptor Art2, C-terminal lysine residues, and the formation of K63-linked ubiquitin polymers. These findings reveal cellular adaptation to sphingolipid depletion by ubiquitin-mediated remodeling of nutrient transporter composition at the cell surface.

Impaired biosynthesis of ergosterol confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin A in a PDR16-dependent manner

Complex sphingolipids and sterols are coordinately involved in various cellular functions, e.g. the formation of lipid microdomains. Here we found that budding yeast exhibits resistance to an antifungal drug, aureobasidin A (AbA), an inhibitor of Aur1 catalyzing the synthesis of inositolphosphorylceramide, under impaired biosynthesis of ergosterol, which includes deletion of ERG6, ERG2, or ERG5 involved in the final stages of the ergosterol biosynthesis pathway or miconazole; however, these defects of ergosterol biosynthesis did not confer resistance against repression of expression of AUR1 by a tetracycline-regulatable promoter. The deletion of ERG6, which confers strong resistance to AbA, results in suppression of a reduction in complex sphingolipids and accumulation of ceramides on AbA treatment, indicating that the deletion reduces the effectiveness of AbA against in vivo Aur1 activity. Previously, we reported that a similar effect to AbA sensitivity was observed when PDR16 or PDR17 was overexpressed. It was found that the effect of the impaired biosynthesis of ergosterol on the AbA sensitivity is completely abolished on deletion of PDR16. In addition, an increase in the expression level of Pdr16 was observed on the deletion of ERG6. These results suggested that abnormal ergosterol biosynthesis confers resistance to AbA in a PDR16-dependent manner, implying a novel functional relationship between complex sphingolipids and ergosterol.

Cellular Responses and Targets in Food Spoilage Yeasts Exposed to Antifungal Prenylated Isoflavonoids.

Prenylated isoflavonoids are phytochemicals with promising antifungal properties. Recently, it was shown that glabridin and wighteone disrupted the plasma membrane (PM) of the food spoilage yeast Zygosaccharomyces parabailii in distinct ways, which led us to investigate further their modes of action (MoA). Transcriptomic profiling with Z. parabailii showed that genes encoding transmembrane ATPase transporters, including Yor1, and genes homologous to the pleiotropic drug resistance (PDR) subfamily in Saccharomyces cerevisiae were upregulated in response to both compounds. Gene functions involved in fatty acid and lipid metabolism, proteostasis, and DNA replication processes were overrepresented among genes upregulated by glabridin and/or wighteone. Chemogenomic analysis using the genome-wide deletant collection for S. cerevisiae further suggested an important role for PM lipids and PM proteins. Deletants of gene functions involved in biosynthesis of very-long-chain fatty acids (constituents of PM sphingolipids) and ergosterol were hypersensitive to both compounds. Using lipid biosynthesis inhibitors, we corroborated roles for sphingolipids and ergosterol in prenylated isoflavonoid action. The PM ABC transporter Yor1 and Lem3-dependent flippases conferred sensitivity and resistance, respectively, to the compounds, suggesting an important role for PM phospholipid asymmetry in their MoAs. Impaired tryptophan availability, likely linked to perturbation of the PM tryptophan permease Tat2, was evident in response to glabridin. Finally, substantial evidence highlighted a role of the endoplasmic reticulum (ER) in cellular responses to wighteone, including gene functions associated with ER membrane stress or with phospholipid biosynthesis, the primary lipid of the ER membrane. IMPORTANCE Preservatives, such as sorbic acid and benzoic acid, inhibit the growth of undesirable yeast and molds in foods. Unfortunately, preservative tolerance and resistance in food spoilage yeast, such as Zygosaccharomyces parabailii, is a growing challenge in the food industry, which can compromise food safety and increase food waste. Prenylated isoflavonoids are the main defense phytochemicals in the Fabaceae family. Glabridin and wighteone belong to this group of compounds and have shown potent antifungal activity against food spoilage yeasts. The present study demonstrated the mode of action of these compounds against food spoilage yeasts by using advanced molecular tools. Overall, the cellular actions of these two prenylated isoflavonoids share similarities (at the level of the plasma membrane) but also differences. Tryptophan import was specifically affected by glabridin, whereas endoplasmic reticulum membrane stress was specifically induced by wighteone. Understanding the mode of action of these novel antifungal agents is essential for their application in food preservation.

New insights into the therapeutic potentials of statins in cancer.

The widespread clinical use of statins has contributed to significant reductions of cardiovascular morbidity and mortality. Increasing preclinical and epidemiological evidences have revealed that dyslipidemia is an important risk factor for carcinogenesis, invasion and metastasis, and that statins as powerful inhibitor of HMG-CoA reductase can exert prevention and intervention effects on cancers, and promote sensitivity to anti-cancer drugs. The anti-cancer mechanisms of statins include not only inhibition of cholesterol biosynthesis, but also their pleiotropic effects in modulating angiogenesis, apoptosis, autophagy, tumor metastasis, and tumor microenvironment. Moreover, recent clinical studies have provided growing insights into the therapeutic potentials of statins and the feasibility of combining statins with other anti-cancer agents. Here, we provide an updated review on the application potential of statins in cancer prevention and treatment and summarize the underneath mechanisms, with focuses on data from clinical studies.

Regulation mechanism of lipids for extracellular yellow pigments production by Monascus purpureus BWY-5.

The biosynthesis and secretion of Monascus pigments are closely related to the integrity of the cell membrane, which determines the composition of lipids and its content in cell membrane. The present study aimed to thoroughly describe the changes of lipid profiling in Monascus purpureus BWY-5, which was screened by carbon ion beam irradiation (12C6+) to almost single yield extracellular Monascus yellow pigments (extra-MYPs), by absolute quantitative lipidomics and tandem mass tags (TMT) based quantitative proteomic. 12C6+ irradiation caused non-lipid oxidation damage to Monascus cell membrane, leading to an imbalance in cell membrane lipid homeostasis. This imbalance was attributed to significant changes not only in the composition but also in the content of lipids in Monascus, especially the inhibition of glycerophospholipid biosynthesis. Integrity of plasma membrane was maintained by the increased production of ergosterol, monogalactosylmonoacylglycerol (MGMG) and sulfoquinovosylmonoacylglycerol (SQMG), while mitochondrial membrane homeostasis was maintained by the increase of cardiolipin production. The growth and extra-MYPs production of Monascus BWY-5 have been regulated by the promotion of sphingolipids (ceramide and sulfatide) biosynthesis. Simultaneous, energy homeostasis may be achieved by increase of TG synthesis and Ca2+/Mg2+-ATPase activity. These finding suggest ergosterol, cardiolipin, sphingolipids, MGMG and SQMG play a key facilitating role in cytomembrane lipid homeostasis maintaining for Monascus purpureus BWY-5, and then it is closely related to cell growth and extra-MYPs production. KEY POINTS: 1. Energy homeostasis in Monascus purpureus BWY-5 was achieved by increase of TG synthesis and Ca2+/Mg2+-ATPase activity. 2. Integrity of plasma membrane in Monascus purpureus BWY-5 was maintained by the increased production of ergosterol. 3. Mitochondrial membrane homeostasis in Monascus purpureus BWY-5 was maintaed by the increase of cardiolipin synthesis.

Bacillus licheniformis: A Producer of Antimicrobial Substances, including Antimycobacterials, Which Are Feasible for Medical Applications.

Bacillus licheniformis produces several classes of antimicrobial substances, including bacteriocins, which are peptides or proteins with different structural composition and molecular mass: ribosomally synthesized by bacteria (1.4-20 kDa), non-ribosomally synthesized peptides and cyclic lipopeptides (0.8-42 kDa) and exopolysaccharides (>1000 kDa). Different bacteriocins act against Gram-positive or Gram-negative bacteria, fungal pathogens and amoeba cells. The main mechanisms of bacteriocin lytic activity include interaction of peptides with membranes of target cells resulting in structural alterations, pore-forming, and inhibition of cell wall biosynthesis. DNase and RNase activity for some bacteriocines are also postulated. Non-ribosomal peptides are synthesized by special non-ribosomal multimodular peptide synthetases and contain unnatural amino acids or fatty acids. Their harmful effect is due to their ability to form pores in biological membranes, destabilize lipid packaging, and disrupt the peptidoglycan layer. Lipopeptides, as biosurfactants, are able to destroy bacterial biofilms. Secreted polysaccharides are high molecular weight compounds, composed of repeated units of sugar moieties attached to a carrier lipid. Their antagonistic action was revealed in relation to bacteria, viruses, and fungi. Exopolysaccharides also inhibit the formation of biofilms by pathogenic bacteria and prevent their colonization on various surfaces. However, mechanism of the harmful effect for many secreted antibacterial substances remains unknown. The antimicrobial activity for most substances has been studied in vitro only, but some substances have been characterized in vivo and they have found practical applications in medicine and veterinary. The cyclic lipopeptides that have surfactant properties are used in some industries. In this review, special attention is paid to the antimycobacterials produced by B. licheniformis as a possible approach to combat multidrug-resistant and latent tuberculosis. In particular, licheniformins and bacitracins have shown strong antimycobacterial activity. However, the medical application of some antibacterials with promising in vitro antimycobacterial activity has been limited by their toxicity to animals and humans. As such, similar to the enhancement in the antimycobacterial activity of natural bacteriocins achieved using genetic engineering, the reduction in toxicity using the same approach appears feasible. The unique capability of B. licheniformis to synthesize and produce a range of different antibacterial compounds means that this organism can act as a natural universal vehicle for antibiotic substances in the form of probiotic cultures and strains to combat various types of pathogens, including mycobacteria.

Arabidopsis-expressing lysine-null SUMO1 reveals a non-essential role for secondary SUMO modifications in plants.

The reversible conjugation of small ubiquitin-like modifier (SUMO) to other proteins has pervasive roles in various aspects of plant development and stress defense through its selective attachment to numerous intracellular substrates. An intriguing aspect of SUMO is that it can be further modified by SUMOylation and ubiquitylation, which isopeptide-link either or both polypeptides to internal lysines within previously bound SUMOs. Although detectable by mass spectrometry, the functions of these secondary modifications remain obscure. Here, we generated transgenic Arabidopsis that replaced the two related and essential SUMO isoforms (SUMO1 and SUMO2) with a lysine-null SUMO1 variant (K0) immune to further SUMOylation/ubiquitylation at these residues. Remarkably, homozygous SUMO1(K0) sumo1 sumo2 plants developed normally, were not hypersensitive to heat stress, and have nearly unaltered SUMOylation profiles during heat shock. However, subtle changes in tolerance to salt, paraquat, and the DNA-damaging agents bleomycin and methane methylsulfonate were evident, as were increased sensitivities to ABA and the gibberellic acid biosynthesis inhibitor paclobutrazol, suggesting roles for these secondary modifications in stress defense, DNA repair, and hormone signaling. We also generated viable sumo1 sumo2 lines expressing a SUMO1(K0) variant specifically designed to help isolate SUMO conjugates and map SUMOylation sites, thus offering a new tool for investigating SUMO in planta.

Investigating the Vital Role of the Identified Abietic Acid from Helianthus annuus L. Calathide Extract against Hyperuricemia via Human Embryonic Kidney 293T Cell Model.

To explore the anti-hyperuricemia components in sunflower (Helianthus annuus L.) calathide extract (SCE), we identified abietic acid (AA) via liquid chromatography-mass spectrometry and found an excellent inhibitor of xanthine oxidase (IC50 = 10.60 µM, Ki = 193.65 nM) without cytotoxicity. Based on the transcriptomics analysis of the human embryonic kidney 293T cell model established using 1 mM uric acid, we evaluated that AA showed opposite modulation of purine metabolism to the UA group and markedly suppressed the intensity of purine nucleoside phosphorylase, ribose phosphate pyrophosphokinase 2, and ribose 5-phosphate isomerase A. Molecular docking also reveals the inhibition of purine nucleoside phosphorylase and ribose phosphate pyrophosphokinase 1. The SCE exhibits similar regulation of these genes, so we conclude that AA was a promising component in SCE against hyperuricemia. This present study provided a novel cell model for screening anti-hyperuricemia natural drugs in vitro and illustrated that AA, a natural diterpenoid, is a potential inhibitor of purine biosynthesis or metabolism.

Profile of cotton flavonoids: Their composition and important roles in development and adaptation to adverse environments

Cotton is a commercial crop that is cultivated in more than 50 countries. The production of cotton has severely diminished in recent years owing to adverse environments. Thus, it is a high priority of the cotton industry to produce resistant cultivars to prevent diminished cotton yields and quality. Flavonoids comprise one of the most important groups of phenolic metabolites in plants. However, the advantage and biological roles of flavonoids in cotton have yet not been studied in depth. In this study, we performed a widely targeted metabolic study and identified 190 flavonoids in cotton leaves that span seven different classes with flavones and flavonols as the dominant groups. Furthermore, flavanone-3-hydroxylase was cloned and silenced to knock down flavonoid production. The results show that the inhibition of flavonoid biosynthesis affects the growth and development of cotton and causes semi-dwarfing in cotton seedlings. We also revealed that the flavonoids contribute to cotton defense against ultraviolet radiation and Verticillium dahliae. Moreover, we discuss the promising role of flavonoids in cotton development and defense against biotic and abiotic stresses. This study provides valuable information to study the variety and biological functions of flavonoids in cotton and will help to profile the advantages of flavonoids in cotton breeding.

Novel thiazolopyridine derivatives of diflapolin as dual sEH/FLAP inhibitors with improved solubility

Inflammatory responses are orchestrated by a plethora of lipid mediators, and perturbations of their biosynthesis or degradation hinder resolution and lead to uncontrolled inflammation, which contributes to diverse pathologies. Small molecules that induce a switch from pro-inflammatory to anti-inflammatory lipid mediators are considered valuable for the treatment of chronic inflammatory diseases. Commonly used non-steroidal anti-inflammatory drugs (NSAIDs) are afflicted with side effects caused by the inhibition of beneficial prostanoid formation and redirection of arachidonic acid (AA) into alternative pathways. Multi-target inhibitors like diflapolin, the first dual inhibitor of soluble epoxide hydrolase (sEH) and 5-lipoxygenase-activating protein (FLAP), promise improved efficacy and safety but are confronted by poor solubility and bioavailability. Four series of derivatives bearing isomeric thiazolopyridines as bioisosteric replacement of the benzothiazole core and two series additionally containing mono- or diaza-isosteres of the phenylene spacer were designed and synthesized to improve solubility. The combination of thiazolo[5,4-b]pyridine, a pyridinylen spacer and a 3,5-Cl2-substituted terminal phenyl ring (46a) enhances solubility and FLAP antagonism, while preserving sEH inhibition. Moreover, the thiazolo[4,5-c]pyridine derivative 41b, although being a less potent sEH/FLAP inhibitor, additionally decreases thromboxane production in activated human peripheral blood mononuclear cells. We conclude that the introduction of nitrogen, depending on the position, not only enhances solubility and FLAP antagonism (46a), but also represents a valid strategy to expand the scope of application towards inhibition of thromboxane biosynthesis.

Effect of prohexadione-calcium onphotosynthetic and yield parameters in basmati rice (Oryza sativa L.) against lodging stress

Basmati rice cultivators with longer internodes and shallow rooting system are prone to lodging especially during panicle development thus ultimately reducing yield, quality as well as efficiency of mechanical harvesting.Manipulation of GA status both via using exogenous application of GA or use of GA biosynthesis inhibitors or either by genetic alteration are regularly used to optimize plant growth and yields. Keeping this in mind the main objective of the study was to assess the role of Prohexadione-calcium (Pro-Ca) to reduce internode elongation against lodging stress without negatively affecting its productivity. A field experiment was conducted on three cultivars of basmati rice (Punjab Basmati 2, Punjab Basmati 3 and Pusa Basmati 1121) in split plot design at three concentration levels (foliar application) of Pro-Ca @5,10 and 20mg/l at vegetative and anthesis stage. Pro-Ca was found to uphill the concentrations of total chlorophyll (~9%)and Carotenoid(~4%) content in leaves at both vegetative and anthesis stages. An increment in the photosynthetic rate in flag leaf was also recorded in Pro-Ca treated sets in comparison to control, A significant increase in sucrose content in fully expanded leaf at vegetative and flag leaf at anthesis stage was recorded.Plant height significantly decreased in Pro-Ca treated plants and this decrease in height was recorded more with increased concentration of Pro-Ca. The increase in the yield contributing parameters viz., number of spikes/plant and grain/m2might be attributed to the blockage of gibberellins synthesis on account of Pro-Ca applicationin selected basmati rice variety PUSA 1121 by upregulating the photosynthetic rate (2%) andalso increase in sucrose content(2 to 18%).