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BACKGROUND: Due to the increasing incidence of ischaemic cerebrovascular diseases, the accurate assessment of internal carotid artery (ICA) stenosis is crucial for the development of treatment plans. This systematic review and meta-analysis aimed to evaluate the diagnostic value of computed tomography angiography (CTA) for severe ICAstenosis, thereby providing support for clinical decision-making and promoting diagnostic updates. METHODS: The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database for Chinese Technical Periodicals (VIP), and Chinese Biomedical Literature (CBM) electronic databases were searched from inception to March 21, 2024, to identify publicly available research literature on the use of CTA to diagnose severe ICA stenosis. Literature screening, data extraction, and quality assessment were conducted based on the inclusion and exclusion criteria as well as the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) standards. Data analysis was performed using Stata 17.0 and Meta-Disc 1.4 software. The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of the included studies were calculated using Stata 17.0 software, and forest plots and summary receiver operating characteristic (SROC) curves were generated. The area under the curve (AUC) was calculated, and funnel plots were constructed to assess publication bias. RESULTS: A total of 16 studies with 2368 vascular segments were included. The meta-analysis revealed that the combined sensitivity and specificity of CTA for severe ICA stenosis were 0.93 (95% CI: 0.88 ~ 0.96) and 0.99 (95% CI: 0.96 ~ 1.00), respectively. The combined positive likelihood ratio and negative likelihood ratio were 92.0 (95% CI: 24.2 ~ 349.6) and 0.07 (95% CI: 0.04 ~ 0.13), respectively. The diagnostic odds ratio was 1302 (95% CI: 257 ~ 6606), and the AUC of the SROC curve was 0.98. The Deeks funnel plot suggested no publication bias among the included studies. CONCLUSION: CTA demonstrated high sensitivity and specificity for diagnosing severe ICA stenosis. Therefore, this study provided important evidence for the accurate diagnosis and treatment of severe ICA stenosis. However, there was considerable heterogeneity among the included studies, thus indicating the need for additional high-quality prospective studies to confirm the clinical applicability of CTA.
Subject(s)
Carotid Artery, Internal , Carotid Stenosis , Computed Tomography Angiography , Sensitivity and Specificity , Humans , Carotid Stenosis/diagnostic imaging , Computed Tomography Angiography/methods , Carotid Artery, Internal/diagnostic imaging , ROC Curve , Severity of Illness IndexABSTRACT
Introduction: Breast cancer is one of the most prevalent cancers, primarily affecting women. Among its subtypes, estrogen receptor-positive (ER+) breast cancer is particularly common. Inhibiting estrogen's effects is crucial for treating ER+ breast cancer, but current therapies often have significant side effects and limitations. Chrysin, a natural flavonoid, has shown potential in reducing estrogen receptor expression, but its poor water solubility hampers clinical application. This study explores the use of mesoporous dopamine nanoparticles (mPDA) to enhance the delivery and efficacy of Chrysin, combined with photothermal therapy (PTT), for breast cancer treatment. Methods: Chrysin-loaded mPDA nanoparticles (Chrysin@mPDA) were synthesized and characterized for their morphology, drug-loading efficiency, stability, and photothermal properties. Network pharmacology was used to predict Chrysin's mechanisms in breast cancer, which were validated through gene expression analysis in cell experiments. The therapeutic efficacy of Chrysin@mPDA with and without PTT was evaluated in a mouse model of breast cancer, with tumor volume and weight measured. Immunohistochemical analysis was conducted to assess estrogen receptor expression and immune cell infiltration in tumor tissues. Results: Chrysin@mPDA nanoparticles demonstrated a high drug-loading capacity and excellent stability. Photothermal studies confirmed the nanoparticles' ability to generate heat upon laser exposure, significantly enhancing Chrysin release in acidic conditions with laser irradiation. Network pharmacology identified key target genes affected by Chrysin, including ESR1, BRCA1, CTNNB1, and BAX, which were validated through qPCR. In vivo, the combination of Chrysin@mPDA and PTT significantly reduced tumor volume and weight, decreased estrogen receptor-positive cells, and increased infiltration of CD3+CD4+ and CD3+CD8+ T cells in tumor tissues. Discussion: The study highlights the potential of Chrysin-loaded mPDA nanoparticles combined with PTT as an effective strategy for breast cancer treatment. This approach addresses the limitations of Chrysin's solubility and enhances its therapeutic efficacy through synergistic mechanisms. The dual action of Chrysin in modulating gene expression and PTT in inducing localized hyperthermia and immune response suggests a promising avenue for improved breast cancer prognosis and reduced recurrence.
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Colistin (CST) is considered as "agent of last resort" against gram-negative bacteria as feed additive. Its clinical effectiveness has reduced since the emergence of mcr-1 gene in ducks. Isopropoxy benzene guanidine (IBG), a new guanidine derivative, showed positive effects on improving animal weights and alleviating intestinal pathogens, therefore, the objective of this study was to evaluate the effect of this compound supplement with CST in ducks and explore the possibilities in feed additive. A total of fifteen duck-origin Escherichia coli carrying the mcr-1 gene were included in this study. A checkerboard microdilution assay was used to evaluate the in vitro antibacterial activity of IBG combined with CST against mcr-1-positive E. coli. A 3-by-2 time-kill array of IBG (16, 32, and 64 µg/mL) and CST (1/2 MIC and 1/4 MIC) over 24 hours was utilized to characterize the activity of the agents alone and in combination against E. coli strain 1 in vitro. The intestinal colonization model was used to evaluate the in vivo effect of IBG combined with CST. These results indicated that the combination of IBG plus CST showed a synergistic effect against all clinical isolates (FICI < 0.5). The bacterial burden was reduced by more than 2 log10 CFU/mL when E. coli strain 1 was tested with 1/2 MIC CST plus 64 µg/mL IBG for 24 h. Further experiments in vivo demonstrated that the CST combined with IBG was able to increase duck weights, reduced intestinal pathogenic E. coli and showed a synergistic antibacterial effect. Combination of CST (4 mg/kg b.w.) plus IBG (32 or 64 mg/kg b.w.) achieved 1.84 to 3.29 log10 CFU/g killing after 7 d of therapy, which was significantly different from that in the challenge control group (p<0.05). In summary, our study demonstrated the potential use of IBG as feed additive for veterinary purposes in ducks and provided new insights into overcoming resistance in the future.
Subject(s)
Anti-Bacterial Agents , Colistin , Drug Synergism , Ducks , Escherichia coli Infections , Escherichia coli Proteins , Escherichia coli , Poultry Diseases , Animals , Escherichia coli/drug effects , Colistin/pharmacology , Colistin/administration & dosage , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/administration & dosage , Escherichia coli Infections/veterinary , Escherichia coli Infections/microbiology , Escherichia coli Infections/drug therapy , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Poultry Diseases/microbiology , Poultry Diseases/drug therapy , Microbial Sensitivity Tests/veterinary , Intestinal Diseases/veterinary , Intestinal Diseases/microbiology , Intestinal Diseases/drug therapy , Guanidine/pharmacology , Animal Feed/analysisABSTRACT
The economic impact of necrotizing enteritis (NE) resulting from Clostridium perfringens infection has been significant within the broiler industry. This study primarily investigated the antibacterial efficacy of hexahydrocolupulone against C. perfringens, and its pharmacokinetics within the ileal contents of broiler chickens. Additionally, a dosing regimen was developed based on the pharmacokinetic/pharmacodynamic (PK/PD) model specific to broiler chickens. Results of the study indicated that the minimum inhibitory concentration (MIC) of hexahydrocolupulone against C. perfringens ranged from 2 mg/L to 16 mg/L in MH broth. However, in ileal content, the MIC ranged from 8 mg/L to 64 mg/L. The mutation prevention concentration (MPC) in the culture medium was found to be 128 mg/L. After oral administration of hexahydrocolupulone at a single dosage of 10-40 mg/kg bodyweight, the peak concentration (Cmax), maximum concentration time (Tmax), and area under the concentration-time curve (AUC) in ileal content of broiler chickens were 291.42-3519.50 µg/g, 1-1.5 h, and 478.99-3121.41 µg h/g, respectively. By integrating the in vivo PK and ex vivo PD data, the AUC0-24h/MIC values required for achieving bacteriostatic, bactericidal, and bacterial eradication effects were determined to be 36.79, 52.67, and 62.71 h, respectively. A dosage regimen of 32.9 mg/kg at 24 h intervals for a duration of 3 days would yield therapeutic efficacy in broiler chickens against C. perfringens, provided that the MIC below 4 mg/L.
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Introduction: Riemerella anatipestifer (R. anatipestifer) is an important pathogen in waterfowl, leading to substantial economic losses. In recent years, there has been a notable escalation in the drug resistance rate of R. anatipestifer. Consequently, there is an imperative need to expedite the development of novel antibacterial medications to effectively manage the infection caused by R. anatipestifer. Methods: This study investigated the in vitro and in vivo antibacterial activities of a novel substituted benzene guanidine analog, namely, isopropoxy benzene guanidine (IBG), against R. anatipestifer by using the microdilution method, time-killing curve, and a pericarditis model. The possible mechanisms of these activities were explored. Results and Discussion: The minimal inhibitory concentration (MIC) range of IBG for R. anatipestifer was 0.5-2 µg/mL. Time-killing curves showed a concentration-dependent antibacterial effect. IBG alone or in combination with gentamicin significantly reduced the bacterial load of R. anatipestifer in the pericarditis model. Serial-passage mutagenicity assays showed a low probability for developing IBG resistance. Mechanistic studies suggested that IBG induced membrane damage by binding to phosphatidylglycerol and cardiolipin, leading to an imbalance in membrane potential and the transmembrane proton gradient, as well as the decreased of intracellular adenosine triphosphate. In summary, IBG is a potential antibacterial for controlling R. anatipestifer infections.
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There are limited investigations on the role of feed additives in easing transition of pullets to egg production phase. We investigated the effects of supplementation of bacitracin methylene disalicylate (BMD) and select feed additives (myristic acid [MA], benzoic acid [BA], and Aspergillus niger probiotic [PRO]) in feeding program for pullets from the onset of lay through to 31 weeks of age (woa). Parameters measured included hen-day egg production (HDEP), feed intake (FI), feed conversion ratio (FCR), egg quality characteristics, ceca microbial activity, apparent retention of components, and plasma metabolites. A total of 1,200 Lohmann LSL Lite pullets were procured at 18 woa and placed in enriched cages (30 birds/cage) based on body weight (BW) and allocated to five diets. The diets were a basal diet formulated to meet specifications or basal mixed with either BMD, MA, BA, or PRO. Birds had free access to feed and water throughout the experiment. Between 18 and 20 woa, birds fed BMD ate a similar (Pâ >â 0.05) amount of feed to BA birds, but more (Pâ =â 0.0003) than birds fed basal, MA, or PRO diets. Basal birds had lower HDEP (Pâ =â 0.001) and lighter eggs (Pâ <â 0.0001) than birds fed any of the feed additives between 21 and 31 woa. The basal hens had a higher (Pâ =â 0.009) abundance of Escherichia coli than birds fed BMD, BA, and PRO diets. Consequently, BMD, BA, and PRO birds had a higher (Pâ =â 0.011) Lactobacilli: E. coli ratio (LER) than hens fed the basal diet. Specifically, relative to basal-fed hens, the LER of the BMD, MA, BA, and PRO hens was higher by 37%, 21%, 26%, and 45%, respectively. Moreover, birds fed PRO tended to have a higher concentration of ceca digesta acetic acid (Pâ =â 0.072) and a lower concentration of isobutyric acid (Pâ =â 0.096). In conclusion, supplementing pullet diets with broad-spectrum antibiotics or feed additives (MA, BA, and PRO) had a positive impact on FI, and egg production linked to modulation of indices of gut health. The results suggested supplementing feed additives in feeding programs for pullets at the onset of lay can bolster productivity outcomes.
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Benzoic acid is a common alternative for antibiotic and zinc oxide use in nursery diets. Free benzoic acid (BZA) is often supplied, but this form is absorbed before it can exert any effect on distal segments of the gut. The study aimed to evaluate the effects of protected benzoic acid on growth performance, nutrient digestibility, plasma metabolites, and gut health indices in starter pigs. A total of 192 pigs were weaned at 28 ± 1 d age (initial body weight, 8.72 ± 1.13 kg). Pens were assigned to one of four treatment diets (n = 8 pens per treatment): (1) no additive (NC), (2) free benzoic acid (BZA; 0.6%), (3) protected benzoic acid (BC50; 0.2%, supplied at a ratio of one to three equivalents of BZA), and (4) antibiotic growth promoter (AGP; Carbadox, 50 ppm). Diets were fed for three weeks over two periods (period 1, 7 d; period 2, 14 d). Body weight and feed intake were measured for each period. Feces were collected at the end of each period to determine apparent total tract digestibility (ATTD) of organic matter (OM), gross energy (GE), and crude protein (CP). One pig per pen was euthanized per period to determine plasma metabolites; jejunum and ileum morphology; jejunum, ileum, and colon cytokine abundance; and jejunum, ileum, and colon tight junction protein expression. The AGP group had increased average daily gain (ADG) and average daily feed intake (ADFI) compared to other groups in period 1 and overall (P < 0.05); however, ADG and ADFI of the BC50 group was intermediate between the NC and BZA groups and the AGP group in period 2. The ATTD of OM, GE, and CP were greater in the AGP group compared to the NC and BC50 groups (P < 0.05), whereas the BZA group was intermediate. Jejunum and ileum villus height and crypt depth increased from period 1 to period 2 (P < 0.01) but were similar across groups. Ileum and colon tumor necrosis factor-α (TNF-α) abundances were greater, whereas colon interleukin (IL)-1ß and colon and ileum IL-8 abundances were less, in the AGP group compared to the BZA group (P < 0.05); the NC and BC50 groups exhibited intermediate TNF-α, IL-1ß, and IL-8 abundance in the ileum and colon. Jejunum cytokine abundance did not vary among groups but declined from period 1 to period 2 (P < 0.05). Tight junction protein expression also did not vary among groups. In summary, protected BZA supported a slight increase in growth performance in starter pigs, suggesting its potential as an alternative feed additive in nursery diets.
ABSTRACT
Hops extracts and their derivatives have many important biological activities, among them, excellent antibacterial and antioxidant properties make them a promising food preservative. However, poor water solubility limits their application in the food industry. This work aimed to improve the solubility of Hexahydrocolupulone (HHCL) by preparing solid dispersion (SD) and investigating the application of the obtained products (HHCL-SD) in actual food systems. HHCL-SD was prepared by solvent evaporation with PVPK30 as a carrier. The solubility of HHCL was dramatically increased to 24.72 mg/mLï¼25 â)by preparing HHCL-SD, much higher than that of raw HHCL (0.002 mg/mL). The structure of HHCL-SD and the interaction between HHCL and PVPK30 were analyzed. HHCL-SD was confirmed to have excellent antibacterial and antioxidant activities. Furthermore, the addition of HHCL-SD proved to be beneficial for the sensory, nutritional quality, and microbiological safety of fresh apple juice, hence prolonging its shelf-life.
Subject(s)
Malus , Antioxidants/pharmacology , Solvents/chemistry , Anti-Bacterial Agents/pharmacology , SolubilityABSTRACT
Isopropoxy benzene guanidine (IBG) is a guanidine derivative with antibacterial activity against multidrug-resistant bacteria. A few studies have revealed the metabolism of IBG in animals. The aim of the current study was to identify potential metabolic pathways and metabolites of IBG. The detection and characterization of metabolites were performed with high-performance liquid chromatography tandem mass spectrometry (UHPLC-Q-TOF-MS/MS). Seven metabolites were identified from the microsomal incubated samples by using the UHPLC-Q-TOF-MS/MS system. The metabolic pathways of IBG in the rat liver microsomes involved O-dealkylation, oxygenation, cyclization, and hydrolysis. Hydroxylation was the main metabolic pathway of IBG in the liver microsomes. This research investigated the in vitro metabolism of IBG to provide a basis for the further pharmacology and toxicology of this compound.
Subject(s)
Microsomes, Liver , Tandem Mass Spectrometry , Rats , Animals , Tandem Mass Spectrometry/methods , Microsomes, Liver/metabolism , Benzene , Guanidine/pharmacology , Chromatography, High Pressure Liquid/methodsABSTRACT
The increasing emergence of antibiotic resistance is an urgent threat to global health care; thus, there is a need for new therapeutics. Guanidine is the preferred functional group for antimicrobial design and development. Herein, the potential antibacterial activity of the guanidine derivative isopropoxy benzene guanidine (IBG) against multidrug-resistant (MDR) bacteria was discovered. The synergistic antibacterial activity of IBG and colistin was determined by checkerboard assay, time-killing curve, and mouse experiments. The antibacterial mechanism of IBG was verified in fluorescent probe experiments, intracellular oxidative phosphorylation assays, and transcriptome analysis. The results showed that IBG displays efficient antibacterial activity against Gram-positive pathogens and Gram-negative pathogens with permeabilized outer membranes. Further mechanistic studies showed that IBG triggers cytoplasmic membrane damage by binding to phosphatidylglycerol and cardiolipin, leading to the dissipation of proton motive force and accumulation of intracellular ATP. IBG combined with low levels of colistin enhances bacterial outer membrane permeability and increases the accumulation of reactive oxygen species, as further evidenced by transcriptome analysis. Furthermore, the efficacy of IBG with colistin against MDR Escherichia coli in three infection models was demonstrated. Together, these results suggest that IBG is a promising adjuvant of colistin, providing an alternative approach to address the prevalent infections caused by MDR Gram-negative pathogens. IMPORTANCE As antibiotic discovery stagnates, the world is facing a growing menace from the emergence of bacteria that are resistant to almost all available antibiotics. The key to winning this race is to explore distinctive mechanisms of antibiotics. Thus, novel efficient antibacterial agents and alternative strategies are urgently required to fill the void in antibiotic development. Compared with the large amount of money and time required to develop new agents, the antibiotic adjuvant strategy is a promising approach to inhibit bacterial resistance and increase killing of bacteria. In this study, we found that the guanidine derivatives IBG not only displayed efficient antibacterial activities against Gram-positive bacteria but also restored colistin susceptibility of Gram-negative pathogens as an antibiotic adjuvant. More in-depth study showed that IBG is a potential lead to overcome antibiotic resistance, providing new insight into future antibiotic discovery and development.
Subject(s)
Benzene , Colistin , Animals , Mice , Colistin/pharmacology , Benzene/metabolism , Benzene/pharmacology , Gram-Negative Bacteria/metabolism , Guanidine/metabolism , Guanidine/pharmacology , Anti-Bacterial Agents/chemistry , Bacteria/metabolism , Escherichia coli/metabolism , Drug Resistance, Multiple, Bacterial , Guanidines/pharmacology , Microbial Sensitivity TestsABSTRACT
This study aimed to evaluate the antibacterial activity of isopropoxy benzene guanidine (IBG) against C. perfringens based on pharmacokinetics/pharmacodynamics (PK/PD) modeling in broilers. The PK parameters of IBG in the plasma and ileal content of C. perfringens-infected broilers following oral administration at 2, 30, and 60 mg/kg body weight were investigated. in vivo PD studies were conducted over oral administration ranging from 2 to 60 mg/kg and repeated every 12 h for 3 days. The inhibitory I max model was used for PK/PD modeling. Results showed that the MIC of IBG against C. perfringens was 0.5-32 mg/L. After oral administration of IBG, the peak concentration (C max ), maximum concentration time (T max ), and area under the concentration-time curve (AUC) in ileal content of broilers were 10.97-1,036.64 mg/L, 2.39-4.27 h, and 38.31-4,266.77 mg·h/L, respectively. After integrating the PK and PD data, the AUC0 - 24h /MIC ratios needed for the bacteriostasis, bactericidal activity, and bacterial eradication were 4.00, 240.74, and 476.98 h, respectively. For dosage calculation, a dosage regimen of 12.98 mg/kg repeated every 12 h for 3 days was be therapeutically effective in broilers against C. perfringens with MIC ≤ 2 mg/L. In addition, IBG showed potent activity against C. perfringens, which may be responsible for cell membrane destruction. These results can facilitate the evaluation of the use of IBG in the treatment of intestinal diseases in broilers caused by C. perfringens.
ABSTRACT
Isopropoxy benzene guanidine (IBG) is a novel substituted benzene guanidine analogue with antibacterial activity against multidrug-resistant bacteria. However, the bioavailability of IBG is not optimal due to its finite aqueous solubility, thus hampering its potential therapeutic exploitation. In this study, we prepared IBG/hydroxypropyl-ß-CD (IBG/HP-ß-CD) complex, and characterized it by differential scanning calorimetry, Fourier transform infrared spectroscopy, powder X-ray diffraction, and scanning electron microscopy. Physicochemical characterization indicated that the crystal morphology of IBG transformed into an amorphous state, thus forming IBG/HP-ß-CD inclusion complexes. Complexation with HP-ß-CD significantly improve the aqueous solubility, pharmaceutical properties, absorption, and bioavailability of IBG.
Subject(s)
Benzene , beta-Cyclodextrins , 2-Hydroxypropyl-beta-cyclodextrin , Biological Availability , Guanidine , Guanidines , Water , beta-Cyclodextrins/chemistryABSTRACT
This study aimed to investigate the role of the probiotic Aspergillus niger on the production performance, egg quality, and cecal microbial load of Clostridium perfringens, Salmonella spp., and Escherichia coli in Hy-Line W-36 laying hens. A total of 72, 45-week-old Hy-Line W-36 laying hens were randomly allocated to one of the three dietary treatments with six replicates, and each replicate had four individually caged laying hens (n = 6 and 4 hens/replicate). The hens in each treatment group were fed a corn and soybean meal diet (Control), a diet supplemented with bacitracin methylene disalicylate (BMD) at a rate of 495 mg/kg of feed (Positive Control), or a diet supplemented with Aspergillus niger (Probioist®) at a rate of 220 mg/kg of feed (Probiotic). Supplementing probiotics in the laying hen diet significantly increased egg production at weeks 3 and 6 compared with the Positive Control. Haugh unit, a measure of egg quality, was significantly higher in laying hens fed the probiotic diet compared with the Control or Positive Control at week 10. Furthermore, the Probiotic group had numerically lower cecal microbial loads of pathogenic bacteria (Clostridium perfringens, Salmonella spp., and Escherichia coli) compared with the Control and Positive Control groups. The results suggest that Aspergillus niger could be used as a probiotic to improve laying hen performance and egg quality.
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Plasmid-borne colistin resistance mediated by mcr-1 is a growing problem, which poses a serious challenge to the clinical application of colistin for Gram-negative bacterial infections. Drug combination is one of the effective strategies to treat colistin-resistant bacteria. Here, we found a guanidine compound, namely, isopropoxy benzene guanidine (IBG), which boosted the efficacy of colistin against mcr-1-positive Salmonella. This study aimed to develop a pharmacokinetics/pharmacodynamics (PK/PD) model by combining colistin with IBG against mcr-1-positive Salmonella in an intestinal infection model. Antibiotic susceptibility testing, checkerboard assays and time-kill curves were used to investigate the antibacterial activity of the synergistic activity of the combination. PK studies of colistin in the intestine were determined through oral gavage of single dose of 2, 4, 8, and 16 mg/kg of body weight in broilers with intestinal infection. On the contrary, PD studies were conducted over 24 h based on a single dose ranging from 2 to 16 mg/kg. The inhibitory effect I max model was used for PK/PD modeling. The combination of colistin and IBG showed significant synergistic activity. The AUC0-24h /MIC index was used to evaluate the relationship between PK and PD, and the correlation was >0.9085. The AUC0-24h /MIC targets in combination required to achieve the bacteriostatic action, 3-log10 kill, and 4-log10 kill of bacterial counts were 47.55, 865.87, and 1894.39, respectively. These results can facilitate the evaluation of the use of IBG as a potential colistin adjuvant in the treatment of intestinal diseases in broilers caused by colistin-resistant Salmonella.
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Colistin is a last-line antibiotic against Gram-negative pathogens. However, the emergence of colistin resistance has substantially reduced the clinical effectiveness of colistin. In this study, synergy between colistin and capric acid was examined against twenty-one Gram-negative bacterial isolates (four colistin-susceptible and seventeen colistin-resistant). Checkerboard assays showed a synergistic effect against all colistin-resistant strains [(FICI, fractional inhibitory concentration index) = 0.02-0.38] and two colistin-susceptible strains. Time-kill assays confirmed the combination was synergistic. We suggest that the combination of colistin and capric acid is a promising therapeutic strategy against Gram-negative colistin-resistant strains.
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Serious infections caused by multidrug-resistant Staphylococcus aureus clearly urge the development of new antimicrobial agents. Drug repositioning has emerged as an alternative approach that enables us to rapidly identify effective drugs. We first reported a guanidine compound, isopropoxy benzene guanidine, had potent antibacterial activity against S. aureus. Unlike conventional antibiotics, repeated use of isopropoxy benzene guanidine had a lower probability of resistance section. We found that isopropoxy benzene guanidine triggered membrane damage by disrupting the cell membrane potential and cytoplasmic membrane integrity. Furthermore, we demonstrated that isopropoxy benzene guanidine is capable of treating invasive MRSA infections in vivo studies. These findings provided strong evidence that isopropoxy benzene guanidine represents a new chemical lead for novel antibacterial agent against multidrug-resistant S. aureus infections.
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BACKGROUND: Bacterial infections cause a serious public health crisis due to the emergence of resistance towards multiple conventional antibacterial drugs. In particular, multidrug-resistant (MDR) Enterococcus faecium which belongs to "ESKAPE" organisms is causing significant problems worldwide. Hence, there is an urgent need to find alternative therapies. Recently, substituted benzene guanidine compounds have been used as lead structures to discover new promising drugs in both synthetic and medicinal chemistry. PURPOSE: Here we investigated the antimicrobial activity of a new substituted benzene guanidine analog, isopropoxy benzene guanidine, against Enterococci. MATERIAL AND METHODS: The isopropoxy benzene guanidine was synthesized by Guangzhou Insighter Biotechnology Co., Ltd and tested on both reference bacterial strain and 32 clinical MDR Enterococci strains. The in vitro antibacterial activity was evaluated by microdilution method and kill kinetic assays. The potential antibacterial mechanism was measured by fluorescence spectrometry using fluorescent membrane potential probe 3, 3-diethyloxacarbocyanine iodide (DiOC2 (3)). RESULTS: Isopropoxy benzene guanidine exhibited potent bactericidal activity against both reference strain and MDR Enterococci isolates. The minimum inhibitory concentration (MIC) range for isopropoxy benzene guanidine was 1-4 µg/mL. Minimum bactericidal concentration (MBC) was about 2-8-fold of its MIC values. Time-kill studies showed that isopropoxy benzene guanidine provided superior bactericidal effect against reference and MDR strains within 12 hrs at 2×MIC. Furthermore, isopropoxy benzene guanidine could cause a large reduction in the magnitude of the generated membrane potential compared to that of the untreated cells. CONCLUSION: The present study highlights the potent bactericidal activity of isopropoxy benzene guanidine on Enterococci by disrupting the cell membrane potential. These findings demonstrate that isopropoxy benzene guanidine may be a good chemical lead for further medicinal chemistry and pharmaceutical development and could be used as a therapeutic agent for infectious diseases caused by MDR Enterococci.
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A 28-year-old man with papillary thyroid cancer underwent bone scintigraphy to assess possible osseous metastasis. He had vigorous workouts 5 days prior, which involved pectorals, rectus abdominis, quadriceps, and glutei. However, the images only showed increased activity in the rectus abdominis, whereas other involved muscles had no obvious uptake. No lesion in the bone was identified.
Subject(s)
Diphosphonates/metabolism , Exercise , Rectus Abdominis/metabolism , Adult , Biological Transport , Bone and Bones/diagnostic imaging , False Positive Reactions , Humans , Male , Radionuclide Imaging , Rectus Abdominis/diagnostic imagingABSTRACT
Accurately determining the adsorbed amount of CH4 on shale is significant for understanding the mechanisms of shale gas storage and shale methane recovery from shale gas reservoirs. Excess CH4 adsorption is measured using the thermogravimetric method. Simplified local density (SLD) theory is applied to calculate the adsorbed CH4 density to obtain the absolute adsorption. Moreover, the modified Langmuir adsorption model is employed to fit the excess adsorption to describe the absolute adsorption. The adsorbed CH4 density from the SLD model is affected by the system pressure and temperature, while such density obtained from the modified Langmuir model is only a function of temperature. Compared to the modified Langmuir model, the SLD model can better capture the adsorbed CH4 density, which allows accurate determination of the absolute CH4 adsorption.