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Inhibitors of the secretion of cancer exosomes, which promote cancer progression and metastasis, may not only accelerate exosome biology research but also offer therapeutic benefits for cancer patients. Here we identify sulfisoxazole (SFX) as an inhibitor of small extracellular vesicles (sEV) secretion from breast cancer cells through interference with endothelin receptor A (ETA). SFX, an FDA-approved oral antibiotic, showed significant anti-tumor and anti-metastatic effects in mouse models of breast cancer xenografts, the reduced expression of proteins involved in biogenesis and secretion of sEV, and triggered co-localization of multivesicular endosomes with lysosomes for degradation. We demonstrate the important role of ETA, as target of SFX, by gain- and loss-of-function studies of the ETA protein, through a direct binding assay, and pharmacological and genetic approaches. These findings may provide a foundation for sEV-targeted cancer therapies and the mechanistic studies on sEV biology. Extracellular vesicles are released from cells and permit communication between different cell types. Here, the authors identify that the FDA approved antibiotic sulfisoxazole, can block the release of these vesicles in breast cancer cells resulting in reduced cell growth in vitro and in vivo.

Despite their potent antitumor activity, clinical application of immune checkpoint inhibitors has been significantly limited by their poor response rates (<30%) in cancer patients, primarily due to immunosuppressive tumor microenvironments. As a representative immune escape mechanism, cancer‐derived exosomes have recently been demonstrated to exhaust CD8+ cytotoxic T cells. Here, it is reported that sulfisoxazole, a sulfonamide antibacterial, significantly decreases the exosomal PD‐L1 level in blood when orally administered to the tumor‐bearing mice. Consequently, sulfisoxazole effectively reinvigorates exhausted T cells, thereby eliciting robust antitumor effects in combination with anti‐PD‐1 antibody. Overall, sulfisoxazole regulates immunosuppression through the inhibition of exosomal PD‐L1, implying its potential to improve the response rate of anti‐PD‐1 antibodies. Biogenesis of cancer‐derived exosomal PD‐L1, responsible for the low response rates of the immune checkpoint inhibitors, is remarkably inhibited by sulfisoxazole as an endothelin receptor A‐selective antagonist. When orally administered to the tumor‐bearing mice, sulfisoxazole reinvigorates exhausted T cells, thereby eliciting potent antitumor effects in combination with an anti‐PD‐1 antibody.

Intensive research in the field of cancer biology has revealed unique methods of communication between cells through extracellular vesicles called exosomes. Exosomes are released from a broad spectrum of cell types and serve as functional mediators under physiological or pathological conditions. Hence, blocking the release of exosome bio carriers may prove useful for slowing the progression of certain types of cancers. Therefore, efforts are being made to develop exosome inhibitors to be used both as research tools and as therapies in clinical trials. Thus, studies on exosomes may lead to a breakthrough in cancer research, for which new clinical targets for different types of cancers are urgently needed. In this review, we briefly outline exosome inhibitors and discuss their modes of action and potential for use as therapeutic tools for cancer. Cancer: Blocking vesicle release from tumors Understanding how cells produce and release exosomes, nano-sized membrane-bound vesicles containing biological molecules, holds promise for developing new cancer therapies. Tumors release exosomes that remodel the nearby environment to promote cancer growth, suppress the immune response and induce drug resistance. Although some aspects of exosomes have been studied, little attention has been paid to exosome inhibitors and how they work. Moon-Chang Baek at Kyungpook National University in Daegu, South Korea, and co-workers have reviewed exosome inhibitors and possible applications to cancer, reporting that several compounds, such as pantethine, suppress exosome production and others, such as sulfisoxazole and macitentan, suppress exosome release. They report that inhibiting exosome release can prevent tumor cells from purging anti-cancer drugs, thus increasing drug accumulation and efficacy. This review highlights new options for alternative therapies for many types of cancer.

Land application of swine manure in commercial hog farms is an integral part of their waste management system which recycles the nutrients back to the soil. However, manure application can lead to the dissemination of bacterial pathogens in the environment and pose a serious public health threat. The aim of this study was to determine the dissemination of antimicrobial resistant Salmonella in the environment due to manure application in commercial swine farms in North Carolina (n = 6) and Iowa (n = 7), two leading pork producing states in the US. We collected manure and soil samples twice on day 0 (before and after manure application) from four distinct plots of lands (5 soil samples/plot) located at 20 feet away from each other in the field. Subsequent soil samples were collected again on days 7, 14, 21 from the same plots. A total of 1,300 soil samples (NC = 600; IA = 700) and 130 manure samples (NC = 60; IA = 70) were collected and analyzed in this study. The overall Salmonella prevalence was 13.22% (189/1,430), represented by 10.69% and 38.46% prevalence in soil and manure, respectively. The prevalence in NC (25.45%) was significantly higher than in IA (2.73%) (P<0.001) and a consistent decrease in Salmonella prevalence was detected from Day 0-Day 21 in all the farms that tested positive. Salmonella serotypes detected in NC were not detected in IA, thereby highlighting serotype association based on manure storage and soil application method used in the two regions. Antimicrobial susceptibility testing was done by the broth microdilution method to a panel of 15 antimicrobial drugs. A high frequency of isolates (58.73%) were multidrug resistant (resistance to three or more class of antimicrobials) and the most frequent resistance was detected against streptomycin (88.36%), sulfisoxazole (67.2%), and tetracycline (57.67%). Genotypic characterization by pulse field gel electrophoresis revealed clonally related Salmonella in both manure and soil at multiple time points in the positive farms. Our study highlights the potential role of swine manure application in the dissemination and persistence of antimicrobial resistant Salmonella in the environment.

To discover alternative substances to compounds used to treat many diseases, especially treating Alzheimer’s disease (AD) and Parkinson’s disease targeting carbonic anhydrase (hCA) and acetylcholinesterase (AChE) enzymes, is important. For this purpose, a series of novel bis-ureido-substituted sulfaguanidine (SG1–4) and sulfisoxazole (SO1–4) derivatives were synthesized, and their inhibitory capacities were screened against hCA isoenzymes (hCA I and II) and AChE. Possible binding mechanisms of inhibitors to the active site were elucidated by in silico studies, and the results were supported by in vitro results. Moreover, the percent radical scavenging capacities of the derivatives were also evaluated. The derivatives (SG1–4 and SO1–4) were more effective against hCAs compared to standard drug acetazolamide (KI values of 98.28–439.17 nM for hCA I and II, respectively) and exhibited the highest inhibition with the KIs in the ranges of 2.54 ± 0.50–41.02 ± 7.52 nM for hCA I, 11.20 ± 2.97–67.14 ± 13.58 nM for hCA II, and 257.60 ± 27.84–442.60 ± 52.13 nM for AChE. Also, compounds SG1 and SO1 also showed ABTS radical scavenging activity at the rate of 70% and 78%, respectively. These results will contribute to the literature for the rational design and synthesis of new potent and selective inhibitors targeting hCAs and AChE with multifunctional effects such as radical scavenging as well as inhibition.This study focused on the synthesis and inhibitory effects of bis-ureido-substituted sulfaguanidine (SG1–4) and sulfisoxazole (SO1–4) derivatives against human hCA I and II isoforms and AChE. In order to test synthesized derivatives’ free radical scavenging potentials were the DPPH and ABTS assays. In silico studies elucidated possible binding mechanisms of inhibitors to the active site.

Laccases are multicopper oxidases (MCOs) with a broad application spectrum, particularly in second-generation ethanol biotechnology and the bioremediation of xenobiotics and other highly recalcitrant compounds. Synthetic pesticides are xenobiotics with long environmental persistence, and the search for their effective bioremediation has mobilized the scientific community. Antibiotics, in turn, can pose severe risks for the emergence of multidrug-resistant microorganisms, as their frequent use for medical and veterinary purposes can generate constant selective pressure on the microbiota of urban and agricultural effluents. In the search for more efficient industrial processes, some bacterial laccases stand out for their tolerance to extreme physicochemical conditions and their fast generation cycles. Accordingly, to expand the range of effective approaches for the bioremediation of environmentally important compounds, the prospection of bacterial laccases was carried out from a custom genomic database. The best hit found in the genome of Chitinophaga sp. CB10, a Bacteroidetes isolate obtained from a biomass-degrading bacterial consortium, was subjected to in silico prediction, molecular docking, and molecular dynamics simulation analyses. The putative laccase CB10_180.4889 (Lac_CB10), composed of 728 amino acids, with theoretical molecular mass values of approximately 84 kDa and a pI of 6.51, was predicted to be a new CopA with three cupredoxin domains and four conserved motifs linking MCOs to copper sites that assist in catalytic reactions. Molecular docking studies revealed that Lac_CB10 had a high affinity for the molecules evaluated, and the affinity profiles with multiple catalytic pockets predicted the following order of decreasing thermodynamically favorable values: tetracycline (−8 kcal/mol) > ABTS (−6.9 kcal/mol) > sulfisoxazole (−6.7 kcal/mol) > benzidine (−6.4 kcal/mol) > trimethoprim (−6.1 kcal/mol) > 2,4-dichlorophenol (−5.9 kcal/mol) mol. Finally, the molecular dynamics analysis suggests that Lac_CB10 is more likely to be effective against sulfisoxazole-like compounds, as the sulfisoxazole-Lac_CB10 complex exhibited RMSD values lower than 0.2 nm, and sulfisoxazole remained bound to the binding site for the entire 100 ns evaluation period. These findings corroborate that LacCB10 has a high potential for the bioremediation of this molecule.

The emergence of antimicrobial-resistant (AR) has a major concern worldwide. This study was designed to determine the AR profiles and serovars distribution of isolated from different breeds of breeder chickens in the province of Henan, China. For this, 2,139 dead embryo samples were collected from 28 breeder chicken hatcheries, representing two domestic and four foreign breeds. The samples were subjected to the isolation and identification of by PCR. The confirmed strains were serotyped according to the Kauffmann-White scheme and their AR profiles against 20 antimicrobial agents were determined by Kirby-Bauer (K-B) disc diffusion method. The results of this study showed the prevalence of in 504 strains (23.56%) with a high abundance in southern regions of Yellow River (28.66%, = 495, = 1,727) compared to the northern regions (2.18%, = 9, = 412) ( < 0.0001). The domestic breeds were more contaminated than imported breeds ( < 0.0001). However, the contamination rate of samples recovered from M-hatcheries was the highest ( < 0.0001). Serotyping method identified 12 serovars, with the dominance of . Pullorum (75.79%), followed by . Enteritidis (7.14%). The AR assay showed high resistant to ciprofloxacin (77.00%), sulfisoxazole (73.00%), and ampicillin (55.60%), as well as 98.81% ( = 498) of the isolated strains, were resistant to at least one antimicrobial and 69.64% ( = 351) were resistant to three or more antimicrobials. Among them, one strain of . Thompson was resistant to 15 antimicrobial agents belonging to eight different classes. In conclusion, strains isolated in this study were multidrug-resistant (MDR), presenting a serious problem for human and animal health. Therefore, it is necessary to monitor, control, and rationalize the use of antimicrobials agents in chicken farms in order to limit the increasing resistance against the recent antimicrobial agents.

Surface waters are important sources of water for drinking, industrial, agricultural, and recreational uses; hence, contamination of water by fecal, pathogenic, or antimicrobial resistant (AR) bacteria is a major environmental and public health concern. However, very little data is available on prevalence of these bacteria in surface water throughout a watershed. This study aimed to characterize Escherichia coli present in the Upper Oconee Watershed, a mixed-use watershed in Athens, GA, USA for potential pathogenicity and AR. E. coli were enumerated by colony counts, cultured by enrichment and direct plating, and characterized by phylo-groups, diarrheagenic pathotypes, and antimicrobial susceptibility. From the analysis, 99.3% (455/458) of the total samples were positive for E. coli resulting in 496 isolates. E. coli counts were as high as 1.2×104 CFU/100 ml, which is above the United States Environmental Protection Agency (U.S. EPA) threshold for recreational water (235 CFU/100 ml based on a one-time measurement). Phylo-groups B2 (31.7%; 157/496) and B1 (30.8%; 153/496) were the most prevalent among the isolates. Enteropathogenic E. coli (EPEC) (19/496) and Shiga toxin-producing E. coli (STEC) (1/496) were the only diarrheagenic pathotypes detected. AR was observed in 6.9% (34/496) of the isolates, 15 of which were multidrug resistant (MDR; resistance to two or more classes of antimicrobials). Tetracycline resistance was most often detected (76.5%; 26/34), followed by ampicillin (32.4%; 11/34), streptomycin (23.5%; 8/34), sulfisoxazole (23.5%; 8/34), and nalidixic acid (14.7%; 5/34). Results from this study showed that E. coli is prevalent in high levels in the Upper Oconee Watershed, suggesting possible widespread fecal contamination. The presence of pathogenic, AR E. coli in the watershed indicates that environmental water can serve as a reservoir of resistant bacteria that may be transferred to humans through drinking and recreational activities.

Guangdong Province is an important area of poultry breeding in China. Zhanjiang city is located in the western part of Guangdong Province, where there are many broiler farms. To investigate antimicrobial resistance (AMR) and the presence of resistance genes in Escherichia coli from broiler farms, a total of 220 samples were collected from soil and feces at eight broiler farms. Subsequently, 220 strains of E. coli were isolated for drug resistance analysis and detection of AMR genes. The results revealed that the isolated E. coli strains exhibited high prevalence of multidrug resistance to 12 antimicrobial drugs including amoxicillin, tetracycline, cotrimoxazole and sulfisoxazole. Among the isolated strains, 95% of the isolates were resistant to more than three antimicrobial agents; notably, thirty-nine strains showed multidrug resistance to ten tested drugs, while four strain exhibits multidrug resistance to as many as fifteen antibacterial drugs. Additionally, seven AMR genes such as bla TEM and sul2 were detected in over half (≥50%) of the isolated E. coli samples; thirteen AMR genes had relatively low detection prevalence (≤30%). Correlation analysis indicated a strong association between certain AMR genes ( bla TEM , pexA, aadA1, bla AIM , ant(3\")-I, sul2, sul3, tet(D) ) and AMR (≥50%). In conclusion, E.coli strains obtained from soil and fecal samples in broiler farms exhibited multidrug resistant phenotypes along with carrying various AMR genes. This provides a reference for the scientific control of E. coli multidrug resistance in this area.