Discovery of Cell-Permeable Allosteric Inhibitors of Liver Pyruvate Kinase: Design and Synthesis of Sulfone-Based Urolithins.

Metabolic dysfunction-associated fatty liver disease (MAFLD) presents a significant global health challenge, characterized by the accumulation of liver fat and impacting a considerable portion of the worldwide population. Despite its widespread occurrence, effective treatments for MAFLD are limited. The liver-specific isoform of pyruvate kinase (PKL) has been identified as a promising target for developing MAFLD therapies. Urolithin C, an allosteric inhibitor of PKL, has shown potential in preliminary studies. Expanding upon this groundwork, our study delved into delineating the structure-activity relationship of urolithin C via the synthesis of sulfone-based urolithin analogs. Our results highlight that incorporating a sulfone moiety leads to substantial PKL inhibition, with additional catechol moieties further enhancing this effect. Despite modest improvements in liver cell lines, there was a significant increase in inhibition observed in HepG2 cell lysates. Specifically, compounds 15d, 9d, 15e, 18a, 12d, and 15a displayed promising IC50 values ranging from 4.3 µM to 18.7 µM. Notably, compound 15e not only demonstrated a decrease in PKL activity and triacylglycerol (TAG) content but also showed efficient cellular uptake. These findings position compound 15e as a promising candidate for pharmacological MAFLD treatment, warranting further research and studies.

Structure-based design, synthesis, and biological characterization of indolylarylsulfone derivatives as novel human immunodeficiency virus type 1 inhibitors with potent antiviral activities and favorable drug-like profiles.

In the current antiretroviral landscape, continuous efforts are still needed to search for novel chemotypes of human immunodeficiency virus type 1 (HIV-1) inhibitors with improved drug resistance profiles and favorable drug-like properties. Herein, we report the design, synthesis, biological characterization, and druggability evaluation of a class of non-nucleoside reverse transcriptase inhibitors. Guided by the available crystallographic information, a series of novel indolylarylsulfone derivatives were rationally discovered via the substituent decorating strategy to fully explore the chemical space of the entrance channel. Among them, compound 11h bearing the cyano-substituted benzyl moiety proved to be the most effective inhibitor against HIV-1 wild-type and mutant strains (EC50 = 0.0039-0.338 µM), being far more potent than or comparable to etravirine and doravirine. Besides, 11h did not exhibit cytotoxicity at the maximum test concentration. Meanwhile, the binding target of 11h was further confirmed to be reverse transcriptase (IC50 = 0.055 µM). Preliminary structure-activity relationship were discussed to guide further optimization work. Molecular docking and dynamics simulation studies were investigated in detail to rationalize the biological evaluation results. Further drug-likeness assessment indicated that 11h possessed excellent physicochemical properties. Moreover, no apparent hERG blockade liability and cytochrome P450 inhibition were observed for 11h. Notably, 11h was characterized by favorable in vitro metabolic stability with moderate clearance rates and long half-lives in human plasma and liver microsomes. Overall, 11h holds great promise as an ideal Anti-HIV-1 lead compound due to its potent antiviral efficacy, low toxicity, and favorable drug-like profiles.

Dapansutrile OLT1177 suppresses foreign body response inflammation while preserving vascularisation of implanted materials.

Mitigating inflammation associated with the foreign body response (FBR) remains a significant challenge in enhancing the performance of implantable medical devices. Current anti-inflammatory approaches aim to suppress implant fibrosis, the major outcome of the FBR, but also inadvertently inhibit beneficial immune signalling necessary for tissue healing and vascularization. In a previous study, we demonstrated the feasibility of 'selective' immunosuppression targeting the NLRP3 inflammasome using the small molecule inhibitor MCC950, leading to reduced implant fibrosis without compromising healing and leading to enhanced vascularization. However, the clinical potential of MCC950 is severely limited due to its failure to pass Phase I clinical safety trials. This has triggered substantial efforts to develop safer analogues of NLRP3 inhibitors. Dapansutrile (OLT1177) is emerging as a leading candidate amongst current NLRP3 inhibitors, demonstrating both safety and effectiveness in a growing number of clinical indications and Phase 2 trials. While the anti-inflammatory effects of OLT1177 have been shown, validation of these effects in the context of implanted materials and the FBR have not yet been demonstrated. In this study, we show OLT1177 possesses beneficial effects on key cell types which drive FBR outcomes, including macrophages, fibroblasts, and smooth muscle cells. Evaluation of OLT1177 in a 28 day subcutaneous implantation model showed OLT1177 reduced fibrotic capsule formation while promoting implant vascularization. Mechanistic studies revealed that this occurred through activation of early pro-angiogenic markers while suppressing late-stage anti-angiogenic markers. These findings establish OLT1177 as a promising therapeutic approach for mitigating implant fibrosis while supporting vascularisation, suggesting a highly promising selective immunosuppressive strategy for the FBR warranting further research to explore its optimal integration into medical materials and devices.

Evaluation of a Covalent Library of Diverse Warheads (CovLib) Binding to JNK3, USP7, or p53.

Purpose: Over the last few years, covalent fragment-based drug discovery has gained significant importance. Thus, striving for more warhead diversity, we conceived a library consisting of 20 covalently reacting compounds. Our covalent fragment library (CovLib) contains four different warhead classes, including five α-cyanoacacrylamides/acrylates (CA), three epoxides (EO), four vinyl sulfones (VS), and eight electron-deficient heteroarenes with a leaving group (SNAr/SN). Methods: After predicting the theoretical solubility of the fragments by LogP and LogS during the selection process, we determined their experimental solubility using a turbidimetric solubility assay. The reactivities of the different compounds were measured in a high-throughput 5,5'-dithiobis-(2-nitrobenzoic acid) DTNB assay, followed by a (glutathione) GSH stability assay. We employed the CovLib in a (differential scanning fluorimetry) DSF-based screening against different targets: c-Jun N-terminal kinase 3 (JNK3), ubiquitin-specific protease 7 (USP7), and the tumor suppressor p53. Finally, the covalent binding was confirmed by intact protein mass spectrometry (MS). Results: In general, the purchased fragments turned out to be sufficiently soluble. Additionally, they covered a broad spectrum of reactivity. All investigated α-cyanoacrylamides/acrylates and all structurally confirmed epoxides turned out to be less reactive compounds, possibly due to steric hindrance and reversibility (for α-cyanoacrylamides/acrylates). The SNAr and vinyl sulfone fragments are either highly reactive or stable. DSF measurements with the different targets JNK3, USP7, and p53 identified reactive fragment hits causing a shift in the melting temperatures of the proteins. MS confirmed the covalent binding mode of all these fragments to USP7 and p53, while additionally identifying the SNAr-type electrophile SN002 as a mildly reactive covalent hit for p53. Conclusion: The screening and target evaluation of the CovLib revealed first interesting hits. The highly cysteine-reactive fragments VS004, SN001, SN006, and SN007 covalently modify several target proteins and showed distinct shifts in the melting temperatures up to +5.1 °C and -9.1 °C.

Effects of a dual functional filler, polyethersulfone-g-carboxymethyl chitosan@MWCNT, for enhanced antifouling and penetration performance of PES composite membranes.

Ultrafiltration technology, separating water from impurities by the core membrane, is an effective strategy for treating wastewater to meet the ever-growing requirement of clean and drinking water. However, the similar nature of hydrophobic organic pollutants and the membrane surface leads to severe adsorption and aggregation, resulting unavoidable membrane degradation of penetration and rejection. The present study presents a novel block amphiphilic polymer, polyethersulfone-g-carboxymethyl chitosan@MWCNT (PES-g-CMC@MWCNT), which is synthesized by grafting hydrophobic polyethersulfone to hydrophilic carboxymethyl chitosan in order to suspend CMC in organic solution. A mixture of hydrophilic carboxymethyl chitosan and hydrophobic polymers (polyethersulfone), in which hydrophilic segments are bonded to hydrophobic segments, could provide hydrophilic groups, as well as gather and remain stable on membrane surfaces by their hydrophobic interaction for improved compatibility and durability. The resultant ultrafiltration membranes exhibit high water flux (198.10 L m-2·h-1), suitable hydrophilicity (64.77°), enhanced antifouling property (82.96%), while still maintains excellent rejection of bovine serum albumin (91.75%). There has also been an improvement in membrane cross-sectional morphology, resulting in more regular pores size (47.64 nm) and higher porosity (84.60%). These results indicate that amphiphilic polymer may be able to significantly promote antifouling and permeability of ultrafiltration membranes.

Simultaneous enhanced antibiotic pollutants removal and sustained permeability of the membrane involving CoFe2O4/MoS2 catalyst initiated with simple H2O2 backwashing.

Membranes for wastewater treatment should ideally exhibit sustainable high permeate production, enhanced pollutant removal, and intrinsic physical rejection. In this study, CoFe2O4/MoS2 serves as a non-homogeneous phase catalyst; it is combined with polyether sulfone membranes via liquid-induced phase separation to simultaneously sustain membrane permeability and enhance antibiotic pollutant degradation. The prepared catalytic membranes have higher pure water flux (329.34 L m-2 h-1) than pristine polyethersulfone membranes (219.03 L m-2 h-1), as well as higher mean pore size, porosity, and hydrophilicity. Under a moderate transmembrane pressure (0.05 MPa), tetracycline (TC) in synthetic and real wastewater was degraded by the optimal catalytic membrane by 72.7 % and 91.2 %, respectively. Owing to the generation of the reactive oxygen species (ROS) during the Fenton-like reaction process, the catalytic membrane could exclude the natural organics during the H2O2 backwash step and selectively promote fouling degradation in the membrane channel. The irreversible fouling ratio of the catalyzed membrane was significantly reduced, and the flux recovery rate increased by up to 91.6 %. A potential catalytic mechanism and TC degradation pathways were proposed. This study offers valuable insights for designing catalytic membranes with enhanced filtration performance.

Insights on the role of blocking agent on the properties of the lipase from Thermomyces lanuginosus immobilized on heterofunctional support for hydroesterification reactions.

Here, we report a study of the effect of the blocking agent on the properties of the lipase from Thermomyces lanuginosus (TLL) immobilized on a heterofunctional support (Purolite C18-ethylnediamina (EDA)- vinyl sulfone (VS)-TLL-blocking agent) in different reactions. The performance of the biocatalysts was compared to those immobilized on standard hydrophobic support (Purolite C18-TLL) and the commercial one (TLL-IM). The nature of the blocking agent (Cys, Gly and Asp) altered the enzyme features. TLL-IM always gave a comparatively worse performance, with its specificity for the oil being very different to the Purolite biocatalysts. Under optimized conditions, Purolite C18-TLL yielded 97 % of hydrolysis conversion after 4 h using a water/waste cooking soybean oil (WCSO) mass ratio of 4.3, biocatalyst load of 6.5 wt% and a temperature of 44.2 °C (without buffer or emulsification agent). In esterification reactions of the purified free fatty acids (FFAs) obtained from WCSO, the best TLL biocatalysts depended on the utilized alcohol: linear amyl alcohol was preferred by Purolite C18-TLL and Purolite C18-EDA-VS-TLL-Gly, while higher activity was achieved utilizing isoamyl alcohol as nucleophile by Purolite C18-EDA-VS-TLL-Cys, Purolite C18-EDA-VS-TLL-Asp and IM-TLL as catalysts. All the results indicate the influence of the blocking step on the final biocatalyst features.

A bioactive sprite: Recent advances in the application of vinyl sulfones in drug design and organic synthesis.

Vinyl sulfones, with their exceptional chemical properties, are known as the "chameleons" of organic synthesis and are widely used in the preparation of various sulfur-containing structures. However, their most alluring feature lies in their biological activity. The vinyl sulfone skeleton is ubiquitous in natural products and drug molecules and boasts a unique molecular structure and drug activity when compared to conventional drug molecules. As a result, vinyl sulfones have been extensively studied, playing a critical role in organic synthesis and pharmaceutical chemistry. In this review, we present a comprehensive analysis of the recent applications of vinyl sulfone structures in drug design, biology, and chemical synthesis. Furthermore, we explore the prospects of vinyl sulfones in diverse fields, offering insight into their potential future applications.

Comparative analyses of adsorbed circulating proteins in the PMMA and PES hemodiafilters in patients on predilution online hemodiafiltration.

Acute and chronic inflammation are common in patients with end-stage kidney disease (ESKD). So, the adsorption of pro-inflammatory cytokines by the hollow fiber of the dialysis membrane has been expected to modify the inflammatory dysregulation in ESKD patients. However, it remains to be determined in detail what molecules of fiber materials can preferably adsorb proteins from the circulating circuit. We aimed this study to analyze directly the adsorbed proteins in the polymethyl methacrylate (PMMA) and polyethersulfone (PES) membranes in patients on predilution online hemodiafiltration (OL-HDF). To compare the adsorbed proteins in the PMMA and PES hemodiafilters membrane, we initially performed predilution OL-HDF using the PES (MFX-25Seco) membrane while then switched to the PMMA (PMF™-A) membrane under the same condition in three patients. We extracted proteins from the collected hemodiafilters by extraction, then SDS-PAGE of the extracted sample, protein isolation, in-gel tryptic digestion, and nano-LC MS/MS analyses. The concentrations of adsorbed proteins from the PMMA and PES membrane extracts were 35.6±7.9 µg/µL and 26.1±9.2 µg/µL. SDS-PAGE analysis revealed distinct variations of adsorbed proteins mainly in the molecular weight between 10 to 25 kDa. By tryptic gel digestion and mass spectrometric analysis, the PMMA membrane exhibited higher adsorptions of ß2 microglobulin, dermcidin, retinol-binding protein-4, and lambda-1 light chain than those from the PES membrane. In contrast, amyloid A-1 protein was adsorbed more potently in the PES membrane. Western blot analyses revealed that the PMMA membrane adsorbed interleukin-6 (IL-6) approximately 5 to 118 times compared to the PES membrane. These findings suggest that PMMA-based OL-HDF therapy may be useful in controlling inflammatory status in ESKD patients.

Photochemical degradation of bisphenol S and its tetrahalogenated derivatives in water.

Bisphenol S (BPS), a widely used plasticizer, is known to have potential endocrine disrupting effects to organisms. Its tetrahalogenated derivatives, tetrachlorobisphenol S (TCBPS) and tetrabromobisphenol S (TBBPS), are flame retardants exhibiting high neurodevelopmental toxicity and cytotoxicity. Halogen substitution has been shown to significantly affect the optical and photochemical properties of organic compounds. In this study, we conducted a comparative investigation into the photochemical behaviors of BPS, TCBPS, and TBBPS in aqueous solutions under both laboratory UV and natural sunlight irradiation. Spectroscopic titration results indicated that the pKa of TCBPS (4.16) and TBBPS (4.13) are approximately 3.7 units smaller than that of BPS (7.85), indicating that the halogenated derivatives are mainly present as the phenolate anions under circumneutral conditions. The halogen substituents also cause a significant bathochromic shift in the absorption spectra of TCBPS and TBBPS compared to BPS, leading to the enhanced absorption of sunlight. Meanwhile, TCBPS and TBBPS showed higher quantum yields than BPS, attributed to the "heavy atom" effect of halogen substituents. GCSOLAR modeling predicted half-lives for BPS, TCBPS, and TBBPS in surface water in Nanjing (32°2'7.3''N, 118°50'21''E) under noon sunlight in clear mid-autumn days as 810.2, 3.4, and 0.7 min, respectively. Toxicity evaluation suggest potential ecological risks of BPS/TCBPS/TBBPS and their photoproducts to aquatic organisms. Our findings highlight direct photolysis as an important mechanism accounting for the attenuation of tetrahalogenated bisphenols in both sunlit surface waters and UV based water treatment processes.engineered (e.g., UV disinfection) and natural aquatic environments (e.g., surface fresh waters).

Light-induced ß-hydroxy sulfone synthesis in DNA-encoded libraries.

We here describe a visible-light photooxidation of sulfinate salts with common alkenes to yield ß-hydroxy sulfones on DNA. This process demonstrates a broad substrate compatibility and achieves conversion rates ranging from moderate to excellent. Most importantly, it presents a straightforward, efficient, and metal-free approach for synthesizing Csp3-rich DNA-encoded libraries.

Performance improvement of polyethersulfone membranes with Ti3AlCN MAX phase in the treatment of organic and inorganic pollutants.

In this work, the hydrophobic polyethersulfone (PES) membrane was modified by incorporating Ti3AlCN MAX phase. Synthesis of Ti3AlCN MAX phase was performed using the reactive sintering method. The scanning electron microscopy (SEM) images showed a 3D compressed layered morphology for the synthesized MAX phase. The Ti3AlCN MAX phase was added to the casting solution, and the mixed-matrix membranes were fabricated by the non-solvent induced phase inversion method. The performance and antifouling features of bare and modified membranes were explored by pure water flux, flux recovery ratio (FRR), and fouling resistance parameters. Through the modification of membranes by introducing the Ti3AlCN MAX phase, the enhancement of these features was observed, in which the membrane containing 1 wt% of MAX phase showed 17.7 L/m2.h.bar of permeability and 98.6% for FRR. Also, the separation efficiency of all membranes was evaluated by rejecting organic and inorganic pollutants. The Ti3AlCN MAX membranes could reject 96%, 95%, and 88% of reactive blue 50, Rose Bengal, and azithromycin antibiotics, respectively, as well as 98%, 80%, 86%, and 36% of Pb2+, As5+, Na2SO4, and NaCl, respectively. Finally, the outcomes indicated the Ti3AlCN MAX phase was an excellent and efficient novel additive for modifying the PES membrane.

Catalytic glycosylation for minimally protected donors and acceptors.

Oligosaccharides have myriad functions throughout biological processes1,2. Chemical synthesis of these structurally complex molecules facilitates investigation of their functions. With a dense concentration of stereocentres and hydroxyl groups, oligosaccharide assembly through O-glycosylation requires simultaneous control of site, stereo- and chemoselectivities3,4. Chemists have traditionally relied on protecting group manipulations for this purpose5-8, adding considerable synthetic work. Here we report a glycosylation platform that enables selective coupling between unprotected or minimally protected donor and acceptor sugars, producing 1,2-cis-O-glycosides in a catalyst-controlled, site-selective manner. Radical-based activation9 of allyl glycosyl sulfones forms glycosyl bromides. A designed aminoboronic acid catalyst brings this reactive intermediate close to an acceptor through a network of non-covalent hydrogen bonding and reversible covalent B-O bonding interactions, allowing precise glycosyl transfer. The site of glycosylation can be switched with different aminoboronic acid catalysts by affecting their interaction modes with substrates. The method accommodates a wide range of sugar types, amenable to the preparation of naturally occurring sugar chains and pentasaccharides containing 11 free hydroxyls. Experimental and computational studies provide insights into the origin of selectivity outcomes.

ß-cyclodextrin modified GO ultrafiltration membranes with enhanced antifouling property for water purification.

The study investigated the influence of additives on the fabrication of mixed matrix membranes comprising polyethersulfone (PES), with a specific focus on hydrophilicity, flux, morphology, and antifouling properties. Carboxymethyl modified ß-cyclodextrin (CMß-CD) was used to enhance the dispersion and hydrophilicity of graphene oxide (GO), leading to the formation of a hydrophilic and stable composite nanoparticle (CMCD@GO). The hydrophilicity (WCA <51.5°) and water flux (32.6 L m-2.h-1) of the modified PES membranes (MCDGO-x) were improved by the incorporation of CMCD@GO nanoparticles, while that of PES membrane was 79.7° and 10.6 L m-2.h-1. The rate of backscattered light intensity (ΔBS) of MCDGO-x suspensions remains stable, suggesting stable dispersion of CMCD@GO in organic solvents. Compared to the bare PES membrane, the MCDGO-x membrane exhibits a thinner active layer and a finger-like structure. The MCDGO-x membrane exhibited excellent naphthenic acids (NAs) rejection (>93.2%) due to reduced roughness and higher hydrophilicity, while the GO-modified PES membrane (MGO-5) exhibited lower NAs rejection (87.2%). Furthermore, the MCDGO-5 membrane showed higher flux recovery ratio (FRR) of 79.3% compared to MGO-5 membrane (68.5%) after three cycles, indicating the antifouling performance of MCDGO-x for NAs was significantly improved. The combination of CMß-CD and GO enhance the flux and antifouling properties of PES ultrafiltration membranes, suggesting significant potential for applications in the purification of oil sands process water and the treatment of oily wastewater.

Role of Microfiltration Membrane Morphology on Nanoparticle Purification to Enhance Downstream Purification of Viral Vectors.

In the rapidly advancing realms of gene therapy and biotechnology, the efficient purification of viral vectors is pivotal for ensuring the safety and efficacy of gene therapies. This study focuses on optimizing membrane selection for viral vector purification by evaluating key properties, including porosity, thickness, pore structure, and hydrophilicity. Notably, we employed adeno-associated virus (AAV)-sized nanoparticles (20 nm), 200 nm particles, and bovine serum albumin (BSA) to model viral vector harvesting. Experimental data from constant pressure normal flow filtration (NFF) at 1 and 2 bar using four commercial flat sheet membranes revealed distinct fouling behaviors. Symmetric membranes predominantly showed internal and external pore blockage, while asymmetric membranes formed a cake layer on the surface. Hydrophilicity exhibited a positive correlation with recovery, demonstrating an enhanced recovery with increased hydrophilicity. Membranes with higher porosity and interpore connectivity showcased superior throughput, reduced operating time, and increased recovery. Asymmetric polyether sulfone (PES) membranes emerged as the optimal choice, achieving ∼100% recovery of AAV-sized particles, an ∼44% reduction in model cell debris (200 nm particles), an ∼35% decrease in BSA, and the fastest operating time of all membranes tested. This systematic investigation into fouling behaviors and membrane properties not only informs optimal conditions for viral vector recovery but also lays the groundwork for advancing membrane-based strategies in bioprocessing.

A new chemical derivatization reagent sulfonyl piperazinyl for the quantification of fatty acids using LC-MS/MS.

In our previous study, a chemical derivatization reagent named 5-(dimethylamino) naphthalene-1-sulfonyl piperazine (Dns-PP) was developed to enhance the chromatographic retention and the mass spectrometric response of free fatty acids (FFAs) in reversed-phase liquid chromatography coupled with electrospray ionization-mass spectrometry (RPLC-ESI-MS). However, Dns-PP exhibited strong preferences for long-chain FFAs, with limited improvement for short- or medium-chain FFAs. In this study, a new series of labeling reagents targeting FFAs were designed, synthesized, and evaluated. Among these reagents, Tmt-PP (N2, N2, N4, N4-tetramethyl-6-(4-(piperazin-1-ylsulfonyl) phenyl)-1,3,5-triazine-2,4-diamine) exhibited the best MS response and was selected for further evaluations. We compared Tmt-PP with Dns-PP and four commonly used carboxyl labeling reagents from existing studies, demonstrating the advantages of Tmt-PP. Further comparisons between Tmt-PP and Dns-PP in measuring FFAs from biological samples revealed that Tmt-PP labeling enhanced the MS response for about 80 % (30/38) of the measured FFAs, particularly for short- and medium-chain FFAs. Moreover, Tmt-PP labeling significantly improved the chromatographic retention of short-chain FFAs. To ensure accurate quantification, we developed a stable isotope-labeled Tmt-PP (i.e., d12-Tmt-PP) to react with chemical standards and serve as one-to-one internal standards (IS). The method was validated for accuracy, precision, sensitivity, linearity, stability, extraction efficiency, as well as matrix effect. Overall, this study introduced a new chemical derivatization reagent Tmt-PP (d12-Tmt-PP), providing a sensitive and accurate option for quantifying FFAs in biological samples.

Removal of Bisphenol S (BPS) by Adsorption on Activated Carbons Commercialized in Brazil.

This study assessed three powdered activated carbons (BETM, COCO, and SIAL) commercialized in Brazil at the bench scale in agitated reactors, analyzing their kinetic behavior and adsorptive capacity for BPS and BPA in ultrapure water. BETM exhibited the highest adsorption capacities (Q0max) for BPS and BPA at 260.62 and 264.64 mg/g, respectively, followed by SIAL, with a Q0max of 248.25 mg/g for BPS and for 231.20 mg/g BPA, and COCO, with a Q0max of 136.51 mg/g for BPS and 150.03 mg/g for BPA. The Langmuir isotherm model can describe the processes well. A pseudo-second-order model can describe the adsorption kinetics, and SIAL carbon had the highest rate constants (7.45 × 10-3 mg/g/min for BPS and 2.84 × 10-3 mg/g/min for BPA). The Weber-Morris intraparticle diffusion model suggests intraparticle diffusion as the rate-limiting step of all adsorption processes. Boyd's model confirmed more than the mechanism actuating in the bisphenol adsorption. The results suggest that adsorbents with basic surfaces, high specific surface areas, and high mesopore volumes tend to remove BPS and BPA efficiently. Therefore, activated carbons can effectively complement the existing treatment in Brazilian water treatment plants (WTPs).

Evaluation of various membranes at different fluxes to enable large-volume single-use perfusion bioreactors.

The growing demand for biological therapeutics has increased interest in large-volume perfusion bioreactors, but the operation and scalability of perfusion membranes remain a challenge. This study evaluates perfusion cell culture performance and monoclonal antibody (mAb) productivity at various membrane fluxes (1.5-5 LMH), utilizing polyvinylidene difluoride (PVDF), polyethersulfone (PES), or polysulfone (PS) membranes in tangential flow filtration mode. At low flux, culture with PVDF membrane maintained higher cell culture growth, permeate titer (1.06-1.34 g/L) and sieving coefficients (≥83%) but showed lower permeate volumetric throughput and higher transmembrane pressure (TMP) (>1.50 psi) in the later part of the run compared to cultures with PES and PS membrane. However, as permeate flux increased, the total mass of product decreased by around 30% for cultures with PVDF membrane, while it remained consistent with PES and PS membrane, and at the highest flux studied, PES membrane generated 12% more product than PVDF membrane. This highlights that membrane selection for large-volume perfusion bioreactors depends on the productivity and permeate flux required. Since operating large-volume perfusion bioreactors at low flux would require several cell retention devices and a complex setup, PVDF membranes are suitable for low-volume operations at low fluxes whereas PES membranes can be a desirable alternative for large-volume higher demand products at higher fluxes.

Development of microfiltration membranes based on polysulfone and polyetherimide blends.

In this study, membranes blended with polysulfone (PSU) and polyetherimide (PEI) polymers in different ratios were fabricated. Their potential to remove pollutants from rivers, which are a potential drinking water source, was investigated. Scanning electron microscopy analysis revealed that the PSU membranes had a dense and homogeneous layer, whereas the addition of PEI formed a spongy substrate. The water content of the fabricated membranes varied between 5.37 and 22.42%, porosities 28.73-89.36%, contact angles 69.18-85.81%, and average pure water fluxes 257.25-375.32 L/m2 h. The blended membranes removed turbidity, chloride, alkalinity, conductivity, sulfate, iron, manganese, and total organic carbon up to 98.32, 92.28, 96.87, 90.67, 99.58, 94.63, 97.48, and 79.11%, respectively. These results show that when PEI was added to the PSU polymer, the filtration efficiency increased owing to an increase in the hydrophilicity of the membranes. Blending these two polymers enabled the optimization of membrane properties such as permeability, selectivity, and mechanical strength. In addition, membrane fabrication processes are simple and incur low costs.

Bisphenol A and its structural analogues exhibit differential potential to induce mitochondrial dysfunction and apoptosis in human granulosa cells.

Bisphenol A (BPA) is an endocrine disruptor strongly associated with ovarian dysfunction. BPA is being substituted by structurally similar chemicals, such as bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF). However, the toxicity of these analogues in female reproduction remains largely unknown. This study evaluated the effects of BPA and its analogues BPS, BPF, and BPAF on the mitochondrial mass and function, oxidative stress, and their potential to induce apoptosis of human granulosa cells (KGN cells). BPA and its analogues, especially BPA and BPAF, significantly decreased mitochondrial activity and cell viability. The potential of bisphenols to reduce mitochondrial mass and function differed in the following order: BPAF > BPA > BPF > BPS. Flow cytometry revealed that exposure to bisphenols significantly increased mitochondrial ROS levels and increased mitochondrial Ca2+ levels. Thus, bisphenols exposure causes mitochondrial stress in KGN cells. At the same time, bisphenols exposure significantly induced apoptosis. These results thus emphasize the toxicity of these bisphenols to cells. Our study suggests the action mechanism of BPA and its analogues in damage caused to ovarian granulosa cells. Additionally, these novel analogues may be regrettable substitutes, and the biological effects and potential risks of BPA alternatives must be evaluated.