Covering: up to 2020
As a main bioactive component of the Chinese, Indian, and American
Podophyllum
species, the herbal medicine, podophyllotoxin (PTOX) exhibits broad spectrum pharmacological ...activity, such as superior antitumor activity and against multiple viruses. PTOX derivatives (PTOXs) could arrest the cell cycle, block the transitorily generated DNA/RNA breaks, and blunt the growth-stimulation by targeting topoisomerase II, tubulin, or insulin-like growth factor 1 receptor. Since 1983, etoposide (VP-16) is being used in frontline cancer therapy against various cancer types, such as small cell lung cancer and testicular cancer. Surprisingly, VP-16 (ClinicalTrials NTC04356690) was also redeveloped to treat the cytokine storm in coronavirus disease 2019 (COVID-19) in phase II in April 2020. The treatment aims at dampening the cytokine storm and is based on etoposide in the case of central nervous system. However, the initial version of PTOX was far from perfect. Almost all podophyllotoxin derivatives, including the FDA-approved drugs VP-16 and teniposide, were seriously limited in clinical therapy due to systemic toxicity, drug resistance, and low bioavailability. To meet this challenge, scientists have devoted continuous efforts to discover new candidate drugs and have developed drug strategies. This review focuses on the current clinical treatment of PTOXs and the prospective analysis for improving druggability in the rational design of new generation PTOX-derived drugs.
Natural product podophyllotoxin exhibited superior broad spectrum antitumor and antiviral activity. Over past 30 years, scientists devoted continuous efforts to develop druggability strategies and discover new podophyllotoxin-derived drugs.
Summary
Estuaries connect rivers with the ocean and are considered transition regions due to the continuous inputs from rivers. Microbiota from different sources converge and undergo succession in ...these transition regions, but their assembly mechanisms along environmental gradients remain unclear. Here, we found that salinity had a stronger effect on planktonic than on benthic microbial communities, and the dominant planktonic bacteria changed more distinctly than the dominant benthic bacteria with changes in salinity. The planktonic bacteria in the brackish water came mainly from seawater, which was confirmed in the laboratory, whereas the benthic bacteria were weakly affected by salinity, which appeared to be a mixture of the bacteria from riverine and oceanic sediments. Benthic bacterial community assembly in the sediments was mainly controlled by homogeneous selection and almost unaffected by changes in salinity, the dominant assemblage processes for planktonic bacteria changed dramatically along the salinity gradient, from homogeneous selection in freshwater to drift in seawater. Our results highlight that salinity is the key driver of estuarine microbial succession and that salinity is more important in shaping planktonic than benthic bacterial communities in the Yellow River estuary.
There is a continuous need for novel microbial natural products to fill the drying‐up drug development pipeline. Herein, we report myxadazoles from Myxococcus sp. SDU36, a family of novel chimeric ...small molecules that consist of N‐ribityl 5,6‐dimethylbenzimidazole and a linear fatty acid chain endowed with an isoxazole ring. The experiments of genome sequencing, gene insertion mutation, isotope labelling, and precursor feeding demonstrated that the fatty acid chain was encoded by a non‐canonical PKS/NRPS gene cluster, whereas the origin of N‐ribityl 5,6‐dimethylbenzimidazole was related to the vitamin B12 metabolism. The convergence of these two distinct biosynthetic pathways through a C‐N coupling led to the unique chemical framework of myxadazoles, which is an unprecedented hybridization mode in the paradigm of natural products. Myxadazoles exhibited potent vasculogenesis promotion effect and moderate antithrombotic activity, underscoring their potential usage for the treatment of cardiovascular diseases.
Herein, we report myxadazoles from Myxococcus sp. SDU36, a family of novel chimeric small molecules with sound cardiovascular activities. Myxadazoles consist of a N‐ribityl 5,6‐dimethylbenzimidazole and a fatty acid chain endowed with an isoxazole ring. The fatty acid chain was encoded by a non‐canonical PKS/NRPS gene cluster, whereas the N‐ribityl 5,6‐dimethylbenzimidazole ring was originated from the endogenous vitamin B12 metabolism pathway. A plausible C−N cross coupling is likely to coordinate the convergence of these two distinct biosynthetic pathways that led to the final construction of the unique chemical scaffold of myxadazoles.
Complex polysaccharides (e.g. cellulose, xylan, and chitin), the most abundant renewable biomass resources available on Earth, are mainly degraded by microorganisms in nature. However, little is ...known about the global distribution of the enzymes and microorganisms responsible for the degradation of cellulose, xylan, and chitin in natural environments. Through large‐scale alignments between the sequences released by the Earth Microbiome Project and sequenced prokaryotic genomes, we determined that almost all prokaryotic communities have the functional potentials to degrade cellulose, xylan, and chitin. The median abundances of genes encoding putative cellulases, xylanases, and chitinases in global prokaryotic communities are 0.51 (0.17–1.01), 0.24 (0.05–0.57), and 0.33 (0.11–0.71) genes/cell, respectively, and the composition and abundance of these enzyme systems are environmentally varied. The taxonomic sources of the three enzymes are highly diverse within prokaryotic communities, and the main factor influencing the diversity is the community's alpha diversity index rather than gene abundance. Moreover, there are obvious differences in taxonomic sources among different communities, and most genera with degradation potentials are narrowly distributed. In conclusion, our analysis preliminarily depicts a panorama of cellulose‐, xylan‐, and chitin‐degrading enzymatic systems across global prokaryotic communities.
Aim
Glycoside hydrolases (GHs) encoded by prokaryotes play a crucial role in the degradation of carbohydrates, which is a key step in the carbon cycle. However, their global distribution remains ...poorly understood. Here, we conducted a comprehensive investigation of the global biogeographic patterns of prokaryotic‐encoded GHs.
Location
Global.
Time period
Present.
Major taxa studied
Prokaryotes.
Methods
We conducted a global survey of GH distribution based on 10,000 samples from the Earth Microbiome Project (EMP) and 17,923 completely sequenced prokaryotic genomes. The samples were retrieved from seven continents, covering all 17 EMP Ontology environments. We evaluated the assembly process and influencing factors of GH functional genes within prokaryotic communities, and analysed the rank abundance distributions (RADs), occupancy frequency distributions (OFDs), and taxonomic sources of GH families across various environments.
Results
The median number of GH genes per thousand genes encoded by global prokaryotic communities was 9.11 (7.16–11.58), with a higher GH abundance in host‐associated communities than in free‐living communities. The median number of GH families in prokaryotic communities was 105 (86–121), with fewer families but tighter functional connections between families in host‐associated communities compared to free‐living communities. In any environment, the RAD of GH families followed a lognormal model, and their OFD was bimodal, with a strong positive correlation between the two. In addition, most GH families had complex and diverse taxonomic sources across different environments.
Main conclusions
This study provides a panoramic view of the functional potentials for carbohydrate degradation across prokaryotic communities under diverse environmental conditions. The composition of GHs encoded by prokaryotic communities exhibits clear habitat specificity, which is driven by a combination of biotic and abiotic factors and generated through highly deterministic assembly processes.
Background
The role of atopy patch test (APT) in the diagnosis of food allergy (FA) remains largely controversial. In our meta‐analysis, we aimed to evaluate the accuracy of APT for diagnosing FA in ...children.
Methods
Pubmed, Embase and Cochrane Library were searched for studies regarding the diagnostic value of APT for FA in children compared to oral food challenge (double‐blind placebo‐controlled food challenge and/or open food challenge). The last search was conducted on November 11, 2017. Two reviewers independently screened relevant studies and assessed the quality by QUADAS‐2. Meta‐analysis was performed to calculate the pooled sensitivity, specificity, DOR (diagnostic odds ratio), PLR (positive likelihood ratio), NLR (negative likelihood ratio) with their 95% confidence intervals (CIs). Subgroup analyses were conducted according to different food allergens, atopic dermatitis, gastrointestinal symptoms, and age younger than 3 years.
Results
Forty‐one studies were included in the meta‐analysis. The pooled sensitivity, specificity, PLR, NLR and DOR were 50.30% (95% CI 48.40%‐52.30%), 86.60% (95% CI 85.30%‐87.80%), 3.405 (95% CI 2.594‐4.470), 0.545 (95% CI 0.469‐0.634) and 7.528 (95% CI 5.507‐11.206), respectively. However, for children with FA‐related gastrointestinal symptoms, the pooled sensitivity and specificity were 57.40% (95% CI 52.10%‐62.50%) and 91.50% (95% CI 88.30%‐94.10%) respectively.
Conclusions
Our findings suggest that APT is specific but not sensitive for diagnosing FA in children, especially in children with FA‐related gastrointestinal symptoms.
•The diluted ferromagnetic spin-3/2 Ising nano-graphene monolayer has been studied.•Magnetization, susceptibility, internal energy and the specific heat have been investigated.•The phase diagrams of ...the blocking temperature for various parameters have been given.•The hysteresis behaviors have been discussed for certain physical parameters.
By means of Monte Carlo simulation, we have explored the magnetic and thermodynamic behaviors of the diluted ferromagnetic spin-3/2 Ising nano-graphene monolayer under the longitudinal magnetic field. The effects of the number of lattice sites, magnetic atom concentration, crystal field and external longitudinal magnetic field on the magnetic phase transition and hysteresis behaviors of the present system have been discussed. The characteristic curves of magnetization, magnetic susceptibility, internal energy and the specific heat as a function of temperature have been displayed specifically. We have presented the phase diagrams for various physical parameters. It is found that the area, coercivity and remanence of the hysteresis loops are strongly dependent on those selected parameters.
o
-Vanillin is a natural product that has been widely applied in the food and pharmaceutical industries. In this study, we determined that
o
-vanillin can strongly inhibit the growth of
Aspergillus ...flavus
mycelia. However, the inhibition mechanism of
o
-vanillin is still elusive. The ultrastructural morphology of mycelia was injured, and the cell walls were destroyed. The OH functional groups on cell walls were altered, and the content of protein in mycelial cell walls was reduced by
o
-vanillin. The content of β-1,3-glucan in cell walls was significantly (
P
< 0.05) reduced by
o
-vanillin in a dose-dependent manner, while chitin was not markedly affected. Moreover,
o
-vanillin led to an increase in the permeability of cell membranes.
o
-Vanillin also exhibited a promising antifungal effect on contaminated corn kernels. Therefore,
o
-vanillin inhibited the growth of mycelia by disrupting the integrity of cell walls and cell membranes. This study not only sheds light on the antifungal mechanism of
o
-vanillin but also indicates that it is a promising agent for the control of
A. flavus
infection.
Key points
• o
-Vanillin has strong inhibitory effects on A. flavus.
• o
-Vanillin destroyed the integrity of cell walls and cell membranes.
• o
-Vanillin could effectively inhibit the growth of A. flavus on corn kernels.
It has been suggested that n‐3 long‐chain polyunsaturated fatty acids (n‐3 LC‐PUFAs) have anti‐inflammatory properties and may reduce the risk of allergic disease. Fish is a great source of n‐3 ...LC‐PUFAs. However, the effect of fish on allergic disease remains controversial. PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) and prospective cohort studies regarding the effect of fish intake during pregnancy or infancy on allergic outcomes in children. The outcomes of interest were atopy, eczema, allergic rhinitis, wheeze, asthma, and food allergy. One RCT and 17 publications from 13 prospective cohort studies were included for maternal fish intake during pregnancy, and eight publications from five prospective cohort studies for fish intake in infancy. Pooled analysis suggested that maternal fish intake during pregnancy was not associated with lower risk of any allergic outcome, both in RCT and observational studies. Consumption of fish during the first year of life reduced the risk of eczema (RR 0.61; 95% CI 0.47, 0.80; p = 0.0003; I2 = 68%) and allergic rhinitis (RR 0.54; 95% CI 0.36, 0.81; p = 0.003; I2 = 74%). Current evidence indicates that fish intake in infancy could reduce the risk of eczema and allergic rhinitis in children, whereas maternal fish intake during pregnancy does not affect any atopic outcome. The intake of fish per se in infancy, not specially n‐3 LC‐PUFAs, may have an allergy protective effect. High‐quality and adequately powered RCTs are warranted to confirm this.
Bacterial genomes encode numerous cryptic biosynthetic gene clusters (BGCs) that represent a largely untapped source of drugs or pesticides. Mining of the cryptic products is limited by the ...unavailability of streamlined genetic tools in native producers. Precise genome engineering using bacteriophage recombinases is particularly useful for genome mining. However, recombinases are usually host-specific. The genome-guided discovery of novel recombinases and their transient expression could boost cryptic BGC mining. Herein, we reported a genetic system employing Red recombinases from Burkholderiales strain DSM 7029 for efficient genome engineering in several Burkholderiales species that currently lack effective genetic tools. Using specialized recombinases-assisted in situ insertion of functional promoters, we successfully mined five cryptic nonribosomal peptide synthetase/polyketide synthase BGCs, two of which were silent. Two classes of lipopeptides, glidopeptins and rhizomides, were identified through extensive spectroscopic characterization. This recombinase expression strategy offers utility within other bacteria species, allowing bioprospecting for potentially scalable discovery of novel metabolites with attractive bioactivities.
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