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Haematologica Mar 2024
Topics: Humans; Multiple Myeloma; Salvage Therapy; Neoplasms, Plasma Cell; Bridged Bicyclo Compounds, Heterocyclic; Sulfonamides
PubMed: 37794827
DOI: 10.3324/haematol.2023.283472 -
Environmental Health Perspectives Nov 2023Perfluorohexane sulfonate (PFHxS) is a frequently detected per- and polyfluoroalkyl substance in most populations, including in individuals who are pregnant, a period...
BACKGROUND
Perfluorohexane sulfonate (PFHxS) is a frequently detected per- and polyfluoroalkyl substance in most populations, including in individuals who are pregnant, a period critical for early life development. Despite epidemiological evidence of exposure, developmental toxicity, particularly at realistic human exposures, remains understudied.
OBJECTIVES
We evaluated the effect of gestational exposure to human-relevant body burden of PFHxS on fetal and placental development and explored mechanisms of action combining alternative splicing (AS) and gene expression (GE) analyses.
METHODS
Pregnant ICR mice were exposed to 0, 0.03, and from gestational day 7 to day 17 via oral gavage. Upon euthanasia, PFHxS distribution was measured using liquid chromatography-tandem mass spectrometry. Maternal and fetal phenotypes were recorded, and histopathology was examined for placenta impairment. Multiomics was adopted by combining AS and GE analyses to unveil disruptions in mRNA quality and quantity. The key metabolite transporters were validated by quantitative real-time PCR (qRT-PCR) for quantification and three-dimensional (3D) structural simulation by AlphaFold2. Targeted metabolomics based on liquid chromatography-tandem mass spectrometry was used to detect amino acid and amides levels in the placenta.
RESULTS
Pups developmentally exposed to PFHxS exhibited signs of intrauterine growth restriction (IUGR), characterized by smaller fetal weight and body length () compared to control mice. PFHxS concentration in maternal plasma was . PFHxS trans-placenta distribution suggested dose-dependent transfer through placental barrier. Histopathology of placenta of exposed dams showed placental dysplasia, manifested with an attenuated labyrinthine layer area and deescalated blood sinus counts and placental vascular development index marker CD34. Combined GE and AS analyses pinpointed differences in genes associated with key biological processes of placental development, proliferation, metabolism, and transport in placenta of exposed dams compared to that of control dams. Further detection of placental key transporter gene expression, protein structure simulation, and amino acid and amide metabolites levels suggested that PFHxS exposure during pregnancy led to impairment of placental amino acid transportation.
DISCUSSION
The findings from this study suggest that exposure to human-relevant very-low-dose PFHxS during pregnancy in mice caused IUGR, likely via downregulating of placental amino acid transporters, thereby impairing placental amino acid transportation, resulting in impairment of placental development. Our findings confirm epidemiological findings and call for future attention on the health risk of this persistent yet ubiquitous chemical in the early developmental stage and provide a new approach for understanding gene expression from both quantitative and qualitative omics approaches in toxicological studies. https://doi.org/10.1289/EHP13217.
Topics: Humans; Pregnancy; Mice; Animals; Female; Placentation; Placenta; Alternative Splicing; Mice, Inbred ICR; Fluorocarbons; Alkanesulfonates; Fetal Growth Retardation; Amino Acids; Gene Expression Profiling
PubMed: 37995155
DOI: 10.1289/EHP13217 -
Molecules (Basel, Switzerland) Aug 2023Numerous plants of medicinal value grow on Hainan Island (China). Given the lack of knowledge on the phytochemical and pharmacological properties of Chun and Y. F. Wu...
Numerous plants of medicinal value grow on Hainan Island (China). Given the lack of knowledge on the phytochemical and pharmacological properties of Chun and Y. F. Wu (), the application of natural antioxidants and antimicrobials in the food industry has attracted increasing interest. This study aimed to compare the chemical composition, free-radical-scavenging capacity, and antibiosis of aqueous extracts of the fresh and dried leaves of The aqueous extract of the leaves of was obtained using steam distillation, and its chemical components were separated and identified via gas chromatography-mass spectrometry (GC-MS). The free-radical-scavenging capacity and antibiosis were determined. Further, 28 and 20 compounds were isolated from the fresh leaf aqueous extract of (MSFLAE) and dried leaf aqueous extract of (MSDLAE), respectively. The free-radical-scavenging capacity of MSFLAE and MSDLAE was determined by the 2,2-diphenyl-1 picrylhydrazyl (DPPH) method, which was 43.43% and 38.74%, respectively. The scavenging capacity of MSFLAE and MSDLAE determined by the 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonate (ABTS)) method was 46.90% and 25.99%, respectively. The iron ion reduction capacity of MSFLAE and MSDLAE was determined by the ferric-reducing antioxidant power (FRAP) method as 94.7 and 62.9 μmol Fe⁺/L, respectively. This indicated that the two leaf aqueous extracts had a certain free-radical-scavenging capacity, and the capacity of MSFLAE was higher than that of MSDLAE. The antibiosis of the two leaf aqueous extracts on the three foodborne pathogenic bacteria was low, but the antimicrobial effects on Gram-positive bacteria were better than those on Gram-negative bacteria. The antibiosis of MSFLAE on and was greater than that of MSDLAE. Finally, MSFLAE and MSDLAE both had certain free-radical-scavenging capacities and antibiosis, confirming that the use of this plant in the research and development of natural antioxidants and antibacterial agents was reasonable. Plant aqueous extracts are an essential source of related phytochemistry and have immense pharmacological potential.
Topics: Antibiosis; Steam; Alkanesulfonates; Anti-Bacterial Agents; Antioxidants; Escherichia coli; Magnoliaceae
PubMed: 37630187
DOI: 10.3390/molecules28165935 -
Frontiers in Immunology 2023In this review, we discuss a variety of immune modulating approaches that could be used to counteract tissue-damaging viral immunoinflammatory lesions which typify many... (Review)
Review
In this review, we discuss a variety of immune modulating approaches that could be used to counteract tissue-damaging viral immunoinflammatory lesions which typify many chronic viral infections. We make the point that in several viral infections the lesions can be largely the result of one or more aspects of the host response mediating the cell and tissue damage rather than the virus itself being directly responsible. However, within the reactive inflammatory lesions along with the pro-inflammatory participants there are also other aspects of the host response that may be acting to constrain the activity of the damaging components and are contributing to resolution. This scenario should provide the prospect of rebalancing the contributions of different host responses and hence diminish or even fully control the virus-induced lesions. We identify several aspects of the host reactions that influence the pattern of immune responsiveness and describe approaches that have been used successfully, mainly in model systems, to modulate the activity of damaging participants and which has led to lesion control. We emphasize examples where such therapies are, or could be, translated for practical use in the clinic to control inflammatory lesions caused by viral infections.
Topics: Humans; Models, Biological; Pyrimethamine; Sulfadiazine
PubMed: 37671156
DOI: 10.3389/fimmu.2023.1257192 -
Environment International Jul 2023Perfluorohexyl sulfonate (PFHxS) is the third most abundant per- and polyfluoroalkyl substances and its developmental toxicity remains very poorly understood. Here,...
Perfluorohexyl sulfonate (PFHxS) is the third most abundant per- and polyfluoroalkyl substances and its developmental toxicity remains very poorly understood. Here, pregnant mice exposed to PFHxS at human relevant dose showed increased fetal death incidence in the high-dose PFHxS-H group (P < 0.01). Body distribution analyses suggested that PFHxS crossed the placental barrier reaching the fetus in a dose-dependent manner. Histopathological data demonstrated impairment in the placenta with reduced blood sinus volume, placental labyrinth area as well as thickness of labyrinthine layer. Further lipidomic and transcriptomic data together showed that PFHxS exposure caused significant disruption in placental lipid homeostasis, including total lipid accumulation in the placenta, and dysregulation in phospholipid and glycerol lipid metabolism. Gene expression analyses uncovered elevation in key placental fatty acid transporters including fabp2, whereas protein expression showed transporter specific disruptions following exposure. Together, gestational exposure to human relevant level of PFHxS may increase the incidence of fetal deaths and caused placental dysplasia via disruption in lipid metabolism homeostasis. These findings raise the concern regarding the highly prevalent and persistent chemical towards early sensitive developing stages and provide basis for further understanding of its effects on lipid metabolism and underlying mechanisms.
Topics: Humans; Pregnancy; Female; Mice; Animals; Placenta; Alkanesulfonates; Fluorocarbons; Fatty Acids; Homeostasis
PubMed: 37315490
DOI: 10.1016/j.envint.2023.108014 -
Sensors (Basel, Switzerland) Nov 2023A pipette-free and fully integrated device that can be used to accurately recognize the presence of infectious pathogens is an important and useful tool in point-of-care...
Pipette-Free and Fully Integrated Paper Device Employing DNA Extraction, Isothermal Amplification, and Carmoisine-Based Colorimetric Detection for Determining Infectious Pathogens.
A pipette-free and fully integrated device that can be used to accurately recognize the presence of infectious pathogens is an important and useful tool in point-of-care testing, particularly when aiming to decrease the unpredictable threats posed by disease outbreak. In this study, a paper device is developed to integrate the three main processes required for detecting infectious pathogens, including DNA extraction, loop-mediated isothermal amplification (LAMP), and detection. All key reagents, including sodium dodecyl sulfate (SDS), NaOH, LAMP reagents, and carmoisine, are placed on the paper device. The paper device is operated simply via sliding and folding without using any bulky equipment, and the results can be directly observed by the naked eye. The optimized concentrations of sodium dodecyl sulfate (SDS), sodium hydroxide (NaOH), and carmoisine were found to be 0.1%, 0.1 M, and 0.5 mg/mL, respectively. The paper device was used to detect at concentrations as low as 10 CFU/mL within 60 min. Also, spiked in milk was successfully detected using the paper device, demonstrating the feasible application in real sample analysis.
Topics: Colorimetry; Sodium Dodecyl Sulfate; Sodium Hydroxide; Nucleic Acid Amplification Techniques; DNA
PubMed: 38005500
DOI: 10.3390/s23229112 -
BMC Public Health Feb 2024Recent studies suggested inconclusive associations between bisphenols exposure and hyperuricemia risk. Our objective was to assess the potential association of bisphenol...
Bisphenol A and its alternatives bisphenol S and F exposure with serum uric acid levels, hyperuricemia, and gout prevalence among US adults: a nationally representative cross-sectional study.
BACKGROUND
Recent studies suggested inconclusive associations between bisphenols exposure and hyperuricemia risk. Our objective was to assess the potential association of bisphenol A (BPA) and its substitutes bisphenol S and F (BPS and BPF) exposure with serum uric acid (SUA) levels, hyperuricemia, and gout prevalence among US adults within the NHANES 2013-2016 datasets.
METHODS
Multivariable linear and logistic regression models were used to explore the associations of urinary bisphenols concentrations with SUA levels, hyperuricemia, and gout prevalence, in total population and different sex groups. The restricted cubic spline (RCS) model was used to explore the dose-response relationship.
RESULTS
In total population, doubling of urinary BPS and ∑BPs concentrations showed associations with an increase of 2.64 μmol/L (95% CI: 0.54, 4.74) and 3.29 μmol/L (95% CI: 0.59, 5.99) in SUA levels, respectively. The RCS model indicated a significantly "J"-shaped dose-response relationship between BPS exposure and SUA levels. Compared to the reference group of urinary BPS, males in the highest quartile displayed a 13.06 μmol/L (95% CI: 0.75, 25.37) rise in SUA levels. For females, doubling of urinary BPS concentrations was associated with a 3.30 μmol/L (95% CI: 0.53, 6.07) increase in SUA levels, with a significant linear dose-response relationship. In total population, doubling of urinary BPA concentrations showed a 1.05-fold (95% CI: 0.97, 1.14) adjusted risk of having hyperuricemia, with an inverted "U" curve. Doubling of urinary ∑BPs concentrations was associated with a 1.05-fold (95% CI: 0.96, 1.14) adjusted risk of hyperuricemia in total population, with a significant monotonic dose-response relationship. In females, doubling of urinary BPS concentrations was associated with a 1.45-fold (95% CI: 1.01, 2.08) adjusted increased risk of having gout, with a "J" shaped relationship.
CONCLUSIONS
BPA and BPS exposure to some extent were associated with elevated SUA levels and increased risk of hyperuricemia, with different dose-response relationships and sex differences.
Topics: Adult; Humans; Male; Female; Hyperuricemia; Uric Acid; Cross-Sectional Studies; Prevalence; Nutrition Surveys; Gout; Benzhydryl Compounds; Phenols; Sulfones
PubMed: 38317153
DOI: 10.1186/s12889-024-17883-6 -
Bioconjugate Chemistry Sep 2023Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have evaluated 2-sulfonylpyrimidines as...
Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have evaluated 2-sulfonylpyrimidines as covalent warheads for the mild, chemoselective, and metal free cysteine -arylation. 2-Sulfonylpyrimidines react rapidly with cysteine, resulting in stable -heteroarylated adducts at neutral pH. Fine tuning the heterocyclic core and exocyclic leaving group allowed predictable SAr reactivity , covering >9 orders of magnitude. Finally, we achieved fast chemo- and regiospecific arylation of a mutant p53 protein and confirmed arylation sites by protein X-ray crystallography. Hence, we report the first example of a protein site specifically -arylated with iodo-aromatic motifs. Overall, this study provides the most comprehensive structure-reactivity relationship to date on heteroaryl sulfones and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines, expanding the arsenal of tunable warheads for modern covalent ligand discovery.
Topics: Cysteine; Mutant Proteins; Crystallography, X-Ray; Sulfones
PubMed: 37657082
DOI: 10.1021/acs.bioconjchem.3c00322 -
Frontiers in Public Health 2024To investigate the relationships between perfluoroalkyl and polyfluoroalkyl substances (PFASs) exposure and glucose metabolism indices.
OBJECTIVE
To investigate the relationships between perfluoroalkyl and polyfluoroalkyl substances (PFASs) exposure and glucose metabolism indices.
METHODS
Data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 waves were used. A total of 611 participants with information on serum PFASs (perfluorononanoic acid (PFNA); perfluorooctanoic acid (PFOA); perfluoroundecanoic acid (PFUA); perfluorohexane sulfonic acid (PFHxS); perfluorooctane sulfonates acid (PFOS); perfluorodecanoic acid (PFDeA)), glucose metabolism indices (fasting plasma glucose (FPG), homeostasis model assessment for insulin resistance (HOMA-IR) and insulin) as well as selected covariates were included. We used cluster analysis to categorize the participants into three exposure subgroups and compared glucose metabolism index levels between the subgroups. Least absolute shrinkage and selection operator (LASSO), multiple linear regression analysis and Bayesian kernel machine regression (BKMR) were used to assess the effects of single and mixed PFASs exposures and glucose metabolism.
RESULTS
The cluster analysis results revealed overlapping exposure types among people with higher PFASs exposure. As the level of PFAS exposure increased, FPG level showed an upward linear trend ( < 0.001), whereas insulin levels demonstrated a downward linear trend ( = 0.012). LASSO and multiple linear regression analysis showed that PFNA and FPG had a positive relationship (>50 years-old group: = 0.059, < 0.001). PFOA, PFUA, and PFHxS (≤50 years-old group: insulin = -0.194, < 0.001, HOMA-IR = -0.132, = 0.020) showed negative correlation with HOMA-IR/insulin. PFNA (>50 years-old group: insulin = 0.191, = 0.018, HOMA-IR = 0.220, = 0.013) showed positive correlation with HOMA-IR/insulin, which was essentially the same as results that obtained for the univariate exposure-response map in the BKMR model. Association of exposure to PFASs on glucose metabolism indices showed positive interactions between PFOS and PFHxS and negative interactions between PFOA and PFNA/PFOS/PFHxS.
CONCLUSION
Our study provides evidence that positive and negative correlations between PFASs and FPG and HOMA-IR/insulin levels are observed, respectively. Combined effects and interactions between PFASs. Given the higher risk of glucose metabolism associated with elevated levels of PFAS, future studies are needed to explore the potential underlying mechanisms.
Topics: Humans; Middle Aged; Environmental Pollutants; Nutrition Surveys; Bayes Theorem; Fluorocarbons; Alkanesulfonates; Glucose; Insulins; Caprylates; Fatty Acids; Sulfonic Acids
PubMed: 38633237
DOI: 10.3389/fpubh.2024.1370971 -
Bone Marrow Transplantation Aug 2023Allogeneic hematopoietic cell transplantation is a potentially curative treatment in high-risk acute lymphoblastic leukemia (ALL). Conditioning regimens based on ≥12...
Total body irradiation versus busulfan based intermediate intensity conditioning for stem cell transplantation in ALL patients >45 years-a registry-based study by the Acute Leukemia Working Party of the EBMT.
Allogeneic hematopoietic cell transplantation is a potentially curative treatment in high-risk acute lymphoblastic leukemia (ALL). Conditioning regimens based on ≥12 Gray total body irradiation (TBI) represent the current standard in patients ≤45 years, whereas elderly patients frequently receive intermediate intensity conditioning (IIC) to reduce toxicity. To evaluate the role of TBI as a backbone of IIC in ALL, a retrospective, registry-based study included patients >45 years transplanted from matched donors in first complete remission, who had received either fludarabine/TBI 8 Gy (FluTBI8, n = 262), or the most popular, irradiation-free alternative fludarabine/busulfan, comprising busulfan 6.4 mg/kg (FluBu6.4, n = 188) or 9.6 mg/kg (FluBu9.6, n = 51). At two years, overall survival (OS) was 68.5%, 57%, and 62.2%, leukemia-free survival (LFS) was 58%, 42.7%, and 45%, relapse incidence (RI) was 27.2%, 40%, and 30.9%, and non-relapse-mortality (NRM) was 23.1%, 20.7%, and 26.8% for patients receiving FluTBI8Gy, FluBu6.4, and FluBu9.6, respectively. In multivariate analysis, the risk of NRM, acute and chronic graft-versus-host disease was not influenced by conditioning. However, RI was higher after FluBu6.4 (hazard ratio [HR] [95% CI]: 1.85 [1.16-2.95]), and LFS was lower after both FluBu6.4 (HR: 1.56 [1.09-2.23]) and FluBu9.6 (HR: 1.63 [1.02-2.58]) as compared to FluTBI8. Although only resulting in a non-significant advantage in OS, this observation indicates a stronger anti-leukemic efficacy of TBI-based intermediate intensity conditioning.
Topics: Humans; Aged; Busulfan; Retrospective Studies; Whole-Body Irradiation; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Acute Disease; Recurrence; Graft vs Host Disease; Transplantation Conditioning; Registries
PubMed: 37147469
DOI: 10.1038/s41409-023-01966-w