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Membranes May 2024This study introduces an innovative approach to enhancing membrane distillation (MD) performance by developing bead-containing superhydrophobic sulfonated...
This study introduces an innovative approach to enhancing membrane distillation (MD) performance by developing bead-containing superhydrophobic sulfonated polyethersulfone (SPES) nanofibers with S-MWCNTs. By leveraging SPES's inherent hydrophobicity and thermal stability, combined with a nanostructured fibrous configuration, we engineered beads designed to optimize the MD process for water purification applications. Here, oxidized hydrophobic S-MWCNTs were dispersed in a SPES solution at concentrations of 0.5% and 1.0% by weight. These bead membranes are fabricated using a novel electrospinning technique, followed by a post-treatment with the hydrophobic polyfluorinated grafting agent to augment nanofiber membrane surface properties, thereby achieving superhydrophobicity with a water contact angle (WCA) of 145 ± 2° and a higher surface roughness of 512 nm. The enhanced membrane demonstrated a water flux of 87.3 Lm h and achieved nearly 99% salt rejection efficiency at room temperature, using a 3 wt% sodium chloride (NaCl) solution as the feed. The results highlight the potential of superhydrophobic SPES nanofiber beads in revolutionizing MD technology, offering a scalable, efficient, and robust membrane for salt rejection.
PubMed: 38921487
DOI: 10.3390/membranes14060120 -
Gels (Basel, Switzerland) Jun 2024The aim of this work was to synthesize and study the functional properties of polymer-clay nanocomposite (PCNCs) based on poly(sodium 4-styrene sulfonate) (NaPSS) and...
Synthesis and Characterization of Nanocomposite Hydrogels Based on Poly(Sodium 4-Styrene Sulfonate) under Very-High Concentration Regimen of Clays (Bentonite and Kaolinite).
The aim of this work was to synthesize and study the functional properties of polymer-clay nanocomposite (PCNCs) based on poly(sodium 4-styrene sulfonate) (NaPSS) and two types of clay in the dispersed phase: bentonite and kaolinite, in order to advance in the development of new geomimetic materials for agricultural and environmental applications. In this study, the effect of adding high concentrations of clay (10-20 wt. %) on the structural and functional properties of a polymer-clay nanocomposite was evaluated. The characterization by infrared spectroscopy made it possible to show that the PCNCs had a hybrid nature structure through the identification of typical vibration bands of the clay matrix and NaPSS. In addition, scanning electron microscopy allowed us to verify its hybrid composition and an amorphous particle-like morphology. The thermal characterization showed degradation temperatures higher than ~300 °C with Tg values higher than 100 °C and variables depending on the clay contents. In addition, the PCNCs showed a high water-retention capacity (>2900%) and cation exchange capacity (>112 meq/100 g). Finally, the results demonstrated the ability of geomimetic conditioners to mimic the structure and functional properties of soils, suggesting their potential application in improving soil quality for plant growth.
PubMed: 38920951
DOI: 10.3390/gels10060405 -
Cells Jun 2024Venetoclax and obinutuzumab are becoming frontline therapies for chronic lymphocytic leukemia (CLL) patients. Unfortunately, drug resistance still occurs, and the...
Lysosome-Disrupting Agents in Combination with Venetoclax Increase Apoptotic Response in Primary Chronic Lymphocytic Leukemia (CLL) Cells Mediated by Lysosomal Cathepsin D Release and Inhibition of Autophagy.
Venetoclax and obinutuzumab are becoming frontline therapies for chronic lymphocytic leukemia (CLL) patients. Unfortunately, drug resistance still occurs, and the combination could be immunosuppressive. Lysosomes have previously been identified as a target for obinutuzumab cytotoxicity in CLL cells, but the mechanism remains unclear. In addition, studies have shown that lysosomotropic agents can cause synergistic cell death in vitro when combined with the BTK inhibitor, ibrutinib, in primary CLL cells. This indicates that targeting lysosomes could be a treatment strategy for CLL. In this study, we have shown that obinutuzumab induces lysosome membrane permeabilization (LMP) and cathepsin D release in CLL cells. Inhibition of cathepsins reduced obinutuzumab-induced cell death in CLL cells. We further determined that the lysosomotropic agent siramesine in combination with venetoclax increased cell death in primary CLL cells through an increase in reactive oxygen species (ROS) and cathepsin release. Siramesine treatment also induced synergistic cytotoxicity when combined with venetoclax. Microenvironmental factors IL4 and CD40L or incubation with HS-5 stromal cells failed to significantly protect CLL cells from siramesine- and venetoclax-induced apoptosis. We also found that siramesine treatment inhibited autophagy through reduced autolysosomes. Finally, the autophagy inhibitor chloroquine failed to further increase siramesine-induced cell death. Taken together, lysosome-targeting drugs could be an effective strategy in combination with venetoclax to overcome drug resistance in CLL.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Bridged Bicyclo Compounds, Heterocyclic; Sulfonamides; Lysosomes; Apoptosis; Autophagy; Cathepsin D; Reactive Oxygen Species; Drug Synergism; Cell Line, Tumor
PubMed: 38920669
DOI: 10.3390/cells13121041 -
Horticulture Research Jun 2024In monoecious species, female flowering constitutes the developmental process that determines the onset and production of fruit and is therefore closely related to crop...
In monoecious species, female flowering constitutes the developmental process that determines the onset and production of fruit and is therefore closely related to crop yield. This article presents the identification and phenotypic and molecular characterization of , an ethylmethane sulfonate loss-of-function mutation that completely blocks the female floral transition, converting all female flowers into male flowers. BSA-seq analysis coupled with WGS showed that corresponds to a C>T transition in the coding region of the gene , generating a premature stop codon and a truncated transcription factor without its N-terminal effector domain. The phenotype was partially rescued by exogenous ethylene application, indicating that the function of is mediated by ethylene. Different evidence supports this conclusion: first, the reduced ethylene production of the mutant, and second, the male flower productive phenotype of the double mutant between and the ethylene-insensitive mutant , which demonstrated that is epistatic over . Furthermore, transcriptomic analysis of WT and apical shoots confirmed that regulates master sex-determining genes, upregulating those encoding the ethylene biosynthesis enzymes and and those encoding for transcription factors that promote the development of carpels(), but downregulating those involved in the arrest of carpels (), In the gene network controlling sex determination in cucurbits, CpMYB62 occupies the most upstream position, activating ethylene and other sex determining genes involved in female flower determination in .
PubMed: 38919554
DOI: 10.1093/hr/uhae115 -
Journal of Cardiothoracic Surgery Jun 2024We previously demonstrated that the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (statins) play an important role in the regulation of alloimmune responses....
Graft protective effects and donor-specific antibody suppression by CD4CD25Foxp3 regulatory T cell induced by HMG-CoA reductase inhibitor rosuvastatin in a murine heart transplant model.
BACKGROUND
We previously demonstrated that the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (statins) play an important role in the regulation of alloimmune responses. However, little is known regarding the effects of statin on allograft protection or donor-specific antibodies (DSA). In this study, we investigated the graft-protective and immunomodulatory effects of rosuvastatin in a model of fully major histocompatibility complex-mismatched murine cardiac allograft transplantation.
METHODS
CBA mice underwent transplantation of C57BL/6 (B6) hearts and received 50 and 500 μg/kg/day of rosuvastatin from the day of transplantation until seven days after the completion of transplantation. To confirm the requirement for regulatory T cells (Tregs), we administered an anti-interleukin-2 receptor alpha antibody (PC-61) to rosuvastatin-treated CBA recipients. Additionally, histological and fluorescent staining, cell proliferation analysis, flow cytometry, and DSA measurements were performed.
RESULTS
CBA recipients with no treatment rejected B6 cardiac graft acutely (median survival time [MST], 7 days). CBA mice treated with 500 μg/kg/day of rosuvastatin prolonged allograft survival (MSTs, 77 days). Fluorescent staining studies showed that rosuvastatin-treated recipients had strong aggregation of CD4Foxp3 cells in the myocardium and around the coronary arteries of cardiac allografts two weeks after grafting. Flow cytometry studies performed two weeks after transplantation showed an increased number of splenic CD4CD25Foxp3 T cells in rosuvastatin-treated recipients. The addition of rosuvastatin to mixed leukocyte cultures suppressed cell proliferation by increasing the number of CD4CD25Foxp3 Tregs. Additionally, Tregs suppressed DSA production in rosuvastatin-treated recipients.
CONCLUSION
Rosuvastatin treatment may be a complementary graft-protective strategy for suppressing DSA production in the acute phase, driven by the promotion of splenic and graft-infiltrating CD4CD25Foxp3 Tregs.
Topics: Animals; Rosuvastatin Calcium; Heart Transplantation; T-Lymphocytes, Regulatory; Mice; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice, Inbred C57BL; Mice, Inbred CBA; Graft Rejection; Graft Survival; Interleukin-2 Receptor alpha Subunit; Male; Forkhead Transcription Factors; Disease Models, Animal; Flow Cytometry
PubMed: 38918849
DOI: 10.1186/s13019-024-02888-4 -
BMC Cancer Jun 2024High-grade B-cell lymphoma (HGBCL), the subtype of non-Hodgkin lymphoma, to be relapsed or refractory in patients after initial therapy or salvage chemotherapy. Dual...
High-grade B-cell lymphoma (HGBCL), the subtype of non-Hodgkin lymphoma, to be relapsed or refractory in patients after initial therapy or salvage chemotherapy. Dual dysregulation of MYC and BCL2 is one of the important pathogenic mechanisms. Thus, combined targeting of MYC and BCL2 appears to be a promising strategy. Dihydroorotate dehydrogenase (DHODH) is the fourth rate-limiting enzyme for the de novo biosynthesis of pyrimidine. It has been shown to be a potential therapeutic target for multiple diseases. In this study, the DHODH inhibitor brequinar exhibited growth inhibition, cell cycle blockade, and apoptosis promotion in HGBCL cell lines with MYC and BCL2 rearrangements. The combination of brequinar and BCL2 inhibitors venetoclax had a synergistic inhibitory effect on the survival of DHL cells through different pathways. Venetoclax could upregulate MCL-1 and MYC expression, which has been reported as a resistance mechanism of BCL2 inhibitors. Brequinar downregulated MCL-1 and MYC, which could potentially overcome drug resistance to venetoclax in HGBCL cells. Furthermore, brequinar could downregulate a broad range of genes, including ribosome biosynthesis genes, which might contribute to its anti-tumor effects. In vivo studies demonstrated synergetic tumor growth inhibition in xenograft models with brequinar and venetoclax combination treatment. These results provide preliminary evidence for the rational combination of DHODH and BCL2 blockade in HGBCL with abnormal MYC and BCL2.
Topics: Humans; Animals; Proto-Oncogene Proteins c-bcl-2; Dihydroorotate Dehydrogenase; Mice; Sulfonamides; Bridged Bicyclo Compounds, Heterocyclic; Proto-Oncogene Proteins c-myc; Xenograft Model Antitumor Assays; Drug Synergism; Cell Line, Tumor; Oxidoreductases Acting on CH-CH Group Donors; Apoptosis; Lymphoma, B-Cell; Gene Rearrangement; Cell Proliferation; Biphenyl Compounds; Quinaldines
PubMed: 38918775
DOI: 10.1186/s12885-024-12534-w -
Reumatismo Jun 2024The safety profile of baricitinib (BARI), a Janus kinase inhibitor broadly used for the treatment of rheumatoid arthritis (RA), includes asymptomatic laboratory...
The safety profile of baricitinib (BARI), a Janus kinase inhibitor broadly used for the treatment of rheumatoid arthritis (RA), includes asymptomatic laboratory abnormalities, such as an increase in creatine kinase (CK). Data from randomized controlled trials suggest that concomitant myalgia is rare in RA and does not lead to drug discontinuation. We describe the case of a 68-year-old Caucasian female with longstanding, multi-failure RA who started BARI and achieved disease remission. However, she developed a symptomatic CK increase, as well as a parallel increase in total cholesterol, low-density lipoprotein, and triglycerides. Dechallenge-rechallenge demonstrated a plausible relationship between the clinical/laboratory abnormalities and BARI. In fact, when the drug was withdrawn, CK returned to normal and myalgia disappeared, whereas symptoms returned and CK levels increased when BARI was restarted. BARI may be rarely associated with symptomatic CK elevation, and this may pose clinical challenges, particularly for patients with multi-failure RA who achieved good disease control with BARI but required drug discontinuation due to intolerance.
Topics: Humans; Arthritis, Rheumatoid; Female; Purines; Aged; Azetidines; Pyrazoles; Sulfonamides; Creatine Kinase; Myalgia; Antirheumatic Agents; Janus Kinase Inhibitors
PubMed: 38916168
DOI: 10.4081/reumatismo.2024.1620 -
BioRxiv : the Preprint Server For... Jun 2024Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034...
Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 ( ) is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad spectrum antiviral activity. Analogs of that varied each of three regions of the molecule were synthesized to establish structure-activity relationships for inhibition of (CHIKV) nsP2 protease and viral replication. The covalent warhead was highly sensitive to modifications of the sulfone or vinyl substituents. However, numerous alterations to the core 5-membered heterocycle and its aryl substituent were well tolerated and several analogs were identified that enhanced CHIKV nsP2 binding. For example, the 4-cyanopyrazole analog exhibited a / ratio >10,000 M s . 3-Arylisoxazole was identified an isosteric replacement for the 5-membered heterocycle, which circumvented the intramolecular cyclization that complicated the synthesis of pyrazole-based inhibitors like . The accumulated structure-activity data was used to build a ligand-based model of the enzyme active site, which can be used to guide the design of covalent nsP2 protease inhibitors as potential therapeutics against alphaviruses.
PubMed: 38915519
DOI: 10.1101/2024.06.12.598722 -
Arthritis Research & Therapy Jun 2024Treatments for rheumatoid arthritis (RA) are associated with complex changes in lipids and lipoproteins that may impact cardiovascular (CV) risk. The objective of this... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Treatments for rheumatoid arthritis (RA) are associated with complex changes in lipids and lipoproteins that may impact cardiovascular (CV) risk. The objective of this study was to examine lipid and lipoprotein changes associated with two common RA treatment strategies, triple therapy or tumor necrosis factor inhibitor (TNFi), and association with CV risk.
METHODS
In this secondary data analysis of the TARGET trial, methotrexate (MTX) inadequate responders with RA were randomized to either add sulfasalazine and hydroxychloroquine (triple therapy), or TNFi for 24-weeks. The primary trial outcome was the change in arterial inflammation measured in the carotid arteries or aorta by FDG-PET/CT at baseline and 24-weeks; this change was described as the target-to-background ratio (TBR) in the most diseased segment (MDS). Routine lipids and advanced lipoproteins were measured at baseline and 24-weeks; subjects on statin therapy at baseline were excluded. Comparisons between baseline and follow-up lipid measurements were performed within and across treatment arms, as well as change in lipids and change in MDS-TBR.
RESULTS
We studied 122 participants, 61 in each treatment arm, with median age 57 years, 76% female, and 1.5 year median RA disease duration. When comparing treatment arms, triple therapy had on average a larger reduction in triglycerides (15.9 mg/dL, p = 0.01), total cholesterol to HDL-C ratio (0.29, p-value = 0.01), and LDL particle number (111.2, p = 0.02) compared to TNFi. TNFi had on average a larger increase in HDL particle number (1.6umol/L, p = 0.006). We observed no correlation between change in lipid measurements and change in MDS-TBR within and across treatment arms.
CONCLUSIONS
Both treatment strategies were associated with improved lipid profiles via changes in different lipids and lipoproteins. These effects had no correlation with change in CV risk as measured by vascular inflammation by FDG-PET/CT.
TRIAL REGISTRATION
ClinicalTrials.gov ID NCT02374021.
Topics: Humans; Arthritis, Rheumatoid; Female; Middle Aged; Male; Antirheumatic Agents; Hydroxychloroquine; Lipids; Drug Therapy, Combination; Methotrexate; Aged; Sulfasalazine; Adult; Tumor Necrosis Factor Inhibitors; Treatment Outcome; Positron Emission Tomography Computed Tomography; Vasculitis
PubMed: 38915065
DOI: 10.1186/s13075-024-03352-3 -
Scientific Reports Jun 2024Investigating surfactant effects on the floatability of Wiser bituminous coal holds significant importance in improving coal cleanliness and utilization value. Using...
Investigating surfactant effects on the floatability of Wiser bituminous coal holds significant importance in improving coal cleanliness and utilization value. Using density functional theory and molecular dynamics simulation methods, this study constructed models of Wiser bituminous coal and examined the impact of different surfactants, including the anionic surfactant sodium dodecyl benzene sulfonate, the cationic surfactant hexadecyl trimethyl ammonium bromide (CTAB), and the non-ionic surfactant fatty alcohol ethoxylated ether. The focus was on investigating the charge distribution characteristics of these molecules and the modifying effect of binary surfactants on the hydrophobicity of bituminous coal. Results revealed that the maximum electrostatic potential was concentrated near oxygen/nitrogen/sulfur-containing functional groups like sulfonic acid groups, quaternary ammonium cations, ethylene oxide, hydroxyl groups, carboxyl groups, and sulfur bonds. These functional groups exhibited a propensity for accepting/delivering electrons to form hydrogen bonds. Among the surfactants tested, CTAB revealed the slightest difference in frontier orbital energy, measuring 3.187 eV, thereby demonstrating a superior trapping ability compared with the other two surfactants. Adsorption reactions within the system were determined to be spontaneous, with over 60% of the interaction force attributed to electrostatic forces. Moreover, the repulsive force magnitude with water molecules followed the trend: sulfonate group (2.20 Å) < ethylene oxide (2.43 Å) < quaternary ammonium cation (2.57 Å), indicating more excellent water repellency of CTAB. Findings showed that CTAE binary surfactants proved most effective in modifying the hydrophobicity of bituminous coal. This study offers valuable insights into reducing waste, pollution, and resource wastage.
PubMed: 38914729
DOI: 10.1038/s41598-024-65466-7