Albiflorin ameliorates thioacetamide-induced hepatic fibrosis: The involvement of NURR1-mediated inflammatory signaling cascades in hepatic stellate cells activation.

Thioacetamide (TAA) within the liver generates hepatotoxic metabolites that can be induce hepatic fibrosis, similar to the clinical pathological features of chronic human liver disease. The potential protective effect of Albiflorin (ALB), a monoterpenoid glycoside found in Paeonia lactiflora Pall, against hepatic fibrosis was investigated. The mouse hepatic fibrosis model was induced with an intraperitoneal injection of TAA. Hepatic stellate cells (HSCs) were subjected to treatment with transforming growth factor-beta (TGF-ß), while lipopolysaccharide/adenosine triphosphate (LPS/ATP) was added to stimulate mouse peritoneal macrophages (MPMs), leading to the acquisition of conditioned medium. For TAA-treated mice, ALB reduced ALT, AST, HYP levels in serum or liver. The administration of ALB reduced histopathological abnormalities, and significantly regulated the expressions of nuclear receptor-related 1 protein (NURR1) and the P2X purinoceptor 7 receptor (P2×7r) in liver. ALB could suppress HSCs epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, and pro-inflammatory factor level. ALB also remarkably up-regulated NURR1, inhibited P2×7r signaling pathway, and worked as working as C-DIM12, a NURR1 agonist. Moreover, deficiency of NURR1 in activated HSCs and Kupffer cells weakened the regulatory effect of ALB on P2×7r inhibition. NURR1-mediated inhibition of inflammatory contributed to the regulation of ALB ameliorates TAA-induced hepatic fibrosis, especially based on involving in the crosstalk of HSCs-macrophage. Therefore, ALB plays a significant part in the mitigation of TAA-induced hepatotoxicity this highlights the potential of ALB as a protective intervention for hepatic fibrosis.

Metabolic Investigation and Auxiliary Enzyme Modelization of the Pyrrocidine Pathway Allow Rationalization of Paracyclophane-Decahydrofluorene Formation.

Fungal paracyclophane-decahydrofluorene-containing natural products are complex polycyclic metabolites derived from similar hybrid PKS-NRPS pathways. Herein we studied the biosynthesis of pyrrocidines, one representative of this family, by gene inactivation in the producer Sarocladium zeae coupled to thorough metabolic analysis and molecular modeling of key enzymes. We characterized nine pyrrocidines and analogues as well as in mutants a variety of accumulating metabolites with new structures including rare cis-decalin, cytochalasan, and fused 6/15/5 macrocycles. This diversity highlights the extraordinary plasticity of the pyrrocidine biosynthetic gene cluster. From accumulating metabolites, we delineated the scenario of pyrrocidine biosynthesis. The ring A of the decahydrofluorene is installed by PrcB, a membrane-bound cyclizing isomerase, on a PKS-NRPS-derived pyrrolidone precursor. Docking experiments in PrcB allowed us to characterize the active site suggesting a mechanism triggered by arginine-mediated deprotonation at the terminal methyl of the substrate. Next, two integral membrane proteins, PrcD and PrcE, each predicted as a four-helix bundle, perform hydroxylation of the pyrrolidone ring and paracyclophane formation, respectively. Modelization of PrcE highlights a topological homology with vitamin K oxido-reductase and the presence of a disulfide bond. Our results suggest a previously unsuspected coupling mechanism via a transient loss of aromaticity of tyrosine residue to form the strained paracyclophane motif. Finally, the lipocalin-like protein PrcX drives the exo-cycloaddition yielding ring B and C of the decahydrofluorene to afford pyrrocidine A, which is transformed by a reductase PrcI to form pyrrocidine B. These insights will greatly facilitate the microbial production of pyrrocidine analogues by synthetic biology.

TRF2 as novel marker of tumor response to taxane-based therapy: from mechanistic insight to clinical implication.

BACKGROUND: Breast Cancer (BC) can be classified, due to its heterogeneity, into multiple subtypes that differ for prognosis and clinical management. Notably, triple negative breast cancer (TNBC) - the most aggressive BC form - is refractory to endocrine and most of the target therapies. In this view, taxane-based therapy still represents the elective strategy for the treatment of this tumor. However, due variability in patients' response, management of TNBC still represents an unmet medical need. Telomeric Binding Factor 2 (TRF2), a key regulator of telomere integrity that is over-expressed in several tumors, including TNBC, has been recently found to plays a role in regulating autophagy, a degradative process that is involved in drug detoxification. Based on these considerations, we pointed, here, at investigating if TRF2, regulating autophagy, can affect tumor sensitivity to therapy. METHODS: Human TNBC cell lines, over-expressing or not TRF2, were subjected to treatment with different taxanes and drug efficacy was tested in terms of autophagic response and cell proliferation. Autophagy was evaluated first biochemically, by measuring the levels of LC3, and then by immunofluorescence analysis of LC3-puncta positive cells. Concerning the proliferation, cells were subjected to colony formation assays associated with western blot and FACS analyses. The obtained results were then confirmed also in mouse models. Finally, the clinical relevance of our findings was established by retrospective analysis on a cohort of TNBC patients subjected to taxane-based neoadjuvant chemotherapy. RESULTS: This study demonstrated that TRF2, inhibiting autophagy, is able to increase the sensitivity of TNBC cells to taxanes. The data, first obtained in in vitro models, were then recapitulated in preclinical mouse models and in a cohort of TNBC patients, definitively demonstrating that TRF2 over-expression enhances the efficacy of taxane-based neoadjuvant therapy in reducing tumor growth and its recurrence upon surgical intervention. CONCLUSIONS: Based on our finding it is possible to conclude that TRF2, already known for its role in promoting tumor formation and progression, might represents an Achilles' heel for cancer. In this view, TRF2 might be exploited as a putative biomarker to predict the response of TNBC patients to taxane-based neoadjuvant chemotherapy.

An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance.

We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory-calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Lastly, we report two additional x-ray crystal structures of CRM in complex with bacterial ribosomes separately modified by the ribosomal RNA methylases, chloramphenicol-florfenicol resistance (Cfr) and erythromycin-resistance ribosomal RNA methylase (Erm), revealing concessive adjustments by the target and antibiotic that permit CRM to maintain binding where other antibiotics fail.

Effects of albiflorin on oxidative stress and inflammatory responses in rats with acute spinal cord injury.

INTRODUCTION: Oxidative stress and inflammatory responses are often the predominant detrimental factors associated with spinal cord injury (SCI). This study investigates the potential therapeutic effects of albiflorin (AF) on alleviating inflammation and oxidative stress in the rat model with SCI. METHODS: Initially, the behavior of SCI-induced rats is examined by Basso-Beattie-Bresnahan score and the inclined plane examination. Then, the immunohistochemical staining of inflammasome-related protein (for instance, NACHT, LRR, and PYD domains-containing protein 3, NLRP3) is performed in combination with enzyme-linked immunosorbent assay (ELISA) of corresponding proinflammatory factors to assess the immunomodulatory effects of AF. Further, the markers involved in oxidative stress are examined by ELISA and western blot analysis analyses. RESULTS: These findings indicated that AF could alleviate motor dysfunction and the loss of neuron cells in SCI-induced rats. Mechanistically, AF could attenuate the inflammatory responses by reducing oxidative stress and activating nuclear erythroid-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in SCI rats. Depleting the antioxidant capacity by inhibiting glutathione biosynthesis could counteract the anti-inflammatory activity of AF in SCI rats. CONCLUSIONS: Together, our data suggested that AF could serve as a potential therapeutic agent against the aggravation of SCI in rats.

Reduction of nicotine and ethanol intake in alcohol-preferring (UChB) female rats by the α4ß2 nicotinic acetylcholine receptor partial agonists 5-bromocytisine and cytisine.

RATIONALE: Neuronal nicotinic acetylcholine receptors (nAChRs) are implicated in the reinforcing effects of nicotine and ethanol. Previous studies have shown that cytisine and its 5-bromo derivative are partial agonists at the α4ß2 nAChRs and that the parent molecule cytisine is effective in reducing both nicotine- and ethanol-self-administration in rats. However, whether 5-bromocytisine affects nicotine or ethanol self-administration was unknown. OBJECTIVES: The present study compared the effects of 5-bromocytisine and cytisine on nicotine self-administration and further assessed the effect of daily drug injection on voluntary ethanol consumption in alcohol-preferring female rats. Animals were administered a 1.5mg/kg i.p. dose of 5-bromocytisine or cytisine every day for 15-16 days. RESULTS: The initial efficacy of 5-bromocytisine and cytisine in reducing nicotine intake was similar (-80%) while for voluntary ethanol intake 5-bromocytisine was a superior inhibitor over cytisine (-78% and -40% respectively). The efficacy of cytisine began to diminish after 10 days of daily administration, which was attributed to tolerance development to its inhibitory effects both on nicotine and ethanol self-administration. Tolerance did not develop for 5-bromocytisine. CONCLUSION: 5-Bromocytisine, a weaker α4ß2 nAChR partial agonist than cytisine, also produces a sustained inhibition of both nicotine and ethanol self-administration, and unlike cytisine, it does not develop tolerance.

Modulation of the Fibrillation Kinetics and Morphology of a Therapeutic Peptide by Cucurbit[7]uril.

Fibrillation is a challenge commonly encountered in the formulation and development of therapeutic peptides. Cucurbit[7]urils (CB[7]), a group of water soluble macrocycles, have been reported to suppress fibrillation in insulin and human calcitonin through association with Phe and Tyr residues which drive fibril formation. Here, we report the effect of CB[7] on the fibrillation behavior of the HIV fusion inhibitor enfuvirtide (ENF) that contains N-terminal Tyr and C-terminal Phe residues. Thioflavin T fluorescence, CD spectroscopy, and transmission electron microscopy were used to monitor fibrillation behavior. Fibrillation onset showed a strong pH dependency, with pH 6.5 identified as the condition most suitable to monitor the effects of CB[7]. Binding of CB[7] to wild-type ENF was measured by isothermal titration calorimetry and was consistent with a single site (Ka = 2.4 × 105 M-1). A weaker interaction (Ka = 2.8 × 103 M-1) was observed for an ENF mutant with the C-terminal Phe substituted for Ala (ENFm), suggesting that Phe was the specific site for CB[7] recognition. The onset of ENF fibrillation onset was delayed, rather than fully suppressed, in the presence of CB[7]. The ENFm mutant showed a greater delay in fibrillation onset but with no observable effect on fibrillation kinetics in the presence of CB[7]. Interestingly, ENF/CB[7] and ENFm fibrils exhibited comparable morphologies, differing from those observed for ENF alone. The results indicate that CB[7] is capable of modulating fibrillation onset and the resulting ENF fibrils by specifically binding to the C-terminal Phe residue. The work reinforces the potential of CB[7] as an inhibitor of fibrillation and highlights its role in determining fibril morphologies.

Preparation and In Vitro Validation of a Cucurbit[7]uril-Peptide Conjugate Targeting the LDL Receptor.

Here we report the coupling of a cyclic peptide (VH4127) targeting the low density lipoprotein (LDL) receptor (LDLR) noncompetitively to cucurbit[7]uril (CB[7]) to develop a new kind of drug delivery system (DDS), namely, CB[7]-VH4127, with maintained binding affinity to the LDLR. To evaluate the uptake potential of this bismacrocyclic compound, another conjugate was prepared comprising a high-affinity group for CB[7] (adamantyl(Ada)-amine) coupled to the fluorescent tracker Alexa680 (A680). The resulting A680-Ada·CB[7]-VH4127 supramolecular complex demonstrated conserved LDLR-binding potential and improved LDLR-mediated endocytosis and intracellular accumulation potential in LDLR-expressing cells. The combination of two technologies, namely, monofunctionalized CB[7] and the VH4127 LDLR-targeting peptide, opens new avenues in terms of targeting and intracellular delivery to LDLR-expressing tissues or tumors. The versatile transport capacity of CB[7], known to bind a large spectrum of bioactive or functional compounds, makes this new DDS suitable for a wide range of therapeutic or imaging applications.

First Approval of Pacritinib as a Selective Janus Associated Kinase-2 Inhibitor for the Treatment of Patients with Myelofibrosis.

Myelofibrosis is one kind of bone marrow blood cancer that gives mainly bone marrow scarring. JAK families include JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) and they control hematopoiesis and immune cell function. JAK-STAT pathways have the critical roles in the pathogenesis of a variety of autoimmune and inflammatory diseases such as myelofibrosis. The 8 JAK inhibitors are approved by the US FDA for the treatment of various diseases. Abrocitinib, baricitinib, oclacitinib, ruxolitinib, tofacitinib, upadacitinib, fedratinib, and pactrinib with their IC50 values against JAK1, JAK2, JAK3, and TYK2 are included. All approved JAK inhibitors with structural similarities and dissimilarities are summarized. The development story of pacritinib and new design route to overcome intellectual property-related issues by connecting the A ring and C ring to form the macrocyclic compounds like 16 without compromising the binding modes in the hinge region are discussed. By using the powerful ring-closing metathesis (RCM), they designed and synthesized and delivered FDA approved pacritinib. In this short perspective, the chemical structure, physicochemical properties, mechanism of action, drug-interactions, adverse events, and pharmacokinetic profile of pacritinib are summarized. Detailed step by step synthesis of pacritinib is provided. Pacritinib is an orally bioavailable and isoform selective JAK-2 inhibitor for the treatment of patients with myelofibrosis. Detailed metabolism pathway with proper explanation is discussed.

Stability and pKa Modulation of Aminophenoxazinones and Their Disulfide Mimics by Host-Guest Interaction with Cucurbit[7]uril. Direct Applications in Agrochemical Wheat Models.

Aqueous solubility and stability often limit the application of aminophenoxazinones and their sulfur mimics as promising agrochemicals in a sustainable agriculture inspired by allelopathy. This paper presents a solution to the problem using host-guest complexation with cucurbiturils (CBn). Computational studies show that CB7 is the most suitably sized homologue due to its strong affinity for guest molecules and its high water solubility. Complex formation has been studied by direct titrations monitored using UV-vis spectroscopy, finding a preferential interaction with protonated aminophenoxazinone species with high binding affinities (CB7·APOH+, Ka = (1.85 ± 0.37) × 106 M-1; CB7·DiS-NH3+, Ka = (3.91 ± 0.53) × 104 M-1; and DiS-(NH3+)2, Ka= (1.27 ± 0.42) × 105 M-1). NMR characterization and stability analysis were also performed and revealed an interesting pKa modulation and stabilization by cucurbiturils (2-amino-3H-phenoxazin-3-one (APO), pKa = 2.94 ± 0.30, and CB7·APO, pKa = 4.12 ± 0.15; 2,2'-disulfanediyldianiline (DiS-NH2), pKa = 2.14 ± 0.09, and CB7·DiS-NH2, pKa = 3.26 ± 0.09), thus favoring applications in different kinds of crop soils. Kinetic studies have demonstrated the stability of the CB7·APO complex at different pH media for more than 90 min. An in vitro bioassay with etiolated wheat coleoptiles showed that the bioactivity of APO and DiS-NH2 is enhanced upon complexation.

Janus kinase 2 inhibition by pacritinib as potential therapeutic target for liver fibrosis.

BACKGROUND AND AIMS: Janus kinase 2 (JAK2) signaling is increased in human and experimental liver fibrosis with portal hypertension. JAK2 inhibitors, such as pacritinib, are already in advanced clinical development for other indications and might also be effective in liver fibrosis. Here, we investigated the antifibrotic role of the JAK2 inhibitor pacritinib on activated hepatic stellate cells (HSCs) in vitro and in two animal models of liver fibrosis in vivo . APPROACH AND RESULTS: Transcriptome analyses of JAK2 in human livers and other targets of pacritinib have been shown to correlate with profibrotic factors. Although transcription of JAK2 correlated significantly with type I collagen expression and other profibrotic genes, no correlation was observed for interleukin-1 receptor-associated kinase and colony-stimulating factor 1 receptor. Pacritinib decreased gene expression of fibrosis markers in mouse primary and human-derived HSCs in vitro . Moreover, pacritinib decreased the proliferation, contraction, and migration of HSCs. C 57 BL/6J mice received ethanol in drinking water (16%) or Western diet in combination with carbon tetrachloride intoxication for 7 weeks to induce alcoholic or nonalcoholic fatty liver disease. Pacritinib significantly reduced liver fibrosis assessed by gene expression and Sirius red staining, as well as HSC activation assessed by alpha-smooth muscle actin immunostaining in fibrotic mice. Furthermore, pacritinib decreased the gene expression of hepatic steatosis markers in experimental alcoholic liver disease. Additionally, pacritinib protected against liver injury as assessed by aminotransferase levels. CONCLUSIONS: This study demonstrates that the JAK2 inhibitor pacritinib may be promising for the treatment of alcoholic and nonalcoholic liver fibrosis and may be therefore relevant for human pathology.

Strategies for the drug discovery and development of taxane anticancer therapeutics.

INTRODUCTION: Paclitaxel and docetaxel have been extensively used in the clinic over the past three decades. Although the patents of these first-generation taxanes have expired, their clinical applications, particularly new formulations and combination therapies, are under active investigations. Inspired by the notable success of Abraxane and Lipusu, new formulations have been extensively developed. In parallel, to overcome multidrug resistance (MDR) and to eradicate cancer stem cells, immense efforts have been made on the discovery and development of new-generation taxanes with improved potency and superior pharmacological properties. AREAS COVERED: This review covers (a) natural sources of advanced intermediates used for semi-synthesis of taxane API, (b) new formulations, (c) the major issues of FDA approved taxanes, (d) the design and development of next-generation taxanes, (e) new mechanisms of action, and (f) a variety of taxane-based drug delivery systems. EXPERT OPINION: As the highly potent next-generation taxanes can eradicate cancer stem cells and overcome MDR, the priority is to develop these compounds as an integral part of cancer therapy, especially for pancreatic, colon and prostate cancers which hardly respond to checkpoint inhibitors. In order to mitigate undesirable side effects, the exploration of effective nanoformulations and tumor-targeted drug delivery systems are essential.

Broad-Spectrum Extracellular Antiviral Properties of Cucurbit[n]urils.

Viruses are microscopic pathogens capable of causing disease and are responsible for a range of human mortalities and morbidities worldwide. They can be rendered harmless or destroyed with a range of antiviral chemical compounds. Cucurbit[n]urils (CB[n]s) are a family of macrocycle chemical compounds existing as a range of homologues; due to their structure, they can bind to biological materials, acting as supramolecular "hosts" to "guests", such as amino acids. Due to the increasing need for a nontoxic antiviral compound, we investigated whether cucurbit[n]urils could act in an antiviral manner. We have found that certain cucurbit[n]uril homologues do indeed have an antiviral effect against a range of viruses, including herpes simplex virus 2 (HSV-2), respiratory syncytial virus (RSV) and SARS-CoV-2. In particular, we demonstrate that CB[7] is the active homologue of CB[n], having an antiviral effect against enveloped and nonenveloped species. High levels of efficacy were observed with 5 min contact times across different viruses. We also demonstrate that CB[7] acts with an extracellular virucidal mode of action via host-guest supramolecular interactions between viral surface proteins and the CB[n] cavity, rather than via cell internalization or a virustatic mechanism. This finding demonstrates that CB[7] acts as a supramolecular virucidal antiviral (a mechanism distinct from other current extracellular antivirals), demonstrating the potential of supramolecular interactions for future antiviral disinfectants.

Cucurbit[7]uril Inhibits Islet Amyloid Polypeptide Aggregation by Targeting N†Terminus Hot Segments and Attenuates Cytotoxicity.

Invited for the cover of this issue is the group of Prof. Hamilton at New York University. The image depicts how cucurbit[7]uril inhibits islet amyloid polypeptide self-assembly that rescues rat insulinoma cells (a pancreatic ß-cell model) from assembly-associated cytotoxicity. Read the full text of the article at 10.1002/chem.202200456.

Antimicrobial Mechanisms of Enterocin CHQS Against Candida albicans.

Candida albicans is the most common fungal pathogen in hospital-acquired infections, which is extremely harmful to health. The increasing fungal infections is requiring the rapid development of novel antifungal agents. In this study, the antimicrobial activity of CHQS, an enterocin isolated from Enterococcus faecalis TG2 against C. albicans was confirmed by the minimum inhibitory concentration, minimum fungicidal concentration, and time-kill curve. Aniline blue and calcofluor white staining methods showed that CHQS remarkably affected ß-1,3-glucan and chitin cell wall components and made cell wall more vulnerable. The C. albicans cell wall rupture and intracellular vacuolation were observed by TEM and SEM. Moreover, CHQS induced the accumulation of intracellular reactive oxygen species and decreased mitochondrial membrane potential. These results suggested that CHQS might have a complex multi-target antimicrobial mechanism against C. albicans. In addition, the use of CHQS combined with amphotericin B showed synergistic antimicrobial effects against C. albicans. In conclusion, enterocin CHQS, a natural product with antimicrobial effect, might has a bright future for the development of new antifungal drugs.

Pacritinib: First Approval.

Pacritinib (VONJO™) is an orally administered, small molecule kinase inhibitor being developed by CTI BioPharma for the treatment of myelofibrosis and graft-versus-host disease. Pacritinib received its first approval in February 2022 in the USA for the treatment of adults with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. The accelerated approval was based on results from the randomized, active-controlled, phase III PERSIST-2 trial, in which spleen volume reduction was demonstrated in pacritinib recipients. This article summarizes the milestones in the development of pacritinib leading to this first approval for myelofibrosis.

FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer.

Elevated expression of non-receptor tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/triple-negative breast cancer (TNBC) patients. Here, we show that high FER levels are also associated with improved outcomes after adjuvant taxane-based combination chemotherapy in high-risk, HER2-negative patients. In TNBC cells, we observe a causal relation between high FER levels and sensitivity to taxanes. Proteomics and mechanistic studies demonstrate that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identify DCTN2 as a FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for the development of tubular recycling domains in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for the benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients.

[Pharmacokinetic behavior and brain tissue distribution of paeoniflorin combined with normal and toxic doses of strychnine in rats after percutaneous administration].

This study aims to establish a rapid and sensitive UPLC-MS/MS method for simultaneously determining the content of strychnine and paeoniflorin in plasma and brain tissue of rats, and compare the pharmacokinetic behavior and brain tissue distribution of paeoniflorin combined with normal and toxic doses of strychnine in rats after percutaneous administration. Compared with those in the toxic-dose strychnine group, the AUC_(0-t), AUC_(0-∞), and C_(max) of strychnine decreased by 51.51%, 45.68%, and 46.03%, respectively(P<0.01), and the corresponding values of paeoniflorin increased by 91.41%, 102.31%, and 169.32%, respectively(P<0.01), in the compatibility group. Compared with the normal-dose strychnine group, the compatibility group showed insignificantly decreased C_(max), AUC_(0-t), and AUC_(0-∞) of strychnine, increased C_(max) and T_(max) of paeoniflorin(P<0.01), 66.88% increase in AUC_(0-t), and 70.55% increase in AUC_(0-∞) of paeoniflorin. In addition, the brain tissue concentration of strychnine decreased and that of paeoniflorin increased after compatibility. The combination of paeoniflorin with normal dose and toxic dose of strychnine can inhibit the percutaneous absorption of strychnine, and greatly promote the percutaneous penetration of paeoniflorin, whereas the interaction mechanism remains to be explored. The UPLC-MS/MS method established in this study is easy to operate and has good precision. It is suitable for in vivo study of pharmacokinetic behavior and brain tissue distribution of paeoniflorin and strychnine after percutaneous administration in rats, which provides reference for the safe and rational clinical use of strychnine and the combined use of drugs, and lays a solid foundation for the development of external preparations containing Strychni Semen.

Tricyclodecan-9-yl-Xanthogenate (D609): Mechanism of Action and Pharmacological Applications.

Tricyclodecan-9-yl xanthogenate (D609) is a synthetic tricyclic compound possessing a xanthate group. This xanthogenate compound is known for its diverse pharmacological properties. Over the last three decades, many studies have reported the biological activities of D609, including antioxidant, antiapoptotic, anticholinergic, anti-tumor, anti-inflammatory, anti-viral, anti-proliferative, and neuroprotective activities. Its mechanism of action is extensively attributed to its ability to cause the competitive inhibition of phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) and sphingomyelin synthase (SMS). The inhibition of PCPLC or SMS affects secondary messengers with a lipidic nature, i.e., 1,2-diacylglycerol (DAG) and ceramide. Various in vitro/in vivo studies suggest that PCPLC and SMS inhibition regulate the cell cycle, block cellular proliferation, and induce differentiation. D609 acts as a pro-inflammatory cytokine antagonist and diminishes Aß-stimulated toxicity. PCPLC enzymatic activity essentially requires Zn2+, and D609 might act as a potential chelator of Zn2+, thereby blocking PCPLC enzymatic activity. D609 also demonstrates promising results in reducing atherosclerotic plaque formation, post-stroke cerebral infarction, and cancer progression. The present compilation provides a comprehensive mechanistic insight into D609, including its chemistry, mechanism of action, and regulation of various pharmacological activities.

Molecular tweezers - a new class of potent broad-spectrum antivirals against enveloped viruses.

A new supramolecular approach to broad spectrum antivirals utilizes host guest chemistry between molecular tweezers and lysine/arginine as well as choline. Basic amino acids in amyloid-forming SEVI peptides (semen-derived enhancers of viral infection) are included inside the tweezer cavity leading to disaggregation and neutralization of the fibrils, which lose their ability to enhance HIV-1/HIV-2 infection. Lipid head groups contain the trimethylammonium cation of choline; this is likewise bound by molecular tweezers, which dock onto viral membranes and thus greatly enhance their surface tension. Disruption of the envelope in turn leads to total loss of infectiosity (ZIKA, Ebola, Influenza). This complexation event also seems to be the structural basis for an effective inihibition of cell-to-cell spread in Herpes viruses. The article describes the discovery of novel molecular recognition motifs and the development of powerful antiviral agents based on these host guest systems. It explains the general underlying mechanisms of antiviral action and points to future optimization and application as therapeutic agents.