PubMed

J Ethnopharmacol. 2023 Nov 2:117383. doi: 10.1016/j.jep.2023.117383. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Danggui Shaoyao San (DSS) is a traditional Chinese medicine (TCM) first recorded in the Synopsis of the Golden Chamber. DSS has proven efficacy in treating hepatic fibrosis (HF). However, the effects and mechanisms of DSS on HF are not clear.AIM OF THE STUDY: To investigate the effect of DSS on HF via gut microbiota and its metabolites (SCFAs, BAs).MATERIALS AND METHODS: HF rats were induced with CCl4 and treated with DSS. Firstly, the therapeutic efficacy of DSS in HF rats and the protection of gut barrier were assessed. Then, 16S rRNA gene sequencing and untargeted fecal metabolomics preliminarily explored the mechanism of DSS in treating HF, and identified different microbiota and metabolic pathways. Finally, targeted metabolomics, RT-qPCR and Elisa were used to further validate the mechanism of DSS for HF based on the metabolism of SCFAs and BAs.RESULTS: After 8 weeks of administration, DSS significantly reduced the degree of HF. In addition, DSS alleviated inflammation in the ileum and reduced the levels of LPS and D-lactate. Furthermore, DSS altered the structure of gut microbiota, especially Veillonella, Romboutsia, Monoglobus, Parabacteroides, norank_f_Coriobacteriales_ Incertae_Sedis. These bacteria have been linked to the production of SCFAs and the metabolism of BAs. Untargeted metabolomics suggested that DSS may play a role via BAs metabolism. Subsequently, targeted metabolomics, RT-qPCR and Elisa further confirmed the key role of DSS in increasing SCFAs levels and regulating BAs metabolism.CONCLUSIONS: DSS can alleviate CCl4-induced HF and protect the intestinal barrier. DSS may exert its beneficial effects on HF by affecting the gut microbiota and its metabolites (SCFAs, BAs).PMID:37925004 | DOI:10.1016/j.jep.2023.117383

J Ethnopharmacol. 2023 Nov 2:117384. doi: 10.1016/j.jep.2023.117384. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The overuse of antibiotics has resulted in Clostridium difficile infection (CDI) as a significant global public health concern. Studies have shown that imbalances in gut microbiota and metabolism play a vital role in the onset of CDI. Shengjiang Xiexin decoction (SJT), a traditional Chinese medicinal formula widely employed in the treatment of gastrointestinal ailments, demonstrates effectiveness in addressing murine CDI. However, the precise mechanistic role of SJT in CDI treatment remains uncertain, particularly regarding its impact on gut microbiota and intestinal metabolism. Thus, further investigation is imperative to shed light on these mechanisms.AIM OF THE STUDY: This study aims to thoroughly investigate the therapeutic potential of SJT in the treatment of CDI, while also examining its impact on the intricate interplay between gut microbiota and bile acid metabolism. By employing a mouse model, we aspire to uncover novel insights that could pave the way for the development of more effective strategies in combating CDI.MATERIALS AND METHODS: We developed a mouse model for CDI and assessed SJT's potential as a therapeutic agent through pharmacological analyses. Our study employed high-throughput sequencing of 16S rRNA to identify changes in gut microbiota composition and untargeted metabolomics analysis to evaluate SJT's intervention on intestinal metabolism. We also conducted targeted analysis of bile acid metabolism to examine the specific effects of SJT. Finally, the growth-inhibitory effect of SJT on C. difficile was confirmed through ex vivo cultivation of the pathogen using cecal contents, supporting its potential role in treating CDI by modulating gut microbiota and bile acid metabolism.RESULTS: In pharmacological studies, SJT was found to effectively reduce the levels of A&B toxins and alleviate colonic inflammation in CDI mice. Mechanistically, SJT demonstrated a mild increase in the abundance and diversity of the gut microbiota. However, its most significant impact was observed in the substantial improvement of the structural composition of the gut microbiota. Specifically, SJT decreased the abundance of gut Polymorphs and Firmicutes while restoring the proportions of family Trichophyton and Bacteroides_S24-7 spp (P < 0.001). Moreover, SJT not only decreased the levels of primary bile acids but also elevated the levels of secondary bile acids. Notably, it enhanced the conversion of taurocholic acid (TCA) to deoxycholic acid (DCA), leading to a balanced bile acid metabolism. Finally, cecal contents of SJT-treated mice showed a significant reduction in the growth of C. difficile, underscoring the therapeutic potential of SJT via modulation of gut microbiota and bile acid metabolism.CONCLUSION: SJT demonstrates remarkable efficacy in treating CDI in mice by not only effectively combating the infection but also restoring the intricate balance of gut microbiota and bile acid metabolism. Furthermore, promising indications suggest that SJT may have the potential to prevent CDI recurrence. These findings underscore the comprehensive therapeutic value of SJT in managing CDI. Moving forward, we plan to transition from the laboratory to clinical settings to conduct further studies, validating our conclusions on SJT's efficacy.PMID:37925000 | DOI:10.1016/j.jep.2023.117384

J Control Release. 2023 Nov 2:S0168-3659(23)00714-9. doi: 10.1016/j.jconrel.2023.10.053. Online ahead of print.ABSTRACTAs the main cause of destructive plant diseases, pathogenic oomycete in plant rhizosphere brings about enormous losses to agricultural production. Although chemical pesticides are still one of the most important prevention and control methods for phytopathogens, the usage of chemical pesticides was limited by the 3R (resistance, residue, and rampant) problem. In the early stage of our research, analysis and comparison of the metabolome of resistance to Phytophthora nicotianae and common strain suggested that naringenin might be a highly efficient potential biogenic antimicrobial agent to prevent and control soil rhizosphere diseases. Unfortunately, the bioactivity and absorption capacity of active ingredients in the environment made it unsuitable for field application; thus, for efficient field application of naringenin, the 24 nm-sized naringenin-loaded nano-star-shaped polymerized (NSPs) were prepared with good loading efficiency 37.3% for naringenin. The soil mobility test indicated that NSPs could effectively reduce the adsorption of active ingredients and enhance the mobility of active ingredients in soil. The bacteriostatic test proved that these NSPs had better antimicrobial activity than the naringenin used alone and could efficiently induce the expression of plant resistance phenylpropanoid compounds. Finally, pot and field experiments showed improved control efficiency of NSPs 41% loaded with naringenin. Transcriptome analysis found that a large number of energy-related genes were downregulated in NSPs nematodes, suggesting that disturbed energy-related genes might lead to the disturbance of energy synthesis and metabolism. Naringenin-loaded nano-carriers were used to prevent and control plant disease-causing pathogens in the rhizosphere, which is of great significance to improve the prevention and control effect and reduce the environmental load of these anti-pathogenic agents.PMID:37924956 | DOI:10.1016/j.jconrel.2023.10.053

Sci Total Environ. 2023 Nov 2:168219. doi: 10.1016/j.scitotenv.2023.168219. Online ahead of print.ABSTRACTThe effect of microplastics (MPs) on plant growth has received increasing attention. However, whether soil texture and MPs size influence the toxicological effects of MPs on plants is unknown. To address this knowledge gap, two soils with different physical structures (lime concretion black and silty loam soils) were selected to explore the potential toxicity of MPs of different particle sizes to maize growth. The results showed that, in both soils, the harm caused by small MPs on maize growth was greater than that caused by large MPs. Low MPs concentrations had no significant effect on maize growth between two soil types; however, when exposed to a concentration of 1 % large MPs, the dry biomass of maize was promoted in lime concretion black soil but inhibited in silty loam soil. All MPs-exposed treatments resulted in a high level of superoxide anions in maize roots, resulting in an increase in the root aerenchyma area and reducing the metabolic activity of maize roots. Metabolomics showed that MPs exposure affected multiple amino acid metabolic pathways, including phenylalanine and tyrosine metabolism, and inhibited lignin biosynthesis in roots. This study provides a theoretical basis for a more comprehensive assessment of the effect of MPs pollution on agricultural production.PMID:37924875 | DOI:10.1016/j.scitotenv.2023.168219

Biomed Pharmacother. 2023 Nov 2;168:115825. doi: 10.1016/j.biopha.2023.115825. Online ahead of print.ABSTRACTAlzheimer's disease (AD) is a progressive neurodegenerative disease for which there is a lack of effective therapeutic drugs. There is great potential for natural products to be used in the development of anti-AD drugs. P-coumaric acid (PCA), a small molecule phenolic acid widely distributed in the plant kingdom, has pharmacological effects such as neuroprotection, but its anti-AD mechanism has not been fully elucidated. In the current study, we investigated the mechanism of PCA intervention in the Aβ25-35-induced AD model using gut microbiomics and serum metabolomics combined with in vitro and in vivo pharmacological experiments. PCA was found to ameliorate cognitive dysfunction and neuronal cell damage in Aβ25-35-injected mice as measured by behavioral, pathological and biochemical indicators. 16S rDNA sequencing and serum metabolomics showed that PCA reduced the abundance of pro-inflammatory-associated microbiota (morganella, holdemanella, fusicatenibacter and serratia) in the gut, which were closely associated with metabolites of the glucose metabolism, arachidonic acid metabolism, tyrosine metabolism and phospholipid metabolism pathways in serum. Next, in vivo and in vitro pharmacological investigations revealed that PCA regulated Aβ25-35-induced disruption of glucose metabolism through activation of PI3K/AKT/Glut1 signaling. Additionally, PCA ameliorated Aβ25-35-induced neuroinflammation by inhibiting nuclear translocation of NF-κB and by modulating upstream MAPK signaling. In conclusion, PCA ameliorated cognitive deficits in Aβ25-35-induced AD mice by regulating glucose metabolism and neuroinflammation, and the mechanism is related not only to restoring homeostasis of gut microbiota and serum metabolites, but also to PI3K/AKT/Glut1 and MAPK/NF-κB signaling.PMID:37924791 | DOI:10.1016/j.biopha.2023.115825

Phytomedicine. 2023 Sep 21;122:155112. doi: 10.1016/j.phymed.2023.155112. Online ahead of print.ABSTRACTBACKGROUND: The prevalence of cardiac fibrosis, intricately linked to various cardiovascular diseases, continues to rise. Aconite, a traditional Chinese herb renowned for its cardiovascular benefits, holds promise in treating heart ailments. However, the mechanisms underlying its anti-fibrotic effects, particularly in cardiac fibrosis, remain elusive.HYPOTHESIS/PURPOSE: This study aims to shed light on aconite's potential as an anti-fibrotic agent and elucidate its mechanisms in a rat model of isoproterenol (ISO)-induced cardiac fibrosis.METHODS: By inducing cardiac fibrosis through ISO injection, the study investigates the role of decoction of white aconite (DWA) in mitigating fibrotic processes. Techniques including metabolomics, RT-qPCR, western blot, and immunofluorescence were employed to unveil the molecular changes induced by DWA.RESULTS: DWA exhibited a remarkable reduction in echocardiographic parameters, cardiac weight increase, myocardial infarction extent, inflammatory cell infiltration, collagen deposition in heart tissue, and serum CK-MB, cTnT, cTnI levels post ISO injection. Metabolomic analysis unveiled DWA's modulation of 27 metabolites, especially in galactose metabolism, addressing metabolic disturbances in cardiac fibrosis. Additionally, DWA suppressed mRNA expression of fibrosis markers (Collagen I, CTGF, TGF-β), inhibited protein levels of MMP-9, α-SMA, and Galectin-3, while elevating TIMP1 expression.CONCLUSION: DWA demonstrated potent anti-fibrotic effects by curbing collagen deposition and alleviating metabolic disruptions in cardiac fibrosis via the galactose metabolism pathway, possibly mediated by the Gal-3/TGF-β/Smad signaling pathway.PMID:37924690 | DOI:10.1016/j.phymed.2023.155112

J Pharm Biomed Anal. 2023 Oct 20;238:115801. doi: 10.1016/j.jpba.2023.115801. Online ahead of print.ABSTRACTLiver injury is a strong independent predictor of mortality in patients with sepsis, in which gut dysbiosis plays a crucial role. Hydroxyl safflower yellow A (HSYA), an important component of safflower, has been used to treat liver injury in animal models. However, its role in sepsis-induced liver dysfunction and the specific molecular mechanisms remain unclear. In the current study, we first discussed the discrepancy in the gut microbiota between the cecal ligation puncture (CLP) and HSYA groups using 16 S RNA sequencing. Our data demonstrated that HSYA supplementation significantly decreased the relative abundance of Proteobacteria, Firmicutes, and Campylobacterota, and further decreased the abundance of Bacteroidota, suggesting that the protective effects of HSYA against sepsis-induced liver injury may be partially attributed to the alteration of these bacteria. In addition, the metabolomic data identified 823 differentially expressed metabolites associated with sepsis-induced liver injury. After HSYA supplementation, the levels of 56 metabolites were restored to sham-like levels. Transcriptomic analysis revealed 4990 differentially expressed genes (DEGs) between the sham and CLP groups, and after HSYA injection, 1613 genes were modulated. Comprehensive analysis demonstrated that the enrichment pathways of the 903 DEGs mainly focused on inflammatory responses, amino acid metabolism, and Lipid reactions. In conclusion, our study revealed the potential mechanism of action of HSYA in sepsis-induced liver injury through a comprehensive analysis of 16 S RNA sequencing, metabolomics, and transcriptomics, thus providing a theoretical basis for further clinical applications of HSYA.PMID:37924577 | DOI:10.1016/j.jpba.2023.115801

J Pharm Biomed Anal. 2023 Oct 21;238:115807. doi: 10.1016/j.jpba.2023.115807. Online ahead of print.ABSTRACTBACKGROUND: Yueju Wan (YJW), defined in Danxi's Mastery of Medicine, has Qi-regulating and Qi-promoting effects. YJW has frequently been applied in the clinic for the treatment of depression. Substantial evidence has shown that depression is related to metabolic abnormalities of the gut microbiota, and traditional Chinese medicine (TCM) can treat depression by adjusting gut microbiota metabolism. The antidepressant effect of YJW is well established, but thus far, whether its mechanism of action is achieved by regulating the intestinal flora has not been elucidated.METHODS: In this study, chronic unpredictable mild stress (CUMS) along with isolated feeding created a rat depression model, and YJW was administered for intervention. Rats were put through behavioral tests to determine their level of depression, and ELISA was utilized for measuring the level of monoamine neurotransmitters (MNTs) in the hippocampus. Metagenomic gene sequencing analysis was used to study the effect of depression on the intestinal flora in rats and the regulatory mechanism of YJW on the intestinal flora. Furthermore, ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was utilized for fecal metabolomics studies to further reveal the antidepressant mechanism of YJW. The antidepressant mechanism of YJW was explored and further verified by Western blot analysis.RESULTS: Different doses of YJW improved the depressive state of rats and raised the levels of MNTs in the hippocampus. The results of metagenomic sequencing indicated that the YJW recovered the structure and diversity of the intestinal flora in depressed rats. Metabolomics revealed sustained changes in 21 metabolites after the treatment of YJW, suggesting that YJW can play an antidepressant role by improving abnormal metabolic pathways. The results of correlation analysis suggested that YJW might mediate Eubacterium, Oscillibacter, Roseburia, Romboutsia and Bacterium to regulate purine metabolism, tryptophan metabolism, primary bile acid biosynthesis, and glutamate metabolism and exert antidepressant effects. Western blot analysis showed that YJW reduced the content of IL-1β in the hippocampus, inhibited the activation of the NLRP3 inflammasome in the hippocampus of rats, and increased the content of ZO-1 in the colon of rats.CONCLUSION: YJW can alleviate depressive symptoms in depressed rats, and its mechanism is connected to improving intestinal flora and regulating body metabolism.PMID:37924576 | DOI:10.1016/j.jpba.2023.115807

J Gastrointest Cancer. 2023 Nov 4. doi: 10.1007/s12029-023-00980-x. Online ahead of print.ABSTRACTBACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common tumors in the gastrointestinal tract, and China has a high incidence area with a high burden on the disease. As early symptoms of ESCC are not obvious, the mortality rate is high, and it is often diagnosed in the intermediate and advanced stages. However, early screening and treatment may reduce morbidity and mortality.METHODS: Screening methods are divided into endoscopic and non-endoscopic screening.RESULTS: Endoscopic screening cannot be widely used because of its invasive nature and high cost. Currently, non-endoscopic screening consists primarily of tumor biomarkers and cytology, and tumor biomarkers including autoantibodies, circulating tumor cells, circulating tumor DNA, exosomes and serum metabolomics are more likely to be effective. But the efficiency of early diagnosis of esophageal cancer is low and the accuracy of screening needs to be improved. The aim of this study is to summarize advances in non-endoscopic esophageal cancer screening and strategies to provide a scientific basis and research idea for esophageal cancer prevention and control.CONCLUSIONS: Non-endoscopic screening is better than endoscopic screening. And the application of tumor biomarkers is much better than other non-endoscopic screening methods.PMID:37924487 | DOI:10.1007/s12029-023-00980-x

Adv Healthc Mater. 2023 Nov 4:e2301332. doi: 10.1002/adhm.202301332. Online ahead of print.ABSTRACTThe continuous reduction of clinically available antibiotics has made it imperative to exploit more effective antimicrobial therapies, especially for difficult-to-treat Gram-negative pathogens. Herein, we showed that the combination of an antimicrobial nanozyme with the clinically compatible basic amino acid L-arginine affords a potent treatment for infections with Gram-negative pathogens. In particular, the antimicrobial activity of the antimicrobial nanozyme was dramatically increased by approximately 1000-fold after L-arginine stimulation. Specifically, the combination therapy enhanced bacterial outer and inner membrane permeability and promoted intracellular reactive oxygen species (ROS) generation. Moreover, the metabolomic and transcriptomic results revealed that combination treatment led to the increased ROS-mediated damage by inhibiting the tricarboxylic acid cycle and oxidative phosphorylation, thereby inducing an imbalance of the antioxidant and oxidant systems. Importantly, L-arginine dramatically significantly accelerated the healing of infected wounds in mouse models of multidrug-resistant peritonitis-sepsis and skin wound infection. Overall, this work demonstrates a novel synergistic antibacterial strategy by combining the antimicrobial nanozymes with L-arginine, which substantively facilitates the nanozyme-mediated killing of pathogens by promoting ROS production. This article is protected by copyright. All rights reserved.PMID:37924312 | DOI:10.1002/adhm.202301332

Mol Plant. 2023 Nov 2:S1674-2052(23)00354-4. doi: 10.1016/j.molp.2023.10.018. Online ahead of print.ABSTRACTParaquat (PQ) has been used as an herbicide worldwide because of its potent activity against weeds. However, it is highly toxic to humans. The very high fatality of PQ poisoning is due to its inherent toxicity and the lack of any effective treatment. Consequently, developing a non-toxic herbicide with comparable efficacy to PQ will contribute to global food security and help prevent PQ-related fatalities. Herein, we report new herbicide called dienediamine, which was discovered from how to intervene the redox cycle of PQ, an inherent toxicity nature. The dienediamine as the "reduced" form of PQ, with no function as an electron transfer agent, proven to be non-toxic through comprehensive in vivo and in vitro experiments at molar concentrations equivalent to PQ's absolute lethal dose. Remarkably, dienediamine can undergo conversion to PQ under natural sunlight and ambient air conditions, exhibiting herbicidal activities that are comparable to those of PQ. The conversion of dienediamine to PQ is the key mechanism underlying its potent herbicidal activity through the chloroplast toxicity. Our study presents dienediamine as a safe and superior alternative to PQ, possessing significant potential for application in sustainable agriculture globally.PMID:37924209 | DOI:10.1016/j.molp.2023.10.018

Microbiome. 2023 Nov 3;11(1):238. doi: 10.1186/s40168-023-01682-z.ABSTRACTBACKGROUND: Minimizing mortality losses due to multiple stress and obtaining maximum performance are the production goals for newly received cattle. In recent years, vaccination and metaphylaxis treatment significantly decreased the mortality rate of newly received cattle, while the growth block induced by treatment is still obvious. Assessment of blood metabolites and behavior monitoring offer potential for early identification of morbid animals. Moreover, the ruminal microorganisms' homeostasis is a guarantee of beef steers' growth and health. The most critical period for newly received cattle is the first-month post-transport. Therefore, analyzing rumen metagenomics, rumen metabolomics, host metabolomics, and their interaction during receiving period (1 day before transport and at days 1/4, 16, and 30 after transport) is key to revealing the mechanism of growth retardation, and then to formulating management and nutritional practices for newly received cattle.RESULTS: The levels of serum hormones (COR and ACTH), and pro-inflammatory factors (IL-1β, TNF-α, and IL-6) were highest at day 16, and lowest at day 30 after arrival. Meanwhile, the antioxidant capacity (SOD, GSH-Px, and T-AOC) was significantly decreased at day 16 and increased at day 30 after arrival. Metagenomics analysis revealed that rumen microbes, bacteria, archaea, and eukaryota had different trends among the four different time points. At day 16 post-transport, cattle had a higher abundance of ruminal bacteria and archaea than those before transport, but the eukaryote abundance was highest at day 30 post-transport. Before transport, most bacteria were mainly involved in polysaccharides digestion. At day 4 post-transport, the most significantly enriched KEGG pathways were nucleotide metabolism (pyrimidine metabolism and purine metabolism). At day 16 post-transport, the energy metabolism (glycolysis/gluconeogenesis, pyruvate metabolism) and ruminal contents of MCP and VFAs were significantly increased, but at the same time, energy loss induced by methane yields (Methanobrevibacter) together with pathogenic bacteria (Saccharopolyspora rectivirgula) were also significantly increased. At this time, the most upregulated ruminal L-ornithine produces more catabolite polyamines, which cause oxidative stress to rumen microbes and their host; the most downregulated ruminal 2',3'-cAMP provided favorable growth conditions for pathogenic bacteria, and the downregulated ruminal vitamin B6 metabolism and serum PC/LysoPC disrupt immune function and inflammation reaction. At day 30 post-transport, the ruminal L-ornithine and its catabolites (mainly spermidine and 1,3-propanediamine) were decreased, and the serum PC/LysoPC and 2',3'-cNMPs pools were increased. This is also consistent with the changes in redox, inflammation, and immune status of the host.CONCLUSIONS: This study provides new ideas for regulating the health and performance of newly received cattle during the receiving period. The key point is to manage the newly received cattle about day 16 post-transport, specifically to inhibit the production of methane and polyamines, and the reproduction of harmful bacteria in the rumen, therefore improving the immunity and performance of newly received cattle. Video Abstract.PMID:37924150 | DOI:10.1186/s40168-023-01682-z

BMC Med. 2023 Nov 3;21(1):417. doi: 10.1186/s12916-023-03131-y.ABSTRACTBACKGROUND: Accumulating evidence has suggested an oncogenic effect of diurnal disruption on cancer progression. To test whether targeting circadian rhythm by dietary strategy suppressed lung cancer progression, we adopted 6-h time-restricted feeding (TRF) paradigm to elucidate whether and how TRF impacts lung cancer progression.METHODS: This study used multiple lung cancer cell lines, two xenograft mouse models, and a chemical-treated mouse lung cancer model. Stable TIM-knockdown and TIM-overexpressing A549 cells were constructed. Cancer behaviors in vitro were determined by colony formation, EdU proliferation, wound healing, transwell migration, flow cytometer, and CCK8 assays. Immunofluorescence, pathology examinations, and targeted metabolomics were also used in tumor cells and tissues. mCherry-GFP-LC3 plasmid was used to detect autophagic flux.RESULTS: We found for the first time that compared to normal ad libitum feeding, 6-h TRF inhibited lung cancer progression and reprogrammed the rhythms of metabolites or genes involved in glycolysis and the circadian rhythm in tumors. After TRF intervention, only timeless (TIM) gene among five lung cancer-associated clock genes was found to consistently align rhythm of tumor cells to that of tumor tissues. Further, we demonstrated that the anti-tumor effect upon TRF was partially mediated by the rhythmic downregulation of the TIM and the subsequent activation of autophagy. Combining TRF with TIM inhibition further enhanced the anti-tumor effect, comparable to treatment efficacy of chemotherapy in xenograft model.CONCLUSIONS: Six-hour TRF inhibits lung cancer progression and reshapes circadian metabolism, which is partially mediated by the rhythmic downregulation of the TIM and the subsequent upregulation of autophagy.PMID:37924048 | DOI:10.1186/s12916-023-03131-y

Commun Biol. 2023 Nov 3;6(1):1115. doi: 10.1038/s42003-023-05478-7.ABSTRACTThe ketogenic diet (KD) has demonstrated benefits in numerous clinical studies and animal models of disease in modulating the immune response and promoting a systemic anti-inflammatory state. Here we investigate the effects of a KD on systemic toxicity in mice following SARS-CoV-2 infection. Our data indicate that under KD, SARS-CoV-2 reduces weight loss with overall improved animal survival. Muted multi-organ transcriptional reprogramming and metabolism rewiring suggest that a KD initiates and mitigates systemic changes induced by the virus. We observed reduced metalloproteases and increased inflammatory homeostatic protein transcription in the heart, with decreased serum pro-inflammatory cytokines (i.e., TNF-α, IL-15, IL-22, G-CSF, M-CSF, MCP-1), metabolic markers of inflammation (i.e., kynurenine/tryptophane ratio), and inflammatory prostaglandins, indicative of reduced systemic inflammation in animals infected under a KD. Taken together, these data suggest that a KD can alter the transcriptional and metabolic response in animals following SARS-CoV-2 infection with improved mice health, reduced inflammation, and restored amino acid, nucleotide, lipid, and energy currency metabolism.PMID:37923961 | DOI:10.1038/s42003-023-05478-7

J Dairy Sci. 2023 Nov 1:S0022-0302(23)00777-4. doi: 10.3168/jds.2023-24154. Online ahead of print.ABSTRACTConstipation is directly related to the intestinal microenvironment, in which the promotion of gastrointestinal (GI) motility and improvement of gut microbiota distribution are important for alleviating symptoms. Herein, after the intervention of probiotic fermented milk (FMMIX) containing Lacticaseibacillus paracasei JY062 and Lactobacillus gasseri JM1 for 14 d in Kunming mice with loperamide-induced constipation, the results indicated that FMMIX significantly increased the secretion of serum motilin (MTL), gastrin (GAS) and 5-hydroxytryptamine (5-HT) and decreased those of peptide YY (PYY), vasoactive intestinal peptide (VIP) and nitric oxide (NO) in mice. As determined by immunohistochemical analysis, FMMIX promoted an augmentation in the quantity of Cajal interstitial cells (ICC). And mRNA and protein expression of c-kit and SCF was upregulated to facilitate intestinal motility. High-throughput sequencing and gas chromatography techniques revealed that FMMIX led to an increase in the relative abundance of beneficial bacteria (Lactobacillus, Oscillospira, Ruminococcus, Coprococcus, and Akkermansia), reduced the presence of harmful bacteria (Prevotella), and resulted in elevated levels of short-chain fatty acids (SCFAs) with a superior improvement compared with UFM. Untargeted metabolomics revealed significant upregulation of functional metabolites such as L-pipecolinic acid, DL-phenylalanine and naringenin in FMMIX, presumably playing a potential role in constipation relief. In conclusion, FMMIX had the potential to alleviate constipation symptoms in mice by improving the secretion of serum GI regulatory peptides and neurotransmitters, increasing the expression of c-kit and SCF proteins, and modulating the gut microbiota structure and SCFAs levels, and may be associated with an increase in the above functional components in FMMIX. This suggested that FMMIX could be a promising adjunctive strategy for managing constipation symptoms and could contribute to the development of functional foods aimed at improving gut health.PMID:37923200 | DOI:10.3168/jds.2023-24154

J Lipid Res. 2023 Nov 1:100469. doi: 10.1016/j.jlr.2023.100469. Online ahead of print.ABSTRACTDeletion of the nuclear hormone receptor small heterodimer partner (Shp) ameliorates the development of obesity and nonalcoholic steatohepatitis (NASH) in mice. Liver-specific SHP plays a significant role in this amelioration. The gut microbiota has been associated with these metabolic disorders, and the interplay between bile acids (BAs) and gut microbiota contributes to various metabolic disorders. Since hepatic SHP is recognized as a critical regulator in BA synthesis, we assessed the involvement of gut microbiota in the anti-obesity and anti-NASH phenotype of Shp-/- mice. Shp deletion significantly altered the levels of a few conjugated BAs. Sequencing the 16S ribosomal RNA gene in fecal samples collected from separately housed mice revealed apparent dysbiosis in Shp-/- mice. Cohousing Shp-/- mice with wild-type (WT) mice during a western diet (WD) regimen impaired their metabolic improvement and effectively disrupted their distinctive microbiome structure, which became indistinguishable from that of WT mice. While the WD challenge significantly increased lipopolysaccharide (LPS) and phenylacetic acid (PAA) levels in the blood of WT mice, their levels were not increased in Shp-/- mice. PAA was strongly associated with hepatic peroxisome proliferator-activated receptor gamma isoform 2 (Pparg2) activation in mice, which may represent the basis of the molecular mechanism underlying the association of gut bacteria and hepatic steatosis. Shp deletion reshapes the gut microbiota possibly by altering BAs. While LPS and PAA are the major driving forces derived from gut microbiota for NASH development, Shp deletion decreases these signaling molecules via dysbiosis, thereby partially protecting mice from diet-induced metabolic disorders.PMID:37922990 | DOI:10.1016/j.jlr.2023.100469

Mar Environ Res. 2023 Oct 27;192:106241. doi: 10.1016/j.marenvres.2023.106241. Online ahead of print.ABSTRACTBiofouling is a specific lifestyle including both marine prokaryotic and eukaryotic communities. Hydrodynamics are poorly studied parameters affecting biofouling formation. This study aimed to investigate how water dynamics in the Etel Estuary (Northwest Atlantic coasts of France) influences the colonization of artificial substrates. Hydrodynamic conditions, mainly identified as shear stress, were characterized by measuring current velocity, turbulence intensity and energy using Acoustic Doppler Current Profiler (ADCP). One-month biofouling was analyzed by coupling metabarcoding (16S rRNA, 18S rRNA and COI genes), untargeted metabolomics (liquid chromatography coupled with high-resolution mass spectrometry, LC-HRMS) and characterization of the main biochemical components of the microbial exopolymeric matrix. A higher richness was observed for biofouling communities (prokaryotes and eukaryotes) exposed to the strongest currents. Ectopleura (Cnidaria) and its putative symbionts Endozoicomonas (Gammaproteobacteria) were dominant in the less dynamic conditions. Eukaryotes assemblages were specifically shaped by shear stress, leading to drastic changes in metabolite profiles. Under high hydrodynamic conditions, the exopolymeric matrix increased and was composed of 6 times more polysaccharides than proteins, these latter playing a crucial role in the adhesion and cohesion properties of biofilms. This original multidisciplinary approach demonstrated the importance of shear stress on both the structure of marine biofouling and the metabolic response of these complex communities.PMID:37922705 | DOI:10.1016/j.marenvres.2023.106241

Biochem Biophys Res Commun. 2023 Oct 26;686:149169. doi: 10.1016/j.bbrc.2023.149169. Online ahead of print.ABSTRACTMetals have been used for many years in medicine, particularly for the treatment of cancer. Cisplatin is one of the most used drugs in the treatment of cancer. Although platinum-containing therapeutics have unparalleled efficacy in cancer treatment, they are coupled with adverse effects and the development of tumour resistance. This has led to the exploration of other metal-based modalities including ruthenium-based compounds. Thus, in our previous study, we synthesized and characterized a novel ruthenium (II) complex (referred to herein as GA113) containing a bis-amino-phosphine ligand. The complex was subsequently screened for its anti-cancerous potential against a human malignant melanoma A375 cell line and findings revealed favourable cytotoxicity. In the current study, a nuclear magnetic resonance (NMR)-based cellular metabolomics approach was applied to probe the possible mechanism of GA113 in A375 cells. In addition, other biological assays including light microscopy, Hoechst-33258 and MitoTracker Orange CM-H2TMRos stain were used to assess cellular viability and apoptosis in GA113-treated cells. Consequently, multivariate statistical data analysis was applied to the metabolomic data to identify potential biomarkers. Six signatory metabolites were altered after treatment. Changes in these metabolites were linked to two metabolic pathways, which include the alanine, aspartate, and glutamate metabolic pathway as well as the glycine, serine, and threonine pathway. By means of an NMR-based metabolomic approach, we identified the potential mechanism of action of complex GA113 in A375 cancer cells thus providing new insights into the metabolic pathways affected by complex GA113 and establishing a foundation for further development, research, and eventual application in cancer.PMID:37922571 | DOI:10.1016/j.bbrc.2023.149169

Dig Liver Dis. 2023 Nov 1:S1590-8658(23)00994-5. doi: 10.1016/j.dld.2023.10.006. Online ahead of print.ABSTRACTBACKGROUND: Alcohol-Associated Liver Disease (ALD) is a leading cause of liver mortality. Mechanisms responsible for severe ALD and the roles of gut microbiota are not fully understood. Multi-omics tools have enabled a better understanding of metabolic alterations and can aid in identifying metabolites as biomarkers for severe ALD.AIMS: Examine differences between cirrhotic and non-cirrhotic ALD, investigate microbial contributions to such changes, and identify potential diagnostic and prognostic metabolites for severe ALD.METHODS: Untargeted metabolomics were performed on the serum of 11 non-cirrhotic and 11 cirrhotic ALD patients. Data were analyzed using MetOrigin and Metaboanalyst to identify enriched pathways.RESULTS: Increased methylated nucleotides, gamma-glutamyl amino acids, bile acids, and specific metabolites kynurenine and campesterol were increased in ALD cirrhosis, whereas branched-chain amino acids, serotonin, and xanthurenate were decreased. Microbial contributions included increases in the short-chain fatty acid indolebutyrate and methionine sulfoxide in ALD cirrhosis. The analysis also identified the potential for serum levels of 3-ureidopropionate, cis-3,3-methyleneheptanoylglycine, retinol, and valine to be used as biomarkers for clinical assessment of alcohol-associated cirrhosis.CONCLUSION: We have identified a set of metabolites that are differentially altered in cirrhotic compared to non-cirrhotic ALD that can potentially be used as biomarkers for the severity of the disease.PMID:37923598 | DOI:10.1016/j.dld.2023.10.006

Small Methods. 2023 Nov 3:e2301192. doi: 10.1002/smtd.202301192. Online ahead of print.ABSTRACTIn vitro diagnosis (IVD) is pivotal in modern medicine, enabling early disease detection and treatment optimization. Omics technologies, particularly proteomics and metabolomics, offer profound insights into IVD. Despite its significance, omics analyses for IVD face challenges, including low analyte concentrations and the complexity of biological environments. In addition, the direct omics analysis by mass spectrometry (MS) is often hampered by issues like large sample volume requirements and poor ionization efficiency. Through manipulating their size, surface charge, and functionalization, as well as the nanoparticle-fluid incubation conditions, nanomaterials have emerged as a promising solution to extract biomolecules and enhance the desorption/ionization efficiency in MS detection. This review delves into the last five years of nanomaterial applications in omics, focusing on their role in the enrichment, separation, and ionization analysis of proteins and metabolites for IVD. It aims to provide a comprehensive update on nanomaterial design and application in omics, highlighting their potential to revolutionize IVD.PMID:37922520 | DOI:10.1002/smtd.202301192