Asymmetric Synthesis and Biological Evaluation of Platensilin, Platensimycin, Platencin, and Their Analogs via a Bioinspired Skeletal Reconstruction Approach.

Platensilin, platensimycin, and platencin are potent inhibitors of ß-ketoacyl-acyl carrier protein synthase (FabF) in the bacterial and mammalian fatty acid synthesis system, presenting promising drug leads for both antibacterial and antidiabetic therapies. Herein, a bioinspired skeleton reconstruction approach is reported, which enables the unified synthesis of these three natural FabF inhibitors and their skeletally diverse analogs, all stemming from a common ent-pimarane core. The synthesis features a diastereoselective biocatalytic reduction and an intermolecular Diels-Alder reaction to prepare the common ent-pimarane core. From this intermediate, stereoselective Mn-catalyzed hydrogen atom-transfer hydrogenation and subsequent Cu-catalyzed carbenoid C-H insertion afford platensilin. Furthermore, the intramolecular Diels-Alder reaction succeeded by regioselective ring opening of the newly formed cyclopropane enables the construction of the bicyclo[3.2.1]-octane and bicyclo[2.2.2]-octane ring systems of platensimycin and platencin, respectively. This skeletal reconstruction approach of the ent-pimarane core facilitates the preparation of analogs bearing different polycyclic scaffolds. Among these analogs, the previously unexplored cyclopropyl analog 47 exhibits improved antibacterial activity (MIC80 = 0.0625 µg/mL) against S. aureus compared to platensimycin.

Asymmetric total synthesis of polycyclic xanthenes and discovery of a WalK activator active against MRSA.

The development of new antibiotics continues to pose challenges, particularly considering the growing threat of multidrug-resistant Staphylococcus aureus. Structurally diverse natural products provide a promising source of antibiotics. Herein, we outline a concise approach for the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners. The strategy involves rapid assembly of the challenging benzopyrano[2,3-a]xanthene core, highly diastereoselective establishment of three contiguous stereocenters through a retro-hemiketalization/double Michael cascade reaction, and a Mitsunobu-mediated chiral resolution approach with high optical purity and broad substrate scope. Quantum mechanical calculations provide insight into stereoselective construction mechanism of the three contiguous stereocenters. Additionally, this work leads to the discovery of an antibacterial agent against both drug-sensitive and drug-resistant S. aureus. This compound operates through a unique mechanism that promotes bacterial autolysis by activating the two-component sensory histidine kinase WalK. Our research holds potential for future antibacterial drug development.

Schisandrin B inhibits inflammation and ferroptosis in S.aureus-induced mastitis through regulating SIRT1/p53/SLC7A11 signaling pathway.

Mastitis, one of the most significant problems in women, is commonly caused by pathogens, especially Staphylococcus aureus (S.aureus). Schisandrin B (SCB), the main abundant derivatives from Schisandra chinensis, has been proven to have the ability to inhibiting inflammation and bacteria. However, few relevant researches systematically illustrate the role SCB in the treatment of mastitis. The aim of the present study is to demonstrate the mechanism that SCB functions in reducing pathological injury to the mammary gland in treating S.aureus-induced mastitis. H&E staining was used to identify pathological changes and injuries in mastitis. The levels of cytokines associated with inflammation were detected by ELISA. Key signals relevant to ferroptosis and Nrf2 signaling pathway were tested by western blot analysis and iron assay kit. Compared with the control group, inflammation-associated factors, such as IL-1ß, TNF-α, MPO activity, increased significantly in S. aureus-treated mice. However, these changes were inhibited by SCB. Ferroptosis-associated factors Fe2+ and MDA increased significantly, and GSH, GPX4 and ferritin expression decreased markedly in S. aureus-treated mice. SCB treatment could attenuate S.aureus-induced ferroptosis. Furthermore, SCB increase SIRT1 and SLC7A11 expression and down-regulated p53 expression and NF-κB activation. In conclusion, SCB alleviates S.aureus-induced mastitis via up-regulating SIRT1/p53/SLC7A11 signaling pathway, attenuating the activation of inflammation-associated cytokines and ferroptosis in the mammary gland tissues.

Characterizing the effects of Dechlorane Plus on ß-cells: a comparative study across models and species.

Epidemiological studies consistently link environmental toxicant exposure with increased Type 2 diabetes risk. Our study investigated the diabetogenic effects of a widely used flame retardant, Dechlorane Plus (DP), on pancreatic ß-cells using rodent and human model systems. We first examined pancreas tissues from male mice exposed daily to oral gavage of either vehicle (corn oil) or DP (10, 100, or 1000 µg/kg per day) and fed chow or high fat diet for 28-days in vivo. DP exposure did not affect islet size or endocrine cell composition in either diet group. Next, we assessed the effect of 48-hour exposure to vehicle (DMSO) or DP (1, 10, or 100 nM) in vitro using immortalized rat ß-cells (INS-1 832/3), primary mouse and human islets, and human stem-cell derived islet-like cells (SC-islets). In INS-1 832/3 cells, DP did not impact glucose-stimulated insulin secretion (GSIS) but significantly decreased intracellular insulin content. DP had no effect on GSIS in mouse islets or SC-islets but had variable effects on GSIS in human islets depending on the donor. DP alone did not affect insulin content in mouse islets, human islets, or SC-islets, but mouse islets co-exposed to DP and glucolipotoxic (GLT) stress conditions (28.7 mM glucose + 0.5 mM palmitate) had reduced insulin content compared to control conditions. Co-exposure of mouse islets to DP + GLT amplified the upregulation of Slc30a8 compared to GLT alone. Our study highlights the importance and challenges of using different in vitro models for studying chemical toxicity.

Copper-Catalyzed Synthesis of Difluoromethylated/C-4- and C-5-Functionalized Polycyclic Coumarin Derivatives.

A facile and novel synthetic method for the synthesis of functionalized polycyclic coumarins at the C-4 and C-5 positions is proposed for the first time, which employs copper-catalyzed addition reactions of undiscovered alkenes with difluoromethyl radicals to construct polycyclic coumarins. This strategy is characterized by high regioselectivity, easy availability of raw materials, and simple operation. Additionally, such undiscovered coumarin alkenes can be reacted with a variety of difluoromethyl precursors to obtain a wide range of valuable C-4 and C-5 position functionalized/difluoromethylated polycyclic coumarins. More importantly, some of the products showed significant inhibition of proliferation in vitro against melanoma B16-F10 and lung cancer A549 cell lines with optimal IC50 values of 8.57 and 16.04 µM, respectively.

Design, synthesis, in vitro and in vivo evaluation and molecular docking study of novel pleuromutilin derivatives as antibacterial agents.

14 novel pleuromutilin derivatives were designed and synthesized as inhibitors against Staphylococcus aureus (S. aureus). The modification was focused on the C22 position of pleuromutilin. We conducted the characterization, in vitro and in vivo biological assessment of the compounds. Compound 18 exhibited the best antibacterial effect against MRSA (MIC = 0.015 µg/mL, MBC = 0.125 µg/mL). Compound 18 was further studied by time-kill kinetic and post-antibiotic effect (PAE) approaches. Besides, most compounds exhibited low cytotoxicity to RAW 264.7 cells. Compound 18 displayed decent bactericidal activity in vivo (-0.51 log10 CFU/mL). Molecular docking study indicated that compound 18 could be located stably at the ribosome (ΔGb = -7.30 kcal/mol). The results revealed that compound 18 might be further developed into a novel antibiotic.

Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Pleuromutilin Derivatives Containing Thiazole.

In this study, we designed and synthesized a series of pleuromutilin derivatives containing thiazole. The in vitro antimicrobial efficacy of these synthesized compounds was examined by using four strains. Compared with tiamulin (MIC = 0.25 µg/mL), compound 14 exhibited potency in inhibiting MRSA growth (MIC = 0.0625 µg/mL) in these derivatives. Meanwhile, the time-killing kinetics further demonstrated that compound 14 could efficiently inhibit the MRSA growth. After exposure at 4 × MIC, the postantibiotic effect (PAE) of compound 14 was 1.29 h. Additionally, in thigh-infected mice, compound 14 exhibited a more potent antibacterial efficacy (-1.78 ± 0.28 log10 CFU/g) in reducing MRSA load compared to tiamulin (-1.21 ± 0.23 log10 CFU/g). Moreover, the MTT assay on RAW 264.7 cells demonstrated that compound 14 (8 µg/mL) had no significant cytotoxicity. Docking studies indicated the strong affinity of compound 14 toward the 50S ribosomal subunit, with a binding free energy of -9.63 kcal/mol. Taken together, it could be deduced that compound 14 was a promising candidate for treating MRSA infections.

Schisandrin B protect inner hair cells from cisplatin by inhibiting celluar oxidative stress and apoptosis.

Cisplatin is an effective chemotherapeutic agent; however, ototoxicity is one of its negative effects that greatly limits the use of cisplatin in clinical settings. Previous research has shown that the most important process cisplatin damage to inner ear cells, such as hair cells (HCs), is the excessive production and accumulation of ROS. Schisandrin B (SchB), is a low-toxicity, inexpensive, naturally occurring antioxidant with a variety of pharmacological effects. Therefore, the potential antioxidant effects of SchB may be useful for cisplatin ototoxicity treatment. In this study, the effects of SchB on cochlear hair cell viability, ROS levels, and expression of apoptosis-related molecules were evaluated by CCK-8, immunofluorescence, flow cytometry, and qRT-PCR, as well as auditory brainstem response (ABR) and dysmorphic product otoacoustic emission (DPOAE) tests to assess the effects on inner ear function. The results showed that SchB treatment increased cell survival, prevented apoptosis, and reduced cisplatin-induced ROS formation. SchB treatment reduced the loss of cochlear HCs caused by cisplatin in exosome culture. In addition, SchB treatment attenuated cisplatin-induced hearing loss and HC loss in mice. This study demonstrates the ability of SchB to inhibit cochlear hair cell apoptosis and ROS generation and shows its potential therapeutic effect on cisplatin ototoxicity.

Design, synthesis, and antibacterial activity of pleuromutilin derivatives.

This paper reports the design, synthesis, and antibacterial activity study of pleuromutilin derivatives with 2-methyl-4-nitroaniline and 2-methoxy-4-nitroaniline side chains at the C22 position. The structures of the new compounds were characterized by 1H-NMR, 13C-NMR and HRMS. The inhibitory activity of the compounds against MSSA, pyogeniccoccus, streptococcus, and MRSA strains was determined using the micro broth dilution method. The results showed that the compounds exhibited certain activity against Gram-positive bacteria, among which compounds A8a, A8b, A8c, A8d, and A7 demonstrated superior antibacterial activity against MSSA, MRSA, and pyogeniccoccus compared to tiamulin, although the derivatives showed lower antibacterial activity against streptococcus compared to the control drug. Based on the favorable in vitro activity of A8c, the time-kill kinetics against MRSA were evaluated, revealing that compound A8c could inhibit bacterial proliferation in a concentration-dependent manner.

In Vivo Immune-Modulatory Activity of Lefamulin in an Influenza Virus A (H1N1) Infection Model in Mice.

Lefamulin is a first-in-class systemic pleuromutilin antimicrobial and potent inhibitor of bacterial translation, and the most recent novel antimicrobial approved for the treatment of community-acquired pneumonia (CAP). It exhibits potent antibacterial activity against the most prevalent bacterial pathogens that cause typical and atypical pneumonia and other infectious diseases. Early studies indicate additional anti-inflammatory activity. In this study, we further investigated the immune-modulatory activity of lefamulin in the influenza A/H1N1 acute respiratory distress syndrome (ARDS) model in BALB/c mice. Comparators included azithromycin, an anti-inflammatory antimicrobial, and the antiviral oseltamivir. Lefamulin significantly decreased the total immune cell infiltration, specifically the neutrophils, inflammatory monocytes, CD4+ and CD8+ T-cells, NK cells, and B-cells into the lung by Day 6 at both doses tested compared to the untreated vehicle control group (placebo), whereas azithromycin and oseltamivir did not significantly affect the total immune cell counts at the tested dosing regimens. Bronchioalveolar lavage fluid concentrations of pro-inflammatory cytokines and chemokines including TNF-α, IL-6, IL-12p70, IL-17A, IFN-γ, and GM-CSF were significantly reduced, and MCP-1 concentrations were lowered (not significantly) by lefamulin at the clinically relevant 'low' dose on Day 3 when the viral load peaked. Similar effects were also observed for oseltamivir and azithromycin. Lefamulin also decreased the viral load (TCID50) by half a log10 by Day 6 and showed positive effects on the gross lung pathology and survival. Oseltamivir and lefamulin were efficacious in the suppression of the development of influenza-induced bronchi-interstitial pneumonia, whereas azithromycin did not show reduced pathology at the tested treatment regimen. The observed anti-inflammatory and immune-modulatory activity of lefamulin at the tested treatment regimens highlights a promising secondary pharmacological property of lefamulin. While these results require confirmation in a clinical trial, they indicate that lefamulin may provide an immune-modulatory activity beyond its proven potent antibacterial activity. This additional activity may benefit CAP patients and potentially prevent acute lung injury (ALI) and ARDS.

Further Polycyclic Quinones of Micromonospora sp.

The crude acetone extract of a marine Micromonospora sp. strain associated with Eudistoma vannnamei was fractioned with hexane and ethyl acetate. The crude extract and both soluble fractions were assayed against several bacteria strains. The new polycyclic quinones 12-hydroxy-9-propyltetracene-6,1-dione (1), 5,12-dihydroxy-4-methoxy-9-propyltetracene-5,12-dione (2), and 4,6-dihydroxy-3-methoxycarbonyl- methyl-6a-(oxobutyl)-5,12-anthraquinone (3), along with the known 4,6-dihydroxy-3-methoxycarbonyl-methyl-6a-(oxo-3-methyl-butyl)-5,12-anthraquinone (4) and 4,6-dihydroxy-3-methoxycarbonyl-methyl-6a-(oxopentyl)-5,12-anthraquinone (5) were isolated from the hexane-soluble fraction, while from the active ethyl acetate fraction were isolated the known 4,6,11-trihydroxy-9-propyltetracene-5,12-dione (6), 4-methoxy-9-propyltetracene-6,11-dione (7), 7,8,9,10-tetrahydro-9-hydroxy-4-methoxy-9-propyltetracene-6,11-dione (8), and 10ß-carbomethoxy-7,8,9,10-tetrahydro-4,6,7α,9α,11-pentahydroxy-9-propyltetracene-5,12-dione (9). The structures of the new compounds were established by interpretation of HRMS and NMR techniques. A study of molecular docking was performed with the compounds from the active ethyl acetate fraction to correlate tentatively with the antimicrobial activity. Molecular docking, RMSD, RMSF, and MM-GBSA evaluations were performed to investigate the inhibitory activity of 6-8 against the protein PDB-codex 1MWT, being considered a promising target for studying drug development responsible for inhibiting replication of Staphylococcus aureus. Penicillin G was used as the standard inhibitory. Anthracyclinones 6-8 were the best hydrolase inhibitor with affinity energy -8.1 to -7.9 kcal/mol compared to penicillin G, which presented -6.9 kcal/mol. Both 8 and 7 present potent inhibitory effects against hydrolase through molecular dynamics simulation and exhibit favorable drug-like properties, promising new hydrolase blockers to fight bacterial infections from Staphylococcus aureus.

Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells.

The antibiotic heliomycin (resistomycin), which is generated from Streptomyces resistomycificus, has multiple activities, including anticancer effects. Heliomycin was first described in the 1960s, but its clinical applications have been hindered by extremely low solubility. A series of 4-aminomethyl derivatives of heliomycin were synthesized to increase water solubility; studies showed that they had anti-proliferative effects, but the drug targets remained unknown. In this study, we conducted cellular thermal shift assays (CETSA) and molecular docking simulations to identify and validate that heliomycin and its water-soluble derivative, 4-(dimethylaminomethyl)heliomycin (designated compound 4-dmH) engaged and targeted with sirtuin-1 (SIRT1) in p53-functional SAS and p53-mutated HSC-3 oral cancer cells. We further addressed the cellular outcome of SIRT1 inhibition by these compounds and found that, in addition to SIRT1, the water-soluble 4-dmH preferentially targeted a tumor-associated NADH oxidase (tNOX, ENOX2). The direct binding of 4-dmH to tNOX decreased the oxidation of NADH to NAD+ which diminished NAD+-dependent SIRT1 deacetylase activity, ultimately inducing apoptosis and significant cytotoxicity in both cell types, as opposed to the parental heliomycin-induced autophagy. We also observed that tNOX and SIRT1 were both upregulated in tumor tissues of oral cancer patients compared to adjacent normal tissues, suggesting their clinical relevance. Finally, the better therapeutic efficacy of 4-dmH was confirmed in tumor-bearing mice, which showed greater tNOX and SIRT1 downregulation and tumor volume reduction when treated with 4-dmH compared to heliomycin. Taken together, our in vitro and in vivo findings suggest that the multifaceted properties of water-soluble 4-dmH enable it to offer superior antitumor value compared to parental heliomycin, and indicated that it functions through targeting the tNOX-NAD+-SIRT1 axis to induce apoptosis in oral cancer cells.

Effect and mechanism of gomisin D on the isoproterenol induced myocardial injury in H9C2 cells and mice.

We established myocardial injury models in vivo and in vitro to investigate the cardioprotective effect of gomisin D obtained from Schisandra chinensis. Gomisin D significantly inhibited isoproterenol-induced apoptosis and hypertrophy in H9C2 cells. Gomisin D decreased serum BNP, ANP, CK-MB, cTn-T levels and histopathological alterations, and inhibited myocardial hypertrophy in mice. In mechanisms research, gomisin D reversed ISO-induced accumulation of intracellular ROS and Ca2+. Gomisin D further improved mitochondrial energy metabolism disorders by regulating the TCA cycle. These results demonstrated that gomisin D had a significant effect on isoproterenol-induced myocardial injury by inhibiting oxidative stress, calcium overload and improving mitochondrial energy metabolism.

The therapeutic effect of ultrasound targeted destruction of schisandrin A contrast microbubbles on liver cancer and its mechanism.

BACKGROUND: The aim of the study was to explore the therapeutic effect of ultrasound targeted destruction of schisandrin A contrast microbubbles on liver cancer and its related mechanism. MATERIALS AND METHODS: The Span-PEG microbubbles loaded with schisandrin A were prepared using Span60, NaCl, PEG-1500, and schisandrin A. The loading rate of schisandrin A in Span-PEG composite microbubbles was determined by ultraviolet spectrophotometry method. The Walker-256 cell survival rate of schisandrin A was determined by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay. The content of schisandrin A in the cells was determined by high performance liquid chromatography. Ultrasound imaging was used to evaluate the therapeutic effect in situ. Enzyme linked immunosorbent assay (ELISA) was used to measure the content of inflammatory factors in serum. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of experimental animals in each group. Immunohistochemistry was used to detect the expression of hypoxia inducible factor-1α (HIF-1α), vascular endothlial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR-2) in tumor tissues, and western blot was used to detect the protein expression of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway in tumor tissues. RESULTS: The composite microbubbles were uniform in size, and the particle size distribution was unimodal and stable, which met the requirements of ultrasound contrast agents. The loading rate of schisandrin A in Span-PEG microbubbles was 8.84 ± 0.14%, the encapsulation efficiency was 82.24±1.21%. The IC50 value of schisandrin A was 2.87 µg/mL. The drug + microbubbles + ultrasound (D+M+U) group had the most obvious inhibitory effect on Walker-256 cancer cells, the highest intracellular drug concentration, the largest reduction in tumor volume, the most obvious reduction in serum inflammatory factors, and the most obvious improvement in pathological results. The results of immunohistochemistry showed that HIF-1α, VEGF and VEGFR-2 protein decreased most significantly in D+M+U group (P < 0.01). WB results showed that D+M+U group inhibited the PI3K/AKT/mTOR signaling pathway most significantly (P < 0.01). CONCLUSIONS: Schisandrin A had an anti-tumor effect, and its mechanism might be related to the inhibition of the PI3K/AKT/mTOR signaling pathway. The schisandrin A microbubbles could promote the intake of schisandrin A in tumor cells after being destroyed at the site of tumor under ultrasound irradiation, thus playing the best anti-tumor effect.

Polycyclic aromatic compounds (PACs) in industrial soils from northwestern of China: occurrence, distribution, exposure risk, and implications on risk-based controls.

Some Polycyclic Aromatic Compounds (PACs) such as nitrated-PAHs (NPAHs), oxygenated-PAHs (OPAHs) and methyl-PAHs (MPAHs) have attracted significant concern due to derivatives have greater potential to be more toxic at low environmental concentrations compared to their PPAHs, particularly in petrochemical industrial region and its surrounding areas surface soils in China. Hence, this article provides an insight into the fate, sources, impacts, and relevance to the external environment of PAH-derivatives based on important emissions source. Moreover, prospective health risk due to their exposure has also been discussed. In this study, the concentration (10-3 ng/g) of Æ©18PPAHs, Æ©11MPAHs, Æ©12NPAHs, and Æ©4OPAHs in the park were 9.67 ± 1.40, 3.24 ± 0.54, 0.03 ± 0.02 and 0.19 ± 0.65, respectively, which were 4.47, 3.89, 2.04 and 1.17 times than of them surrounding the region. A decreasing trend of the low molecular weight (2-4Rings) contribution to the total amount of PAHs, while the fraction of high molecular weight (5-6Rings) species showed the opposite trend. According to the principal component analysis (PCA) and diagnostic ratios indicated PAHs in the soil samples have mixed sources from industrial activities, solid fuel combustion, and heavy traffic. Despite the high concentrations of MPAHs and OPAHs, the toxicity equivalency quotients (TEQs) of them were not calculated due to the lack of toxic equivalent factors (TEF), thus current studies on PAH and derivatives could have underestimated their exposure risks. The quality and sustainable management of soils are crucial for human health and sustainable development, while there is lack of public awareness of the severe issue of soil pollution. It is recommended to conduct more intensive monitoring and regional assessments in the future.

Recent advances in developing modified C14 side chain pleuromutilins as novel antibacterial agents.

Owing to the increasing resistance to most existing antimicrobial drugs, research has shifted towards developing novel antimicrobial agents with mechanisms of action distinct from those of current clinical options. Pleuromutilins are antibiotics known for their distinct mechanism of action, inhibiting bacterial protein synthesis by binding to the peptidyl transferase center of the ribosome. Recent studies have revealed that pleuromutilin derivatives can disrupt bacterial cell membranes, thereby enhancing antibacterial efficacy. Both marketed pleuromutilin derivatives and those in clinical trials have been developed by structurally modifying the pleuromutilin C14 side chain to improve their antimicrobial activity. Therefore, this review aims to review advancement in the chemical structural characteristics, antibacterial activities, and structure-activity relationship studies of pleuromutilins, specifically focusing on modifications made to the C14 side chain in recent years. These findings provide a valuable reference for future research and development of pleuromutilins.

Dibenzocyclooctadiene Lignans from Schisandra chinensis with Anti-Inflammatory Effects.

Schisandra chinensis (Schisandraceae) is a medicinal plant widely used in traditional Chinese medicine. Under the name Wu Wei Zi, it is used to treat many diseases, especially as a stimulant, adaptogen, and hepatoprotective. Dibenzocyclooctadiene lignans are the main compounds responsible for the effect of S. chinensis. As a part of ongoing studies to identify and evaluate anti-inflammatory natural compounds, we isolated a series of dibenzocyclooctadiene lignans and evaluated their biological activity. Furthermore, we isolated new sesquiterpene 7,7-dimethyl-11-methylidenespiro[5.5]undec-2-ene-3-carboxylic acid. Selected dibenzocyclooctadiene lignans were tested to assess their anti-inflammatory potential in LPS-stimulated monocytes by monitoring their anti-NF-κB activity, antioxidant activity in CAA assay, and their effect on gap junction intercellular communication in WB-ras cells. Some S. chinensis lignans showed antioxidant activity in CAA mode and affected the gap junction intercellular communication. The anti-inflammatory activity was proven for (-)-gomisin N, (+)-γ-schisandrin, rubrisandrin A, and (-)-gomisin J.

Schisandrin B enhances embryo competence and potentially mitigates endoplasmic reticulum stress during porcine preimplantation development.

Endoplasmic reticulum (ER) stress induced by agents such as tunicamycin (TM) substantially impedes the developmental progression of porcine embryos. Lignan compounds such as Schisandrin B (Sch-B), may have the potential to mitigate this stress. However, there are few studies on the effects of Sch-B on embryo development. To address this research gap, this study evaluates the protective efficacy of Sch-B against TM-induced ER stress during pivotal stages of porcine embryogenesis. Notably, embryos treated with Sch-B exhibited pronounced resistance to TM-induced developmental arrest, particularly at the 4-cell stage, facilitating progression to the 8-cell stage and subsequent blastocyst formation. It was also observed that Sch-B effectively reduced reactive oxygen species (ROS) levels and improved mitochondrial membrane potential (MMP). Furthermore, Sch-B positively influenced the expression of several stress-related genes. These findings highlight the promising role of Sch-B in improving porcine embryo development and mitigating ER stress.

Schisandrin B from Schisandra chinensis alleviated pain via glycine receptors, Nav1.7 channels and Cav2.2 channels.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis, the dried and ripe fruit of the magnolia family plant Schisandra chinensis (Turcz.) Baill, was commonly used in traditional analgesic prescription. Studies have shown that the extract of Schisandra chinensis (SC) displayed analgesic activity. However, the analgesic active component and the exact mechanisms have yet to be revealed. AIM OF THE STUDY: The present study was to investigate the anti-nociceptive constituent of Schisandra chinensis, assess its analgesic effect, and explore the potential molecular mechanisms. MATERIALS AND METHODS: The effects of a series of well-recognized compounds from SC on glycine receptors were investigated. The analgesic effect of the identified compound was evaluated in three pain models. Mechanistic studies were performed using patch clamp technique on various targets expressed in recombinant cells. These targets included glycine receptors, Nav1.7 sodium channels, Cav2.2 calcium channels et al. Meanwhile, primary cultured spinal dorsal horn (SDH) neurons and dorsal root ganglion (DRG) neurons were also utilized. RESULTS: Schisandrin B (SchB) was a positive allosteric modulator of glycine receptors in spinal dorsal horn neurons. The EC50 of SchB on glycine receptors in spinal dorsal horn neurons was 2.94 ± 0.28 µM. In three pain models, the analgesic effect of SchB was comparable to that of indomethacin at the same dose. Besides, SchB rescued PGE2-induced suppression of α3 GlyR activity and alleviated persistent pain. Notably, SchB could also potently decrease the frequency of action potentials and inhibit sodium and calcium channels in DRG neurons. Consistent with the data from DRG neurons, SchB was also found to significantly block Nav1.7 sodium channels and Cav2.2 channels in recombinant cells. CONCLUSION: Our results demonstrated that, Schisandrin B, the primary lignan component of Schisandra chinensis, may exert its analgesic effect by acting on multiple ion channels, including glycine receptors, Nav1.7 channels, and Cav2.2 channels.

Molecular Simulation of SO2 Separation and Storage Using a Cryptophane-Based Porous Liquid.

A theoretical molecular simulation study of the encapsulation of gaseous SO2 at different temperature conditions in a type II porous liquid is presented here. The system is composed of cage cryptophane-111 molecules that are dispersed in dichloromethane, and it is described using an atomistic modelling of molecular dynamics. Gaseous SO2 tended to almost fully occupy cryptophane-111 cavities throughout the simulation. Calculations were performed at 300 K and 283 K, and some insights into the different adsorption found in each case were obtained. Simulations with different system sizes were also studied. An experimental-like approach was also employed by inserting a SO2 bubble in the simulation box. Finally, an evaluation of the radial distribution function of cryptophane-111 and gaseous SO2 was also performed. From the results obtained, the feasibility of a renewable separation and storage method for SO2 using porous liquids is mentioned.