Cephalotane diterpenoids: structural diversity, biological activity, biosynthetic proposal, and chemical synthesis.

Covering: up to the end of 2023Cephalotane diterpenoids are a unique class of natural products exclusive to the genus Cephalotaxus, featuring a rigid 7,6,5,6-fused tetracyclic architecture. The study of cephalotanes dates back to the 1970s, when harringtonolide (1), a Cephalotaxus troponoid with a peculiar norditerpenoid carbon skeleton, was first discovered. In recent years, prototype C20 diterpenoids proposed as cephalotane were disclosed, which triggered intense studies on this diterpenoid family. To date, a cumulative total of 105 cephalotane diterpenoids with great structural diversity and biological importance have been isolated. In addition, significant advances have been made in the field of total synthesis and biosynthesis of cephalotanes in recent years. This review provides a complete overview of the chemical structures, bioactivities, biosynthetic aspects, and completed total synthesis of all the isolated cephalotane diterpenoids, which will help guide future research on this class of compounds.

1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long-sought-after mimetics for ortho/meta-substituted arenes.

The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.

Crotonoids A-H, Labdane-Type Diterpenoids with Anti-Inflammatory Activity from Croton sublyratus.

Croton sublyratus (Euphorbiaceae) is a traditional medicinal plant used by the Thai populace to treat helminthic infections and dermatologic conditions. In present study, eight new labdane-type diterpenoids, crotonoids A-H (1-8) and one known analogue (9) were isolated from the aerial parts of C. sublyratus. Compounds 6 and 7 belong to the rare class of 14,15-dinor-labdane diterpenoids. Compound 8 exhibited a rare 14,15,17-trinor-labdane skeleton. The structures of all these diterpenoids were elucidated by spectroscopic data analysis, electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Compound 9 exhibited moderate anti-inflammatory activity via the inhibition of NO production in lipopolysaccharide-induced RAW 264.7 cells.

Therapeutic Potential of Intravenous Phage as Standalone Therapy for Recurrent Drug-Resistant Urinary Tract Infections.

Recurrent urinary tract infections (rUTI) are common in kidney transplant recipients (KTR) and are associated with multidrug resistance and increased morbidity/mortality. Novel antibiotic alternatives to reduce UTI recurrence are critically needed. We describe a case of rUTI due to extended spectrum beta lactamase (ESBL) Klebsiella pneumoniae in a KTR that was treated successfully with 4 weeks of adjunctive intravenous bacteriophage therapy alone, without concomitant antibiotics, and with no recurrence in a year of follow-up.

Maternal tamoxifen exposure leads to abnormal primordial follicle assembly.

Tamoxifen (TAM) is an accredited drug used for treatment and prevention of breast cancer. Due to the long-term taking and the trend for women to delay childbearing, inadvertent conception occasionally occurs during TAM treatment. To explore the effects of TAM on a fetus, pregnant mice at gestation day 16.5 were orally administrated with different concentrations of TAM. Molecular biology techniques were used to analyze the effects of TAM on primordial follicle assembly of female offspring and the mechanism. It was found that maternal TAM exposure affected primordial follicle assembly and damaged the ovarian reserve in 3 dpp offspring. Up to 21 dpp, the follicular development had not recovered, with significantly decreased antral follicles and decreased total follicle number after maternal TAM exposure. Cell proliferation was significantly inhibited; however, the cell apoptosis was induced by maternal TAM exposure. Epigenetic regulation was also involved in the process of TAM induced abnormal primordial follicle assembly. The changed levels of H3K4me3, H3K9me3, and H3K27me3 presented the function of histone methylation in the regulation of the effects of maternal TAM exposure on the reproduction of female offspring. Moreover, the changed level of RNA m6A modification and the changed expression of genes related to transmethylation and demethylation proved the role of m6A in the process. Maternal TAM exposure led to abnormal primordial follicle assembly and follicular development by affecting cell proliferation, cell apoptosis, and epigenetics.

Highly Modified Sesquiterpene Lactones with Cytotoxic Activities from Strobocalyx chunii.

Three new germacranolide sesquiterpene lactones (SLs), strochunolides A-C (1-3, respectively), and a new guaianolide SL, strochunolide D (4), were isolated from Strobocalyx chunii and structurally characterized. Compound 1 is the first example of a dihomo-germacranolide SL, characterized by an unprecedented 6/10/5 tricyclic scaffold incorporating an additional fused δ-lactone C-ring. The structure of a known germacranolide SL, spicatolide C (5), was revised as its 8-epimer. Compound 3 exhibited potent in vitro cytotoxic activity against the HL-60 cell line, with an IC50 value of 0.18 ± 0.01 µM.

Sumatranins A-J: Lignans with Immunosuppressive Activity from Cleistanthus sumatranus.

Chemical investigation of the twigs of Cleistanthus sumatranus (Phyllanthaceae) led to the isolation of 10 undescribed lignans, sumatranins A-J (1-10). Compounds 1-4 are unprecedented furopyran lignans characterized by a unique 2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromene heterotricyclic framework. Compounds 9 and 10 are rare 9'-nor-dibenzylbutane lignans. Structures were established based on analyses of spectroscopic data, X-ray crystallographic data, and experimental ECD spectra. Immunosuppressive assays revealed compounds 3 and 9 displayed moderate inhibitory effects with good selectivity indexes against LPS-induced B lymphocyte proliferation.

Inwardly rectifying potassium channels mediate polymyxin-induced nephrotoxicity.

Polymyxin antibiotics are often used as a last-line defense to treat life-threatening Gram-negative pathogens. However, polymyxin-induced kidney toxicity is a dose-limiting factor of paramount importance and can lead to suboptimal treatment. To elucidate the mechanism and develop effective strategies to overcome polymyxin toxicity, we employed a whole-genome CRISPR screen in human kidney tubular HK-2 cells and identified 86 significant genes that upon knock-out rescued polymyxin-induced toxicity. Specifically, we discovered that knockout of the inwardly rectifying potassium channels Kir4.2 and Kir5.1 (encoded by KCNJ15 and KCNJ16, respectively) rescued polymyxin-induced toxicity in HK-2 cells. Furthermore, we found that polymyxins induced cell depolarization via Kir4.2 and Kir5.1 and a significant cellular uptake of polymyxins was evident. All-atom molecular dynamics simulations revealed that polymyxin B1 spontaneously bound to Kir4.2, thereby increasing opening of the channel, resulting in a potassium influx, and changes of the membrane potential. Consistent with these findings, small molecule inhibitors (BaCl2 and VU0134992) of Kir potassium channels reduced polymyxin-induced toxicity in cell culture and mouse explant kidney tissue. Our findings provide critical mechanistic information that will help attenuate polymyxin-induced nephrotoxicity in patients and facilitate the design of novel, safer polymyxins.

The chain mediating roles of anxiety and depression in the relationship between the effects of the COVID-19 pandemic and procrastination in adolescents: a longitudinal study.

BACKGROUND: The relationship between the Coronavirus Disease 2019 (COVID-19) pandemic, which is a traumatic event for adolescents, and procrastination is not clear. Mental health may play an important role in this relationship; however, the underlying mechanisms remain unknown. This study aimed to construct chain mediation models to examine whether anxiety and depression symptoms mediate the effects of the COVID-19 pandemic on procrastination in adolescents. METHODS: A convenience sample of 12 middle and high schools in Harbin, China, with four follow-up online surveys was conducted during the COVID-19 pandemic. A total of 4,156 Chinese adolescents were enrolled in this study, of whom ages 11-18 (Mean = 13.55; SD = 1.18), 50.75% were male, and 93.24% were middle school students. Descriptive demographic analysis and Pearson's correlation analysis of the effects of the COVID-19 pandemic (T1), anxiety(T2), depression (T3), and procrastination (T4) were performed in SPSS 22.0. Chain mediation analysis performed with Mplus 8.3. RESULTS: The effects of the COVID-19 pandemic, anxiety symptoms, depression symptoms, and procrastination were positively correlated (P < 0.01). The effects of the COVID-19 pandemic have a direct link on adolescent procrastination (effect = 0.156; SE = 0.031; 95%CI: 0.092, 0.214), and have three indirect paths on procrastination: the independent mediating role of anxiety symptoms was 29.01% (effect = 0.047; SE = 0.012; 95%CI: 0.024, 0.072), the independent mediating role of depression symptoms was 29.01% (effect = 0.047; SE = 0.010; 95%CI: 0.030, 0.068), as well as the completely chain mediating role of anxiety and depression symptoms was 15.43% (effect = 0.025; SE = 0.005; 95%CI: 0.017, 0.036). CONCLUSIONS: Our results suggest that anxiety and depressive symptoms are part of a causal chain between the effects of the COVID-19 pandemic and procrastination among Chinese adolescents. To effectively reduce their procrastination, attention should be paid to the emotional distress caused to adolescents by major events such as the COVID-19 epidemic. All data were taken from self-reported measures and one city in China, which may bias the results and limit their generalizability.

Visual exploration of large metabolic models.

MOTIVATION: Large metabolic models, including genome-scale metabolic models, are nowadays common in systems biology, biotechnology and pharmacology. They typically contain thousands of metabolites and reactions and therefore methods for their automatic visualization and interactive exploration can facilitate a better understanding of these models. RESULTS: We developed a novel method for the visual exploration of large metabolic models and implemented it in LMME (Large Metabolic Model Explorer), an add-on for the biological network analysis tool VANTED. The underlying idea of our method is to analyze a large model as follows. Starting from a decomposition into several subsystems, relationships between these subsystems are identified and an overview is computed and visualized. From this overview, detailed subviews may be constructed and visualized in order to explore subsystems and relationships in greater detail. Decompositions may either be predefined or computed, using built-in or self-implemented methods. Realized as add-on for VANTED, LMME is embedded in a domain-specific environment, allowing for further related analysis at any stage during the exploration. We describe the method, provide a use case and discuss the strengths and weaknesses of different decomposition methods. AVAILABILITY AND IMPLEMENTATION: The methods and algorithms presented here are implemented in LMME, an open-source add-on for VANTED. LMME can be downloaded from www.cls.uni-konstanz.de/software/lmme and VANTED can be downloaded from www.vanted.org. The source code of LMME is available from GitHub, at https://github.com/LSI-UniKonstanz/lmme.

Cephalotane-type C20 diterpenoids from Cephalotaxus fortunei var. alpina.

Seventeen new cephalotane-type diterpenoids, fortalides A-Q (1-17), along with five known analogues, were isolated from the seeds of Cephalotaxus fortunei var. alpina. Their structures were determined by extensive spectroscopic methods, as well as electronic circular dichroism (ECD) and X-ray crystallographic data analyses. Some isolates exhibited unusual structural features that were first found in cephalotane-type diterpenoids, such as the occurrence of the 7-oxabicyclo[4.1.1]octane moiety in 14 and 15 and the cis-arrangement of 3-OH and Me-19 in 9. Besides, the antiplasmodial activity of these compounds was evaluated in this study.

Down-conversion luminescence and temperature sensing characteristics of LaSrGaO4 :Er3.

Erbium(III) ion (Er3+ ) has abundant energy levels that can emit light covering a quite broad wavelength range in many hosts. Here we synthesized LaSrGaO4 :Er3+ phosphors by a high-temperature solid-state method. Upon excitation at the ultraviolet (UV) band, LaSrGaO4 :Er3+ phosphors could emit green, red and near-infrared emission simultaneously. The temperature dependent emission characteristics of the as-prepared samples was then studied and two kinds of luminescent ratiometric thermometry were constructed. The first one is on the basis of two green emission bands that stems from the 2 H11/2 → 4 I15/2 and 4 S3/2 → 4 I15/2 transitions of Er3+ . The intensity ratio between these two emission bands was found to follow well with the Boltzmann distribution, and its maximum relative sensitivity was calculated to be 0.84% K-1 at 299 K. The other one depends on the 4 F9/2 → 4 I15/2 transition of Er3+ and self-luminescence of the host LaSrGaO4 , considering that these two emission lines have different temperature response. The relative sensitivity of this type of luminescence intensity ratio (LIR) thermometry could reach 1.86% K-1 at 299 K, we have successfully developed materials with one of the largest relative sensitivities to date, which provides some basis for the subsequent development of a new type of non-contact temperature sensor.

Multispecies comparative analysis reveals transcriptional specificity during Mongolian horse testicular development.

Mongolian horses have been bred and used for labor and transport for centuries. Nevertheless, traits of testicular development in Mongolian horses have rarely been studied; particularly, studies regarding the transcriptional regulation characteristics of testicular development are lacking. In this paper, transcription specificity during testicular development in Mongolian horses is highlighted via a multispecies comparative analysis and weighted gene co-expression network analysis (WGCNA). Interestingly, the results showed that most genes were up-regulated in the testes after sexual maturity, which is a phenomenon conserved across species. Moreover, we observed nine key genes involved in regulating Mongolian horse testicular development. Notably, unique transcription signatures of testicular development in Mongolian horses are emphasized, which provides a novel insight into the mechanistic study of their testicular development.

Enhanced cadmium immobilization by sulfate-mediated microbial zero-valent iron corrosion.

A biotic iron (Fe0) treatment system combined with mixed microorganisms was applied to remediate cadmium (Cd)-contaminated groundwater under the intervention of sulfate. Due to hydrogenotrophic desulfuration effect, severe iron corrosion was observed in this microbe-collaborative Fe0 system according to surface morphology analysis as lots of secondary minerals (e.g. magnetite, green rust and lepidocrocite) were generated, which was essential for Cd(II) adsorption and immobilization. The sulfate-mediated biotic Fe0 system thereafter achieved a significantly enhanced Cd(II) removal efficiency of 86.1%, over 3.3 times than that in the abiotic Fe0 system. Increasing initial sulfate concentration could improve the removal of cadmium, which further proved that hydrogenotrophic desulfuration played a key role for enhanced Cd removal. According to the experimental results and current reports, the mechanism of Cd(II) removal was revealed into three pathways including adsorption to secondary iron minerals, co-precipitation with iron (hydr)oxides and formation of cadmium sulfide precipitation. Increasing Fe0 dosages showed positive correlation to Cd(II) removal and neutral pH was preferred to sulfate-mediated biotic Fe0 corrosion. These results indicated that sulfate-mediated biotic Fe0 corrosion could greatly relieve the limitation of Fe0 in Cd(II) immobilization, which could be a promising method to eliminate Cd(II) pollution from groundwater.

Outer membrane vesicles derived from hypervirulent Klebsiella pneumoniae stimulate the inflammatory response.

Hypervirulent Klebsiella pneumoniae (hvKP), an increasing important pathotype, was initially recognized as a cause of severe liver abscesses and subsequently as a cause of other complications posing a clinical threat. Outer membrane vesicles (OMVs) secreted from abundant gram-negative bacteria are considered an important vehicle for delivery of effector molecules to target cells. However, the products and role in bacterial pathogenesis of OMVs secreted from hvKP, have not yet been determined. In order to examine the production of OMVs from hvKP and to determine their effects on the stimulation of the host innate immune response, we used ultracentrifugation to obtain homogeneous OMVs from hvKP ATCC 1706 cultured in vitro. Proteomic analysis was performed and hvKP OMVs were found to contain diverse proteins. Furthermore, hvKP OMVs exhibited discrepant cytotoxic effects on different cell types, in vitro. The vesicles induced the expression of proinflammatory cytokines including interleukin (IL)-6 and IL-8 in host cells. In addition, transtracheal injection of hvKP OMVs in wild-type mice led to an inflammatory response manifested by elevated levels of pro-inflammatory mediators including IL-6, IL-8 and TNF-α in bronchoalveolar lavage fluid (BAL), in accord with in vitro experiments. However, hvKP OMVs were insufficient to kill mice. In summary, OMVs originating from hvKP may serve to provoke the inflammatory response.

Near-Infrared Emitting Phosphor LaMg0.5(SnGe)0.5O3:Cr3+ for Plant Growth Applications: Crystal Structure, Luminescence, and Thermal Stability.

Corresponding to the absorption curve of plant photosensitive pigment Pfr, near-infrared light has a broad application prospect in plant lighting. In order to explore this plant growth lamp, the novel near-infrared emitting phosphor LaMg0.5Sn0.5O3:Cr3+ was synthesized, which can be efficiently excited by 467 nm blue light. There are two luminescence centers, which were proven by testing the low-temperature spectrum, the excitation spectrum at different wavelengths, and the lifetime decay curve, and the two cell sequence substitution processes were obtained by Rietveld refinements of XRD. By introducing Ge4+, its luminescence intensity has been increased 1.6 times and the intensity at 150 °C remains at almost 80% that at room temperature. Finally, two different kinds of illumination experiments for plant growth were carried out, and the feasibility of the LaMg0.5(SnGe)0.5O3:Cr3+ phosphor for plant growth was confirmed.

Sublyratins A-O, Labdane-Type Diterpenoids from Croton sublyratus.

Fifteen new labdane-type diterpenoids, sublyratins A-O (1-15), along with four known analogues (16-19) were isolated from the aerial parts of Croton sublyratus. Their structural assignments were challenging due to the stereoisomeric features evident and were achieved by analyzing comprehensively the spectroscopic data and electronic circular dichroism spectra and using X-ray crystallographic analysis. Compounds 9 and 16-18 displayed cytotoxic activity against the HL-60 cell line with IC50 values of 1.5-2.8 µM.

Polymyxin Triple Combinations against Polymyxin-Resistant, Multidrug-Resistant, KPC-Producing Klebsiella pneumoniae.

Resistance to polymyxin antibiotics is increasing. Without new antibiotic classes, combination therapy is often required. We systematically investigated bacterial killing with polymyxin-based combinations against multidrug-resistant (including polymyxin-resistant), carbapenemase-producing Klebsiella pneumoniae Monotherapies and double- and triple-combination therapies were compared to identify the most efficacious treatment using static time-kill studies (24 h, six isolates), an in vitro pharmacokinetic/pharmacodynamic model (IVM; 48 h, two isolates), and the mouse thigh infection model (24 h, six isolates). In static time-kill studies, all monotherapies (polymyxin B, rifampin, amikacin, meropenem, or minocycline) were ineffective. Initial bacterial killing was enhanced with various polymyxin B-containing double combinations; however, substantial regrowth occurred in most cases by 24 h. Most polymyxin B-containing triple combinations provided greater and more sustained killing than double combinations. Standard dosage regimens of polymyxin B (2.5 mg/kg of body weight/day), rifampin (600 mg every 12 h), and amikacin (7.5 mg/kg every 12 h) were simulated in the IVM. Against isolate ATH 16, no viable bacteria were detected across 5 to 25 h with triple therapy, with regrowth to ∼2-log10 CFU/ml occurring at 48 h. Against isolate BD 32, rapid initial killing of ∼3.5-log10 CFU/ml at 5 h was followed by a slow decline to ∼2-log10 CFU/ml at 48 h. In infected mice, polymyxin B monotherapy (60 mg/kg/day) generally was ineffective. With triple therapy (polymyxin B at 60 mg/kg/day, rifampin at 120 mg/kg/day, and amikacin at 300 mg/kg/day), at 24 h there was an ∼1.7-log10 CFU/thigh reduction compared to the starting inoculum for all six isolates. Our results demonstrate that the polymyxin B-rifampin-amikacin combination significantly enhanced in vitro and in vivo bacterial killing, providing important information for the optimization of polymyxin-based combinations in patients.

Complete genome sequence and genome-scale metabolic modelling of Acinetobacter baumannii type strain ATCC 19606.

Multidrug-resistant (MDR) Acinetobacter baumannii is a critical threat to global health. The type strain ATCC 19606 has been widely used in studying the virulence, pathogenesis and mechanisms of antimicrobial resistance in A. baumannii. However, the lack of a complete genome sequence is a hindrance towards detailed bioinformatic studies. Here we report the generation of a complete genome for ATCC 19606 using PacBio sequencing. ATCC 19606 genome consists of a 3,980,848-bp chromosome and a 9,450-bp plasmid pMAC, and harbours a chromosomal dihydropteroate synthase gene sul2 conferring resistance to sulphonamides and a plasmid-borne ohr gene conferring resistance to peroxides. The genome also contains 69 virulence genes involved in surface adherence, biofilm formation, extracellular phospholipase, iron uptake, immune evasion and quorum sensing. Insertion sequences ISCR2 and ISAba11 are embedded in a 36.1-Kb genomic island, suggesting an IS-mediated large-scale DNA recombination. Furthermore, a genome-scale metabolic model (GSMM) iATCC19606v2 was constructed using the complete genome annotation. The model iATCC19606v2 incorporated a periplasmic compartment, 1,422 metabolites, 2,114 reactions and 1,009 genes, and a set of protein crowding constraints taking into account enzyme abundance limitation. The prediction of bacterial growth on 190 carbon and 95 nitrogen sources achieved a high accuracy of 85.6% compared to Biolog experiment results. Based upon two transposon mutant libraries of AB5075 and ATCC 17978, the predictions of essential genes reached the accuracy of 87.6% and 82.1%, respectively. Together, the complete genome sequence and high-quality GSMM iATCC19606v2 provide valuable tools for antimicrobial systems pharmacological investigations on A. baumannii.

Marinobacter vulgaris sp. nov., a moderately halophilic bacterium isolated from a marine solar saltern.

A facultatively anaerobic, Gram-stain-negative and non-gliding bacterium, designated F01T, was isolated from marine solar saltern in Weihai, PR China. Cells of F01T were 0.2-0.4 µm wide and 1.4-4.1 µm long, weakly catalase-positive and oxidase-negative. Growth of F01T was determined to occur at 4-40 °C (optimum, 33-37 °C), pH 6.5-8.5 (optimum, 7.0-8.0), and with 0.5-18.0 % (w/v) NaCl (optimum, 3.0-6.0 %). The 16S rRNA gene sequence analysis indicated that F01T represented a member of the genus Marinobacter within the family Alteromonadaceae. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the isolate was most closely related to Marinobacter algicola DSM 16394T, with a sequence similarity of 97.5 %. The DNA G+C content of the isolate was 57.6 mol%. The major respiratory quinone of F01T was ubiquinone-9 (Q-9) and the major fatty acids were anteiso-C15 : 0, C16 : 0 and C18 : 1ω9c. The major polar lipids were phosphoaminolipid, phosphatidylglycerol and phosphatidylethanolamine. On the basis of the results of the phylogenetic analysis and phenotypic properties, it is concluded that F01T can be considered to represent a novel species in the genus Marinobacter, for which the name Marinobacter vulgaris sp. nov. is proposed. The type strain is F01T (=MCCC 1H00290T=KCTC 52700T).