Enzymatic Synthesis and Antimicrobial Activity of Oligomer Analogues of Medicinal Biopolymers from Comfrey and Other Species of the Boraginaceae Family

This study reports the first enzymatic synthesis leading to several oligomer analogues of poly[3-(3,4-dihydroxyphenyl)glyceric acid]. This biopolymer, extracted from plants of the Boraginaceae family has shown a wide spectrum of pharmacological properties, including antimicrobial activity. Enzymatic ring opening polymerization of 2-methoxycarbonyl-3-(3,4-dibenzyloxyphenyl)oxirane (MDBPO) using lipase from Candida rugosa leads to formation of poly[2-methoxycarbonyl-3-(3,4-dibenzyloxyphenyl)oxirane] (PMDBPO), with a degree of polymerization up to 5. Catalytic debenzylation of PMDBPO using H2 on Pd/C yields poly[2-methoxycarbonyl-3-(3,4-dihydroxyphenyl)oxirane] (PMDHPO) without loss in molecular mass. Antibacterial assessment of natural polyethers from different species of Boraginaceae family Symhytum asperum, S. caucasicum,S. grandiflorum, Anchusa italica, Cynoglossum officinale, and synthetic polymers, poly[2-methoxycarbonyl-3-(3,4-dimethoxyphenyl)oxirane (PMDMPO) and PMDHPO, reveals that only the synthetic analogue produced in this study (PMDHPO) exhibits a promising antimicrobial activity against pathogenic strains S.aureus ATCC 25923 and E.coli ATCC 25922 the minimum inhibitory concentration (MIC) being 100 µg/mL.

Evaluation of the effectiveness of drug treatment in patients with arterial hypertension and insomnia

Objective: chronic sleep disturbance is a comorbid condition with arterial hypertension, often combined with affective disorders, anxiety, depression. Forced sleep deprivation in patients with hypertension indicates a high activity of the renin‑angiotensin‑aldosterone system (RAAS) and desynchronosis of biological rhythms caused by a probable deficit in melatonin secretion during the night. Timely elimination of any pathological process associated with insomnia and arterial hypertension (AH) in the early stages of its development is a prerequisite for the effectiveness of therapy. Therefore, initial therapy should help neutralize the adverse effects of RAAS and improve the 24‑hour blood pressure (BP) profile. The aim of this study was to determine the therapeutic effect of monotherapy with an angiotensin converting enzyme (ACE) inhibitor, As well as in combination with a synthetic analogue of melatonin, on the course of hypertension and parameters of systemic hemodynamics in patients with first degree hypertension with insomnia at the onset of the disease. Combined therapy with an ACE inhibitor and a synthetic analogue of MT in patients with hypertension and insomnia was accompanied by an improvement in the clinical state, achievement of the target blood pressure level in most patients, positive dynamics of central blood pressure parameters and indicators reflecting the rigidity of peripheral arteries.

THE WAY OF DEVELOPMENT OF NATURAL LINTISITE FROM A MINERAL TO ITS SYNTHETIC ANALOGUE: USEFUL PROPERTIES, POTENTIAL AREAS OF PRACTICAL APPLICATION

The article presents a general description of lintisite – a rare mineral of the Khibiny and Lovozersky alkaline massifs. The mineral is considered as a base for the creation of a number of new interesting and useful substances for the modern science of materials. The characteristics of a natural sample are compared with its synthetic analogue AM-4. Examples of potential applications of AM-4 and its new form as the "nano-scale puzzle" for the field of organic synthesis are given. Different methods of AM-4 granulation are shown. The text is presented as a science fiction in order to attract the interest of people to the publication.

Effects of Menadione on Survival, Feeding, and Tunneling Activity of the Formosan Subterranean Termite

The Formosan subterranean termite, Coptotermes formosanus Shiraki, is a highly destructive pest and a cosmopolitan invasive species. Sustainable termite management methods have been improving with the search for novel insecticides that are effective, safe, and cost efficient. Menadione, also known as vitamin K3, is a synthetic analogue and biosynthetic precursor of vitamin K with low mammalian toxicity. Menadione has shown insecticidal activity in several insects, presumably due to interference with mitochondrial oxidative phosphorylation. However, little is known about its effectiveness against termites. In this study, we evaluated the toxicity and repellency of menadione in C. formosanus. Our results showed that menadione affected the survival and feeding activity of termites both in filter paper and substrate (sand) treatments, and menadione influenced termite tunneling activity in treated sand. In a no-choice assay, ≥90% mortality after seven days and minimal or no food consumption were recorded when sand was treated with menadione at 6 to 600 ppm. In a two-choice assay with a combination of treated and untreated sand, termites were deterred by menadione at 6 to 600 ppm and exhibited low mortality (≤30%) over seven days, while tunneling activity was prevented with 60 to 600 ppm of menadione treatment. Overall, our study demonstrated dose-dependent toxicity and repellency of menadione in C. formosanus. The potential use of menadione as an alternative termite control agent is discussed.

Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney

Ifosfamide is an alkylating agent, a synthetic analogue of cyclophosphamide, used to treat various solid cancers. In this study, the toxicity of ifosfamide was evaluated using single-and multiple-dose intraperitoneal administration in rats under Good Laboratory Practice guidelines, and an additional microarray experiment was followed to support toxicological findings. A single dose of ifosfamide (50 mg/kg) did not induce any pathological changes. Meanwhile, severe renal toxicity was observed in the 7 and 28 days consecutively administered groups, with significant increases in blood urea nitrogen and creatinine levels. In the tox-list analysis, cholesterol synthesis-related genes were mostly affected in the liver and renal failure-related genes were affected in the kidney after ifosfamide administration. Moreover, interferon regulatory factor 7 was selected as the main upstream regulator that changed in both the liver and kidney, and was found to interact with other target genes, such as ubiquitin specific peptidase 18, radical S-adenosyl methionine domain containing 2, and interferon-stimulated gene 15, which was further confirmed by real-time RT-PCR analysis. In conclusion, we confirmed kidney-biased ifosfamide organ toxicity and identified identically altered genes in both the liver and kidney. Further comprehensive toxicogenomic studies are required to reveal the exact relationship between ifosfamide-induced genes and organ toxicity.

Kynurenic Acid and Its Analogue SZR-72 Ameliorate the Severity of Experimental Acute Necrotizing Pancreatitis

The pathophysiology of acute pancreatitis (AP) is not well understood, and the disease does not have specific therapy. Tryptophan metabolite L-kynurenic acid (KYNA) and its synthetic analogue SZR-72 are antagonists of the N-methyl-D-aspartate receptor (NMDAR) and have immune modulatory roles in several inflammatory diseases. Our aims were to investigate the effects of KYNA and SZR-72 on experimental AP and to reveal their possible mode of action. AP was induced by intraperitoneal (i.p.) injection of L-ornithine-HCl (LO) in SPRD rats. Animals were pretreated with 75-300 mg/kg KYNA or SZR-72. Control animals were injected with physiological saline instead of LO, KYNA and/or SZR-72. Laboratory and histological parameters, as well as pancreatic and systemic circulation were measured to evaluate AP severity. Pancreatic heat shock protein-72 and IL-1β were measured by western blot and ELISA, respectively. Pancreatic expression of NMDAR1 was investigated by RT-PCR and immunohistochemistry. Viability of isolated pancreatic acinar cells in response to LO, KYNA, SZR-72 and/or NMDA administration was assessed by propidium-iodide assay. The effects of LO and/or SZR-72 on neutrophil granulocyte function was also studied. Almost all investigated laboratory and histological parameters of AP were significantly reduced by administration of 300 mg/kg KYNA or SZR-72, whereas the 150 mg/kg or 75 mg/kg doses were less or not effective, respectively. The decreased pancreatic microcirculation was also improved in the AP groups treated with 300 mg/kg KYNA or SZR-72. Interestingly, pancreatic heat shock protein-72 expression was significantly increased by administration of SZR-72, KYNA and/or LO. mRNA and protein expression of NMDAR1 was detected in pancreatic tissue. LO treatment caused acinar cell toxicity which was reversed by 250 µM KYNA or SZR-72. Treatment of acini with NMDA (25, 250, 2000 µM) did not influence the effects of KYNA or SZR-72. Moreover, SZR-72 reduced LO-induced H2O2 production of neutrophil granulocytes. KYNA and SZR-72 have dose-dependent protective effects on LO-induced AP or acinar toxicity which seem to be independent of pancreatic NMDA receptors. Furthermore, SZR-72 treatment suppressed AP-induced activation of neutrophil granulocytes. This study suggests that administration of KYNA and its derivative could be beneficial in AP.

EF24 exerts cytotoxicity against NSCLC via inducing ROS accumulation

Background The role of Diphenyldifluoroketone (EF24), a synthetic analogue of curcumin with noteworthy antitumor potential, remains unclear in non-small cell lung cancer (NSCLC). Herein, the inhibitory effect of EF24 on NSCLC and its mechanism were studied. Methods Cytotoxicity was measured by MTT assay, colony formation assay and xenograft model. Cell apoptosis and reactive oxygen species (ROS) level were quantified by flow cytometer. Protein level was detected by western blot assay. Mitochondria and autophagosomes were observed using transmission electron microscope and confocal microscopy. Results In-vitro, EF24 significantly induced proliferation inhibition, apoptosis, mitochondrial fission and autophagy of NSCLC cell lines. These cytotoxic effects were significantly attenuated by two reactive oxygen species (ROS) scavengers, indicating its anti-cancer effects largely depend on ROS accumulation. In-vivo, EF24 inhibited tumor growth in a dose-dependent manner. Moreover, no pathological changes of heart, lung, spleen, kidney and liver of mice were observed. Collectively, EF24 induced ROS accumulation, in turn activates cell apoptosis, and then exerts its cytotoxicity on NSCLC cells. Conclusions The results showed that EF24 exerted cytotoxicity against NSCLC via ROS accumulation. Thus, EF24 might serve as a potential anti-cancer agent for the treatment of NSCLC.

8 Effects of a Bovine Appeasing Substance Application at Weaning on Temperament and Growth of Bos Indicus Influenced Heifers

The objective of this study was to evaluate the effects of a synthetic analogue of the bovine appeasing pheromone (i.e. bovine appeasing substance; BAS) on growth and temperament of heifers. At weaning (d 0), 30 heifers (Aberdeen Angus ′ Nelore; 8 ± 1 mo) were stratified by body weight (199.8 ± 16 kg) and randomly assigned to receive a single dose of BAS (n = 15; SecureCattle; Nutricorp, Araras, SP, Brazil) or saline (CON; n = 15; saline 0.9% NaCl). Treatments (5 ml) were topically applied to the nuchal skin area of each animal on d0. Body weight was collected on d 0, 6, 15, 45, and 150. Chute score (1 to 5; 1 = calm, no movement; 5 = violent and continuous struggling) and chute entrance and exit score (1 to 3; 1 = slow; 3 = fast) were collected on d 0, 2, 6, 15, 45 and 150. Scores were averaged across 4 trained technicians. Data were analyzed using the MIXED procedure of SAS. Heifers assigned to BAS had greater (P < 0.01) average daily gain (ADG) than heifers assigned to CON treatment from d 6 to 15 (2.35 and 1.88 kg/d ± 0.16) and from d 15 to 45 (1.79 vs. 1.56 kg/d ± 0.08). Heifers assigned to BAS had lower (P < 0.01) chute entrance score on d 6, 15, and 45, and chute exit score on d 2 to 45 (P = 0.05) when compared to heifers assigned to CON. Additionally, heifers assigned to BAS tended (P = 0.08) to have lower chute score, from d 1 to 150 than heifers assigned to CON. The application of BAS at weaning improved heifers ADG, likely due to an improvement in temperament, suggesting that BAS application has calming effects in the beef cattle herd.

PSX-B-17 Appeasing substance application at weaning enhanced growth and temperament of bos indicus-influenced weaned calves in grazing system

The objective of this study was to evaluate the effects of a synthetic analogue of the bovine appeasing pheromone (i.e. bovine appeasing substance; BAS) on growth and temperament of weaned calves grazing Capim-Marandú (Urochloa brizantha cv Marandú). At weaning (d 0), 86 calves (47 steers and 39 heifers; Aberdeen Angus ′ Nelore; 8 ± 1 mo) were stratified by body weight (197.9 ± 24.9 kg) and randomly assigned to receive a single dose of BAS (n = 43; SecureCattle; Nutricorp, Araras, SP, Brazil) or saline (CON; n = 43; saline 0.9% NaCl). Treatments (5 ml) were topically applied to the nuchal skin area of each animal on d0. Body weight was collected on d 0, 8, 15, 51 and 100. Chute score (1 to 5; 1 = calm, no movement; 5 = violent and continuous struggling) and chute entrance and exit scores (1 to 3; 1 = slow; 3 = fast) were collected on d 3, 8, 15, 51 and 100. Scores were averaged across 3 trained technicians. Data were analyzed using the MIXED procedure of SAS. Calves assigned to BAS treatment had greater (P < 0.01) average daily gain (ADG) from d 8 to 15 (0.158 and -0.284 kg/d ± 0.07). Calves assigned to BAS treatment tended (P = 0.10) to have lower chute entrance score on d 8 and 51 and had lower (P = 0.02) chute exit score on d 8 than calves assigned to CON treatment. Additionally, calves assigned to BAS treatment tended (P = 0.07) to have lower chute score on d 8 when compared to calves assigned to CON treatment. The application of BAS at weaning improved calf ADG and improved calf temperament as observed by chute score and chute entrance and exit scores, suggesting that BAS application has calming effects.

Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination

Chiral total syntheses of both enantiomers of the anti-MRSA active plymuthipyranone B and all of the both enantiomers of three unnatural and synthetic analogues were performed. These two pairs of four chiral compounds are composed of the same 3-acyl-5,6-dihydro-2H-pyran-2-one structure. The starting synthetic step utilized a privileged asymmetric Mukaiyama aldol addition using Ti(OiPr)4/(S)-BINOL or Ti(OiPr)4/(R)-BINOL catalysis to afford the corresponding (R)- and (S)-δ-hydroxy-β-ketoesters, respectively, with highly enantiomeric excess (>98%). Conventional lactone formation and successive EDCI-mediated C-acylation produced the desired products, (R)- and (S)-plymuthipyranones B and three (R)- and (S)- synthetic analogues, with an overall yield of 42–56% with a highly enantiomeric excess (95–99%). A bioassay of the anti-MRSA activity against ATCC 43300 and 33591 revealed that (i) the MICs of the synthetic analogues against ATCC 43300 and ATCC 33591 were between 2 and 16 and 4 and 16 μg/mL, respectively, and those of vancomycin (reference) were 1 μg/mL. (ii) The natural (S)-plymuthipyranone B exhibited significantly higher activity than the unnatural (R)-antipode against both AACCs. (iii) The natural (R)-plymuthipyranone B and (R)-undecyl synthetic analogue at the C6 position exhibited the highest activity. The present work is the first investigation of the SAR between chiral R and S forms of this chemical class.