Secretion Of Metabolites Research Articles

Proximal Tubule Secretory Clearance, Injury, and Kidney Viability in Cirrhosis.

Cirrhosis affects all structures of the kidney, in particular the tubules which are responsible for secretion of protein-bound metabolites and electrolyte/water homeostasis. Yet, prevailing assessments of kidney function focus solely on glomerular filtration rate (GFR) which may incompletely reflect these processes. We sought to characterize markers of tubular function, injury, and viability in patients with and without cirrhosis. We recruited outpatients undergoing liver transplantation evaluation for a collection of plasma and 24-hour urine, matching by GFR to control participants without cirrhosis. We measured urinary kidney injury molecule-1 (KIM-1), a marker of proximal tubular injury, as well as epidermal growth factor (EGF), a marker of viability necessary for tubular epithelial cell proliferation after injury. We also estimated secretory clearance by measuring several highly secreted endogenous metabolites in urine and plasma. We recruited 39 patients with cirrhosis (mean MELD-Na 17±4, Child-Pugh 8±2, eGFR 66±20 ml/min/1.73m2) and 58 GFR-matched controls without cirrhosis (eGFR 66±21 ml/min/1.73m2). Urinary KIM-1 was 4.4-fold higher than controls (95% CI:2.9-6.5), and EGF averaged 7.41-fold higher than controls (95% CI:2.15-25.53). We found that of 8 solutes, 5 had significantly greater kidney clearance in cirrhosis (1.3-2.1-fold higher): indoxyl sulfate, p-cresol sulfate, pyridoxic acid, tiglylglycine, and xanthosine. Cirrhosis was characterized by molecular signs of tubular injury in stable outpatients without acute kidney injury, accompanied by largely preserved tubular secretory clearance and greater signs of tubular viability. Within the limitations of the study, this suggests a phenotype of chronic ischemic injury but with initial preservation of tubular function in cirrhosis.

12440 Exploring The Potential Protective Role Of The Bacterial-derived Metabolite Indole-3-propionic Acid Against Obesogenic Insults In Placenta Cell Lines

Abstract Disclosure: J. Ernst: None. L. Conlon: None. R. Gupta: None. L. Kang: None. M.E. Heard-Lipsmeyer: None. Obesity during pregnancy is associated with detrimental changes in placental function that lead to the development of complications such as gestational diabetes and preeclampsia as well as altered metabolism in the offspring. With the incidence of obesity reaching epidemic levels world-wide, it is imperative to find mechanisms to mitigate these risks during pregnancy. The gut-microbiome is a diverse system that regulates numerous body functions through the secretion of specific metabolites. Gut dysbiosis has recently emerged as one mechanism that contributes to placental dysfunction and clear associations between obesity and gut dysbiosis are evident. Indole-3-propionic acid (IPA) is a gut microbiome-derived metabolite that has anti-inflammatory, anti-oxidative stress and glucose regulatory functions, all of which are dysregulated in obesity. Previous studies have found diminished levels of IPA in serum of women with overweight/obesity. However, it remains unknown what the physiological functions of IPA are in the placenta and if it could have potential protective effects against perturbations caused by obesity. The objective of this study is to determine what physiological role IPA plays in the placenta and if IPA can protect against obesogenic insults that contribute to placental pathology. For this study, we developed an in vitro model of obesity where two human placental cell lines, BeWo (choriocarcinoma) and HTR8 (normal immortalized trophoblasts) were cultured in media conditioned by mature human adipocytes (ACM). RNA sequencing (RNAseq) analysis was used to determine acute effects of IPA treatment after 24 hours in the presence and absence of ACM. We further examined the influence of IPA on insulin signaling with physiological and hyperinsulinemia levels of insulin at 24 and 72 hours utilizing QPCR and western blot analyses. RNAseq analysis revealed treatment with physiological levels of IPA induced changes in genes associated with normal placental function, autophagy and inflammatory mediated processes and other pathways. Our RNAseq analysis offers initial insight into the molecular mechanisms of IPA in placental cells. Future analyses will investigate the potential role of insulin signaling, glucose homeostasis and oxidative stress. Collectively, this study highlights the importance of a healthy gut microbiome and potentially serves as a window of opportunity to mitigate the onset or severity of pregnancy-related disorders such as gestational diabetes by enhancing the gut microbiome prior to pregnancy. Presentation: 6/1/2024

12440 Exploring The Potential Protective Role Of The Bacterial-derived Metabolite Indole-3-propionic Acid Against Obesogenic Insults In Placenta Cell Lines

Abstract Disclosure: J. Ernst: None. L. Conlon: None. R. Gupta: None. L. Kang: None. M.E. Heard-Lipsmeyer: None. Obesity during pregnancy is associated with detrimental changes in placental function that lead to the development of complications such as gestational diabetes and preeclampsia as well as altered metabolism in the offspring. With the incidence of obesity reaching epidemic levels world-wide, it is imperative to find mechanisms to mitigate these risks during pregnancy. The gut-microbiome is a diverse system that regulates numerous body functions through the secretion of specific metabolites. Gut dysbiosis has recently emerged as one mechanism that contributes to placental dysfunction and clear associations between obesity and gut dysbiosis are evident. Indole-3-propionic acid (IPA) is a gut microbiome-derived metabolite that has anti-inflammatory, anti-oxidative stress and glucose regulatory functions, all of which are dysregulated in obesity. Previous studies have found diminished levels of IPA in serum of women with overweight/obesity. However, it remains unknown what the physiological functions of IPA are in the placenta and if it could have potential protective effects against perturbations caused by obesity. The objective of this study is to determine what physiological role IPA plays in the placenta and if IPA can protect against obesogenic insults that contribute to placental pathology. For this study, we developed an in vitro model of obesity where two human placental cell lines, BeWo (choriocarcinoma) and HTR8 (normal immortalized trophoblasts) were cultured in media conditioned by mature human adipocytes (ACM). RNA sequencing (RNAseq) analysis was used to determine acute effects of IPA treatment after 24 hours in the presence and absence of ACM. We further examined the influence of IPA on insulin signaling with physiological and hyperinsulinemia levels of insulin at 24 and 72 hours utilizing QPCR and western blot analyses. RNAseq analysis revealed treatment with physiological levels of IPA induced changes in genes associated with normal placental function, autophagy and inflammatory mediated processes and other pathways. Our RNAseq analysis offers initial insight into the molecular mechanisms of IPA in placental cells. Future analyses will investigate the potential role of insulin signaling, glucose homeostasis and oxidative stress. Collectively, this study highlights the importance of a healthy gut microbiome and potentially serves as a window of opportunity to mitigate the onset or severity of pregnancy-related disorders such as gestational diabetes by enhancing the gut microbiome prior to pregnancy. Presentation: 6/1/2024

Acetate-producing bacterium Paenibacillus odorifer hampers lung cancer growth in lower respiratory tract: an in vitro study.

Lung cancer accounts for the large majority of cancer incidence and mortality worldwide for decades. The dysbiotic microbiome and its metabolite secretions in the gut have been regarded as the dominant biological factors in oncogenesis, development, and progression, adding probiotic components of which have come to be potential therapeutic regimes. However, there still exists little knowledge about whether probiotic microorganisms in lower airways inhibit lung cancer by lung microenvironment remodulation. In this study, we performed bioinformatics analysis from previous sequencing data and specific microbiome databases to identify the potent protective microbes in lower airways, followed by bacterial cultivation and morphological verifications in vitro. We found that Paenibacillus odorifer was correlated closely with the anti-tumorous by-product acetic acid in lower respiratory tract. Additionally, the enrichment of this microorganism in the health, rather than in lung neoplasms from public data sets, further confirmed its protective activity in preserving pulmonary homeostasis. Colony cultivation of this strain and targeted metabolite analysis indicated that Paenibacillus odorifer proliferation was weakened at 37°C but lasted longer than it did at the optimal temperature. And performing as a candidate origin of acetic acid, this strain was liable to inhibit the growth of lung cancer cells in time- and dose-dependent approaches which was validated by colony formation assays. These results suggested that Paenibacillus odorifer functions as a candidate probiotic in lower airways to restrict lung cancer cell growth by releasing protective molecules, indicating a potential preventive microbial strategy.IMPORTANCEVarious types of microorganisms in lower respiratory tracts protect local homeostasis against oncogenesis. Although extensive efforts engaged in gut microbiome-mediated pulmonary carcinogenesis, emerging evidence suggested the crucial role of microbial metabolites from respiratory tracts in modulating carcinogenesis-related host inflammation and DNA damage in lung cancer, which was still not fully understood in lower respiratory tract microbes and its metabolite-mediated microecological environment homeostasis in preventing or alleviating lung cancer. In this study, we analyzed the lower respiratory tract microbiome and SCFAs expression among different lung segments from the same participants, further identifying that Paenibacillus odorifer was correlated closely with anti-tumorous by-product, acetate acid in lower respiratory tract by multi-omics analysis. And previous experiments showed this strain could inhibit the growth of lung cancer cells in vitro. These findings indicated that Paenibacillus odorifer in lower respiratory tracts might perform as a candidate probiotic against lung carcinogenesis by releasing protective factor acetate, which further presented a promising diagnostic and interventional approach in clinical settings of lung cancer.

Polymorphism in the Drug Transporter Gene ABCB1 as a Potential Disease Modifier in Cortisol-Producing Adrenal Adenomas.

Endogenous hypercortisolism presents with variable phenotypes. Etiological factors accounting for the level of hypercortisolism or varying severity of associated comorbidities are lacking. Recently, the adrenal ATP-binding cassette B1 (ABCB1) gene was identified as a modulator of glucocorticoid secretion. To evaluate the effect of ABCB1 polymorphism rs2032582 on steroid metabolome and clinical phenotypes in patients with endogenous hypercortisolism. In this cross-sectional cohort study, 137 patients prospectively enrolled in the German Cushing's registry were included (41 with ACTH-producing pituitary adenoma, 21 with cortisol-producing adrenal adenoma, and 75 with excluded hypercortisolism). In all patients, ABCB1 polymorphism was analyzed using a TaqMan genotyping assay, glucocorticoid metabolite excretion in 24-hour urine samples was analyzed by gas chromatography-mass spectrometry, and the clinical phenotype was assessed systematically. In patients with cortisol-producing adrenal adenomas, but not in patients with ACTH-producing pituitary adenomas, homozygous major allele GG of ABCB1 polymorphism rs2032582 was associated with higher overall cortisol metabolite secretion (median 13515 [IQR 10347; 25669] µg/24h vs. 9645 [6146; 10732] µg/24h in minor homo- and heterozygotes, p=0.036) and elevated major cortisol metabolites αTHF, THF and THE (9339 [6929; 17789] µg/24h vs. 6288 [4184; 7455] µg/24h, p=0.045). Moreover, these patients showed higher mean arterial pressure (116 [111; 131] mmHg in major homozygotes vs. 105 [96; 112] mmHg in minor homo- and heterozygotes, p=0.036). The genotype of drug transporter gene ABCB1 rs2032582 polymorphism is associated with the degree of cortisol metabolite secretion in cortisol-producing adrenal adenomas and could, therefore, represent a modifier of disease severity in this context.

Pisolithus microcarpus isolates with contrasting abilities to colonise Eucalyptus grandis exhibit significant differences in metabolic signalling

Biotic factors in fungal exudates impact plant-fungal symbioses establishment. Mutualistic ectomycorrhizal fungi play various ecological roles in forest soils by interacting with trees. Despite progress in understanding secreted fungal signals, dynamics of signal production in situ before or during direct host root contact remain unclear. We need to better understand how variability in intra-species fungal signaling at these stages impacts symbiosis with host tissues. Using the ECM model Pisolithus microcarpus, we selected two isolates (Si9 and Si14) with different abilities to colonize Eucalyptus grandis roots. Hypothesizing that distinct early signalling and metabolite profiles between these isolates would influence colonization and symbiosis, we used microdialysis to non-destructively collect secreted metabolites from either the fungus, host, or both, capturing the dynamic interplay of pre-symbiotic signalling over 48 hours. Our findings revealed significant differences in metabolite profiles between Si9 and Si14, grown alone or with a host root. Si9, with lower colonization efficiency than Si14, secreted a more diverse range of compounds, including lipids, oligopeptides, and carboxylic acids. In contrast, Si14's secretions, similar to the host's, included more aminoglycosides. This study emphasizes the importance of intra-specific metabolomic diversity in ectomycorrhizal fungi, suggesting that early metabolite secretion is crucial for establishing successful mutualistic relationships.

Single-cell transcriptional atlas of tumor-associated macrophages in breast cancer

BackgroundThe internal heterogeneity of breast cancer, notably the tumor microenvironment (TME) consisting of malignant and non-malignant cells, has been extensively explored in recent years. The cells in this complex cellular ecosystem activate or suppress tumor immunity through phenotypic changes, secretion of metabolites and cell-cell communication networks. Macrophages, as the most abundant immune cells within the TME, are recruited by malignant cells and undergo phenotypic remodeling. Tumor-associated macrophages (TAMs) exhibit a variety of subtypes and functions, playing significant roles in impacting tumor immunity. However, their precise subtype delineation and specific function remain inadequately defined.MethodsThe publicly available single-cell transcriptomes of 49,141 cells from eight breast cancer patients with different molecular subtypes and stages were incorporated into our study. Unsupervised clustering and manual cell annotation were employed to accurately classify TAM subtypes. We then conducted functional analysis and constructed a developmental trajectory for TAM subtypes. Subsequently, the roles of TAM subtypes in cell-cell communication networks within the TME were explored using endothelial cells (ECs) and T cells as key nodes. Finally, analyses were repeated in another independent publish scRNA datasets to validate our findings for TAM characterization.ResultsTAMs are accurately classified into 7 subtypes, displaying anti-tumor or pro-tumor roles. For the first time, we identified a new TAM subtype capable of proliferation and expansion in breast cancer-TUBA1B+ TAMs playing a crucial role in TAMs diversity and tumor progression. The developmental trajectory illustrates how TAMs are remodeled within the TME and undergo phenotypic and functional changes, with TUBA1B+ TAMs at the initial point. Notably, the predominant TAM subtypes varied across different molecular subtypes and stages of breast cancer. Additionally, our research on cell-cell communication networks shows that TAMs exert effects by directly modulating intrinsic immunity, indirectly regulating adaptive immunity through T cells, as well as influencing tumor angiogenesis and lymphangiogenesis through ECs.ConclusionsOur study establishes a precise single-cell atlas of breast cancer TAMs, shedding light on their multifaceted roles in tumor biology and providing resources for targeting TAMs in breast cancer immunotherapy.

Rhizosphere flavonoids alleviates the inhibition of soybean nodulation caused by shading under maize-soybean strip intercropping

The flavonoids produced by legume roots are signal molecules that induce nod genes for symbiotic rhizobium. Nevertheless, the promoting effects of flavonoids in root exudates in intercropping system on soybean nodulation are still unknown. A two years of field experiments was carried with maize soybean strip intercropping, i.e., the interspecific row spacing of 30 cm (MS30), 45 cm (MS45), 60 cm (MS60), and sole soybean/maize:SS/MM, and root interaction, i.e., root no barrier (NB) and root polythene-plastic barrier (PB), to evaluate relationships between flavonoids in root exudates and nodulation. We found that root-root interaction between soybean and maize enhances the nodules number and fresh weight in intercropped soybean. This enhancement increase gradually with expansion of interspecific distance. Proportion of nodules with diameter greater than 0.4cm was higher in intercropped soybean with NB than with PB. The expressions of nodules-related genes (GmENOD40, GmNIN2b and GmEXPB2) were up-regulated. Furthermore, compared with monocropping, isoflavones secretion of soybean roots reduced, flavonoids and flavonols secretion of maize and soybean roots increased under intercropping. The secretion of differential metabolites of flavonoids in the rhizosphere of maize and soybean declined with root barrier. The expressions of GmCHS8 and GmIFS1 in soybean roots were up-regulated and GmICHG was down-regulated under root interaction. The most of the flavonoids and flavonol compounds were positively correlated with nodule diameter. The nodules number, the nodules fresh weight and the proportion of nodules with a diameter greater than 0.2 cm increased in different genotypes of soybean treated with maize root exudate, which promoted the improvement of nitrogen fixation capacity. Therefore, maize-soybean strip intercropping combined with reasonable spacing to enhance the positive effect of underground root interaction, and improve the nodulation and nitrogen fixation capacity of intercropping soybean.

Metabolic specialization drives reduced pathogenicity in Pseudomonas aeruginosa isolates from cystic fibrosis patients.

Metabolism provides the foundation for all cellular functions. During persistent infections, in adapted pathogenic bacteria metabolism functions radically differently compared with more naïve strains. Whether this is simply a necessary accommodation to the persistence phenotype or if metabolism plays a direct role in achieving persistence in the host is still unclear. Here, we characterize a convergent shift in metabolic function(s) linked with the persistence phenotype during Pseudomonas aeruginosa colonization in the airways of people with cystic fibrosis. We show that clinically relevant mutations in the key metabolic enzyme, pyruvate dehydrogenase, lead to a host-specialized metabolism together with a lower virulence and immune response recruitment. These changes in infection phenotype are mediated by impaired type III secretion system activity and by secretion of the antioxidant metabolite, pyruvate, respectively. Our results show how metabolic adaptations directly impinge on persistence and pathogenicity in this organism.

O-Methylated Isoflavones Induce nod Genes of Mesorhizobium ciceri and Pratensein Promotes Nodulation in Chickpea.

Legume plants form symbiotic relationships with rhizobia, which allow plants to utilize atmospheric nitrogen as a nutrient. This symbiosis is initiated by secretion of specific signaling metabolites from the roots, which induce the expression of nod genes in rhizobia. These metabolites are called nod gene inducers (NGIs), and various flavonoids have been found to act as NGIs. However, NGIs of chickpea, the second major pulse crop, remain elusive. We conducted untargeted metabolome analysis of chickpea root exudates to explore metabolites with increased secretion under nitrogen deficiency. Principal component (PC) analysis showed a clear difference between nitrogen deficiency and control, with PC1 alone accounting for 37.5% of the variance. The intensity of two features with the highest PC1 loading values significantly increased under nitrogen deficiency; two prominent peaks were identified as O-methylated isoflavones, pratensein and biochanin A. RNA-seq analysis showed that they induce nodABC gene expression in the Mesorhizobium ciceri symbiont, suggesting that pratensein and biochanin A are chickpea NGIs. Pratensein applied concurrently with M. ciceri at sowing promoted chickpea nodulation. These results demonstrate that pratensein and biochanin A are chickpea NGIs, and pratensein can be useful for increasing nodulation efficiency in chickpea production.

Plant infection by the necrotrophic fungus Botrytis requires actin-dependent generation of high invasive turgor pressure.

The devastating pathogen Botrytis cinerea infects a broad spectrum of host plants, causing great socio-economic losses. The necrotrophic fungus rapidly kills plant cells, nourishing their wall and cellular contents. To this end, necrotrophs secrete a cocktail of cell wall degrading enzymes, phytotoxic proteins and metabolites. Additionally, many fungi produce specialized invasion organs that generate high invasive pressures to force their way into the plant cell. However, for most necrotrophs, including Botrytis, the biomechanics of penetration and its contribution to virulence are poorly understood. Here, we use a combination of quantitative micromechanical imaging and CRISPR-Cas-guided mutagenesis to show that Botrytis uses substantial invasive pressure, in combination with strong surface adherence, for penetration. We found that the fungus establishes a unique mechanical geometry of penetration that develops over time during penetration events, and which is actin cytoskeleton dependent. Furthermore, interference of force generation by blocking actin polymerization was found to decrease Botrytis virulence, indicating that also for necrotrophs, mechanical pressure is important in host colonization. Our results demonstrate for the first time mechanistically how a necrotrophic fungus such as Botrytis employs this 'brute force' approach, in addition to the secretion of lytic proteins and phytotoxic metabolites, to overcome plant host resistance.

Lignocellulosic Biomass for Bioethanol Recovery: A way towards Environmental Sustainability

The increasing population and industrialization have increased the day to day demand of energy. Global warming and other climatic disasters caused due to burning of conventional fossil fuels have laid the need for an alternative and renewable fuel. Concurrently, the worldwide demand and production of bio-ethanol, a bio-based sustainable fuel is increasing continuously. Fungal saccharification of lignocellulosic biomass takes place simultaneously with the secretion of various metabolites, which function as a catalytic system to liberate soluble sugars from insoluble composite biomass. Cellulase holds a major role for converting lignocellulosic feedstock into fermentable sugar. Fungi, especially filamentous fungi preferably the Aspergillus species are known to produce cellulase. Amongst the lignocellulosic biomass, rice straw is considered as one of the most attractive materials for producing bioethanol because of its high cellulosic and hemicellulosic content, which can be hydrolyzed into fermentable sugars. However, the recalcitrant nature of the substrate imposes considerable challenges and limitations to bioethanol production. To combat these challenges, various pretreatment techniques such as chemical, physical, and physico-chemical processes are known to be effective enough to enhance the efficiency of enzymatic saccharification to make the complete process economically feasible. The present work deals with the isolation and selection of hypercellulase-producing fungal species. These species were used along with the pretreatment techniques either alone or in combination for efficient hydrolysis of rice straw to obtain the maximum amount of the released sugar.

Barley polysaccharides inhibit colorectal cancer by two relatively independent pathways

Colorectal cancer is one of the most common types of cancer worldwide that can lead to serious injury and death. Although polysaccharides are widely recognized as having antitumor activity, there has been little research on the role of barley polysaccharides (BP)11BP: barley polysaccharides. in colorectal cancer. The results of our research suggest that BP (300 mg/kg) had a significant inhibitory effect on colorectal cancer, and this effect was achieved through two pathways. First, BP can directly promote the secretion of protective metabolites like 5-(4-Hydroxyphenyl)-5-phenylimidazolidine-2,4-dione and 2,3-Bis(4-hydroxyphenyl)propionitrile thereby inhibiting the cancer pathways such as ERK, PI3K, WNT, JAK-STAT, Calcium, and Cell cycle cancer pathways to alleviate inflammation. Second, BP also can enrich beneficial intestinal bacteria such as Colidextribacter, Bilophila, and UCG-003 improve the intestinal barrier, promote the production of beneficial metabolites such as 5,8-Epoxy-5,8-dihydro-3-hydroxy-8′-apo-b,y-carotenal and L-Glutamic acid, and thus inhibit cancer pathways such as ERK, PI3K, Nuclear receptor, Cell cycle, Apoptosis and TGF-β. In conclusion, our findings suggest for the first time that BP can alleviate colorectal cancer by two relatively independent pathways: direct action and indirect action via the gut microbiota on both colon tumor cells and microbiota.

Function and Global Regulation of Type III Secretion System and Flagella in Entomopathogenic Nematode Symbiotic Bacteria.

Currently, it is widely accepted that the type III secretion system (T3SS) serves as the transport platform for bacterial virulence factors, while flagella act as propulsion motors. However, there remains a noticeable dearth of comparative studies elucidating the functional disparities between these two mechanisms. Entomopathogenic nematode symbiotic bacteria (ENS), including Xenorhabdus and Photorhabdus, are Gram-negative bacteria transported into insect hosts by Steinernema or Heterorhabdus. Flagella are conserved in ENS, but the T3SS is only encoded in Photorhabdus. There are few reports on the function of flagella and the T3SS in ENS, and it is not known what role they play in the infection of ENS. Here, we clarified the function of the T3SS and flagella in ENS infection based on flagellar inactivation in X. stockiae (flhDC deletion), T3SS inactivation in P. luminescens (sctV deletion), and the heterologous synthesis of the T3SS of P. luminescens in X. stockiae. Consistent with the previous results, the swarming movement of the ENS and the formation of biofilms are dominated by the flagella. Both the T3SS and flagella facilitate ENS invasion and colonization within host cells, with minimal impact on secondary metabolite formation and secretion. Unexpectedly, a proteomic analysis reveals a negative feedback loop between the flagella/T3SS assembly and the type VI secretion system (T6SS). RT-PCR testing demonstrates the T3SS's inhibition of flagellar assembly, while flagellin expression promotes T3SS assembly. Furthermore, T3SS expression stimulates ribosome-associated protein expression.

Screening the Potential f Fungal Derived Bioherbicide in Weed Management

Synthetic herbicides have long been a cornerstone of modern agriculture, providing effective weed control but often at significant environmental and health costs. These chemicals can persist in the environment, leach into groundwater, and harm non-target organisms, including humans. Additionally, the overuse of synthetic herbicides has led to the development of herbicide-resistant weeds, further complicating weed management strategies. In response to these challenges, researchers and farmers alike are increasingly turning to bioherbicides derived from fungi as a sustainable alternative. Fungal bioherbicides harness the natural antagonistic properties of fungi to target weeds. Unlike synthetic herbicides, which are chemically synthesized and often broad-spectrum in action, fungal bioherbicides utilize either the fungi themselves as pathogens or their metabolites to disrupt weed growth. This approach offers several distinct advantages:Target Specificity: Fungal bioherbicides can be highly specific to certain weed species or even to specific stages of weed growth. This specificity reduces collateral damage to non-target plants and organisms, making them particularly suitable for environmentally sensitive areas such as organic farms, riparian zones, and protected ecosystems. Environmental Friendliness: Unlike synthetic herbicides that can persist in the environment and accumulate in soil and water bodies, fungal bioherbicides generally have lower persistence. They degrade more rapidly and often have minimal impact on non-target organisms, thereby preserving biodiversity and ecosystem health. Reduced Risk of Resistance: Synthetic herbicides often face the challenge of herbicide-resistant weeds, which evolve due to continuous and widespread use. Fungal bioherbicides, by contrast, pose a lower risk of resistance development. This is because they typically act through multiple modes of action or biochemical pathways within the weed, making it harder for weeds to develop resistance mechanisms. Research into fungal-derived bioherbicides is actively exploring and harnessing these advantages. Scientists are screening diverse fungal species to identify potent pathogens or metabolites that effectively inhibit weed growth. Moreover, advances in biotechnology and genetic engineering allow for the enhancement of fungal strains to optimize their bioherbicidal properties while ensuring safety and efficacy. One promising example is the use of fungal pathogens like Phomamacrostoma and Colletotrichum truncatum, which have demonstrated efficacy against various weed species including common agricultural weeds like velvetleaf and pigweed. These fungi infect weeds through mechanisms such as spore attachment, penetration of plant tissues, and secretion of phytotoxic metabolites that inhibit weed growth. In addition to their direct impact on weed management, fungal bioherbicides contribute to sustainable agricultural practices by reducing reliance on synthetic chemicals. They align with principles of integrated pest management (IPM) by offering a biological control method that complements cultural and mechanical weed control strategies. Moving forward, continued research and development efforts are essential to refine fungal bioherbicides, optimize application techniques, and expand their practical use in diverse agricultural settings. Challenges such as formulation stability, cost-effectiveness, and regulatory approvals also need to be addressed to facilitate widespread adoption by farmers.

Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development.

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.

Assessment of secondary metabolites in Pennisetum purpureum planted into constructed wetlands using shale and laterite as substrate for wastewater treatment

Constructed wetlands (CWs) are systems designed to maximize pollutants removal by various mechanisms, most of which are associated with the presence of plants. However, the substances secreted by plants to defend themselves against external aggressions during their growth are very little studied in these systems. This study aimed to characterize the chemical constituents of Pennisetum purpureum extracts used in an experimental mesocosm filled with shale and laterite treating domestic wastewater. Above-ground biomass, strain diameter and secondary metabolites of P. purpureum plants grown on the different substrates (shale and laterite) were monitored, as were those grown on the experimental site (control). In addition, the removal performance of chemical oxygen demand (COD), biochemical oxygen demand (BOD5), total Kjedahl nitrogen (TKN) and Total Phosphorus (TP) was determined at the outlet of CWs. Plant biomass measured on the shale bed (13.7 ± 0.5 kg m−2) was higher than on the laterite bed (12.5 ± 0.1 kg m−2), both lower than the biomass obtained in the natural environment (14.9 ± 0.6 kg m−2). Performances ranged from 83 ± 5.4 to 76.9 ± 7 % (COD), 84.7 ± 6.8 to 78 ± 8.1 % (BOD5), 72.2 ± 10.7 to 55.5 ± 16.4 % (NTK) and 72.4 ± 4.9 to 58.4 ± 3.4 % (TP), with higher efficiencies in the shale-filled bed. Plant extracts from the experimental site were richer in secondary metabolites (total polyphenol [73.5 mgEAG/gMS], total flavonoids [18.1 mgEQ/gMS] and condensed tannin [13.3 mgEC/gMS]) than those from plants grown in CWs. However, plants in the shale-filled bed secreted more total polyphenol (57.7 mgEAG/gMS), total flavonoids (12.1 mgEQ/gMS) and condensed tannin (12 mgEC/gMS) than those in the laterite-filled bed. In short, wastewater and filtration materials have an influence on the secretion of secondary plant metabolites. However, of the two materials, shale seems to be better suited to CWs, as it promotes an environment close to the natural environment.

Intratumoral Microbiota: Unraveling their Oncogenic Impact on Cancer Progression With Focus on Breast Cancer Therapeutic Outcomes.

The gut microbiota has been implicated in many cancers through the secretion of blood-traveling metabolites or activation of oncogenic signaling. Currently, specific microbial signatures have been detected in the human breast, which are different from other microbial-rich compartments, such as the intestine and skin. Changes in the breast microbiome profile have been shown to positively or negatively correlate with breast cancer development, progression, and therapeutic outcomes. However, studies regarding the role and underlying mechanism of intratumoral microbiota in breast cancer have remained concealed. This review aimed to provide an overview of the role of the intratumoral microbiome in tumorigenesis and tumor progression, and how these intratumoral microbiota affect breast cancer. We also discuss the potential of using the intratumoral microbiome as a biomarker or treatment alternative in breast cancers.

Dietary fibre supplementation enhances radiotherapy tumour control and alleviates intestinal radiation toxicity

BackgroundNon-toxic approaches to enhance radiotherapy outcomes are beneficial, particularly in ageing populations. Based on preclinical findings showing that high-fibre diets sensitised bladder tumours to irradiation by modifying the gut microbiota, along with clinical evidence of prebiotics enhancing anti-cancer immunity, we hypothesised that dietary fibre and its gut microbiota modification can radiosensitise tumours via secretion of metabolites and/or immunomodulation. We investigated the efficacy of high-fibre diets combined with irradiation in immunoproficient C57BL/6 mice bearing bladder cancer flank allografts.ResultPsyllium plus inulin significantly decreased tumour size and delayed tumour growth following irradiation compared to 0.2% cellulose and raised intratumoural CD8+ cells. Post-irradiation, tumour control positively correlated with Lachnospiraceae family abundance. Psyllium plus resistant starch radiosensitised the tumours, positively correlating with Bacteroides genus abundance and increased caecal isoferulic acid levels, associated with a favourable response in terms of tumour control. Psyllium plus inulin mitigated the acute radiation injury caused by 14 Gy. Psyllium plus inulin increased caecal acetate, butyrate and propionate levels, and psyllium alone and psyllium plus resistant starch increased acetate levels. Human gut microbiota profiles at the phylum level were generally more like mouse 0.2% cellulose profiles than high fibre profiles.ConclusionThese supplements may be useful in combination with radiotherapy in patients with pelvic malignancy.C3P3Z-i-BEWcsPG8U_9P4fVideo

Sulfadiazine proliferated antibiotic resistance genes in the phycosphere of Chlorella pyrenoidosa: Insights from bacterial communities and microalgal metabolites

The phycosphere is an essential ecological niche for the proliferation of antibiotic resistance genes (ARGs). However, how ARGs’ potential hosts change and the driving mechanism of metabolites under antibiotic stress in the phycosphere have seldom been researched. We investigated the response of Chlorella pyrenoidosa and the structure and abundance of free-living (FL) and particle-attached (PA) bacteria, ARGs, and metabolites under sulfadiazine by using real-time quantitative PCR, 16 S rRNA high-throughput. The linkage of key bacterial communities, ARGs, and metabolites through correlations was established. Through analysis of physiological indicators, Chlorella pyrenoidosa displayed a pattern of "low-dose promotion and high-dose inhibition" under antibiotic stress. ARGs were enriched in the PA treatment groups by 117 %. At the phylum level, Proteobacteria, Bacteroidetes, and Actinobacteria as potential hosts for ARGs. At the genus level, potential hosts included Sphingopyxis, SM1A02, Aquimonas, Vitellibacter, and Proteiniphilum. Middle and high antibiotic concentrations induced the secretion of metabolites closely related to potential hosts by algae, such as phytosphingosine, Lysophosphatidylcholine, and α-Linolenic acid. Therefore, changes in bacterial communities indirectly influenced the distribution of ARGs through alterations in metabolic products. These findings offer essential details about the mechanisms behind the spread and proliferation of ARGs in the phycosphere.