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Hepatology (Baltimore, Md.) Sep 2021Hypoxia is a common feature of the tumor microenvironment (TME), which promotes tumor progression, metastasis, and therapeutic drug resistance through a myriad of cell...
BACKGROUND AND AIMS
Hypoxia is a common feature of the tumor microenvironment (TME), which promotes tumor progression, metastasis, and therapeutic drug resistance through a myriad of cell activities in tumor and stroma cells. While targeting hypoxic TME is emerging as a promising strategy for treating solid tumors, preclinical development of this approach is lacking in the study of HCC.
APPROACH AND RESULTS
From a genome-wide CRISPR/CRISPR-associated 9 gene knockout screening, we identified aldolase A (ALDOA), a key enzyme in glycolysis and gluconeogenesis, as an essential driver for HCC cell growth under hypoxia. Knockdown of ALDOA in HCC cells leads to lactate depletion and consequently inhibits tumor growth. Supplementation with lactate partly rescues the inhibitory effects mediated by ALDOA knockdown. Upon hypoxia, ALDOA is induced by hypoxia-inducible factor-1α and fat mass and obesity-associated protein-mediated N -methyladenosine modification through transcriptional and posttranscriptional regulation, respectively. Analysis of The Cancer Genome Atlas shows that elevated levels of ALDOA are significantly correlated with poor prognosis of patients with HCC. In a screen of Food and Drug Administration-approved drugs based on structured hierarchical virtual platforms, we identified the sulfamonomethoxine derivative compound 5 (cpd-5) as a potential inhibitor to target ALDOA, evidenced by the antitumor activity of cpd-5 in preclinical patient-derived xenograft models of HCC.
CONCLUSIONS
Our work identifies ALDOA as an essential driver for HCC cell growth under hypoxia, and we demonstrate that inhibition of ALDOA in the hypoxic TME is a promising therapeutic strategy for treating HCC.
Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Fructose-Bisphosphate Aldolase; Gene Knockdown Techniques; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lactic Acid; Liver Neoplasms; Loss of Function Mutation; Mice; Neoplasm Transplantation; Sulfamonomethoxine; Tumor Hypoxia; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 33813748
DOI: 10.1002/hep.31846 -
The Journal of Veterinary Medical... Jul 2023The efficacy of orally administered drugs in cattle is thought to be slow because of the anatomical and physiological features of their forestomach. Thus, parenteral...
The efficacy of orally administered drugs in cattle is thought to be slow because of the anatomical and physiological features of their forestomach. Thus, parenteral routes are mainly preferred to administer drugs. However, the effect of some drugs with unique physicochemical properties was promptly obtained even after oral administration in clinically ill cattle. Therefore, the present study aimed to investigate pharmacokinetically the usefulness of the oral route in cattle by comparing the oral pharmacokinetic properties of two sulfonamides with different physicochemical properties. Sulfadiazine (SDZ) and sulfamonomethoxine (SMM) were administered by intravenous and oral route to four female Holstein cows with a 4-weeks washout period. Blood samples were collected over time, and SDZ and SMM concentrations in plasma were analyzed by HPLC. Data obtained from the same animal after intravenous and oral administration were simultaneously analyzed with the one compartment model, and kinetic parameters were calculated. The T (mean ± SD) of SMM (2.75 ± 0.96 hr) was significantly achieved earlier than that of SDZ (5.00 ± 1.15 hr). Further, the mean absorption time of SMM (5.24 ± 0.69 hr) was significantly shorter than that of SDZ (5.92 ± 1.11 hr). Also, the half-life of absorption of SMM (3.91 ± 0.51 hr) was significantly shorter than that of SDZ (4.51 ± 0.82 hr). These data suggest that the absorption rates of highly unionized drugs (such as SMM) from the forestomach of cattle may be markedly higher than less unionized ones (such as SDZ).
Topics: Cattle; Female; Animals; Sulfamonomethoxine; Sulfadiazine; Sulfanilamide; Sulfonamides; Administration, Intravenous; Administration, Oral
PubMed: 37225451
DOI: 10.1292/jvms.23-0110 -
Poultry Science Jun 2022Antibiotic residues contained in poultry eggs pose threat to human health. However, the classes and concentrations of antibiotics in poultry egg in southwestern China is...
Antibiotic residues contained in poultry eggs pose threat to human health. However, the classes and concentrations of antibiotics in poultry egg in southwestern China is unknown due to insufficient monitoring and research. A total of 513 egg samples were collected from supermarkets and farm markets in Kunming city in 2020 and the levels of 7 antibiotics were analyzed using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. The linear correlation coefficients were above 0.990 for all antibiotics tested. The limits of detection and limits of quantification in poultry eggs were 0.002 to 0.010 μg/g and 0.007 to 0.033 μg/g, respectively. The average recoveries of the 7 analytes from poultry egg samples were 80.00 to 128.01%, with relative standard deviations of less than 13.97%. A total of 93 (18.13%) samples tested positive for antibiotics, with the highest concentration being 2.48 μg/g. The concentration range of ofloxacin, danofloxacin, difloxacin, sulfadimethoxine, sulfamonomethoxine, sulfamethoxypyridazine, and sulfamethoxazole in poultry eggs was 0.01 to 0.37 μg/g, 0.06 to 0.48 μg/g, 0.05 to 0.29 μg/g, 0.03 to 0.16 μg/g, 0.06 to 1.00 μg/g, 0.05 to 0.37, and 0.07 to 2.48 μg/g, respectively. Sulfamonomethoxine was detected from hen eggs with the highest concentration level at 1.00 μg/g. Sulfamethoxazole was detected with the highest concentration level from both duck and quail eggs, at 1.87 and 2.48 μg/g, respectively. The antibiotic with the highest residue level in pheasant eggs was danofloxacin, which was 0.37 μg/g. Sulfamethoxypyridazine was identified in 30 samples with the highest positive rate of 5.85%, sulfadimethoxine was identified in 3 samples with the lowest positive rate of 0.58%. We observed that 7 targeted antibiotic residues in quail eggs and 3 targeted antibiotic residues in pheasant eggs. We also found that there were antibiotic residues in free-range hen eggs and the concentration was not low. The antibiotic with the highest residue level in free-range eggs was sulfamonomethoxine, which was 1.00 μg/g. These findings suggest that continual antibiotic residue monitoring of poultry eggs is essential in China.
Topics: Animals; Anti-Bacterial Agents; Chickens; Chromatography, High Pressure Liquid; Drug Residues; Eggs; Female; Fluoroquinolones; Food Contamination; Ovum; Poultry; Solid Phase Extraction; Sulfadimethoxine; Sulfamethoxazole; Sulfamethoxypyridazine; Sulfamonomethoxine; Sulfonamides; Tandem Mass Spectrometry
PubMed: 35523046
DOI: 10.1016/j.psj.2022.101892 -
The Journal of Veterinary Medical... Jan 2015In the present study, we examined the oral pharmacokinetics of the acidic drugs, diclofenac (DF) and sulfamonomethoxine (SMM), which have different physicochemical...
In the present study, we examined the oral pharmacokinetics of the acidic drugs, diclofenac (DF) and sulfamonomethoxine (SMM), which have different physicochemical properties, in Shiba goats. DF and SMM were intravenously and orally administered to 5 male goats using a crossover design. The T(max) of DF and SMM were reached 1.5 and 5.6 hr after they have been orally administered, respectively, and this was followed by their slow elimination. The elimination of both drugs was markedly faster after being intravenously rather than orally administered, which indicated flip-flop phenomena after the oral administration. The mean absorption times (MATs) of DF and SMM were 6 and 15 hr, respectively. This slow absorption may have been due to slow gastric emptying in goats. The large difference observed in MATs between DF and SMM may have been because DF, which is more lipophilic than SMM, was partly absorbed from the forestomach. Therefore, these results suggest that the absorption of highly lipophilic drugs from the forestomach may be markedly high in Shiba goats. In case of drugs whose elimination is quite fast, their efficacies may appear from the early stage after oral administration even in ruminants, because elimination rate is the determinant factor of T(max) in flip-flop phenomena. Such drugs may be used orally even in ruminants.
Topics: Administration, Oral; Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Cross-Over Studies; Diclofenac; Goats; Male; Rumen; Sulfamonomethoxine
PubMed: 25311913
DOI: 10.1292/jvms.14-0261 -
Journal of Food and Drug Analysis Jan 2019A precise and reliable analytical method to measure trace levels of sulfamonomethoxine (SMM) and N-acetyl metabolite in tilapia samples using liquid...
Determination of sulfamonomethoxine in tilapia (Oreochromis niloticus × Oreochromis mossambicus) by liquid chromatography-tandem mass spectrometry and its application pharmacokinetics study.
A precise and reliable analytical method to measure trace levels of sulfamonomethoxine (SMM) and N-acetyl metabolite in tilapia samples using liquid chromatography-tandem mass spectrometry was developed. Optimized chromatographic separation was performed on C18 reversed-phase columns using gradient elution with methanol and 5 mmol/L of an ammonium acetate aqueous solution (adjusted to pH 3.5 using formic acid). This study investigated the pharmacokinetic properties and tissue distribution of SMM and its major metabolite N-acetyl sulfamonomethoxine (AC-SMM) in tilapia after a single dose of 100 mg kg body weight of orally administered SMM. Blood and tissues were collected between 0.5 and 192 h with 14 total sampling time points. SMM was rapidly absorbed, and extensively distributed in the bile and liver through systemic circulation. Enterohepatic circulation of SMM was observed in the tilapia body. Acetylation percentages were 45% (blood), 90% (liver), 62% (kidney), 98% (bile), and 52% (muscle). High concentrations of AC-SMM accumulated in the tilapia bile. At 192 h, AC-SMM concentration in the bile remained at 4710 μg kg. The k value of AC-SMM (0.015 h) in the blood was lower than that of SMM (0.032 h). This study demonstrated effective residue monitoring and determined the pharmacokinetic properties of SMM and AC-SMM in tilapia.
Topics: Animals; Anti-Bacterial Agents; Bile; Chromatography, High Pressure Liquid; Cichlids; Liver; Sulfamonomethoxine; Tandem Mass Spectrometry
PubMed: 30648589
DOI: 10.1016/j.jfda.2018.08.007 -
MicrobiologyOpen Nov 2020To investigate the possible effects of sulfamonomethoxine (SMM) on Nile tilapia (Oreochromis niloticus), we quantitatively evaluated the microbial shifts in the...
To investigate the possible effects of sulfamonomethoxine (SMM) on Nile tilapia (Oreochromis niloticus), we quantitatively evaluated the microbial shifts in the intestines of Nile tilapia in response to different doses of SMM (200 and 300 mg/kg) using 16S rRNA gene sequencing. At the phylum level, the control group (0 mg kg SMM) was dominated by Actinobacteria, Proteobacteria, and Firmicutes. In the treatment groups, Firmicutes, Proteobacteria, and Chloroflexi were the dominant phyla. Cluster analysis indicated that the two groups treated with SMM clustered together. Similarly, the bacterial families that dominated the control group differed from those dominating the treatment groups. The changes in intestinal microbial composition over time were similar between the two SMM treatment groups. In both groups, the abundances of some families, including the Bacillaceae, Streptococcaceae, and Pseudomonadaceae, increased first and then decreased. Overall, the addition of SMM to the feed changed the structure of the intestinal microbiota in Nile tilapia. This study improves our understanding of the impact of SMM on the intestinal microenvironment of Nile tilapia. Our results provide guidelines for the feasibility of SMM use in aquaculture production.
Topics: Actinobacteria; Animal Feed; Animals; Anti-Infective Agents; Bacteria; Chloroflexi; Cichlids; Firmicutes; Gastrointestinal Microbiome; Intestines; Proteobacteria; RNA, Ribosomal, 16S; Sulfamonomethoxine
PubMed: 32965800
DOI: 10.1002/mbo3.1116 -
ChemMedChem May 2022The use of synergistic antibiotic combinations has emerged as a viable approach to contain the rapid spread of antibiotic-resistant pathogens. Here we report the...
The use of synergistic antibiotic combinations has emerged as a viable approach to contain the rapid spread of antibiotic-resistant pathogens. Here we report the discovery of a new strongly synergistic pair - microcin J25 and sulfamonomethoxine. The former is a lasso peptide that inhibits the function of RNA polymerase and the latter is a sulfonamide antibacterial agent that disrupts the folate pathway. Key to our discovery was a screening strategy that focuses on an antibiotic (microcin J25) that targets a hub (transcription) in the densely interconnected network of cellular pathways. The rationale was that disrupting such a hub likely weakens the entire network, generating weak links that potentiate the growth inhibitory effect of other antibiotics. We found that MccJ25 potentiates five other antibiotics as well. These results showcase the merit of taking a more targeted approach in the search and study of synergistic antibiotic pairs.
Topics: Anti-Bacterial Agents; Bacteriocins; Escherichia coli; Escherichia coli Infections; Folic Acid; Humans; Peptides
PubMed: 35201676
DOI: 10.1002/cmdc.202200075 -
Frontiers in Cellular and Infection... 2023The bacterium is a multispecies pathogen associated with meningitis-like disease that has been isolated from several amphibian species, including the bullfrog, but this...
INTRODUCTION
The bacterium is a multispecies pathogen associated with meningitis-like disease that has been isolated from several amphibian species, including the bullfrog, but this is the first isolation in Guangxi. In the present study, the dominant bacteria were isolated from the brains of five bullfrogs with meningitis-like disease on a South China farm in Guangxi.
METHODS
The NFEM01 isolate was identified by Gram staining; morphological observations; , and -based phylogenetic tree analysis; and physiochemical characterization and was subjected to drug sensitivity and artificial infection testing.
RESULTS AND DISCUSSION
As a result of identification, the NFEM01 strain was found to be . An artificial infection experiment revealed that NFEM01 infected bullfrogs and could cause symptoms of typical meningitis-like disease. As a result of the bacterial drug sensitivity test, NFEM01 is highly sensitive to mequindox, rifampicin, enrofloxacin, nitrofural, and oxytetracycline and there was strong resistance to gentamicin, florfenicol, neomycin, penicillin, amoxicillin, doxycycline, and sulfamonomethoxine. This study provides a reference to further study the pathogenesis mechanism of -induced bullfrog meningitislike disease and its prevention and treatment.
Topics: Animals; Rana catesbeiana; RNA, Ribosomal, 16S; Phylogeny; China; Meningitis
PubMed: 36998635
DOI: 10.3389/fcimb.2023.1094050 -
BMC Veterinary Research May 2019Breast cancer resistance protein (BCRP) and multidrug resistance protein 4 (MRP4) are involved in uric acid excretion in humans and mice. Despite evidence suggesting...
BACKGROUND
Breast cancer resistance protein (BCRP) and multidrug resistance protein 4 (MRP4) are involved in uric acid excretion in humans and mice. Despite evidence suggesting that renal proximal tubular epithelial cells participate in uric acid excretion in chickens, the roles of BCRP and MRP4 therein remain unclear. This study evaluated the relationship between BCRP and MRP4 expression and renal function in chickens.
RESULTS
Sixty laying hens were randomly divided into four treatment groups: a control group (NC) fed a basal diet; a sulfonamide-treated group (SD) fed the basal diet and supplemented with sulfamonomethoxine sodium via drinking water (8 mg/L); a fish meal group (FM) fed the basal diet supplemented with 16% fishmeal; and a uric acid injection group (IU) fed the basal diet and intraperitoneally injected with uric acid (250 mg/kg body weight). The results showed that serum uric acid, creatinine, and blood urea nitrogen levels were significantly higher in the SD and IU, but not FM, than in the NC groups. Renal tubular epithelial cells in the SD and IU groups were damaged. Liver BCRP and MRP4 mRNA and protein levels were significantly decreased in the SD and IU groups, but slightly increased in the FM group. In the SD group, BCRP and MRP4 were significantly increased in the ileum and slightly increased in the kidney. In the FM group, BCRP and MRP4 were significantly increased in the kidney and slightly increased in the ileum. In the IU group, BCRP and MRP4 were significantly increased in the kidney and ileum. BCRP and MRP4 expression in the jejunum was not affected by the treatments.
CONCLUSION
Together, these results demonstrate that BCRP and MRP4 are involved in renal and intestinal uric acid excretion in chickens and that BCRP is positively related to MRP4 expression. Further, impairment of renal function results in an increase in serum uric acid as well as a compensatory increase in BCRP and MRP4 in the ileum; however, under normal renal function, renal BCRP and MRP4 are the main regulators of uric acid excretion.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Animals; Blood Urea Nitrogen; Chickens; Epithelial Cells; Female; Intestinal Mucosa; Kidney; Kidney Tubules; Liver; Multidrug Resistance-Associated Proteins; RNA, Messenger; Uric Acid
PubMed: 31146764
DOI: 10.1186/s12917-019-1886-9 -
Ultrasonics Sonochemistry Oct 2023Antibiotics (ABX) residues frequently occurred in water and cow milk. This work aims to understand the kinetics and mechanisms of sonolytic degradation of four ABX, i.e....
Antibiotics (ABX) residues frequently occurred in water and cow milk. This work aims to understand the kinetics and mechanisms of sonolytic degradation of four ABX, i.e. ceftiofur hydrochloride (CEF), sulfamonomethoxine sodium (SMM), marbofloxacin (MAR), and oxytetracycline (OTC) in water and milk. In both water and milk, the sonolytic degradation of ABX follows pseudo-first order (PFO) kinetics well (R: 0.951-0.999), with significantly faster ABX degradation in water (PFO kinetics constants (k): 1.5 × 10-1.2 × 10 min) than in milk (k: 3.5 × 10-5.6 × 10 min). The k values for SMM degradation in water increased by 118% with ultrasonic frequency (40-120 kHz), 174% with ultrasonic frequency (80-500 kHz), 649% with ultrasonic power (73-259 W), 22% with bulk temperature (12-40℃), and by 68% with reaction volume (50-250 mL), respectively, in other things being equal. The relevant k values in milk increased by 326%, 231%, 122%, 10% as well as 82% with the above same effective factors, respectively. The oxidation by free radicals generated in situ dominates ABX degradation, and the hydrophobic CEF (54.0-971.7 nM min) and SMM (39.2-798.4 nM min) underwent faster degradation than the hydrophilic MAR (33.9-751.9 nM min) and OTC (33.8-545.3 nM min) in both water and milk. Adding an extra 0.5 mM HO accelerated SMM degradation by 19% in water and 33% in milk. After 130-150 min sonication of 100 mL of 2.0 mg L (6.62 μM) SMM in various milk with 500 kHz and 259 W, the residue concentrations (52.9-96.3 μg L) can meet the relevant maximum residue limit (100 μg L).
Topics: Animals; Anti-Bacterial Agents; Milk; Hydrogen Peroxide; Water; Kinetics; Water Pollutants, Chemical; Water Purification
PubMed: 37572426
DOI: 10.1016/j.ultsonch.2023.106518