Pectolinarigenin ameliorates osteoporosis via enhancing Wnt signaling cascade in PPARß-dependent manner.

BACKGROUND: Osteoporosis is a prevalent metabolic bone disease in older adults. Peroxisome proliferator-activated receptor ß (PPARß), the most abundant PPAR isotype expressed in bone tissues, plays a critical role in regulating the energy metabolism of osteoblasts. However, the botanical compounds targeting PPARß for the treatment of osteoporosis remain largely unexplored. PURPOSE: To discover a potent PPARß agonist from botanical compounds, as well as to investigate the anti-osteoporosis effects and to elucidate the underlying mechanisms of the newly identified PPARß agonist. METHODS: The PPARß agonist effects of botanical compounds were screened by an in vitro luciferase reporter gene assay. The PPARß agonist effects of pectolinarigenin (PEC) in bone marrow mesenchymal stromal cells (BMSCs) were validated by Western blotting. RNA-seq transcriptome analyses were conducted to reveal the underlying osteoporosis mechanisms of PEC in BMSCs. The PPARß antagonist (GSK0660) and Wnt signaling inhibitor (XAV969) were used to explore the role of the PPARß and Wnt signaling cascade in the anti-osteoporosis effects of PEC. PEC or the PEG-PLGA nanoparticles of PEC (PEC-NP) were intraperitoneally administrated in both wild-type mice and ovariectomy-induced osteoporosis mice to examine its anti-osteoporotic effects in vivo. RESULTS: PEC, a newly identified naturally occurring PPARß agonist, significantly promotes osteogenic differentiation and up-regulates the osteogenic differentiation-related genes (Runx2, Osterix, and Bmp2) in BMSCs. RNA sequencing and functional gene enrichment analysis suggested that PEC could activate osteogenic-related signaling pathways, including Wnt and PPAR signaling pathways. Further investigations suggested that PEC could enhance Wnt/ß-catenin signaling in a PPARß-dependent manner in BMSCs. Animal tests showed that PEC-NP promoted bone mass and density, increased the bone cell matrix protein, and accelerated bone formation in wild-type mice, while PEC-NP also played a preventive role in ovariectomy-induced osteoporosis mice via maintaining the expression level of bone cell matrix protein, balancing the rate of bone formation, and slowing down bone loss. Additionally, PEC-NP did not cause any organ injury and body weight loss after long-term use (11 weeks). CONCLUSION: PEC significantly promotes bone formation and reduces bone loss in both BMSCs and ovariectomy-induced osteoporosis mice via enhancing the Wnt signaling cascade in a PPARß-dependent manner, providing a new alternative therapy for preventing estrogen deficiency-induced osteoporotic diseases.

Fenton-like membrane reactor assembled by electron polarization and defect engineering modifying Co3O4 spinel for flow-through removal of organic contaminants.

The application of Fenton-like membrane reactors for water purification offers a promising solution to overcome technical challenges associated with catalyst recovery, reaction efficiency, and mass transfer typically encountered in heterogeneous batch reaction modes. This study presents a dual-modification strategy encompassing electron polarization and defect engineering to synthesize Al-doped and oxygen vacancies (OV)-enriched Co3O4 spinel catalysts (ACO-OV). This modification empowered ACO-OV with exceptional performance in activating peroxymonosulfate (PMS) for the removal of organic contaminants. Moreover, the ACO-OV@polyethersulfone (PES) membrane/PMS system achieved organic contaminant removal through filtration (with a reaction kinetic constant of 0.085 ms-1), demonstrating outstanding resistance to environmental interference and high operational stability. Mechanistic investigations revealed that the exceptional catalytic performance of this Fenton-like membrane reactor stemmed from the enrichment of reactants, exposure of reactive sites, and enhanced mass transfer within the confined space, leading to a higher availability of reactive species. Theoretical calculations were conducted to validate the beneficial intrinsic effects of electron polarization, defect engineering, and the confined space within the membrane reactor on PMS activation and organic contaminant removal. Notably, the ACO-OV@PES membrane/PMS system not only mineralized the targeted organic contaminants but also effectively mitigated their potential environmental risks. Overall, this work underscores the significant potential of the dual-modification strategy in designing spinel catalysts and Fenton-like membrane reactors for efficient organic contaminant removal.

Post-treatment of soft drink industrial wastewater using a new antibacterial ultra-filtration membrane prepared of Polyethersulfone blended with boehmite-tannic acid-graphene quantum dot.

Polymeric membranes have garnered great interest in wastewater treatment; however, fouling is known as their main limitation. Therefore, the blending of hydrophilic nanoparticles in polymeric membranes' structure is a promising approach for fouling reduction. Herein, a hydrophilic boehmite-tannic acid-graphene quantum dot (BM-TA-GQD) nanoparticle was synthesized and blended in a polyethersulfone polymeric membrane in different percentages. The fabricated membranes were characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM) images, water contact angle, porosity measurement, and antibacterial and antifouling properties. Surface SEM images of the modified membranes showed good dispersion of nanoparticles up to 0.5 wt%, which resulted in hydrophilicity and pure water flux enhancement. Based on AFM images, the mean roughness (Sa) of the fabricated membranes decreased from 2.07 to 0.84 nm for the bare and optimum membranes, respectively. In terms of performance, increasing the nanoparticle percentages up to 0.5 wt% resulted in the flux recovery ratio developing from 44.58% for the bare membrane to 71.35% for the 0.5 wt% BM-TA-GQD/PES membrane (optimum membrane). The antibacterial property of fabricated membranes was studied against biologically treated soft drink industrial wastewater (BTSDIW) as a bacterial source. The results showed that the turbidity of solutions containing permeated wastewater from the modified membranes (0.1, 0.5, and 1 wt% of BM-TA-GQD) was lower than that obtained from the unmodified membrane. These results confirmed the antibacterial properties of fabricated membranes. Finally, the optimal membrane (0.5 wt% BM-TA-GQD) was examined for post-treatment of the BTSDIW. An effluent COD of 13 mg/L and turbidity of 2 NTU showed a successful performance of the filtration process. PRACTITIONER POINTS: Ultrafiltration PES membranes were modified by different loadings of BM-TA-GQD. Hydrophilicity improvement was achieved by adding BM-TA-GQD nanoparticles. Expansion of size and number of macro-voids in modified membranes was confirmed. Membrane roughness was reduced in the BM-TA-GQD blended membranes. The optimum membrane was efficient in COD and turbidity removal.

Interventions for Dry Eye: An Overview of Systematic Reviews.

Importance: Dry eye is a common ocular disease that can have substantial morbidity. Systematic reviews provide evidence for dry eye interventions and can be useful for patients, clinicians, and clinical guideline developers. Overviews of reviews use explicit and systematic methods to synthesize findings from multiple systematic reviews, but currently, there are no overviews of systematic reviews investigating interventions for dry eye. Objective: To summarize the results of reliable systematic reviews of dry eye interventions and to highlight the evidence gaps identified. Evidence Review: We searched the Cochrane Eyes and Vision US satellite database and included reliable systematic reviews evaluating dry eye interventions published from 2016 to 2022. We reported the proportion of systematic reviews that were reliable with reasons for unreliability. Critical and important outcomes from reliable systematic reviews were extracted and verified. Critical outcomes included dry eye-related patient-reported outcome measures. Results were synthesized from reliable systematic reviews to provide summaries of evidence for each intervention. Evidence for each intervention was defined as conclusive or inconclusive depending on whether high-certainty evidence across systematic reviews was available according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria and whether findings reached statistical or clinical significance. Recommendations were made for further research. Findings: Within the Cochrane Eyes and Vision US satellite database, 138 potentially relevant systematic reviews were identified, 71 were considered eligible, and 26 (37%) were assessed as reliable. Among reliable systematic reviews, no conclusive evidence was identified for any dry eye intervention. Inconclusive evidence suggested that environmental modifications, dietary modifications, artificial tears and lubricants, punctal occlusion, intense pulsed light therapy, vectored thermal pulsation therapy (Lipiflow), topical corticosteroids, topical cyclosporine A, topical secretagogues, and autologous serum may be effective. Only unreliable systematic reviews evaluated lifitegrast, oral antibiotics, and moisture chamber devices. Conclusions and Relevance: This overview of systematic reviews found some evidence that dry eye interventions may be effective, but no conclusive evidence was available. The conduct and reporting of most systematic reviews for dry eye interventions warrant improvement, and reliable systematic reviews are needed to evaluate lifitegrast, oral antibiotics, and moisture chamber devices.

CoFe2O4 modified bentonite-based mixed matrix loose nanofiltration membranes for effective wastewater treatment.

Mixed-matrix membranes (MMMs) with an ideal polymer/hydrophilic flux enhancer interface considerably recuperates the separation and purification performance of membrane. In this direction, a novel CoFe2O4 functionalized natural clay-bentonite (CoFe2O4@BT) material as a compatible flux enhancer was synthesized for preparation of mixed matrix based in polyethersulfone (PES) matrix. Here, the influences of CoFe2O4@BT on the morphology and performance of the MMMs membranes were systematically investigated using various analytical techniques. Meanwhile, the water flux and sepration eficiency of the CoFe2O4@BT-PES membranes significantly enhanced due to the incorporation of CoFe2O4@BT that altered hydrophilicity, pore and surface characteristic features. The water flux as well as separation efficiency range up to 95%, 94.69%, 94.16% of Congo red (CR), Crystal violet (CV), and humic acid (HA) respectively. Meanwhile, the fouling parameters demonstrated that the CoFe2O4@BT-PES membranes exhibited better antifouling property in the long term experiment comparing with commercial polyamide membrane. CoFe2O4@BT material incorporated membranes showed less decline ratio and a better recovery ratio. The high rejection of dyes with a high permeation flux of the newly designed membranes indicated an amazing possibility for dye purification. In this study, a potential dye mechanism for composite membranes impacted by synthetic CoFe2O4@BT was also put forth. Within the context of application considerations for environmental protection, new materials stock in membranes show good potential for the separation of different organic contaminants.

Iron-catalyzed regioselective synthesis of (E)-vinyl sulfones mediated by unprotected hydroxylamines.

An Fe-catalyzed unprotected hydroxylamine mediated Heck-type coupling between sulfinic acids and alkenes for the regioselective synthesis of (E)-vinyl sulfones has been developed. Mechanism studies indicated for the first time that a radical process may be involved and that hydroxylamines play multiple roles, including those of a mild oxidant and an in situ base. It was found for the first time that this transformation not only realizes C-S bond construction promoted by unprotected hydroxylamines, but also provides a practical and complementary method for the preparation of structurally important (E)-vinyl sulfones.

Sustained Delivery of Methylsulfonylmethane from Biodegradable Scaffolds Enhances Efficient Bone Regeneration.

Introduction: As a popular dietary supplement containing sulfur compound, methylsulfonylmethane (MSM) has been widely used as an alternative oral medicine to relieve joint pain, reduce inflammation and promote collagen protein synthesis. However, it is rarely used in developing bioactive scaffolds in bone tissue engineering. Methods: Three-dimensional (3D) hydroxyapatite/poly (lactide-co-glycolide) (HA/PLGA) porous scaffolds with different doping levels of MSM were prepared using the phase separation method. MSM loading efficiency, in vitro drug release as well as the biological activity of MSM-loaded scaffolds were investigated by incubating mouse pre-osteoblasts (MC3T3-E1) in the uniform and interconnected porous scaffolds. Results: Sustained release of MSM from the scaffolds was observed, and the total MSM release from 1% and 10% MSM/HA/PLGA scaffolds within 16 days was up to 64.9% and 68.2%, respectively. Cell viability, proliferation, and alkaline phosphatase (ALP) activity were significantly promoted by incorporating 0.1% of MSM in the scaffolds. In vivo bone formation ability was significantly enhanced for 1% MSM/HA/PLGA scaffolds indicated by the repair of rabbit radius defects which might be affected by a stimulated release of MSM by enzyme systems in vivo. Discussion: Finding from this study revealed that the incorporation of MSM would be effective in improving the osteogenesis activity of the HA/PLGA porous scaffolds.

Methylsulfonylmethane and Sesame Seed Oil Improve Dyslipidemia and Modulate Polyunsaturated Fatty Acid Metabolism in Two Mouse Models of Diabetes.

The objective of this study was to identify alterations in lipids and polyunsaturated fatty acid (PUFA) metabolism in both the streptozotocin (STZ)-induced type 1 diabetic (T1D) mouse and the mutant db/db type 2 diabetic (T2D) mouse to establish a biological signature for the evaluation of natural products with purported lipid-altering activity. Eight-week-old male C57BL/6J mice were randomized to nondiabetic group or STZ-induced diabetic groups (n = 10/group). STZ-induced diabetic mice and 6-week-old male db/db mice (n = 10/group) were randomized to the following groups: (1) diabetic control, no treatment, (2) methylsulfonylmethane (MSM) treatment, (3) sesame seed oil (SSO) treatment, and (4) MSM+SSO combination treatment. Clinical parameters measured included weights, blood glucose, serum lipid panels, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) detection of free fatty acids in serum, liver, brain, and eyes. Blood glucose significantly decreased after 4 weeks of MSM treatment in T1D mice. Serum PUFA levels were significantly reduced in T2D mice compared with control mice. In contrast, treatment with SSO reversed this effect in T2D mice, exhibiting serum PUFA levels comparable to control mice. Serum triglycerides were significantly increased in both diabetic models compared to nondiabetic control, mimicking diabetes in people. High-density lipoprotein (HDL) was significantly increased in T1D receiving MSM+SSO and all T2D treatment groups. A corresponding significant decrease in non-HDL cholesterol was seen in T2D mice in all treatment groups. MSM+SSO treatment's effects on HDL and non-HDL cholesterol and PUFA metabolism could lead to improved clinical outcomes in diabetics by improving the lipid profile.

Use of an alfa-lipoic, Methylsulfonylmethane, Boswellia serrata and Bromelain dietary supplement (OPERA®) for aromatase inhibitors-related arthralgia management (AIA): a prospective phase II trial (NCT04161833).

Aromatase Inhibitors (AIs) are recommended for the adjuvant treatment of hormone receptor positive breast cancer in both high-risk pre-menopausal and post-menopausal population; arthralgia is the main cause of discontinuation of therapy and affects up to 25% of population on AI treatment. The objective of the study was to prospectively evaluate OPERA® (GAMFARMA srl, Milan, Italy), a new dietary supplement where α-Lipoic acid, Boswellia serrata, Methylsulfonylmethane and Bromelain are combined in a single hard-gelatin capsule to be taken once a day. Fifty-three patients with arthralgia (NCI-CTCAE v4.0 grade ≥ 1) occurring during AI therapy were enrolled. All patients received OPERA® from enrollment (T0) up to sixth months (T3). Patients' AI-related arthralgia was evaluated every two months with VAS Scale, PRAI questionnaire, and CTCAE scale. Primary endpoint was the number of patients with symptom resolution (G0) at T3 if compared to T0, according to CTCAE and VAS scale. Secondary endpoints were decrease in arthralgia intensity measured with PRAI score at T3 compared to baseline, safety of OPERA® and rate of AI interruption. Treatment with OPERA® supplement was overall well tolerated; no relevant toxicities related to OPERA® intake were reported. Seven subjects (13.2%) were not included in the final analysis because of consent withdrawal. 46 participants were eligible for final analysis. According to CTCAE scale, 10 out of 46 patients reported symptoms resolution at 6-month follow-up from the time of enrollment T0 (p = 0.0009). According to VAS score, 5 patients reported complete resolution of symptoms at T3 if compared to baseline starting situation T0 (p = 0.0222). Analysis of PRAI score showed a significant reduction in arthralgia-related pain perceived (p = 0.0001). OPERA® was able to reduce the intensity of arthralgia related to AI therapy. Randomized, double-blind studies are warranted to confirm the effectiveness of this dietary supplement.

Influence of various shapes of alumina nanoparticle in integrated polysulfone membrane for separation of lignin from woody biomass and salt rejection.

Lignin valorization is essential in proposing an economic perspective as a raw material for valuable compounds. The bio-refineries require adequate processing to improve the high purity of lignin. Meanwhile, nanofiltration is fascinated attention to obtain high purity value-added products. The effect of alumina nanoparticles on the fabrication of mixed matrix membranes (MMM) has contributed to improvising filtration performance. However, incorporating nanoparticles is a significant issue regarding appropriate size and shape integrated into membrane for better filtration efficiency. The influence of shapes of alumina nanoparticles has been investigated into polysulfone (PSf) membranes for salt and lignin separation. The morphology of alumina was tailored with spindle, cubic, and spherical shapes synthesized at a different calcination temperature of 250, 500, 700 and 900 °C, respectively. The phase transitions were confirmed in X-ray diffraction (XRD) analysis, and the shape of the nanoparticles was observed in a high-resolution transmission electron microscope (HRTEM). The separation efficiency of membranes was tested with salt rejection using sodium sulfate, calcium chloride, potassium sulfate, and sodium chloride. The lignin was extracted from prehydrolysed sawdust, and the synthetic lignosulfonic acid sodium salt solution was separated. The higher lignin rejection of 98.6% and 97.9% were obtained for cubic shaped gamma phase alumina mixed matrix membrane. The high rejection of lignin occurred due to narrow pores channels that could resist the transfer of lignin through the membrane. The results proved that the controllable organization of PSf/alumina mixed matrix membranes could apply for lignocellulose compounds with good efficiency.

Leakage of Endotoxins through the Endotoxin Retentive Filter: An in vitro Study.

INTRODUCTION: Ultrapurification of dialysis fluid has enabled highly efficient dialysis treatments. Online hemodiafiltration is one such treatment that uses a purified dialysis fluid as a supplemental fluid. In this method, an endotoxin retentive filter (ETRF) is used in the final step of dialysis fluid purification, with the aim of preventing leakage of endotoxins. Sodium hypochlorite and peracetic acid are used as disinfecting agents for the dialysis fluid pipes containing the ETRF; however, the effects of these agents on ETRF membrane pores have not been fully clarified. METHODS: Water permeability (flux) and endotoxin permeability were assessed in 3 types of ETRFs made with different membrane materials: polyester polymer alloy (PEPA), polyether sulfone (PES), and polysulfone (PS). High-concentration sodium hypochlorite and 2 types of peracetic acid were used as disinfecting agents, and the changes in flux and the endotoxin sieving coefficient (SC) were measured. RESULTS: After repeated use of high concentrations of sodium hypochlorite and peracetic acid, the PEPA and PES ETRFs did not permit passage of endotoxins, regardless of their flux. However, in the PS ETRF, the flux and endotoxin SC increased with the number of cleaning cycles. No differences were observed according to the concentration of peracetic acid disinfecting agents. CONCLUSION: PEPA and PES ETRFs completely prevent endotoxin leakage and can be disinfected at concentrations higher than the conventionally recommended concentration without affecting pore expansion. Even new PS ETRFs have low levels of endotoxin leakage, which increase after disinfection cycles using sodium hypochlorite and peracetic acid.

Optimized Curcumin, Pomegranate Extract, and Methylsulfonylmethane Reduce Acute, Systemic Inflammatory Response to a Half-marathon Race.

Context: Endurance running places substantial physiological strain on the body, which can develop into chronic inflammation and overuse injuries, negatively affecting subsequent training and performance. A recent study found that dietary polyphenols and methlysulfonylmethane (MSM) can reduce systemic inflammation and oxidative stress without adverse side effects. Objective: The purpose was to identify a set of candidate protein and RNA biomarkers that are associated with improved outcomes related to inflammation and muscle injury, when athletes used 3 proprietary supplements both prior to and during early recovery from a half-marathon race. Design: The study was an open-label pilot study. Setting: The study was field based, with sample analysis conducted in the Applied Physiology Laboratory in the Department of Kinesiology, Health Promotion and Recreation at the University of North Texas in Denton, Texas. Participants: Participants were 15 young, exercise-trained men and women. Intervention: The intervention group consumed 1000 mg/d of a proprietary 50-50 mix of optimized curcumin and pomegranate extract for 26 days. The group also consumed 500 mg/d of a proprietary MSM for the same period. Three days prior to and one day after a race, the daily dosage was doubled. The control group received no supplements. Outcome Measures: Venous blood samples were collected at pre-race and at 4h and 24h after running a half-marathon race. The research team evaluated results for target proteins that have been associated with inflammation and muscle injury in the scientific literature. The team also performed an analysis of RNA biomarkers. Results: At the 4h and 24h time points, a significant treatment-response was observed that included increases in proteins: (1) osteonectin/SPARC-osteonectin/secreted protein acidic and rich in cysteine and (2) BDNF-brain-derived neurotrophic factor. At the same points, the study also found increased RNA: (1) PACER-P50-associated COX-2 extragenic RNA, (2) PTGES-prostaglandin E synthase, (3) MYD88-innate immune signal transduction adaptor MYD88, (4) TNFS14-tumor necrosis factor (TNF) superfamily member 14, (5) THRIL-TNF and heterogeneous nuclear ribonucleoprotein L (HNRNPL)-related immunoregulatory long noncoding RNA, (6) TRAF6-TNF receptor associated factor 6, (7) CX3CL1-C-X3-C motif chemokine ligand 1, (8) MALAT1-metastasis-associated lung adenocarcinoma transcript 1, and (9) LINC00305-long intergenic nonprotein coding RNA 305. Conclusions: The combination of polyphenol and MSM supplementation resulted in a systemic response that may translate to an accelerated rate of muscle recovery, allowing participants return to exercise and normal activities more quickly. This pilot study is the foundation for a larger investigation in the research team's laboratory.

Impact of soy lecithin, zinc oxide, and methylsulfonylmethane, as excipient ingredients, on the bioaccessibility and intestinal transport of branched-chain amino acids from animal and plant protein mixtures.

To maximize the biological activity of branched-chain amino acids (BCAAs), it is necessary to find a new excipient agent to increase the bioavailability of BCAAs in protein mixtures. The aim of the current study was to investigate the effects of soy lecithin (SLC), zinc oxide (ZnO), and methylsulfonylmethane (MSM) on the bioaccessibility and intestinal transport of BCAAs from animal and plant protein mixtures (PMs) via an in vitro digestion model with human intestinal epithelial (Caco-2) cells. The bioaccessibility of total BCAAs in PMs considerably increased by 107.51 ± 1.50% with the addition of SLC, and the combined effects of SLC, ZnO, and MSM on enhancing the bioaccessibility of total BCAAs was observed (107.14 ± 0.18%). Interestingly, SLC showed a major role in binding bile acid, showing 65.78 ± 1.66% of binding capacity. Intestinal transport of BCAAs was measured to be at 100.48, 110.86, and 130.29 µg mL-1 for leucine, isoleucine, and valine, respectively, in PMs with SLC + ZnO + MSM, and it eventually amplified the amount of the total transported BCAAs (341.63 ± 6.34 µg mL-1), which was about 8.72 times higher than that of PM only. The cellular integrity of digesta-treated Caco-2 cells tended to decrease according to the incubation time, but it was recovered in the treatment of PM + SLC + ZnO + MSM, and nearly reached the control levels with 92.82 ± 0.53%. Results from the current study suggest that the co-consumption of proteins equally consisting of plant and animal sources with SLC, ZnO, and MSM could improve the bioavailability of total BCAAs, resulting in the improvement of health benefits.

Development and validation of UPLC-MS/MS method for the simultaneous quantification of anaplastic lymphoma kinase inhibitors, alectinib, ceritinib, and crizotinib in Wistar rat plasma with application to bromelain-induced pharmacokinetic interaction.

Bromelain, the aqueous extract of pineapple, has been used as a food supplement with reported nutritional and therapeutic benefits. Bromelain has anti-cancer, anti-inflammatory, antithrombotic, and fibrinolytic effects. Anaplastic lymphoma kinase (ALK) inhibitors, including alectinib (ALC), ceritinib (CER), and crizotinib (CRZ), have been efficiently used in the management of non-small cell lung cancer (NSCLC). The solubility of ALC, CER, and CRZ is much higher at low acidic pH (pH 1) and it decreases as the pH increases affecting their absorption with a subsequent decrease in their bioavailability. It was thought that the intake of bromelain could result in a decrease in the bioavailability of ALC, CER, and CRZ due to bromelain-induced alkalizing effect following digestion. On the contrary, bromelain could possibly increase plasma exposure of the cited drugs due to its known muco-permeation enhancing effect. The therapeutic-anticancer effect of bromelain can be possibly increased/enhanced with concomitant intake of other anticancer medications or it can add to the value of food supplements for its known nutritional benefits. Thus, this work aims at studying the possibility of any PK interaction when bromelain was taken while on ALC/CER/CRZ therapy. In this work, a new UPLC-MS/MS method was developed and validated for the simultaneous determination of ALC, CER, and CRZ in rat plasma. Further application of the proposed method was performed to test the possibility of the PK interaction between bromelain and the selected ALK inhibitors in Wistar rats. Simple protein precipitation with acetonitrile was used for sample preparation. Chromatographic analysis was performed on Waters BEH™ C18 column with a mixture of acetonitrile/water containing 0.1 % formic acid (70: 30, v/v) as the mobile phase. The method permitted the analysis of ALC, CER, and CRZ in concentration ranges of 2-200, 0.4-200, and 4.0-200 ng/mL, respectively. Bromelain administration caused a significant decrease in plasma levels of CER and CRZ with lowered Cmax, AUC0-t and AUC0-∞, along with an increase in the apparent clearance. However, no significant effect was noticed with ALC. Thus, attention should be paid to avoid the intake of bromelain with CER or CRZ.

Bisphenol S and Bisphenol F Are Less Disruptive to Cardiac Electrophysiology, as Compared With Bisphenol A.

Bisphenol A (BPA) is a high-production volume chemical used to manufacture consumer and medical-grade plastic products. Due to its ubiquity, the general population can incur daily environmental exposure to BPA, whereas heightened exposure has been reported in intensive care patients and industrial workers. Due to health concerns, structural analogs are being explored as replacements for BPA. This study aimed to examine the direct effects of BPA on cardiac electrophysiology compared with recently developed alternatives, including BPS (bisphenol S) and BPF (bisphenol F). Whole-cell voltage-clamp recordings were performed on cell lines transfected to express the voltage-gated sodium channel (Nav1.5), L-type voltage-gated calcium channel (Cav1.2), or the rapidly activating delayed rectifier potassium channel (hERG). Cardiac electrophysiology parameters were measured using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and intact, whole rat heart preparations. BPA was the most potent inhibitor of fast/peak (INa-P) and late (INa-L) sodium channel (IC50 = 55.3, 23.6 µM, respectively), L-type calcium channel (IC50 = 30.8 µM), and hERG channel current (IC50 = 127 µM). Inhibitory effects on L-type calcium channels were supported by microelectrode array recordings, which revealed a shortening of the extracellular field potential (akin to QT interval). BPA and BPF exposures slowed atrioventricular (AV) conduction and increased AV node refractoriness in isolated rat heart preparations, in a dose-dependent manner (BPA: +9.2% 0.001 µM, +95.7% 100 µM; BPF: +20.7% 100 µM). BPS did not alter any of the cardiac electrophysiology parameters tested. Results of this study demonstrate that BPA and BPF exert an immediate inhibitory effect on cardiac ion channels, whereas BPS is markedly less potent. Additional studies are necessary to fully elucidate the safety profile of bisphenol analogs on the heart.

Behavioral changes and hyperglycemia in NODEF mice following bisphenol S exposure are affected by diets.

Bisphenol S (BPS), an analogue of the controversial bisphenol A (BPA) that is found in epoxy resins and plastics, is a potential endocrine-disrupting chemical that can mimic endogenous hormone signaling. However, little is known about the behavioral or immunologic effects of BPS. The purpose of this study was to examine the impact of diets in BPS-treated mice in relation to hyperglycemia, development of type 1 diabetes, immunomodulation, and behavioral changes. Adult male and female nonobese diabetic excluded flora (NODEF) mice were exposed to environmentally relevant doses of BPS (VH, 30, or 300 µg/kg BW) and fed either a soy-based diet, a phytoestrogen-free diet, or a Western diet. NODEF male mice fed a soy-based diet exhibited a decreased curiosity/desire to explore, and possibly increased anxiety-like behavior and decreased short-term memory when exposed to BPS (300 µg/kg BW). In addition, these mice had significant increases in non-fasting blood glucose levels along with increased insulin sensitivity, impaired glucose tolerance, resistance to fasting and proinflammation. Although BPS had little effect on the glucose parameters in NODEF male mice fed a Western diet, there were decreases in %CD24+CD5+ and %B220+CD40L-cell populations and increases in distance traveled during the novel object test, suggesting hyperactivity. NODEF females fed a phytoestrogen-free diet exhibited slight decreases in time spent immobile during the tail suspension test in both the 30 and 300 µg/kg BW dose groups along with increases in %CD4+CD8+ and %Mac3+CD45R+ cell populations, signifying increased hyperactivity and anxiety-like behavior. In conclusion, BPS-exposed NODEF mice exhibited sex and diet-related changes in hyperglycemia, behaviors and immune endpoints.

Incorporation of lanthanum particles to polyethersulfone ultrafiltration membrane for specific phosphorus uptake: Method comparison and performance assessment.

It is known that phosphorus is a major contributor to the occurrence of eutrophication. As such, it is of importance to remove it from water. Nanofiltration (NF) has low phosphorus selectivity and requires a relatively high pressure to achieve the separation, though it is capable of removing phosphorus. In this paper, we report our findings of method development on fabrication and application of a lanthanum (La)-incorporated polyethersulfone (PES)/sulfonated polyphenylenesulfone membrane for phosphorus treatment. The performances of membranes fabricated by the in situ and ex situ methods were examined in a series of batch adsorption and dead-end filtration experiments. The membrane fabricated by the in situ method demonstrated higher adsorption capacity (48.0 mg/g), faster kinetics (equilibrium in 6 h) and higher water permeance (>100 LMH/bar), which outperformed that by the ex situ method. Furthermore, the PES/La (in situ) membrane showed a comparable phosphate removal with a much higher permeance (about 20 times) than the NF90 (a nanofiltration commercial membrane). Moreover, the multiple cycles of filtration study showed that the membrane was reused satisfactorily in treating low-phosphate contaminated water and meeting the stringent phosphate standard limit of 0.15 mg/L. The removal of phosphate by the membranes was attributed to the mechanisms of ion exchange and electrostatic attraction/complexation. The study reported here provides a better approach in fabrication of functionalized membrane for water treatment, such as phosphate removal in either batch adsorption or membrane filtration process.

A patient with ALK-positive lung adenocarcinoma who survived alectinib-refractory postoperative recurrence for 4 years by switching to ceritinib.

Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements are found in ~ 5% of patients with non-small cell lung cancer (NSCLC). Several tyrosine kinase inhibitors (TKIs) have been developed for treatment of so-called ALK-positive NSCLC. In cases of tumor progression during treatment with second-generation ALK-TKIs, such as alectinib, brigatinib, or ceritinib, National Comprehensive Cancer Network guidelines propose a switch to lorlatinib, a third-generation ALK-TKI, or to cytotoxic chemotherapy. However, they do not mention switching to other second-generation ALK-TKIs. Here, we present a rare case of a 53-year-old Japanese woman, who had never smoked, with ALK-positive lung adenocarcinoma who survived alectinib-resistant postoperative recurrence for 4 years by switching to ceritinib. She underwent curative resection for lung adenocarcinoma, but the cancer recurred at the bronchial stump and mediastinal lymph nodes. After platinum-doublet chemotherapy, the patient still had a single growing liver metastasis, but the tumor was found to harbor EML4-ALK rearrangement. Therefore, the patient started to take ALK-TKIs. Alectinib was the second ALK-TKI used to treat this patient. Alectinib shrank the liver metastasis, which was surgically resected. The tumor relapsed again during continued treatment with alectinib, which was switched to ceritinib. Ceritinib was effective for the relapsed tumor and treatment continued well for 4 years. This case report suggests that, in case of tumor progression during treatment with a second-generation ALK-TKI, switching to another second-generation ALK-TKI may be one of the treatment options. Further analyses are warranted to find robust markers to determine which ALK-TKI is best for each patient.

Divanillyl sulfone suppresses NLRP3 inflammasome activation via inducing mitophagy to ameliorate chronic neuropathic pain in mice.

BACKGROUND: Chronic neuropathic pain is a frequent sequel to peripheral nerve injury and maladaptive nervous system function. Divanillyl sulfone (DS), a novel structural derivative of 4,4'-dihydroxydibenzyl sulfoxide from a traditional Chinese medicine Gastrodia elata with anti-nociceptive effects, significantly alleviated neuropathic pain following intrathecal injection. Here, we aimed to investigate the underlying mechanisms of DS against neuropathic pain. METHODS: A chronic constrictive injury (CCI) mouse model of neuropathic pain induced by sciatic nerve ligation was performed to evaluate the effect of DS by measuring the limb withdrawal using Von Frey filament test. Immunofluorescence staining was used to assess the cell localizations and expressions of Iba-1, ASC, NLRP3, and ROS, the formation of autolysosome. The levels of NLRP3-related proteins (caspase-1, NLRP3, and IL-1ß), mitophagy-related proteins (LC3, Beclin-1, and p62), and apoptosis-related proteins (Bcl-XL and Bax) were detected by Western blotting. The apoptosis of BV-2 cell and caspase activity were evaluated by flow cytometry. RESULTS: DS significantly alleviated the neuropathic pain by increasing the mechanical withdrawal threshold and inhibiting the activation of NLRP3 in CCI-induced model mice. Our findings indicated that DS promoted the mitophagy by increasing the LC3II and Beclin 1 and decreasing the levels of p62 protein in BV-2 cell. This is accompanied by the inhibition of NLRP3 activation, which was shown as inhibited the expression of NLRP3 in lysates as well as the secretion of mature caspase-1 p10 and IL-1ß p17 in supernatants in cultured BV-2 microglia. In addition, DS could promote mitophagy-induced improvement of dysfunctional mitochondria by clearing intracellular ROS and restoring mitochondrial membrane potential. CONCLUSION: Together, our findings demonstrated that DS ameliorate chronic neuropathic pain in mice by suppressing NLRP3 inflammasome activation induced by mitophagy in microglia. DS may be a promising therapeutic agent for chronic neuropathic pain.

A Novel Sulfone Derivative Controls Lasiodiplodia theobromae in Tea Leaf Spot by Reducing the Ergosterol Content.

Diseases caused by fungi can affect the quality and yield of the leaves of tea [Camellia sinensis (L.) Kuntze]. At present, the availability of highly effective and safe fungicides for controlling tea plants remains limited. The objectives of this study were to identify novel compounds with antifungal activities and to determine their molecular mechanisms. A series of sulfone compounds containing 1,3,4-oxadiazole were evaluated in China for their antifungal activities against several pathogens causing foliar diseases and high production losses. Transcriptomics and bioinformatics were used to analyze the differentially expressed genes of Lasiodiplodia theobromae treated with a representative compound, jiahuangxianjunzuo (JHXJZ). Moreover, the effects of JHXJZ on ergosterol content, membrane permeability, cell structure, and seven key genes involved in the ergosterol biosynthetic pathway were investigated. JHXJZ had a strong antifungal activity against L. theobromae in vitro, with an effective concentration giving 50% inhibition of 3.54 ± 0.55 µg/ml, and its curative efficacies on detached tea leaves reached 41.78% at 100 µg/ml. JHXJZ upregulated 899 genes (P < 0.05) and downregulated 1,185 genes (P < 0.05) in L. theobromae. These genes were found to be associated with carbohydrate metabolic processes, which are closely related to steroid biosynthesis in the Kyoto Encyclopedia of Genes and Genomes pathways. Because JHXJZ regulates the key genes of sterol biosynthesis, it decreased the ergosterol content, increased cell-membrane permeability, changed the cellular structure, enhanced the roughness of the surface of the hyphae, and resulted in degradation of the hyphal nuclei and necrosis of the hyphal cytoplasm. Our study demonstrates that JHXJZ is a fungicide with a novel mechanism of action that differs from that of triazole fungicides. JHXJZ has potential for applications in controlling tea plant diseases.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.