Multi-omics insights into the interplay between gut microbiota and colorectal cancer in the "microworld" age.

Colorectal cancer (CRC) is a multifactorial heterogeneous disease largely due to both genetic predisposition and environmental factors including the gut microbiota, a dynamic microbial ecosystem inhabiting the gastrointestinal tract. Elucidation of the molecular mechanisms by which the gut microbiota interacts with the host may contribute to the pathogenesis, diagnosis, and promotion of CRC. However, deciphering the influence of genetic variants and interactions with the gut microbial ecosystem is rather challenging. Despite recent advancements in single omics analysis, the application of multi-omics approaches to integrate multiple layers of information in the microbiome and host to introduce effective prevention, diagnosis, and treatment strategies is still in its infancy. Here, we integrate host- and microbe-based multi-omics studies, respectively, to provide a strategy to explore potential causal relationships between gut microbiota and colorectal cancer. Specifically, we summarize the recent multi-omics studies such as metagenomics combined with metabolomics and metagenomics combined with genomics. Meanwhile, the sample size and sample types commonly used in multi-omics research, as well as the methods of data analysis, were also generalized. We highlight multiple layers of information from multi-omics that need to be verified by different types of models. Together, this review provides new insights into the clinical diagnosis and treatment of colorectal cancer patients.

Nanoparticle-Based Photodynamic Inhibition of Candida albicans Biofilms with Interfering Quorum Sensing.

Biofilm formation is a critical event in the pathogenesis and virulence of fungal infections caused by Candida albicans, giving rise to about a 1000-fold increase in the resistance to antifungal agents. Although photodynamic treatment (PDT) has been excellently implicated in bacterial infections, studies on its potential against fungal infection through the clearance of fungal biofilm formation remain at its infancy stage. Here, we have designed photodynamic nanoparticles with different sizes, modifications, and the ability of generating reactive oxygen species (ROS) to examine their effects on inhibiting biofilm formation and destructing mature biofilms of C. albicans. We found that the nanoparticles modified with oligo-chitosan exhibited a better binding efficiency for planktonic cells, leading to stronger inhibitory efficacy of the filamentation and the early-stage biofilm formation. However, for mature biofilms, the nanoparticles with the smallest size (∼15 nm) showed the fastest penetration speed and a pronounced destructing effect albeit conferring the lowest ROS-producing capability. The inhibitory effect of photodynamic nanoparticles was dependent on the disruption of fungal quorum sensing (QS) by the upregulation of QS molecules, farnesol and tyrosol, mediated through the upregulation of ARO 8 and DPP 3 expression. Our findings provide a powerful strategy of nanoparticulate PDT to combat fungal infections through the inhibition of both hyphal and biofilm formation by disrupting QS.

Synthesis of Secondary Trifluoromethylated Alkyl Bromides Using 2-Bromo-3,3,3-trifluoropropene as a Radical Acceptor.

Herein, the first example using commercially available 2-bromo-3,3,3-trifluoropropene (BTP) as a radical acceptor has been reported. Taking advantage of this strategy, a wide range of secondary trifluoromethylated alkyl bromides were synthesized in good to excellent yields with broad functional group tolerance by using redox-active esters as a radical precursor. The practicality of this protocol was further demonstrated by diverse derivations and direct modification of biologically active molecules.

Multi-kingdom microbiota analyses identify bacterial-fungal interactions and biomarkers of colorectal cancer across cohorts.

Despite recent progress in our understanding of the association between the gut microbiome and colorectal cancer (CRC), multi-kingdom gut microbiome dysbiosis in CRC across cohorts is unexplored. We investigated four-kingdom microbiota alterations using CRC metagenomic datasets of 1,368 samples from 8 distinct geographical cohorts. Integrated analysis identified 20 archaeal, 27 bacterial, 20 fungal and 21 viral species for each single-kingdom diagnostic model. However, our data revealed superior diagnostic accuracy for models constructed with multi-kingdom markers, in particular the addition of fungal species. Specifically, 16 multi-kingdom markers including 11 bacterial, 4 fungal and 1 archaeal feature, achieved good performance in diagnosing patients with CRC (area under the receiver operating characteristic curve (AUROC) = 0.83) and maintained accuracy across 3 independent cohorts. Coabundance analysis of the ecological network revealed associations between bacterial and fungal species, such as Talaromyces islandicus and Clostridium saccharobutylicum. Using metagenome shotgun sequencing data, the predictive power of the microbial functional potential was explored and elevated D-amino acid metabolism and butanoate metabolism were observed in CRC. Interestingly, the diagnostic model based on functional EggNOG genes achieved high accuracy (AUROC = 0.86). Collectively, our findings uncovered CRC-associated microbiota common across cohorts and demonstrate the applicability of multi-kingdom and functional markers as CRC diagnostic tools and, potentially, as therapeutic targets for the treatment of CRC.

Nickel-Catalyzed Cross-Coupling of Amino-Acid-Derived Alkylzinc Reagents with Alkyl Bromides/Chlorides: Access to Diverse Unnatural Amino Acids.

Unnatural α-amino acids are important synthetic targets in the field of peptide science. Herein we report an efficient, versatile, and straightforward strategy for the synthesis of homophenylalanine derivatives via the nickel-catalyzed Csp3-Csp3 cross-coupling of (fluoro)benzyl bromides/chlorides with natural α-amino-acid-derived alkylzinc reagents. The current protocol features the advantages of a low-cost nickel catalyst system, synthetic convenience, and the tolerance of rich functionality and stereochemistry.

Effects of intensive blood pressure control on mortality and cardiorenal function in chronic kidney disease patients.

BACKGROUND: Blood pressure (BP) variability is highly correlated with cardiovascular and kidney outcomes in patients with chronic kidney disease (CKD). However, appropriate BP targets in patients with CKD remain uncertain. METHODS: We searched PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) of CKD patients who underwent intensive BP management. Kappa score was used to assess inter-rater agreement. A good agreement between the authors was observed to inter-rater reliability of RCTs selection (kappa = 0.77; P = 0.005). RESULTS: Ten relevant studies involving 20 059 patients were included in the meta-analysis. Overall, intensive BP management may reduce the incidence of cardiovascular disease mortality (RR: 0.69, 95% CI: 0.53 to 0.90, P: 0.01), all-cause mortality (RR: 0.77, 95% CI: 0.67 to 0.88, P < 0.01) and composite cardiovascular events (RR: 0.84 95% CI: 0.75 to 0.95, P < 0.01) in patients with CKD. However, reducing BP has no significant effect on the incidence of doubling of serum creatinine level or 50% reduction in GFR (RR: 1.26, 95% CI: 0.66 to 2.40, P = 0.48), composite renal events (RR 1.07, 95% CI: 0.81 to 1.41, P = 0.64) or SAEs (RR: 0.97, 95% CI: 0.90 to 1.05, P = 0.48). CONCLUSION: In patients with CKD, enhanced BP management is associated with reduced all-cause mortality, cardiovascular mortality, and incidence of composite cardiovascular events.

Identification of microbial markers across populations in early detection of colorectal cancer.

Associations between gut microbiota and colorectal cancer (CRC) have been widely investigated. However, the replicable markers for early-stage adenoma diagnosis across multiple populations remain elusive. Here, we perform an integrated analysis on 1056 public fecal samples, to identify adenoma-associated microbial markers for early detection of CRC. After adjusting for potential confounders, Random Forest classifiers are constructed with 11 markers to discriminate adenoma from control (area under the ROC curve (AUC) = 0.80), and 26 markers to discriminate adenoma from CRC (AUC = 0.89), respectively. Moreover, we validate the classifiers in two independent cohorts achieving AUCs of 0.78 and 0.84, respectively. Functional analysis reveals that the altered microbiome is characterized with increased ADP-L-glycero-beta-D-manno-heptose biosynthesis in adenoma and elevated menaquinone-10 biosynthesis in CRC. These findings are validated in a newly-collected cohort of 43 samples using quantitative real-time PCR. This work proves the validity of adenoma-specific markers across multi-populations, which would contribute to the early diagnosis and treatment of CRC.

Metabolic and transcriptomic analysis of two Cucurbita moschata germplasms throughout fruit development.

BACKGROUND: Pumpkins (Cucurbita moschata; Cucurbitaceae) are valued for their fruits and seeds and are rich in nutrients. Carotenoids and sugar contents, as main feature of pumpkin pulp, are used to determine the fruit quality. RESULTS: Two pumpkin germplasms, CMO-X and CMO-E, were analyzed regarding the essential quality traits such as dry weight, soluble solids, organic acids, carotenoids and sugar contents. For the comparison of fruit development in these two germplasms, fruit transcriptome was analyzed at 5 different developmental stages from 0 d to 40 d in a time course manner. Putative pathways for carotenoids biosynthesis and sucrose metabolism were developed in C. moschata fruit and homologs were identified for each key gene involved in the pathways. Gene expression data was found consistent with the accumulation of metabolites across developmental stages and also between two germplasms. PSY, PDS, ZEP, CRTISO and SUS, SPS, HK, FK were found highly correlated with the accumulation of carotenoids and sucrose metabolites, respectively, at different growth stages of C. moschata as shown by whole transcriptomic analysis. The results of qRT-PCR analysis further confirmed the association of these genes. CONCLUSION: Developmental regulation of the genes associated with the metabolite accumulation can be considered as an important factor for the determination of C. moschata fruit quality. This research will facilitate the investigation of metabolic profiles in other cultivars.

Visible light promoted fluoroalkylation of alkenes and alkynes using 2-bromophenol as a catalyst.

We report a new protocol for the fluoroalkylation of alkenes and alkynes by using 2-bromophenol as a catalyst. This reaction can be tailored for different reaction modes by altering the base and solvent, which feature a wide substrate scope and excellent functional group tolerance with high chemo- and regioselectivities. We further propose a mechanism involving an electron donor-acceptor (EDA) complex.

Palladium-catalyzed cross-coupling of unactivated alkylzinc reagents with 2-bromo-3,3,3-trifluoropropene and its application in the synthesis of fluorinated amino acids.

A palladium-catalyzed cross-coupling of unactivated alkylzinc reagents with 2-bromo-3,3,3-trifluoropropene (BTP) has been developed, which was used as a key step to prepare a series of trifluoromethylated and difluoromethylated amino acids that are of great interest in peptide/protein based chemical biology. The advantages of the synthesis of these fluorinated amino acids are synthetic simplicity and diversity from a simple and readily available key intermediate α-trifluoromethylalkene-containing amino acid, providing a facile route for applications in medicinal chemistry and life science.