Major Chemical Classes Research Articles

Outpatient prescribing and prophylactic antibiotic use for recurrent urinary tract infections in British Columbia, Canada.

Urinary tract infection (UTI) is one of the most common infections, has frequent recurrences, and may debilitate quality of life. UTI is considered recurrent if there are three individual cases of UTI within 12 months. The objective of this study was to set a baseline for recurrent urinary tract infections (rUTI) in women, and rUTI-associated antibiotic prescribing in the presence of antimicrobial stewardship efforts. Data for rUTI in women were organized through a provincial prescription database, physician billing system, and a consolidation file to combine antibiotic prescribing, diagnoses, and patient demographics. Rates of rUTI cases and prescriptions were examined, and trends of antibiotics were separated by major anatomical therapeutic chemical classes. A total of 2 234 903 rUTI-associated prescriptions were dispensed for 674 785 rUTI cases from 2008-2018; 2 205 703 prescriptions were for treatment and 29 310 prescriptions were for prophylaxis of rUTI. The prevalence of rUTI cases declined by 59%, while overall rUTI-associated antibiotic prescribing decreased by 73%. The greatest decrease was seen in quinolones (87%), while nitrofurantoin became the most common rUTI antibiotic dispensed, accounting for 42% of prescriptions overall. Implementation of numerous antimicrobial stewardship efforts may have contributed to the decrease in antibiotic prescribing, particularly for quinolones. In line with local antibiograms and guidelines, nitrofurantoin is the most used antibiotic for rUTI by far, distinctly preferred over other antibiotics secondary to the lack of E. coli resistance.

Analytical Methods of Dihydropyridines Based Calcium Channel Blockers - Amlodipine, Lacidipine, Isradipine, Nifedipine, Felodipine, Cilnidipine and its related formulations: A Review

Objectives: Various analytical techniques are applied in pharmaceutical field to estimate the quality of active pharmaceutical ingredients, amount of drug in biological fluids and in formulations. The aim of this review article is to provide utmost existing analytical methods for analysis of dihydropyridines based calcium channel blockers for estimation of Amlodipine, Lacidipine, Isradipine, Nifedipine, Felodipine, and Cilnidipine in pure form, biological fluids (like Human Plasma, Human Serum, Human Urine etc.,) and its related formulations including novel formulations. Dihydropyridines based Calcium Channel blockers is a major chemical class of drugs used in the treatment of hypertension and various coronary artery diseases. Evidence acquisition: Current analytical techniques available for active pharmaceutical ingredients and its related formulations are tabulated with extensive method conditions which can be used in analysis of dihydropyridines based calcium channel blockers drugs outlined from official pharmacopoeias and other relevant research articles. Conclusion: Various analytical techniques such as HPLC, HPTLC, UPLC, GC, LC-MS, and GC-MS are involved. This review assists in appropriate selection of analytical technique, solvent, mobile phase, column, detector based on available analytical instruments and chemicals, by referring tabulated extensive method conditions. It can be implemented in quality control and quality assurance department for quality assessment of diverse pharmaceutical formulations.

Preliminary Phytochemical Analysis and in Vitro Antioxidant Activity of Boscia arabica Leaves

Boscia arabica (Capparaceae), popularly known as “Sarh”, is a plant utilized in Yemen in traditional medicine for treatment of many ailments, but very few studies have been carried out on this plant. The Boscia arabica leaves were selected to phytochemical analysis and evaluate antioxidant activity. Physico-chemical parameters of leaves powder were established and are within the acceptable ranges. The leaves powder was treated with various reagents and the mixture was observed under day light and under UV light to see the type of fluorescence. Different fluorescence colours were observed. Chemical analysis was carried out to determine the major chemical classes, phytoconstituents like carbohydrates, saponins, flavonoids, triterpenes, sterols and alkaloids were identified in studied extracts. The presence of phytoconstituents was further confirmed by thin layer chromatography and Rf values of developed spots were calculated with color intensity. Antioxidant activity of Boscia arabica leaf extracts was carried out via DPPH staining technique. The result of dot-blot assay showed yellow-coloured spots when stained with DPPH solution. The free radical scavenging activity of 80% methanol extract and it’s fractions was determined and antioxidants activity ranged from (14.81±3.22) for methanol 80% extract to (85.31±3.12) for n-butanol fraction. Ethyl acetate (84.30±2.44) and n-butanol (85.31±3.12) are exhibited high free radical scavenging activity when compared with quercetin (99.10±4.22). The results obtained in this study support the use of Boscia arabica in traditional medicine, which may be a promising source for the development of natural antioxidants.

Reasons for 2-furaldehyde and 5-hydroxymethyl-2-furaldehyde resistance in Saccharomyces cerevisiae: current state of knowledge and perspectives for further improvements.

Common toxic compounds 2-furaldehyde (furfural) and 5-hydroxymethyl-2-furaldehyde (HMF) are formed from dehydration of pentose and hexose, respectively, during decomposition of lignocellulosic biomass polymers. Furfural and HMF represent a major class of aldehyde toxic chemicals that inhibit microbial growth and interfere with subsequent fermentation for production of renewable fuels and chemicals. Understanding mechanisms of yeast tolerance aids development of tolerant strains as the most economic means to overcome the toxicity. This review updates current knowledge on yeast resistance to these toxic chemicals obtained from rapid advances in the past few years. Findings are largely exemplified by an adapted strain NRRL Y-50049 compared with its progenitor, the industrial yeast Saccharomyces cerevisiae type strain NRRL Y-12632. Newly characterized molecular phenotypes distinguished acquired resistant components of Y-50049 from innate stress response of its progenitor Y-12632. These findings also raised important questions on how to address more deeply ingrained changes in addition to local renovations for yeast adaptation. An early review on understandings of yeast tolerance to these inhibitory compounds is available and its contents omitted here to avoid redundancy. Controversial and confusing issues on identification of yeast resistance to furfural and HMF are further clarified aiming improved future research. Propositions and perspectives on research understanding molecular mechanisms of yeast resistance and future improvements are also presented. KEY POINTS: • Distinguished adapted resistance from innate stress response in yeast. • Defined pathway-based molecular phenotypes of yeast resistance. • Proposed genomic insight and perspectives on yeast resistance and adaptation.

Pomegranate peel modifies growth, essential oil and certain chemicals of sage (Salvia officinalis L.) herb

Sage dry leaves are used to obtain natural raw products that are used in many purposes such as perfume, food and pharmaceutical industries. Using organic fertilizers is a way to overcome the harms of chemical fertilizers during cultivation and production of medicinal and aromatic plants (MAP). Pomegranate peel (PP) considered as organic fertilizer. In this trial, the impacts of PP formulations [powder (PF), water extract (WEF) and ethanol extract (EEF)] on growth and chemical composition of sage plant were evaluated in an attempt to replace chemical fertilizers with organic wastes. Sage plants were treated with various rates of PF, WEF, EEF and control (chemical fertilizers). ANOVA-1 was used to analyze the data. 6 g/L (WEF) gave the greatest values of fresh mass (68.5 g/plant), dry mass (18 g/plant), essential oil (EO) content (1.6%, v/w) and EO yield (28.8 ml/100 plants) during the second harvest. Oxygenated monoterpenes (OM, 62.3–74.3%) was the major chemical class of EO isolated under various PP treatments; while α-thujone (27–40.2%) was the major constituent. α-thujone and OM were varied in response to various formulations and their rates. Plants treated with 6 g/L (PF) produced the greatest values of total phenols (25.7%) and inhibition of free radical scavenging (70%) at second harvest. 4 g/pot (PF) and 4 g/L (WEF) produced the ultimate rates of total carbohydrates (25.7%) during the first harvest and total flavonoids (11.2 mg/g) at the second harvests. Different variations were found in NPK values and their uptakes due to PP formulations. It may be concluded that positive effects were found in the productivity of sage in response to PP applications.

Evaluation of Essential Oils in Two Artemisia Species that are Grown Wildly in Eastern Desert of Egypt

The aerial parts of Artemisia judaica L. (A. judaica) and Artemisia monosperma (Delile) (A. monosperma) were collected from wild plant populations located in the eastern desert of Egypt. The essential oils (EOs) of both aerial parts were isolated by hydro-distillation (HD) and analyzed by GC/MS. The EO yields of A. judaica and A. monosperma were 6.0 and 4.0 ml/500 g herb, respectively. Piperitone (43.8 % ± 3.6), artemisia ketone (38.3 % ± 3.2) and artemisia alcohol (3.1 % ± 0.6) were the main components of A. judaica EO, while the major components of A. monosperma EO were β-pinene (56.4 % ± 4.8), δ-cadinene (18.4 % ± 2.1), α-pinene (6.8 % ± 0.9), limonene (5.4 % ± 1.1) and cis-β-ocimene (3.1 % ± 0.5). Various constituents of A. judaica EO belonged to monoterpene hydrocarbons (MH) and oxygenated monoterpenes (OM). The chemical groups of A. monosperma EO were MH, OM, sesquiterpene hydrocarbons (SH), and oxygenated sesquiterpenes (OS). The major chemical classes of A. judaica and A. monosperma EOs were OM (90.3 % ± 6.1) and MH (77.4 % ± 4.9), respectively.

Role of Endocrine System and Hypothalamic Neuropeptides in Hyperphagia Associated Obesity

Activities occurring in an animal’s body are performed and regulated via certain chemicals. These chemical on the basis of multiple factors are divided into various classes. Hormones forma major class of such chemicals. Hormones are integral part of animal’s body that are involved in the mediation of a variety of vital functions. Hormonal secretions are precisely regulated in order to mediate relevant function as needed. They are important maintainers of a variety of homeostatic mechanisms including food intake, digestion, absorption and utilization. Like all other parts of animal’s body, adipose tissue is also under the influence of chemical messengers. Some of the endocrine messengers are Leptin, Insulin and Ghrelin hormone while neural chemicals include orexigenic hypothalamic neuropeptides (like Neuropeptide Y). While performing normal assigned function these chemical substances strive to maintain a balance between body energy need and energy intake. If concentration or functionality of any of them is disturbed due to certain change for sufficient time period then they fail to perform their duty resulting gradual increase in body mass index. Deficiency or hypersecretion, structural deformity and functional impairment are some of the aspects that contribute towards hormonal abnormalities. Present review is based on a concise discussion about obesogenic role of Leptin, Insulin and Ghrelin hormones and hypothalamic neuropeptides.

Characterization of the Volatile Components of Essential Oils of Selected Plants in Kenya.

Essential oils are secondary metabolites that plants produce for protection from pests and predators, attraction of pollinators, and seed dispersal. The oils are made up of a mixture of compounds that give a characteristic flavour and odour. Currently, essential oils are receiving great attention in research for their phytochemical and antimicrobial activities. However, there is scanty information on the chemical composition of many plants. This study provides a detailed analysis of the chemical composition of essential oils of ginger, garlic, tick berry, and Mexican marigold in Kenya. The essential oils were extracted by steam distillation and analysed by gas chromatography–mass spectrometry. The study identified a total of 52 different chemical classes from the essential oils of the four different plants that were analysed. Their percentage composition was also found to vary between the test plants. The essential oils of Mexican marigold constituted the highest composition of the identified chemical classes at 71.2%, followed by ginger at 55.8%, while both tick berry and garlic oils constituted 53.8% of the total classes identified. Terpenes constituted the highest composition in the essential oils of all the four test plants. Other major chemical classes included esters, ketones, organosulfurs, alkanes, cycloalkanes, steroids, aromatic hydrocarbons, and alkanols. Some of these chemical compounds have been shown to have a huge utility potential in biopesticides, pharmaceutical, and food industries, and hence, their industrial extraction and purification from the essential oils of these plants are recommended.

Recognition of the molecular characterization and mechanisms of heterogeneously formed organic pollutants from metallurgical industries by FT-ICR-MS and GC/Q-TOF-MS

Emissions of numerous targeted and non-targeted organic pollutants from industrial activities are one of the major contributors to the global air pollution. However, comprehensive recognition of their molecular characterization and real industrial scale mechanisms have never been achieved. Herein, by using high resolution mass spectrometry, we firstly give an insight into the molecular characterization and mechanisms of organic pollutants formed on fly ashes from secondary smelting of Al, Cu, Pb, and Zn and electric arc furnace steel-making. We found that lipid-like, unsaturated hydrocarbon and carboxyl-rich alicyclic molecule-like structures were the major chemical classes. Methylation- and oxidation-related reactions were suggested to be the major formation mechanisms. The predominance of carboxyl-rich structures in the fly ash further proved the contribution of metallurgical industrial emissions to air pollution. Findings in this study could be significant for further understanding the contribution of industrial emissions to air pollutions and conducting their source emission control.

Metabolomic differences of seminal plasma between boars with high and low average conception rates after artificial insemination.

Seminal plasma is a complex biological fluid containing many metabolites including amino acids, fructose, carbohydrates and lipids Metabolites play important roles in multiple biological processes, but details and significance of the seminal plasma metabolome related to boar fertility are unknown. The aim of the present study was to compare the comprehensive metabolome of seminal plasma from boars with different conception rate after artificial insemination and to identify the potential biomarkers. Semen samples were collected from boars which divided into two groups according to the conception rates in the offspring. Seminal plasma metabolites were isolated, purified, and then subjected to Ultra-high Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (UHPLC-qTOF-MS) procession. A total of 576 (Positive ion mode) and 377 (Negative ion mode) metabolites were identified in seminal plasma. Metabolites were identified and categorized according to their major chemical classes, including carboxylic acids and derivatives, organooxygen compounds, amino acids, peptides, and alogues, fatty amides, fatty acyls, benzene and substituted derivatives, purine nucleotides, pyrimidine nucleotides, glycosyl compounds, fatty acids and conjugates. The results showed that 4-Aminobenzoate, Pro-Asn, Ile-Tyr, Homoveratric acid and D-Biotin were higher in semen of boar with higher conception rate (HG) versus lower conception rate (LG) (p<.05), whereas L-Serine, Butoxyacetic acid, S-Methyl-5'-thioadenosine, Capsaicin and 1-O-(cis-9-Octadecenyl)-2-O-acetyl-sn-glycero-3-phosphocholine (PAF) were lower in HG than in LG (p<.05). These metabolites may be considered as candidate biomarkers for different fertility in boars.

Chemical Composition Analysis, Antioxidant, and Antibacterial Activities of Eggplant Leaves.

Agricultural by-products represent one of the biggest pollutants for the environment, therefore, investigating new sources for the extraction of bioactive compounds is a topic of great interest for the entire scientific community. This work is aimed at studying the chemical composition (pigments, phenolics, volatile compounds) and biological activities (antioxidant and antimicrobial properties) of young and mature leaves of five eggplant cultivars (Solanum melongena L.) grown in Tunisia (Tizona, A1014, Nawel, A336, and Mirval). Pigment analysis showed no statistical variations between the two types of leaves, whereas higher levels of anthocyanins were recorded in young leaves of three out of five cultivars (24.7-52.8 mg 100 g-1 ). Total phenolic compounds (966.5-2072.6 mg 100 g-1 ) and o-diphenols (343.9-741.2 mg 100 g-1 ) contents varied significantly according to leaf age and cultivar. However, no statistically significant variation between young and mature leaves was found in flavonols and tannins content. As for volatile profiles, 62 constituents were characterized with non-terpene derivatives (52.0-61.6 %) and apocarotenes (19.9-35.6 %) as major chemical classes. Regarding the antioxidant activity, methanol extracts of Tizona cultivar mature leaves displayed important antiradical properties using DPPH, ABTS, and phosphomolybdenum assays (IC50 0.1, 0.2 and 0.01 mg mL-1 , respectively). With regards to reducing power determination, the most active extract was obtained from mature A1014 leaves. Further, young Mirval leaves proved to be significantly active from a bactericidal point of view against Candida albicans and Staphylococcus aureus of 3.1 mg mL-1 and 0.2 mg mL-1 MBC, respectively. In conclusion, eggplant leaves are a noteworthy source of antioxidant and antimicrobial compounds with potential use in the pharmaceutical, the cosmetics and the food industries.

The Global Burden of Exposure to Pesticide Mixtures

Background: The increasing use of pesticides is raising attention on the pervasiveness of contamination far from emission points and the pathways to human exposure. Recent progress in mapping global pesticide use can substantiate an assessment of human exposure and intake worldwide and the risks of attenuated life expectancy. Methods: We quantified the human intake ratio (INTR) relative to the acceptable level for 92 active substances. We intersected INTR with the Global Burden of Diseases (GBD) dataset, and we analysed the disability-adjusted life years (DALY) of both aggregated and individual non-communicable diseases (NCDs) against the INTR of major pesticide chemical classes. Using a stochastic two-stage regression analysis, we estimated the associations between pesticide INTR and DALYs, and we determined whether these associations were positive (i.e., adverse effect on life expectancy), uncertain, or negative. Findings: About 5.7 billion people exceed the acceptable pesticide intake; about 4.6 billion exceed this by 100 times. Pesticides are associated with DALYs of NCDs in 47% of countries; organophosphates, inorganics, triazines, and triazoles are associated with NCDs in 100%, 68%, 66% and 66% of countries, respectively. Prevalent NCDs are musculoskeletal disorders, neoplasms, and mental disorders in 72%, 62%, and 54% of countries. In average, an increase by one order in INTR is associated with a decrease of 1.35 days/person in neoplasms (95% CI, 0.27-2.48 days/person), and 1.09 days/person in musculoskeletal disorders (95% CI, 0.45-1.74 days/person). In spite of geographic variability, high income countries are more affected than low income countries due to raised health risk factors. Interpretation: Although the biological mechanisms determining health effects in human subjects remain largely undiscovered, statistically significant associations of chronic exposure to pesticide mixtures on various NCDs show the relative impact of different pesticide classes on exposed populations and indicate geographic regions, socioeconomic, and health indicators associated to risks of attenuated life expectancy. Funding Statement: The University of Sydney, SREI2020 EnviroSphere Program, SOAR Fellowship (FM). Declaration of Interests: The authors declare no competing interests.

A novel study approach on Scutellaria altissima L. cultivated at the Ghirardi Botanic Garden (Lombardy, Italy).

Within an Open Science project, research was carried out to describe to the public of the Ghirardi Botanic Garden (BS, Lombardy, Italy) the invisible features of plants. This work is dedicated to Scutellaria altissima L. (Lamiaceae). Micromorphological, histochemical and phytochemical investigations were conducted on the vegetative and reproductive organs to correlate the structures involved in the emission of substances and their unique productivity. This work reports volatile organic compound (VOC) profiles of leaves and flowers and the composition of essential oil (EO) obtained from aerial parts of plants cultivated in Italy that have never been described before. Three morphotypes of glandular trichomes were observed: peltate, short-stalked capitate and long-stalked capitate. Peltate trichomes were the main producers of terpenes, short-stalked capitates of polysaccharides and long-stalked capitates of terpenes and polyphenols. The leaf VOC profile showed heterogeneous composition, with non-terpene derivatives as the major chemical class (71.04%), while monoterpene hydrocarbons represented almost the totality of the flower (99.73%). The leaf presented a higher number of total (37 versus 11) and exclusive (33 versus 7) compounds. (Z)-3-Hexenol acetate was most abundant in the leaf and (E)-β-ocimene in the flower. Four common compounds were detected: β-pinene, β-caryophyllene, γ-muurolene and germacrene-D. The EO contaied 21 compounds, dominated by β-caryophyllene, linalool and hexahydrofarnesyl acetone. This research allowed us to correlate morphotypes of the secretory structures with the production of secondary metabolites, with the aim of providing the public of the Ghirardi Botanic Garden with a dedicated iconographic approach, which accounts for olfactory perception linked to S. altissima.

Diversity, phytochemical and medicinal potential of the genus Ocimum L. (Lamiaceae)

Ocimum, commonly known as Tulsi, is a huge genus within family Lamiaceae, comprising about 64 species of annual to perennial aromatic medicinal herbs with a long history of traditional uses. The aromatic plants of the genus Ocimum have long been used as flavouring agents, as well as diverse medicinal applications. Our comprehensive review covers the published literature through the period from 1961 to April 2019 and provides a complete survey of nearly all the studied species up to date. Additionally, all related taxonomic data, geographical distribution as well as different traditional uses are discussed here in details. The major chemical classes within the genus Ocimum include flavonoids, phenolic acids and terpenes. The bioactivities of various extracts or individual compounds, both in vitro and in vivo, include antimicrobial, cytotoxic, antinociceptive, anti-inflammatory, antihyperglycemic and antioxidant. This comprehensive review will serve as a database for future research and drug development from the genus Ocimum.

Probiotic Fermentation of Rice Bran with Six Genetically Diverse Strains Effects Nutrient and Phytochemical Composition; a Non-Targeted Metabolomics Approach

Abstract Objectives This study examined the contributions of native gut probiotic bacteria in production of rice bran microbial metabolites with bioactivity and nutritional importance. The study hypothesize that bacteria and yeast probiotics utilize distinct genes for bidirectional influence on bacterial cross feeding and host bioavailability of rice bran vitamins, while decreasing undesirable molecules. Methods A one/two step fermentation protocol was applied to rice bran (RBT-300) with the following strains Lactobacillus fermentum ATCC 23271, L. paracasei ATCC 21052_R1, L. rhamnosus GG, Escherichia coli Nissle 1917, and Bifidobacterium longum ATCC 55813 before and after incubation with yeast probiotic Saccharomyces boulardii. Metabolomic analysis was performed following 80% methanol-water under vigorous shaking (2 min) followed by centrifugation to remove proteins. Extracts were applied to reverse phase (RP)/UPLC-MS/MS methods with positive and negative ion mode electrospray ionization. Results The rice bran metabolite profile in the presence of fermentation yielded 613 unique biochemical compounds of known identity across 8 major chemical classes. The bacterial strains used alone or after yeast fermentation modified about 70% of the metabolome and 60% total vitamins. For instance, vitamin B6 changed by strain L. rhamnosus GG (increased fivefold) when compared to rice bran, and supports the role for bacterial gene/enzyme in increased production. Findings were supported by decreased metabolite precursor. Phytate degradation persisted across this cocktail of probiotics that can further enhance nutrient bioavailability. Conclusions The metabolomics approach for fermented rice bran analysis allows for information across other diverse pathways including protein, lipids, prebiotics and phenolics. The inclusion of the probiotics genetic potential and diversity are criteria for rice bran fermentation that merit continued attention for its functional impact on gut health and immunity. Funding Sources National Institutes of Health-National Cancer Institute (3R01CA201112-04S1).

The Impact of Environmental Chemicals on the Gut Microbiome.

Since the surge of microbiome research in the last decade, many studies have provided insight into the causes and consequences of changes in the gut microbiota. Among the multiple factors involved in regulating the microbiome, exogenous factors such as diet and environmental chemicals have been shown to alter the gut microbiome significantly. Although diet substantially contributes to changes in the gut microbiome, environmental chemicals are major contaminants in our food and are often overlooked. Herein, we summarize the current knowledge on major classes of environmental chemicals (bisphenols, phthalates, persistent organic pollutants, heavy metals, and pesticides) and their impact on the gut microbiome, which includes alterations in microbial composition, gene expression, function, and health effects in the host. We then discuss health-related implications of gut microbial changes, which include changes in metabolism, immunity, and neurological function.

The Romanian Map of Organic Pollution from Domestic Wastewaters � Seasonal Variations of Anionic Surfactants And Organic Load (COD)

Surfactants represent the major class of chemicals used in the composition of detergents where the predominant groups are anionic surfactants. Because of the large utilization of detergents in different activities (agricultural, industrial, domestic) an important amount of surfactants can accumulate in the domestic and industrial wastewaters, that are discarded to wastewater-treatment plants (WWTP). Furthermore, surfactants could affect the process of biological wastewater treatment due the inhibition of activated sludge and subsequently the water bodies quality through discharge of WWTPs` effluents. In addition, the soil quality decreased through various modes of sludge applied. The concentrations of organic matters discharged in the wastewater systems from Romania have raised the attention of environmental authorities regarding the toxic impact of their components such as anionic surfactants on the environment. The present paper proposed to highlight the background of organic pollution from Romania through the monitoring of the organics amount in water by Chemical Oxygen Demand (COD) and by the specific indicator � Anionic Surfactants (AS). Temporal (winter, spring and summer, 2019) and spatial (six areas: West, North-West, North-East, East, South and South-West) monitoring of organic matter was performed. It has been found that the spatial and temporal variation of AS concentrations were well correlated with COD load, leading to the conclusion that surfactants represented an important part of the global organic matter.

Modified Clerodanes from the Essential Oil of Dodonea viscosa Leaves.

Dodonea viscosa (L.) Jacq from Reunion Island (Indian Ocean) was investigated for its leaf essential oil composition. The plant was extracted by hydrodistillation and its essential oil analysed by gas chromatography coupled to mass spectrometry. This study revealed that oxygenated nor-diterpenes and diterpenes were one of the major chemical classes (> 50%) mainly consisting of three modified cyclopropylclerodanes containing a bicyclo[5.4.0]undecane ring system: one new furanoid norditerpene, dodovisate C, and two furanoid diterpenes, the known methyl dodovisate A and the new methyl iso-dodovisate A. These three compounds were isolated by liquid chromatography and their structures established on the basis of spectroscopic studies. The absolute configuration of dodovisate C was elucidated through a joint experimental and theoretical (B3LYP/6-311+G(d,p)) electronic circular dichroism study. The relative configurations of methyl dodovisate A and methyl iso-dodovisate A were determined using linear regressions of theoretical chemical shifts versus experimental values with the (B3LYP/6-311+G(d,p)) method.

A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2\u2212/\u2212 phenotype

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal failure in humans and results from germline mutations in PKD1 or PKD2. Despite the recent approval of tolvaptan, safer and more effective alternative drugs are clearly needed to slow disease progression. As a first step in drug discovery, we conducted an unbiased chemical screen on zebrafish pkd2 mutant embryos using two publicly available compound libraries (Spectrum, PKIS) totalling 2,367 compounds to identify novel treatments for ADPKD. Using dorsal tail curvature as the assay readout, three major chemical classes (steroids, coumarins, flavonoids) were identified from the Spectrum library as the most promising candidates to be tested on human PKD1 cystic cells. Amongst these were an androgen, 5α−androstane 3,17-dione, detected as the strongest enhancer of the pkd2 phenotype but whose effect was found to be independent of the canonical androgen receptor pathway. From the PKIS library, we identified several ALK5 kinase inhibitors as strong suppressors of the pkd2 tail phenotype and in vitro cyst expansion. In summary, our results identify ALK5 and non-canonical androgen receptors as potential therapeutic targets for further evaluation in drug development for ADPKD.

The Control of Heparanase Through the Use of Small Molecules.

Despite the enormous progress made in recent years with antibodies, vaccines, antisense oligonucleotides, etc., the so-called "biological" approaches for tackling the control of various diseases, medicinal chemistry remains a bulwark to refer to for the development of new drugs. Also in the case of heparanase, medicinal chemistry has always been in the forefront to identify new inhibitors, through modification of natural macromolecules, e.g., sulfated polysaccharides like heparin, or of natural compounds isolated from bacteria or plants, or through rational design. In this chapter, the reader will find a detailed description of the most relevant small-molecule heparanase inhibitors reported so far in the scientific literature and in patent applications, with mention to the design strategy and to structure-activity relationships. Starting from heparanase inhibitors of natural origin and the attempts to improve their potency and selectivity, the reader will be guided through the major chemical classes of synthetic inhibitors, with representation of the structure of the most relevant compounds. The last paragraph is dedicated to a brief description of inhibitors that have reached clinical trials, highlighting their structure, mechanism, and improved derivatives.