1H-Pyrrole-2,5-dicarboxylic acid, a quorum sensing inhibitor from one endophytic fungus in Areca catechu L., acts as antibiotic accelerant against Pseudomonas aeruginosa.

Pseudomonas aeruginosa has already been stipulated as a "critical" pathogen, emphasizing the urgent need for researching and developing novel antibacterial agents due to multidrug resistance. Bacterial biofilm formation facilitates cystic fibrosis development and restricts the antibacterial potential of many current antibiotics. The capacity of P. aeruginosa to form biofilms and resist antibiotics is closely correlated with quorum sensing (QS). Bacterial QS is being contemplated as a promising target for developing novel antibacterial agents. QS inhibitors are a promising strategy for treating chronic infections. This study reported that the active compound PT22 (1H-pyrrole-2,5-dicarboxylic acid) isolated from Perenniporia tephropora FF2, one endophytic fungus from Areca catechu L., presents QS inhibitory activity against P. aeruginosa. Combined with gentamycin or piperacillin, PT22 functions as a novel antibiotic accelerant against P. aeruginosa. PT22 (0.50 mg/mL, 0.75 mg/mL, and 1.00 mg/mL) reduces the production of QS-related virulence factors, such as pyocyanin and rhamnolipid, and inhibits biofilm formation of P. aeruginosa PAO1 instead of affecting its growth. The architectural disruption of the biofilms was confirmed by visualization through scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). Real-time quantitative PCR (RT-qPCR) indicated that PT22 significantly attenuated the expression of QS-related genes followed by docking analysis of molecules against QS activator proteins. PT22 dramatically increased the survival rate of Galleria mellonella. PT22 combined with gentamycin or piperacillin presents significant inhibition of biofilm formation and eradication of mature biofilm compared to monotherapy, which was also confirmed by visualization through SEM and CLSM. After being treated with PT22 combined with gentamycin or piperacillin, the survival rates of G. mellonella were significantly increased compared to those of monotherapy. PT22 significantly enhanced the susceptibility of gentamycin and piperacillin against P. aeruginosa PAO1. Our results suggest that PT22 from P. tephropora FF2 as a potent QS inhibitor is a candidate antibiotic accelerant to combat the antibiotic resistance of P. aeruginosa.

Repurposing promethazine hydrochloride to inhibit biofilm formation against Burkholderia thailandensis.

Melioidosis is a severe infectious disease caused by Burkholderia pseudomallei, an intracellular pathogen with a high mortality rate and significant antibiotic resistance. The high mortality rate and resistance to antibiotics have drawn considerable attention from researchers studying melioidosis. This study evaluated the effects of various concentrations (75, 50, and 25 µg/mL) of promethazine hydrochloride (PTZ), a potent antihistamine, on biofilm formation and lipase activity after 24 h of exposure to B. thailandensis E264. A concentration-dependent decrease in both biofilm biomass and lipase activity was observed. RT-PCR analysis revealed that PTZ treatment not only made the biofilm structure loose but also reduced the expression of btaR1, btaR2, btaR3, and scmR. Single gene knockouts of quorum sensing (QS) receptor proteins (∆btaR1, ∆btaR2, and ∆btaR3) were successfully constructed. Deletion of btaR1 affected biofilm formation in B. thailandensis, while deletion of btaR2 and btaR3 led to reduced lipase activity. Molecular docking and biological performance results demonstrated that PTZ inhibits biofilm formation and lipase activity by suppressing the expression of QS-regulated genes. This study found that repositioning PTZ reduced biofilm formation in B. thailandensis E264, suggesting a potential new approach for combating melioidosis.

Dopamine, an exogenous quorum sensing signaling molecule or a modulating factor in Pseudomonas aeruginosa?

Pseudomonas aeruginosa is recognized globally as an opportunistic pathogen of considerable concern due to its high virulence and pathogenicity, especially in immunocompromised individuals. While research has identified several endogenous quorum sensing (QS) signaling molecules that enhance the virulence and pathogenicity of P. aeruginosa, investigations on exogenous QS signaling molecules or modulating factors remain limited. This study found that dopamine serves as an exogenous QS signaling molecule or modulating factor of P. aeruginosa PAO1, enhancing the production of virulence factors and biofilms. Compared to the control group, treatment with 40 µM dopamine resulted in a 33.1 % increase in biofilm formation, 68.1 % increase in swimming mobility, 63.1 % increase in swarming mobility, 147.2 % increase in the signaling molecule 3-oxo-C12-HSL, and 50.5 %, 28.5 %, 27.0 %, and 33.2 % increases in the virulence factors alginate, rhamnolipids, protease, and pyocyanin, respectively. This study further explored the mechanism of dopamine regulating the biofilm formation and virulence of P. aeruginosa PAO1 through transcriptome and metabolome. Transcriptomic analysis showed that dopamine promoted the expression of virulence genes psl, alg, lasA, rhlABC, rml, and phz in P. aeruginosa PAO1. Metabolomic analysis revealed changes in the concentrations of tryptophan, pyruvate, ethanolamine, glycine, 3-hydroxybutyric acid, and alizarin. Furthermore, KEGG enrichment analysis of altered genes and metabolites indicated that dopamine enhanced phenylalanine, tyrosine, and tryptophan in P. aeruginosa PAO1. The results of this study will contribute to the development of novel exogenous QS signaling molecules or modulating factors and advance our understanding of the interactions between P. aeruginosa and the host environment.

Enhancing hospice care with psychological support and a nomogram to predict delirium in patients with advanced solid tumors.

To assesses the impact of integrating hospice care with psychological interventions on patient well-being and to introduce a predictive nomogram model for delirium that incorporates clinical and psychosocial variables, thereby improving the accuracy in hospice care environments. Data from 381 patients treated from September 2018 to February 2023 were analyzed. The patients were divided into a control group (n=177, receiving standard care) and an experimental group (n=204, receiving combined hospice care and psychological interventions) according to the treatment modality. The duration of care extended until the patient's discharge from the hospital or death. The experimental group demonstrated significant improvements in emotional well-being and a lower incidence of delirium compared to the control group. Specifically, emotional well-being assessments revealed marked improvements in the experimental group, as evidenced by lower scores on the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) post-intervention. The nomogram model, developed using logistic regression based on clinical characteristics, effectively predicted the risk of delirium in patients with advanced cancer. Significant predictors in the model included ECOG score ≥3, Palliative Prognostic Index score ≥6, opioid usage, polypharmacy, infections, sleep disorders, organ failure, brain metastases, electrolyte imbalances, activity limitations, pre-care SAS score ≥60, pre-care SDS score ≥63, and pre-care KPS score ≥60. The model's predictive accuracy was validated, showing AUC values of 0.839 for the training cohort and 0.864 for the validation cohort, with calibration and Decision Curve Analysis (DCA) confirming its clinical utility. Integrating hospice care with psychological interventions not only significantly enhanced the emotional well-being of advanced cancer patients but also reduced the actual incidence of delirium. This approach, offering a valuable Nomogram model for precise care planning and risk management, underscores the importance of integrated, personalized care strategies in advanced cancer management.

An Investigation of Quorum Sensing Inhibitors against Bacillus cereus in The Endophytic Fungus Pithomyces sacchari of the Laurencia sp.

Bacillus cereus, a common food-borne pathogen, forms biofilms and generates virulence factors through a quorum sensing (QS) mechanism. In this study, six compounds (dankasterone A, demethylincisterol A3, zinnimidine, cyclo-(L-Val-L-Pro), cyclo-(L-Ile-L-Pro), and cyclo-(L-Leu-L-Pro)) were isolated from the endophytic fungus Pithomyces sacchari of the Laurencia sp. in the South China Sea. Among them, demethylincisterol A3, a sterol derivative, exhibited strong QS inhibitory activity against B. cereus. The QS inhibitory activity of demethylincisterol A3 was evaluated through experiments. The minimum inhibitory concentration (MIC) of demethylincisterol A3 against B. cereus was 6.25 µg/mL. At sub-MIC concentrations, it significantly decreased biofilm formation, hindered mobility, and diminished the production of protease and hemolysin activity. Moreover, RT-qPCR results demonstrated that demethylincisterol A3 markedly inhibited the expression of QS-related genes (plcR and papR) in B. cereus. The exposure to demethylincisterol A3 resulted in the downregulation of genes (comER, tasA, rpoN, sinR, codY, nheA, hblD, and cytK) associated with biofilm formation, mobility, and virulence factors. Hence, demethylincisterol A3 is a potentially effective compound in the pipeline of innovative antimicrobial therapies.

Dynamic alterations in physiological and biochemical indicators of Cirrhinus mrigala hatchlings: A sublethal exposure of triclosan.

Triclosan (TCS), a biocide used in various day-to-day products, has been associated with several toxic effects in aquatic organisms. In the present study, biochemical and hematological alterations were evaluated after 14 d (sublethal) exposure of tap water (control), acetone (solvent control), 5, 10, 20, and 50 µg/L (environmentally relevant concentrations) TCS to the embryos/hatchlings of Cirrhinus mrigala, a major freshwater carp distributed in tropic and sub-tropical areas of Asia. A concentration-dependent increase in the content of urea and protein carbonyl, while a decrease in the total protein, glucose, cholesterol, triglycerides, uric acid, and bilirubin was observed after the exposure. Hematological analysis revealed a decrease in the total erythrocyte count, hemoglobin, and partial pressure of oxygen, while there was an increase in the total leucocyte count, carbon dioxide, and partial pressure of carbon dioxide and serum electrolytes. Comet assay demonstrates a concentration-dependent increase in tail length, tail moment, olive tail moment, and percent tail DNA. An amino acid analyzer showed a TCS-dose-dependent increase in various amino acids. Sodium dodecyl sulphate polyacrylamide gel electrophoresis analysis revealed different proteins ranging from 6.5 to 200 kDa, demonstrating TCS-induced upregulation. Fourier transform infrared spectra analysis exhibited a decline in peak area percents with an increase in the concentration of TCS in water. Curve fitting of amide I (1,700-1600 cm-1) showed a decline in α-helix and turns and an increase in ß-sheets. Nuclear magnetic resonance study also revealed concentration-dependent alterations in the metabolites after 14 d exposure. TCS caused alterations in the biomolecules and heamatological parameters of fish, raising the possibility that small amounts of TCS may change the species richness in natural aquatic habitats. In addition, consuming TCS-contaminated fish may have detrimental effects on human health. Consequently, there is a need for the proper utilisation and disposal of this hazardous compound in legitimate quantities.

Carbazole and Quinazolinone Derivatives from a Fluoride-Tolerant Streptomyces Strain OUCMDZ-5511.

Six new 9H-carbazole derivatives (1-6) and nine previously reported compounds (7-15) were isolated from a fermented solid medium of the Thailand mangrove-derived Streptomyces strain, OUCMDZ-5511, under fluoride stress. Compounds 2-5, 12, and 15 were exclusively present in the fluoride-supplemented fermentation medium, while compounds 7-9, 13, and 14 were newly discovered natural products. The molecular structures of the compounds were identified by a spectroscopic analysis. The new compound 2 displayed antiquorum sensing activity against Chromobacterium violaceum ATCC 12472 by reducing the violacein production and inhibiting the biofilm formation in a concentration-dependent manner. The study revealed that compound 2 could be a novel potential inhibitor of quorum sensing.

Untargeted metabolomics-based network pharmacology reveals fermented brown rice towards anti-obesity efficacy.

There is a substantial rise in the global incidence of obesity. Brown rice contains metabolic substances that can help minimize the prevalence of obesity. This study evaluated nine brown rice varieties using probiotic fermentation using Pediococcus acidilacti MNL5 to enhance bioactive metabolites and their efficacy. Among the nine varieties, FBR-1741 had the highest pancreatic lipase inhibitory efficacy (87.6 ± 1.51%), DPPH assay (358.5 ± 2.80 mg Trolox equiv./100 g, DW), and ABTS assay (362.5 ± 2.32 mg Trolox equiv./100 g, DW). Compared to other fermented brown rice and FBR-1741 varieties, UHPLC-Q-TOF-MS/MS demonstrated significant untargeted metabolite alterations. The 17 most abundant polyphenolic metabolites in the FBR-1741 variety and 132 putative targets were assessed for obesity-related target proteins, and protein interaction networks were constructed using the Cystoscope software. Network pharmacology analysis validated FBR-1741 with active metabolites in the C. elegans obesity-induced model. Administration of FBR-1741 with ferulic acid improved lifespan decreased triglycerides, and suppressed the expression of fat-related genes. The enhanced anti-obesity properties of FBR-1741 suggest its implementation in obesity-functional food.

Advanced detection tools in food fraud: A systematic review for holistic and rational detection method based on research and patents.

Modern food chain supply management necessitates the dire need for mitigating food fraud and adulterations. This holistic review addresses different advanced detection technologies coupled with chemometrics to identify various types of adulterated foods. The data on research, patent and systematic review analyses (2018-2023) revealed both destructive and non-destructive methods to demarcate a rational approach for food fraud detection in various countries. These intricate hygiene standards and AI-based technology are also summarized for further prospective research. Chemometrics or AI-based techniques for extensive food fraud detection are demanded. A systematic assessment reveals that various methods to detect food fraud involving multiple substances need to be simple, expeditious, precise, cost-effective, eco-friendly and non-intrusive. The scrutiny resulted in 39 relevant experimental data sets answering key questions. However, additional research is necessitated for an affirmative conclusion in food fraud detection system with modern AI and machine learning approaches.

Methyl gallate from Camellia nitidissima Chi flowers reduces quorum sensing related virulence and biofilm formation against Aeromonas hydrophila.

Aeromonas hydrophila, a Gram-negative zoonotic bacterium, causes high mortality in fish farming and immunocompromised patients. This study aimed to extract methyl gallate (MG) from the flowers of Camellia nitidissima Chi and evaluate its potential as a quorum sensing inhibitor (QSI) against Aeromonas hydrophila SHAe 115. MG reduced QS-associated virulence factors, including hemolysis, protease, and lipase, while impairing swimming motility and biofilm formation. Additionally, MG down-regulated positive regulatory genes (ahyR, fleQ) and up-regulated negative regulators (litR, fleN). This highlights MG's promise as a potent QSI for A. hydrophila SHAe 115, advancing strategies against infections in aquaculture and human health.

Anti-Biofilm and Antivirulence Activities of 1,2,6-tri-O-galloyl-ß-á´ -glucose against Proteus penneri.

AIMS: The present study investigated the anti-virulence and anti-biofilm effects of 1,2,6-tri-O-galloyl-ß-ᴅ-glucose (TGG), isolated from Camellia nitidissima Chi flowers, on Proteus penneri ALK 1200. METHODS AND RESULTS: TGG was isolated from C. nitidissima Chi flowers using various chromatographic techniques. The milk plate assay, azocasein assay, and exopolysaccharides (EPS) inhibition assay revealed that TGG effectively inhibited the production of crucial virulence factors, including protease and EPS, in P. penneri ALK 1200. Furthermore, fourier transform infrared spectroscopic (FT-IR) analysis indicated that TGG interfered with the composition of P. penneri ALK 1200's cellular component, potentially reducing the bacteria's pathogenicity. In addition, crystal violet assay, scanning electron microscopy (SEM), and confocal laser scanning microscopy (CLSM) analysis indicated a significant reduction in biofilm formation following TGG treatment. The swimming and swarming assays also showed that TGG reduced the motility of P. penneri ALK 1200. Furthermore, the qRT-PCR assay demonstrated that TGG down-regulated the expression of positive regulatory genes (hfq and flhD) responsible for motility and biofilm formation, while up-regulating the expression of the negative regulator of the quorum sensing system, bssS, in P. penneri ALK 1200. CONCLUSIONS: TGG displayed potent anti-QS and anti-biofilm activity towards P. penneri ALK 1200.

Synthesis of Azepino[4,5-b]indole via Ring Expansion of Tetrahydro-ß-carbolines Ammonium Ylide.

The formal cyclization strategy was generally used to construct azepino[4,5-b]indole. Herein, we reported a novel and expeditious protocol for the synthesis of quaternary carbon azepino[4,5-b]indole via ring expansion of ammonium ylide, which was formed by the reaction of tetrahydro-ß-carbolines with the diazo compound. The easily available substrates, mild reaction conditions, and broad functional tolerance rendered this method a practical strategy that may significantly afford an efficient method of scaffold hopping in drug discovery.

Phloretin Inhibits Quorum Sensing and Biofilm Formation in Serratia marcescens.

This study investigated the antivirulence capacity and mechanism of apple-skin-derived phloretin against Serratia marcescens NJ01, a vegetable spoilage bacterium. At 0.5 to 2 mg/mL doses, phloretin considerably inhibited the secretion of acyl homoserine lactones (AHLs), indicating that phloretin disrupted quorum sensing (QS) in S. marcescens NJ01. The dysfunction of QS resulted in reduced biofilms and the decreased production of protease, prodigiosin, extracellular polysaccharides (EPSs), and swimming and swarming motilities. Dysfunctional QS also weakened the activity of antioxidant enzymes and improved oxidative injury. The improved oxidative injury changed the composition of the membrane, improved membrane permeability, and eventually increased the susceptibility of biofilm cells to amikacin, netilmicin, and imipenem. The disrupted QS and enhanced oxidative stress also caused disorders of amino acid metabolism, energy metabolism, and nucleic acid metabolism, and ultimately attenuated the ability of S. marcescens NJ01 to induce spoilage. Our results indicated that phloretin can act as a potent drug to defend against spoilage by S. marcescens.

Synergistic effect of kanamycin and amikacin with setomimycin on biofilm formation inhibition of Listeria monocytogenes.

Listeria monocytogenes, a foodborne pathogen that causes listeriosis with high fatality rate, exhibits multidrug resistance (MDR) known to be progressively increasing. Alternative antibacterial strategies are in high demand for treating this well-known pathogen. Anti-biofilm and anti-virulence strategies are being explored as novel approaches to treat bacterial infections. In this study, one rare antibacterial named setomimycin was isolated from Streptomyces cyaneochromogenes, which showed potent antibacterial activity against L. monocytogenes. Next, the inhibition of biofilm formation and listeriolysin O (LLO) production against L. monocytogenes were investigated at sub-minimal inhibitory concentrations (sub-MICs) of setomimycin alone or combined with kanamycin and amikacin. Crystal violet staining confirmed that setomimycin combining with kanamycin or amikacin could dramatically reduce biofilm formation against L. monocytogenes at sub-MICs, which was further evaluated by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). In the meantime, sub-MICs of setomimycin could significantly suppress the secretion of LLO. Furthermore, the transcription of genes associated with biofilms and main virulence factors, such as LLO, flagellum, and metalloprotease, were suppressed by setomimycin at sub-MICs. Hence, the study provided a deep insight into setomimycin as an alternative antibacterial agent against L. monocytogenes.

Developing 3-(2-Isocyano-6-methylbenzyl)-1H-indole Derivatives to Enhance the Susceptibility of Serratia marcescens by Occluding Quorum Sensing.

Quorum sensing (QS) inhibition is recognized as a novel antimicrobial target for infections caused by drug-resistant pathogens and is an attractive strategy for antipathogenic agent development. We designed and synthesized three parts of 3-(2-isocyanobenzyl)-1H-indole derivatives and tested their activity as novel quorum sensing inhibitors (QSIs). 3-(2-Isocyanobenzyl)-1H-indole derivatives demonstrated promising QS, biofilms, and prodigiosin inhibitory activities against Serratia marcescens at subminimum inhibitory concentrations (sub-MICs). In particular, 3-(2-isocyano-6-methylbenzyl)-1H-indole (IMBI, 32) was identified as the best candidate based on several screening assays, including biofilm and prodigiosin inhibition. Further studies demonstrated that exposure to IMBI at 1.56 µg/mL to S. marcescens NJ01 significantly inhibited the formation of biofilms by 42%. The IMBI treatment on S. marcescens NJ01 notably enhanced the susceptibility of the formed biofilms, destroying the architecture of the biofilms by up to 40%, as evidenced by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). For interference of virulence factors in S. marcescens NJ01, IMBI at 3.12 µg/mL inhibited the activity of protease and extracellular polysaccharides (EPS) by 17% and 51%, respectively, which were higher than that of the positive control vanillic acid (VAN). Furthermore, IMBI downregulated the expression of QS- and biofilm-related genes fimA, bsmA, pigP, flhC, rssB, fimC, and rsmA by 1.02- to 2.74-fold. To confirm these findings, molecular docking was performed, which indicated that the binding of IMBI to SmaR, RhlI, RhlR, LasR, and CviR could antagonize the expression of QS-linked traits. In addition, molecular dynamic simulations (MD) and energy calculations indicated that the binding of receptors with IMBI was extremely stable. The biofilms of S. marcescens NJ01 were markedly reduced by 50% when IMBI (0.39 µg/mL) was combined with kanamycin (0.15 µg/mL). In conclusion, this study highlights the potency of IMBI in inhibiting the virulence factors of S. marcescens. IMBI has all the potential to be developed as an effective and efficient QS inhibitor and antibiofilm agent in order to restore or improve antimicrobial drug sensitivity.

Tyramine, one quorum sensing inhibitor, reduces pathogenicity and restores tetracycline susceptibility in Burkholderia cenocepacia.

Burkholderia cenocepacia is an opportunistic respiratory pathogen of particular relevance to patients with cystic fibrosis (CF), primarily regulating its biological functions and virulence factors through two quorum sensing (QS) systems (CepI/R and CciI/R). The highly persistent incidence of multidrug resistant Burkholderia cenocepacia poses a global threat to public health. In this study, we investigated the effects of tyramine, one biogenic amine, on the QS systems of Burkholderia cenocepacia. Genetic and biochemical analyses revealed that tyramine inhibited the production of N-hexanoyl-homoserine (AHL) signaling molecules (C8-HSL and C6-HSL) by blocking the CepI/R and CciI/R systems. As a result, the inhibition of QS systems leads to reduced production of various virulence factors, such as biofilm formation, extracellular polysaccharides, lipase, and swarming motility. Notably, as a potential quorum sensing inhibitor, tyramine exhibits low toxicity in vivo in Galleria mellonella larvae and is well characterized by Lipinski's five rules. It also shows high gastrointestinal absorption and the ability to cross the blood-brain barrier according to SwissADME database and ProTox-II server. Additionally, tyramine was found to enhance the efficacy of tetracycline in reducing the infectivity of Burkholderia cenocepacia in Galleria mellonella larvae infection model. Therefore, tyramine could be a promising candidate for combination therapy with traditional antimicrobials to improve their effectiveness against Burkholderia cenocepacia.

Cladosporium sphaerospermum extract inhibits quorum sensing associated virulence factors of Serratia marcescens.

Serratia marcescens is now becoming a propensity for its highly antimicrobial-resistant clinical infections. Currently, it provides a novel strategy to prevent and control microbial infection by regulating S. marcescens quorum sensing (QS). Deep-sea-derived fungi are rich in QS bioactive constituents. In this work, the extracts from Cladosporium sphaerospermum SCSGAF0054 showed potent QS-related virulence factors and biofilm-inhibiting activities against S. marcescens NJ01. The swimming motility and multiple virulence factors such as prodigiosin, exopolysaccharide (EPS), lipase, protease and hemolysin were moderately inhibited by the extracts at varied concentrations. The confocal laser scanning microscope (CLSM) and scanning electron microscope (SEM) images revealed that C. sphaerospermum extracts moderately arrested biofilm formation and cell viability. Further, real-time quantitative PCR (RT-qPCR) analysis revealed that expressions of genes associated with virulence factors, flhD, fimA, fimC, bsmA, bsmB, pigA, pigC, and shlA, were significantly down-regulated compared with control. In addition, the extracts combined with imipenem inhibited the QS system of S. marcescens NJ01, disrupted its preformed biofilm, released the intra-biofilm bacteria and killed the bacteria gradually. Therefore, the extracts combined with imipenem can partially restore bacterial drug sensitivity. These results suggest that the extracts from SCSGAF0054 effectively interfere with the QS system to treat S. marcescens infection alone or combining with classical antimicrobial drugs.

Expanding germ-organ theory: Understanding non-communicable diseases through enterobacterial translocation.

Diverse microbial communities colonize different habitats of the human body, including gut, oral cavity, nasal cavity and tissues. These microbial communities are known as human microbiome, plays a vital role in maintaining the health. However, changes in the composition and functions of human microbiome can result in chronic low-grade inflammation, which can damage the epithelial cells and allows pathogens and their toxic metabolites to translocate into other organs such as the liver, heart, and kidneys, causing metabolic inflammation. This dysbiosis of human microbiome has been directly linked to the onset of several non-communicable diseases. Recent metabolomics studies have revealed that pathogens produce several uraemic toxins. These metabolites can serve as inter-kingdom signals, entering the circulatory system and altering host metabolism, thereby aggravating a variety of diseases. Interestingly, Enterobacteriaceae, a critical member of Proteobacteria, has been commonly associated with several non-communicable diseases, and the abundance of this family has been positively correlated with uraemic toxin production. Hence, this review provides a comprehensive overview of Enterobacterial translocation and their metabolites role in non-communicable diseases. This understanding may lead to the identification of novel biomarkers for each metabolic disease as well as the development of novel therapeutic drugs.

Discovery of Pyrimidinediamine Derivatives as Potent Methuosis Inducers for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a leading malignancy among women that currently lack effective targeted therapeutic agents, and the limitations of treatment have prompted the emergence of new strategies. Methuosis is a novel vacuole-presenting cell death modality that promotes tumor cell death. Hence, a series of pyrimidinediamine derivatives were designed and synthesized through evaluation of their abilities that inhibit proliferation as well as induce methuosis against TNBC cells. Among them, JH530 showed excellent anti-proliferative activities and vacuolization capacity in TNBC. The mechanism research indicated that JH530 caused cell death through inducing methuosis of cancer cells. Furthermore, JH530 inhibited tumor growth remarkably in the HCC1806 xenograft model without an apparent decrease in body weight. Overall, JH530 is a methuosis inducer that displayed remarkable suppression of TNBC growth in vitro and in vivo, which provides a basis for the future progress of more small molecules for TNBC treatment.

Combination of 2-tert-Butyl-1,4-Benzoquinone (TBQ) and ZnO Nanoparticles, a New Strategy To Inhibit Biofilm Formation and Virulence Factors of Chromobacterium violaceum.

Drug-resistant bacteria have been raising serious social problems. Bacterial biofilms and different virulence factors are the main reasons for persistent infections. As a conditioned pathogen, Chromobacterium violaceum has evolved a vast network of regulatory mechanisms to modify and fine-tune biofilm development, contributing to multidrug resistance. However, there are few therapies to combat drug-resistant bacteria. Quorum sensing (QS) inhibitors (QSIs) are a promising strategy to solve antibiotic resistance. Our previous work suggested that 2-tert-butyl-1,4-benzoquinone (TBQ) is a potent QSI. In this study, the combination of zinc oxide nanoparticles (ZnO-NPs) and TBQ (ZnO-TBQ) was investigated for the treatment of Chromobacterium violaceum ATCC 12472 infection. ZnO-NPs attach to cell walls or biofilms, and the local dissolution of ZnO-NPs can lead to increased Zn2+ concentrations, which could destroy metal homeostasis, corresponding to disturbances in amino acid metabolism and nucleic acid metabolism. ZnO-NPs significantly improved the efficiency of TBQ in inhibiting the QS-related virulence factors and biofilm formation of C. violaceum ATCC 12472. ZnO-TBQ effectively reduces the expression of genes related to QS, which is conducive to limiting the infectivity of C. violaceum ATCC 12472. Caenorhabditis elegans nematodes treated with ZnO-TBQ presented a significant improvement in the survival rate by 46.7%. Overall, the combination of ZnO-NPs and TBQ offers a new strategy to attenuate virulence factors and biofilm formation synergistically in some drug-resistant bacteria. IMPORTANCE The combination of ZnO-NPs and TBQ (ZnO-TBQ) can compete with the inducer N-decanoyl-homoserine lactone (C10-HSL) by binding to CviR and downregulate genes related to the CviI/CviR system to interrupt the QS system of C. violaceum ATCC 12472. The downstream genes responding to cviR were also downregulated so that virulence factors and biofilm formation were inhibited. Furthermore, ZnO-TBQ presents multiple metabolic disturbances in C. violaceum ATCC 12472, which results in the reduced multidrug resistance and pathogenicity of C. violaceum ATCC 12472. In an in vivo assay, C. elegans nematodes treated with ZnO-TBQ presented a significant improvement in the survival rate by 46.7% by limiting the infectivity of C. violaceum ATCC 12472. In addition, ZnO-TBQ inhibited the generation of virulence factors and biofilm formation 2-fold compared to either ZnO-NPs or TBQ alone. The combination of ZnO-NPs with TBQ offers a potent synergistic strategy to reduce multidrug resistance and pathogenicity.