Energy Pathways Research Articles

Design single-stranded DNA aptamer of cluster of differentiation 47 protein by stochastic tunnelling-basin hopping-discrete molecular dynamics method

The formation of the Cluster of Differentiation 47 (CD47, PDB code: 2JJT)/signal regulatory protein α (SIRPα) complex is very important as it protects healthy cells from immune clearance while promoting macrophage phagocytosis for tumour elimination. Although several antibodies have been developed for cancer therapy, new function-blocking aptamers are still under development. This study aims to design the aptamer AptCD47, which can block the formation of the CD47/SIRPα complex. This study employs the MARTINI coarse-grained (CG) force field and the stochastic tunnelling-basin hopping-discrete molecular dynamics (STUN-BH-DMD) method to identify the most stable AptCD47/CD47 complexes. Coarse-grained molecular dynamics (CGMD) simulations were used to obtain root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) analyses. The results demonstrate that the formation of AptCD47/CD47 complexes renders the CD47 structure more stable than the single CD47 molecule in a water environment. The minimum energy pathway (MEP) obtained by the nudged elastic band (NEB) method indicates that the binding processes of 5′-ATTCAATTCC-3′ and 5′-AGTGCAATCT-3′ to CD47 are barrierless, which is much lower than the binding barrier of SIRPα to CD47 of about 14.23 kcal/mol. Therefore, these two AptCD47/CD47 complexes can create a high spatial binding barrier for SIRPα, preventing the formation of a stable CD47/SIRPα complex. The proposed numerical process with the MARTINI CG force field can be used to design CD47 aptamers that efficiently block SIRPα from binding to CD47. Communicated by Ramaswamy H. Sarma

Enhanced Decomposition of Ammonium Perchlorate-Ethyl Cellulose-Molybdenum Disulfide Nanocomposites.

Ammonium perchlorate (AP) is commonly used in propulsion technology. Recent studies have demonstrated that two-dimensional (2D) nanomaterials such as graphene (Gr) and hexagonal boron nitride (hBN) dispersed with nitrocellulose (NC) can conformally coat the surface of AP particles and enhance the reactivity of AP. In this work, the effectiveness of ethyl cellulose (EC) as an alternative to NC was studied. Using a similar encapsulation procedure as in recent work, Gr and hBN dispersed with EC were used to synthesize the composite materials Gr-EC-AP and hBN-EC-AP. Additionally, EC was used because the polymer can be used to disperse other 2D nanomaterials, specifically molybdenum disulfide (MoS2), which has semiconducting properties. While Gr and hBN dispersed in EC had a minimal effect on the reactivity of AP, MoS2 dispersed in EC significantly enhanced the decomposition behavior of AP compared to the control and other 2D nanomaterials, as evidenced by a pronounced low-temperature decomposition event (LTD) centered at 300 °C and then complete high-temperature decomposition (HTD) below 400 °C. Moreover, thermogravimetric analysis (TGA) showed a 5% mass loss temperature (Td5%) of 291 °C for the MoS2-coated AP, which was 17 °C lower than the AP control. The kinetic parameters for the three encapsulated AP samples were calculated using the Kissinger equation and confirmed a lower activation energy pathway for the MoS2 (86 kJ/mol) composite compared to pure AP (137 kJ/mol). This unique behavior of MoS2 is likely due to enhanced oxidation-reduction of AP during the initial stages of the reaction via a transition metal-catalyzed pathway. Density functional theory (DFT) calculations showed that the interactions between AP and MoS2 were stronger than AP on the Gr or hBN surfaces. Overall, this study complements previous work on NC-wrapped AP composites and demonstrates the unique roles of the disperagent and 2D nanomaterial in tuning the thermal decomposition of AP.

Food web structure in the Xingu River rapids prior to operation of the Amazon’s largest hydropower plant

The results of recent theoretical studies suggest that food webs are size-structured, with top predators coupling across different energy sources. However, evidence supporting this hypothesis is still scarce, especially in highly diverse tropical rivers. In the present study, we explored the association between body size, trophic position, and the use of allochthonous and autochthonous basal production sources in the Volta Grande rapids of the Xingu River, a major clearwater tributary of the Amazon River, during the period prior to operation of the Belo Monte Hydropower Plant (BMHP). This section of the river contains a maze of channels with rocky shoals that support dozens of endemic fishes, mollusks and other aquatic taxa that may be impacted by flow regulation by the Pimental Dam located upstream. During the low-water season, we surveyed fish, crustaceans, mollusks, sponges, aquatic and terrestrial insects, zooplankton, and basal production sources to obtain tissue samples for analysis of stable isotope ratios of carbon (δ13C) and nitrogen (δ15N). The results indicated that the biomass of most aquatic organisms appears to be largely supported by riparian vegetation, highlighting the importance of the lateral connectivity between aquatic and terrestrial habitats. In contrast to expectation, we did not observe a gradual increase in the coupling of energy pathways with increasing body size and trophic position. These findings provide a baseline for the trophic ecology of this river under the natural flow regime that can be used for future impact assessments, and they also indicate that more complex food web models, potentially including additional functional traits (e.g., gut length) are needed to describe resource and habitat use in highly diverse tropical ecosystems.

On the Stereochemistry of the NH Bond Activation of Ammonia or Amines by Disilenes: Predictability.

The stereochemistry of the addition of NH3 to the stereoisomers of 1,2-di-tert-butyl-1,2-bis(2,4,6-triisopropylphenyl)disilene (Z-5 or E-5) is 100 % stereospecific giving two isomeric disilylamines 6 and 7, respectively, derived from syn-addition to the stereoisomeric disilenes. Variable Time Normalization Analysis studies of the reaction of tetramesityldisilene (3) with isopropylamine (iPrNH2) revealed that the order in both amine and disilene is 1. The kinetic isotope effect for the addition of iPrNH2/iPrND2 to tetramesityldisilene was determined to be 3.04 ± 0.06 at 298 K, a primary KIE, indicating that the proton is transferred in the rate determining step. Competition studies between the addition of PrNH2 and iPrNH2 to tetramesityldisilene resulted in the exclusive formation of the PrNH2 adduct consistent with a nucleophilic addition. Computational studies of the mechanism of the addition of ammonia to E-5 revealed the lowest energy pathway involves the formation of the donor adduct derived from syn-addition, followed by intramolecular syn-transfer of the proton. The results of this studyallow for a refinement of our understanding of the mechanism of this important fundamental reaction in disilene chemistry, and allow us to understand our ability to reliably predict the stereochemical outcomes of future NH σ-bond activation reactions.

Systems biology elucidates the distinctive metabolic niche filled by the human gut microbe Eggerthella lenta.

Human gut bacteria perform diverse metabolic functions with consequences for host health. The prevalent and disease-linked Actinobacterium Eggerthella lenta performs several unusual chemical transformations, but it does not metabolize sugars and its core growth strategy remains unclear. To obtain a comprehensive view of the metabolic network of E. lenta, we generated several complementary resources: defined culture media, metabolomics profiles of strain isolates, and a curated genome-scale metabolic reconstruction. Stable isotope-resolved metabolomics revealed that E. lenta uses acetate as a key carbon source while catabolizing arginine to generate ATP, traits which could be recapitulated in silico by our updated metabolic model. We compared these in vitro findings with metabolite shifts observed in E. lenta-colonized gnotobiotic mice, identifying shared signatures across environments and highlighting catabolism of the host signaling metabolite agmatine as an alternative energy pathway. Together, our results elucidate a distinctive metabolic niche filled by E. lenta in the gut ecosystem. Our culture media formulations, atlas of metabolomics data, and genome-scale metabolic reconstructions form a freely available collection of resources to support further study of the biology of this prevalent gut bacterium.

Drying, more than warming, alters ecosystem functioning in streams with different energy pathways

Abstract Empirical evidence and theory suggest that climate warming and an increase in the frequency and duration of drying events will alter the metabolic balance of freshwater ecosystems. However, the impacts of climate change on ecosystem metabolism may depend on whether energy inputs are of autochthonous or allochthonous origin. To date, few studies have examined how warming and drying may interact to alter stream metabolism, much less how their impacts may depend on the energy‐base of the food web. To address this research gap, we conducted a multi‐factorial experiment using outdoor mesocosms to investigate the individual and synergistic effects of warming and drought on metabolic processes in stream mesocosms with green (algal‐based) vs. mixed (algal‐ and detritus‐based) vs. brown (detritus‐based) energy pathways. We set up 48 mesocosms with one of three different levels of shade and leaf litter input combinations to create mesocosms with different primary energy channels. In addition, we warmed half of the mesocosms by ~2–3°C. We assessed changes in ecosystem respiration (ER), gross primary production (GPP), net ecosystem production (NEP) and organic matter biomass in warmed and ambient temperature mesocosms before a 24 day drying event and after rewetting. Surprisingly, experimental warming had little effect on metabolic processes. Drying, however, led to decreased rates of ER and GPP and led to an overall reduction in NEP. Although the effects of drying were similar across energy channel treatments, reductions in ER and GPP were primarily driven by decreases in biomass of benthic and filamentous algae. Overall, we demonstrate that drying led to lower rates of NEP in mesocosms regardless of energy inputs. While warming showed little effect in our study, our results suggest that an increase in the frequency of stream drying events could greatly alter the metabolic balance of many aquatic ecosystems. Read the free Plain Language Summary for this article on the Journal blog.

Medium- and time-related effects on hypothermic storage of rat testicular cells.

Testicular samples obtained for fertility preservation often need to be transported between clinics. This study aimed to mimic this short-term hypothermic storage (4-8 °C) and explore the impact of these conditions and the transport medium composition on prepubertal rat testicular tissue samples. Testicular tissue samples obtained from seven days post-partum rats were transferred to six compositionally different basal culture media and a balanced salt solution, which had been kept at 4-8 °C prior to transfer. The samples were preserved for either 12 or 24 hours in these hypothermic conditions. The potential effects of the short-term storage were evaluated by assessing the morphology, measuring the testosterone levels by radioimmunoassay and analysing 96 genes with TaqMan Low-Density Arrays. Summarizing results: Levels of gene expression related to energy, apoptosis and angiogenesis pathways were altered after hypothermic storage for 12 and especially 24 hours. We observed only minor differences in gene expression profiles for germ and testicular somatic cells, and no differences in tissue morphology and testosterone production levels. Short-term hypothermic storage of testicular tissue with a maximum duration of 24 hours does not affect the overall expression profile of testicular cell-specific genes; however, in a minor way, it affects the expression of specific cellular genes.

The Effect of Calorie Restriction on Protein Quality Control in Yeast.

Initially, protein aggregates were regarded as a sign of a pathological state of the cell. Later, it was found that these assemblies are formed in response to stress, and that some of them serve as signalling mechanisms. This review has a particular focus on how intracellular protein aggregates are related to altered metabolism caused by different glucose concentrations in the extracellular environment. We summarise the current knowledge of the role of energy homeostasis signalling pathways in the consequent effect on intracellular protein aggregate accumulation and removal. This covers regulation at different levels, including elevated protein degradation and proteasome activity mediated by the Hxk2 protein, the enhanced ubiquitination of aberrant proteins through Torc1/Sch9 and Msn2/Whi2, and the activation of autophagy mediated through ATG genes. Finally, certain proteins form reversible biomolecular aggregates in response to stress and reduced glucose levels, which are used as a signalling mechanism in the cell, controlling major primary energy pathways related to glucose sensing.

Transcriptome profile analysis of Indian mustard (Brassica juncea L.) during seed germination reveals the drought stress-induced genes associated with energy, hormone, and phenylpropanoid pathways

Indian mustard (Brassica juncea L. Czern and Coss) is an important oil and vegetable crop frequently affected by seasonal drought stress during seed germination, which retards plant growth and causes yield loss considerably. However, the gene networks regulating responses to drought stress in leafy Indian mustard remain elusive. Here, we elucidated the underlying gene networks and pathways of drought response in leafy Indian mustard using next-generation transcriptomic techniques. Phenotypic analysis showed that the drought-tolerant leafy Indian mustard cv. ‘WeiLiang’ (WL) had a higher germination rate, antioxidant capacity, and better growth performance than the drought-sensitive cv. ‘ShuiDong’ (SD). Transcriptome analysis identified differentially expressed genes (DEGs) in both cultivars under drought stress during four germination time points (i.e., 0, 12, 24, and 36 h); most of which were classified as drought-responsive, seed germination, and dormancy-related genes. In the Kyoto Encyclopedia of Genes and Genome (KEGG) analyses, three main pathways (i.e., starch and sucrose metabolism, phenylpropanoid biosynthesis, and plant hormone signal transduction) were unveiled involved in response to drought stress during seed germination. Furthermore, Weighted Gene Co-expression Network Analysis (WGCNA) identified several hub genes (novel.12726, novel.1856, BjuB027900, BjuA003402, BjuA021578, BjuA005565, BjuB006596, novel.12977, and BjuA033308) associated with seed germination and drought stress in leafy Indian mustard. Taken together, these findings deepen our understanding of the gene networks for drought responses during seed germination in leafy Indian mustard and provide potential target genes for the genetic improvement of drought tolerance in this crop.

Hollow Hierarchical Cu2 O-Derived Electrocatalysts Steering CO2 Reduction to Multi-Carbon Chemicals at Low Overpotentials.

The electrochemical reduction of carbon dioxideinto multi-carbon products (C2+ ) using renewably generated electricity provides a promising pathway for energy and environmental sustainability. Various oxide-derived copper (OD-Cu) catalysts have been showcased, but still require high overpotential to drive C2+ production owing to sluggish carbon-carbon bond formation and low CO intermediate (*CO) coverage. Here, the dilemma is circumvented by elaborately devising the OD-Cu morphology. First, computational studies propose a hollow and hierarchical OD-Cu microstructure that can generate a core-shell microenvironment to inhibit CO evolution and accelerate *CO dimerization via intermediate confinement and electric field enhancement, thereby boosting C2+ generation. Experimentally, the designed nanoarchitectures are synthesized through a heteroseed-induced approach followed by electrochemical activation. In situ spectroscopic studies further elaborate correlation between *CO dimerization and designed architectures. Remarkably, the hierarchical OD-Cu manifests morphology-dependent selectivity of CO2 reduction, giving a C2+ Faradaic efficiency of 75.6% at a considerably positive potential of -0.55V versus reversible hydrogen electrode.

Hydrogen-promoted in-void diffusion of helium in a 3C-SiC(310) twin boundary: a first-principles study

The role of H atoms in the formation of irradiation-induced He bubbles in SiC grain boundaries (GBs) is unclear. The effects of H on the formation energies (Ef s) and diffusion behaviour of He in the 3C-SiC twin boundary (TB) were studied using the density functional theory. We observed that a He atom stabilises at three typical sites in the 3C-SiC (310) TB with Ef s = 1.95, 2.05, and 1.67 eV, which are significantly lower than those in the SiC grains. The addition of the H atom shifts the stable sites of He in the TB and increases Ef s to 4.66, 3.96, and 5.13 eV. The minimum energy pathways for He diffusion in TB were changed by the addition of H atom. Moreover, the H atom reduces the barrier from 3.69 to 1.04 eV for the He diffusion in one TB void and increases it from 1.30 to 4.08 eV for the He diffusion between adjacent TB voids. We interpreted the above results through the Bader charge, density of states, and atomic force analysis. The results indicate that H promotes the in-void diffusion but suppresses the inter-void diffusion of He atoms in SiC GBs, which favours the aggregation and nucleation of He in SiC GBs.

Plankton depletion by mussel grazing negatively impacts the fitness of lobster larvae

Bivalve aquaculture has rapidly expanded in shallow coastal habitats, leading to substantial changes in the natural environment. While the grazing pressure of mussels (Mytilus edulis) on phytoplankton and zooplankton has been well documented, cascading effects of plankton depletion on the development and survival of resident fish and invertebrate larvae remains largely unexplored. This study experimentally assessed the impact of control (no mussel grazing), low (20 mussels·m−3) and high (80 mussels·m−3) mussel densities on a model community composed of various phytoplankton and zooplankton and how changes in plankton characteristics influence the development and survival of lobster (Homarus americanus) larvae. Mussels fed primarily on nanophytoplankton, while the picophytoplankton experienced significantly less grazing. Zooplankton was readily ingested by mussels, showing a sharp decline under low mussel density, whereas it was eliminated from the plankton under high density of mussels. A 65% decrease of polyunsaturated fatty acids (∑ PUFA) was observed in the plankton under mussel filtration compared to control. Lobster larvae reared under control plankton conditions exhibited the fastest development, highest survival rate, carapace length, total lipid and ∑ PUFA contents, and TAG/ST (triacylglycerols/sterols) ratio, indicating the best nutritional condition. Larvae reared under low mussel density showed longer developmental time, lower survival rate and carapace length than that for controls. In addition, these larvae showed a significant reduction in total lipid, ∑ PUFA, and TAG/ST, which collectively suggests poor nutritional status due to limited dietary intake. Under high mussel density, larvae did not molt to stage II and died within 14 days, suggesting that the depleted plankton community was unable to sustain physiological requirements for survival and development of the larvae. Overall, mussel grazing altered the meroplankton community structure and its biochemical composition, ultimately impacting the development, survival, and quality of lobster larvae. These findings provide novel information on complex trophic interactions between bivalves and a meroplankton species and adds a new perspective to fuel discussions on energy and nutrient pathways, particularly long-chain PUFA, in ecosystem carrying capacity studies for shellfish aquaculture in shallow coastal habitats.

Theoretical study on the adsorption and oxidation of glucose on Au(111) surface.

While Au-based catalysts recently have shown tremendous potential in glucose oxidation to gluconic acid, the detailed reaction mechanism is still unclear, which impedes the development of direct glucose fuel cell (DGFC). Using density functional theory (DFT), we exhibit some new adsorption configurations and oxidation mechanisms by considering both the open chain form and the ring form of glucose on Au(111) surface in the presence of OH. The strong interactions between glucose and the OH adsorbed surface are obtained. Moreover, form the calculated energy pathways, the oxidation of glucose in the open chain involves the dissociation of the formyl C - H bond by the adsorbed OH, while the ring form glucose oxidation is initiated by O - H bond rupture rather than C - H bond scission and preferentially undergoes the ring-open process to generate the open chain form glucose. Meanwhile, the results demonstrate that the adsorbed OH assists in reducing the activation energy of reaction process.

Activated dissociation of H2 on the Cu(001) surface: The role of quantum tunneling

The activation and dissociation of hydrogen molecules (H2) on the Cu(001) surface are studied theoretically. Using first-principles calculations, the activation barrier for the dissociation of H2 on Cu(001) is determined to be ∼ 0.59 eV in height. It is found that the electron transfer from the copper substrate to H2 plays a key role in the activation and breaking of the H–H bond, and the formation of the Cu–H bonds. Two stationary states are identified at around the critical height of bond breaking, corresponding to the molecular and the dissociative states, respectively. Using the transfer matrix method, we also investigate the role of quantum tunneling in the dissociation process along the minimum energy pathway (MEP), which is found to be significant at or below room temperature. At a given temperature, the tunneling contributions due to the translational and the vibrational motions of H2 are quantified for the dissociation process. Within a wide range of temperature, the effects of quantum tunneling on the effective barriers of dissociation and the rate constants are observed. The deduced energetic parameters associated with the thermal equilibrium and non-equilibrium (molecular beam) conditions are comparable to experimental data. In the low-temperature region, the crossover from classical to quantum regime is identified.

Boosting the selectivity and efficiency of nitrate reduction to ammonia with a single-atom Cu electrocatalyst

Electrochemically reducing nitrate to ammonia provides an efficient pathway to alleviate nitrate pollution and produce ammonia. However, it remains challenging to regulate the low selectivity of ammonia production and the sluggish kinetics of nitrate-to-ammonia conversion. Here, a single-atom Cu catalyst is prepared for selective and efficient nitrate reduction to ammonia, achieving an ammonia production rate of 2602 μg cm-1h−1 (5302 μg h−1 mgcat.-1) at −1.1 V (vs. RHE) with 87.2% Faradic efficiency and 94.1% ammonia selectivity in 0.01 M PBS buffer solution (pH about 7, containing 500 mg L-1 nitrate-N), outcompeting to most of the reported catalysts. DFT calculations reveal that the CuN4 site facilitates both the *NO formation and the subsequent ammonia generation for nitrate reduction in a complete downhill free energy pathway, thus providing the remarkable activity and selectivity of ammonia production for the single-atom Cu catalyst superior to the Cu nanoparticle catalyst. This study provides a strategy for designing electrocatalysts in efficient and selective ammonia production via nitrate reduction.

Estimation of energy pathway fluxes in cancer cells - Beyond the Warburg effect

Glycolytic and respiratory fluxes were analyzed in cancer and non-cancer cells. The steady-state fluxes in energy metabolism were used to estimate the contributions of aerobic glycolytic and oxidative phosphorylation (OxPhos) pathways to the cellular ATP supply. The rate of lactate production - corrected for the fraction generated by glutaminolysis - is proposed as the appropriate way to estimate glycolytic flux. In general, the glycolytic rates estimated for cancer cells are higher than those found in non-cancer cells, as originally observed by Otto Warburg. The rate of basal or endogenous cellular O2 consumption corrected for non-ATP synthesizing O2 consumption, measured after inhibition by oligomycin (a specific, potent and permeable ATP synthase inhibitor), has been proposed as the appropriate way to estimate mitochondrial ATP synthesis-linked O2 flux or net OxPhos flux in living cells. Detecting non-negligible oligomycin-sensitive O2 consumption rates in cancer cells has revealed that the mitochondrial function is not impaired, as claimed by the Warburg effect. Furthermore, when calculating the relative contributions to cellular ATP supply, under a variety of environmental conditions and for different types of cancer cells, it was found that OxPhos pathway was the main ATP provider over glycolysis. Hence, OxPhos pathway targeting can be successfully used to block in cancer cells ATP-dependent processes such as migration. These observations may guide the re-design of novel targeted therapies.

Mechanisms for generating and connecting the Yanai-mode and Rossby-mode tropical instability waves in the equatorial Pacific

It is generally believed that both barotropic and baroclinic instabilities may account for the tropical instability wave (TIW) variabilities in the equatorial Pacific Ocean. However, the coupling mechanisms between the two different meridional TIW modes, i.e., the Yanai-mode at the equator and the Rossby-mode around 5°N, and the associated vertical connections, are yet to be clarified. This is done here using a recently developed multiscale decomposition tool, multiscale window transform (MWT), and the MWT-based theory of canonical transfer and TIW-scale eddy kinetic energy (EKE) budget analysis, based on the (1/12.5)∘ HYCOM reanalysis data. In the subsurface layer (30–200 m), barotropic instability is the primary energy source for the Yanai-mode TIWs, while baroclinic instability dominates the EKE generation of the Rossby-mode TIWs. In contrast, the two TIW modes in the surface layer (0–30 m) are largely modulated by nonlocal mechanisms through pressure work, which functions to transport EKE upward from the subsurface to the surface layer, and southward from the Rossby-mode region to the Yanai-mode region. The pressure fluxes substantially couple the two TIW modes in both the meridional and vertical directions, leading to significant coherence between EKE in different vertical layers and regions of the TIWs. In addition, the prevailing vertical pressure flux identified north of the equator explains why the EKE signal is more vertically coherent in the Rossby-mode region than the Yanai-mode region. This nonlocal energy pathway, as well as the well-known instability processes, undergoes strong seasonal variations that determine the seasonal cycles of the TIWs in the equatorial Pacific Ocean.

Additive energy functions have predictable landscape topologies.

Recent work [Mirth et al., J. Chem. Phys. 154, 114114 (2021)] has demonstrated that sublevelset persistent homology provides a compact representation of the complex features of an energy landscape in 3 N-dimensions. This includes information about all transition paths between local minima (connected by critical points of index ≥1) and allows for differentiation of energy landscapes that may appear similar when considering only the lowest energy pathways (as tracked by other representations, such as disconnectivity graphs, using index 1 critical points). Using the additive nature of the conformational potential energy landscape of n-alkanes, it became apparent that some topological features-such as the number of sublevelset persistence bars-could be proven. This work expands the notion of predictable energy landscape topology to any additive intramolecular energy function on a product space, including the number of sublevelset persistent bars as well as the birth and death times of these topological features. This amounts to a rigorous methodology to predict the relative energies of all topological features of the conformational energy landscape in 3N dimensions (without the need for dimensionality reduction). This approach is demonstrated for branched alkanes of varying complexity and connectivity patterns. More generally, this result explains how the sublevelset persistent homology of an additive energy landscape can be computed from the individual terms comprising that landscape.

Integrated serum pharmacochemistry and metabolomics reveal potential effective components and mechanisms of Shengjiang Xiexin decoction in the treatment of Clostridium difficile infection

Shengjiang Xiexin Decoction (SXD) is a widely recognized formula in Traditional Chinese Medicine (TCM) for treating diarrhea and is commonly used in clinical practice. Clostridium difficile infection (CDI) is a type of antibiotic-associated diarrhea with a rising incidence rate that has severe consequences for humans. Recent clinical applications have found significant efficacy in using SXD as an adjunct to CDI treatment. However, the pharmacodynamic substance basis and therapeutic mechanism of SXD remain unclear. This study aimed to systematically analyze the metabolic mechanisms and key pharmacodynamic components of SXD in CDI mice by combining non-targeted metabolomics of Chinese medicine and serum medicinal chemistry. We established a CDI mouse model to observe the therapeutic effect of SXD on CDI. We investigated the mechanism of action and active substance composition of SXD against CDI by analyzing 16S rDNA gut microbiota, untargeted serum metabolomics, and serum pharmacochemistry. We also constructed a multi-scale, multifactorial network for overall visualization and analysis. Our results showed that SXD significantly reduced fecal toxin levels and attenuated colonic injury in CDI model mice. Additionally, SXD partially restored CDI-induced gut microbiota composition. Non-targeted serum metabolomics studies showed that SXD not only regulated Taurine and hypotaurine metabolism but also metabolic energy and amino acid pathways such as Ascorbate and aldarate metabolism, Glycerolipid metabolism, Pentose and glucuronate interconversions, as well as body and other metabolite production in the host. Through the implementation of network analysis methodologies, we have discerned that Panaxadiol, Methoxylutcolin, Ginsenoside-Rf, Suffruticoside A, and 10 other components serve as critical potential pharmacodynamic substance bases of SXD for CDI. This study reveals the metabolic mechanism and active substance components of SXD for the treatment of CDI mice using phenotypic information, gut microbiome, herbal metabolomics, and serum pharmacochemistry. It provides a theoretical basis for SXD quality control studies.

Interplay of Metabolome and Gut Microbiome in Individuals With Major Depressive Disorder vs Control Individuals

Metabolomics reflect the net effect of genetic and environmental influences and thus provide a comprehensive approach to evaluating the pathogenesis of complex diseases, such as depression. To identify the metabolic signatures of major depressive disorder (MDD), elucidate the direction of associations using mendelian randomization, and evaluate the interplay of the human gut microbiome and metabolome in the development of MDD. This cohort study used data from participants in the UK Biobank cohort (n = 500 000; aged 37 to 73 years; recruited from 2006 to 2010) whose blood was profiled for metabolomics. Replication was sought in the PREDICT and BBMRI-NL studies. Publicly available summary statistics from a 2019 genome-wide association study of depression were used for the mendelian randomization (individuals with MDD = 59 851; control individuals = 113 154). Summary statistics for the metabolites were obtained from OpenGWAS in MRbase (n = 118 000). To evaluate the interplay of the metabolome and the gut microbiome in the pathogenesis of depression, metabolic signatures of the gut microbiome were obtained from a 2019 study performed in Dutch cohorts. Data were analyzed from March to December 2021. Outcomes were lifetime and recurrent MDD, with 249 metabolites profiled with nuclear magnetic resonance spectroscopy with the Nightingale platform. The study included 6811 individuals with lifetime MDD compared with 51 446 control individuals and 4370 individuals with recurrent MDD compared with 62 508 control individuals. Individuals with lifetime MDD were younger (median [IQR] age, 56 [49-62] years vs 58 [51-64] years) and more often female (4447 [65%] vs 2364 [35%]) than control individuals. Metabolic signatures of MDD consisted of 124 metabolites spanning the energy and lipid metabolism pathways. Novel findings included 49 metabolites, including those involved in the tricarboxylic acid cycle (ie, citrate and pyruvate). Citrate was significantly decreased (β [SE], -0.07 [0.02]; FDR = 4 × 10-04) and pyruvate was significantly increased (β [SE], 0.04 [0.02]; FDR = 0.02) in individuals with MDD. Changes observed in these metabolites, particularly lipoproteins, were consistent with the differential composition of gut microbiota belonging to the order Clostridiales and the phyla Proteobacteria/Pseudomonadota and Bacteroidetes/Bacteroidota. Mendelian randomization suggested that fatty acids and intermediate and very large density lipoproteins changed in association with the disease process but high-density lipoproteins and the metabolites in the tricarboxylic acid cycle did not. The study findings showed that energy metabolism was disturbed in individuals with MDD and that the interplay of the gut microbiome and blood metabolome may play a role in lipid metabolism in individuals with MDD.