Polyphosphoric Acid-Promoted Efficient Synthesis of Cinnamides via Aldol Condensation of Amide.

Cinnamides are common core structures that exist in a great number of pharmaceuticals and natural products. The development of efficient methods for preparing cinnamides is in great need. We report herein an efficient polyphosphoric acid (PPA)-promoted direct aldol condensation of an amide for the convenient and straightforward preparation of cinnamides. A variety of cinnamides were obtained in moderate-to-excellent yields (65-89%). This strategy features the use of equivalent amides and a short reaction time.

Investigation of the Pharmacodynamic Components of Gastrodia elata Blume for Treatment of Type 2 Diabetes Mellitus through HPLC, Bioactivity, Network Pharmacology and Molecular Docking.

The occurrence of type 2 diabetes mellitus (T2DM), a worldwide chronic disease, is mainly caused by insufficient insulin production and places a huge burden on the health system. Gastrodia elata Blume (GE), a food of medicine-food homology, has been reported to have the ability to inhibit glycosidase activity, indicating its potential in the treatment of diabetes. However, the main pharmacological components of GE for the treatment of T2DM have not been fully clarified. Therefore, this study aims to clarify the pharmacological components changes of GE with different drying methods and the treatment of T2DM using HPLC, network pharmacology, molecular docking and experimental evaluations. The results showed that the GE samples processed by the steam-lyophilized method possessed the highest total content of the six marker components and the strongest antioxidant and α-glucosidase inhibitory abilities. Meanwhile, the six marker compounds had a total of 238 T2DM-related gene targets. Notably, these active compounds have good affinity for key gene targets associated with T2DM signaling pathways. In conclusion, this study revealed that different drying methods of GE affect the content of its major active compounds, antioxidant capacity, α-glucosidase inhibitory capacity and potential pharmacological effects on T2DM, indicating that it is a potential treatment of T2DM.

Therapeutic potential of Rosa roxburghii folium extract in insomnia treatment: a comprehensive evaluation of behavioral and neurochemical effects in a PCPA-induced mouse model.

BACKGROUND: Insomnia, a prevalent sleep disorder, detrimentally affects quality of life and is often challenging to manage with conventional treatments. This study delved into identifying and quantifying the main compounds by employing ultra-performance liquid chromatography-Q-Exactive-Orbitrap mass spectrometry, and further to evaluate the therapeutic potential of Rosa roxburghii folium (RRF) extract, with multiple pharmacological activities. Previous research had hinted at the efficacy of glycosides in influencing the γ-aminobutyric acid (GABAergic) system, which plays a pivotal role in sleep regulation. Utilizing a p-chlorophenylalanine-induced insomnia model in BALB/C mice, this investigation aimed to unravel the effects of various dosages of RRF extract on sleep quality and elucidated its mechanism of action. RESULTS: A total of 66 compounds in the RRF extract were analyzed. Behavioral assessments demonstrated notable enhancements in sleep duration and latency. Biochemical analyses further corroborated these findings, revealing modulation in neurotransmitter levels indicative of a potential mechanism through the GABAergic and serotoninergic pathways. Additionally, histological evaluations suggested anti-inflammatory and antioxidant effects of the RRF extract. CONCLUSION: The findings from this study underscored the therapeutic efficacy of RRF extract in combating insomnia, particularly highlighting its glycoside components' role. The extract's significant improvement in sleep duration and latency, alongside its modulation of neurotransmitter levels, showcases its potential as a natural remedy for insomnia. Through its action on the GABAergic and serotoninergic pathways, as well as its anti-inflammatory and antioxidant effects, RRF extract emerges as a promising candidate for insomnia treatment, offering a holistic approach to sleep disorder management. © 2024 Society of Chemical Industry.

Fermented Gastrodia elata Bl. Alleviates Cognitive Deficits by Regulating Neurotransmitters and Gut Microbiota in D-Gal/AlCl3-Induced Alzheimer's Disease-like Mice.

Alzheimer's disease (AD) is a common neurological disease with recognition ability loss symptoms and a major contributor to dementia cases worldwide. Gastrodia elata Bl. (GE), a food of medicine-food homology, has been reported to have a mitigating effect on memory and learning ability decline. However, the effect of GE fermented by Lactobacillus plantarum, Acetobacter pasteurianus, and Saccharomyces (FGE) on alleviating cognitive deficits in AD was not studied. Mice were randomly divided into six groups, control, model, donepezil, low, medium, and high doses of FGE, and D-Galactose/Aluminum chloride (D-Gal/AlCl3) was used to establish an AD-like mouse model. The results indicated that FGE could improve the production of neurotransmitters and relieve oxidative stress damage in AD-like mice, which was evidenced by the declined levels of amyloid-ß (Aß), Tau, P-Tau, acetylcholinesterase (AchE), and malondialdehyde (MDA), and increased acetylcholine (Ach), choline acetyltransferase (ChAT), and superoxide dismutase (SOD) levels in brain tissue. Notably, FGE could enhance the richness of the gut microbiota, especially for beneficial bacteria such as Lachnospira and Lactobacillus. Non-target metabolomics results indicated that FGE could affect neurotransmitter levels by regulating amino acid metabolic pathways to improve AD symptoms. The FGE possessed an ameliorative effect on AD by regulating neurotransmitters, oxidative stress levels, and gut microbiota and could be considered a good candidate for ameliorating AD.

Polymeric nanocarriers delivery systems in ischemic stroke for targeted therapeutic strategies.

Ischemic stroke is a complex, high-mortality disease with multifactorial etiology and pathogenesis. Currently, drug therapy is mainly used treat ischemic stroke in clinic, but there are still some limitations, such as limited blood-brain barrier (BBB) penetration efficiency, a narrow treatment time window and drug side effects. Recent studies have pointed out that drug delivery systems based on polymeric nanocarriers can effectively improve the insufficient treatment for ischemic stroke. They can provide neuronal protection by extending the plasma half-life of drugs, enhancing the drug's permeability to penetrate the BBB, and targeting specific structures and cells. In this review, we classified polymeric nanocarriers used for delivering ischemic stroke drugs and introduced their preparation methods. We also evaluated the feasibility and effectiveness and discussed the existing limitations and prospects of polymeric nanocarriers for ischemic stroke treatment. We hoped that this review could provide a theoretical basis for the future development of nanomedicine delivery systems for the treatment of ischemic stroke.

The efficacy of robot-assisted surgery on minor basal ganglia cerebral hemorrhage with neurological dysfunction.

OBJECTIVE: This study aims to compare the outcomes of robot-assisted drainage and conservative treatment in minor basal ganglia hemorrhage (10ml< hemorrhage volume ≤ 30 ml) patients with neurological dysfunction, and analyze patients treated with robot-assisted drainage in order to optimize this treatment strategy. METHODS: In a retrospective study conducted in December 2021 to December 2023, minor basal ganglia cerebral hemorrhage patients with neurological dysfunction were enrolled from the Department of Neurosurgery, Shanghai Ninth People's Hospital. The patients included both the surgical (robot-assisted drainage) and conservative groups. The efficacy of robot-assisted drainage compared with conservative treatment in patients with minor cerebral hemorrhage and neurological dysfunction was evaluated by modified Rankin Scale (mRS) score after 3 months, muscle strength (grade 1 to 5) and cost of hospitalization. RESULTS: Of the patients included, 23 received robot-assisted drainage and 20 received conservative treatment. There were no significant differences in gender, age, history of hypertension and diabetes, muscle strength and mRS score at admission. Female patients accounted for 32.6%, and male patients accounted for 67.4%. About 90% of the patients enrolled had a pre-existing hypertension history. The mRS score after 3 months indicated that prognosis of the patients was significantly better in the surgical treatment group than the conservative treatment group (favorable prognosis 69.57% VS. 35%, P = 0.034) while the patients underwent surgery paid higher hospital bills than patients treated conservatively. CONCLUSION: Compared with traditional conservative treatment, robot-assisted drainage surgery is more helpful to improve the prognosis of patients with minor basal ganglia hemorrhage (volume ≤ 30mL) accompanied by neurological dysfunction. Robot assisted surgery can safely and effectively remove the hematoma of minor basal ganglia hemorrhage, and there were 69.6% of surgery group patients had a good prognosis in this study.

Isolation, Identification, Phytochemical Characterization, and In Vitro Anti-Inflammatory Property of an Endophytic Trametes versicolor CL-1 Isolated from Rosa roxburghii.

This study explores the anti-inflammatory potential of an endophytic fungus, Trametes versicolor CL-1, isolated from the fruit tissues of Rosa roxburghii. Morphological and molecular analyses confirmed the identity of CL-1. An ethyl acetate extract (CL-E) from its fermentation broth was subjected to UPLC-HRMS and GNPS molecular networking. The analysis revealed a diverse array of secondary metabolites, including 11 terpenes, 7 flavonoids, 10 cinnamic acid derivatives, 6 oligopeptides, and 9 fatty acids, as verified by LC-MS/MS. Notably, CL-E exhibited significant in vitro anti-inflammatory activity in RAW264.7 cells. Furthermore,  molecular docking studies predicted favorable binding interactions of key compounds 1 within CL-E with the NLRP3 inflammasome (PDB ID: 6NPY). These findings suggest T. versicolor CL-1 as a promising source of natural anti-inflammatory agents and unveil R. roxburghii as a potential reservoir for discovering novel bioactive metabolites.

Predicting long-term outcomes in patients with classical trigeminal neuralgia following microvascular decompression with an MRI-based radiomics nomogram: a multicentre study.

OBJECTIVES: This study aimed to develop a clinical-radiomics nomogram to predict the long-term outcomes of patients with classical trigeminal neuralgia (CTN) following microvascular decompression (MVD). MATERIALS AND METHODS: This retrospective study included 455 patients with CTN who underwent MVD from three independent institutions A total of 2030 radiomics features from the cistern segment of the trigeminal nerve were extracted computationally from the three-dimensional steady-state free precession and three-dimensional time-of-flight magnetic resonance angiography sequences. Using the least absolute shrinkage and selection operator regression, 16 features were chosen to develop radiomics signatures. A clinical-radiomics nomogram was subsequently developed in the development cohort of 279 patients via multivariate Cox regression. The predictive performance and clinical application of the nomogram were assessed in an external cohort consisting of 176 patients. RESULTS: Sixteen highly outcome-related radiomics features extracted from multisequence images were used to construct the radiomics model, with concordance indices (C-index) of 0.804 and 0.796 in the development and test cohorts, respectively. Additionally, a clinical-radiomics nomogram was developed by incorporating both radiomics features and clinical characteristics (i.e., pain type and degree of neurovascular compression) and yielded higher C-indices of 0.865 and 0.834 in the development and test cohorts, respectively. K‒M survival analysis indicated that the nomogram successfully stratified patients with CTN into high-risk and low-risk groups for poor outcomes (hazard ratio: 37.18, p < 0.001). CONCLUSION: Our study findings indicated that the clinical-radiomics nomogram exhibited promising performance in accurately predicting long-term pain outcomes following MVD. CLINICAL RELEVANCE STATEMENT: This model had the potential to aid clinicians in making well-informed decisions regarding the treatment of patients with CTN. KEY POINTS: Trigeminal neuralgia recurs in about one-third of patients after undergoing MVD. The clinical-radiomics nomogram stratified patients into high- and low-risk groups for poor surgical outcomes. Using this nomogram could better inform patients of recurrence risk and allow for discussion of alternative treatments.

Combined Metabolite and Transcriptomic Profiling Unveil a Potential Gene Network Involved in the Triterpenoid Metabolism of Rose roxburghii.

Rose roxburghii, a horticulturally significant species within the Rosa genus of the Rosaceae family, is renowned for its abundance of secondary metabolites and ascorbate, earning it the title 'king of vitamin C'. Despite this recognition, the mechanisms underlying the biosynthesis and regulation of triterpenoid compounds in R. roxburghii remain largely unresolved. In this study, we conducted high-performance liquid chromatography profiling across various organs of R. roxburghii, including fruit, root, stem, and leaves, revealing distinct distributions of triterpenoid compounds among different plant parts. Notably, the fruit exhibited the highest total triterpenoid content, followed by root and stem, with leaf containing the lowest levels, with leaf containing the lowest levels. Transcriptomic analysis unveiled preferential expression of members from the cytochrome P450 (CYP) and glycosyltransferase (UGT) families, likely contributing to the higher accumulation of both ascorbate and triterpenoid compounds in the fruits of R. roxburghii compared to other tissues of R. roxburghii. Transcriptomic analysis unveiled a potential gene network implicated in the biosynthesis of both ascorbate and triterpenoid compounds in R. roxburghii. These findings not only deepen our understanding of the metabolic pathways in this species but also have implications for the design of functional foods enriched with ascorbate and triterpenoids in R. roxburghii.

Protective effect of soluble dietary fiber from Rosa roxburghii Tratt residue on dextran sulfate sodium-induced ulcerative colitis by regulating serum metabolism and NF-κB pathway in mice.

BACKGROUND: Ulcerative colitis (UC) refers to an idiopathic chronic inflammatory bowel disease that starts with inflammation of the intestinal mucosa. Dietary fiber plays a crucial role in maintaining the normal architecture of the intestinal mucosa. In this study, the protective effect and potential mechanism of soluble dietary fiber from Rosa roxburghii Tratt residue (SDFR) on dextran sulfate sodium (DSS)-induced UC mice were explored. RESULTS: The results revealed that SDFR could ameliorate body weight loss and pathological injury, improve the structure and crypt destruction in colon in DSS-induced mice. Moreover, the levels of NO, IL-1ß, TNF-α, MPO and protein expression of iNOS and COX-2 were decreased after administration of SDFR. Notably, nontargeted metabolomics analysis indicated that there were significant differences in 51 potential metabolites in serum between the DSS and control groups. SDFR intervention could regulate aberrant alterations of these metabolites and mitigate UC via regulating metabolic pathways, including arachidonic acid and glycerophospholipid metabolism. CONCLUSION: This study provides novel evidence that SDFR could be used as a potential modulator to relieve UC. Also, the results provide a theoretical basis for the utilization of byproducts in Rosa roxburghii Tratt fruit processing. © 2024 Society of Chemical Industry.

Alleviating iatrogenic effects of paclitaxel via antiinflammatory treatment.

BACKGROUND: Paclitaxel (PTX) is touted as an essential medicine due to its extensive use as a chemotherapeutic agent for various cancers and an antiproliferative agent for endovascular applications. Emerging studies in cardio-oncology implicate various vascular complications of chemotherapeutic agents. METHODS: We evaluated the inflammatory response induced by the systemic administration of PTX. The investigation included RNAseq analysis of primary human endothelial cells (ECs) treated with PTX to identify transcriptional changes in pro-inflammatory mediators. Additionally, we used dexamethasone (DEX), a well-known antiinflammatory compound, to assess its effectiveness in counteracting these PTX-induced changes. Further, we studied the effects of PTX on monocyte chemoattractant protein-1 (MCP-1) levels in the media of ECs. The study also extended to in vivo analysis, where a group of mice was injected with PTX and subsequently harvested at different times to assess the immediate and delayed effects of PTX on inflammatory mediators in blood and aortic ECs. RESULTS: Our RNAseq analysis revealed that PTX treatment led to significant transcriptional perturbations in pro-inflammatory mediators such as MCP-1 and CD137 within primary human ECs. These changes were effectively abrogated when DEX was administered. In vitro experiments showed a marked increase in MCP-1 levels in EC media following PTX treatment, which returned to baseline upon treatment with DEX. In vivo, we observed a threefold increase in MCP-1 levels in blood and aortic ECs 12 h post-PTX administration. Similar trends were noted for CD137 and other downstream mediators like tissue factor, vascular cell adhesion molecule 1, and E-selectin in aortic ECs. CONCLUSION: Our findings illustrate that PTX exposure induces an upregulation of atherothrombotic mediators, which can be alleviated with concurrent administration of DEX. Considering these observations, further long-term investigations should focus on understanding the systemic implications associated with PTX-based therapies and explore the clinical relevance of DEX in mitigating such risks.

Hybrid Ghost Phonon Polaritons in Thin-Film Heterostructure.

Ghost phonon polaritons (g-PhPs), a unique class of phonon polaritons in the infrared, feature ultralong diffractionless propagation (>20 µm) across the surface and tilted wavefronts in the bulk. Here, we study hybrid g-PhPs in a heterostructure of calcite and an ultrathin film of the phase change material (PCM) In3SbTe2, where the optical field is bound in the PCM film with enhanced confinement compared with conventional g-PhPs. Near-field optical images for hybrid g-PhPs reveal a lemniscate pattern in the momentum distribution. We fabricated In3SbTe2 gratings and investigated how different orientations and periodicities of gratings impact the propagation of hybrid g-PhPs. As the grating period decreases to zero, the wavefront of hybrid g-PhPs can be dynamically steered by varying the grating orientation. Our results highlight the promise of hybrid g-PhPs with tunable functionalities for nanophotonic studies.

Spatiotemporal beating and vortices of van der Waals hyperbolic polaritons.

In conventional thin materials, the diffraction limit of light constrains the number of waveguide modes that can exist at a given frequency. However, layered van der Waals (vdW) materials, such as hexagonal boron nitride (hBN), can surpass this limitation due to their dielectric anisotropy, exhibiting positive permittivity along one optic axis and negativity along the other. This enables the propagation of hyperbolic rays within the material bulk and an unlimited number of subdiffractional modes characterized by hyperbolic dispersion. By employing time-domain near-field interferometry to analyze ultrafast hyperbolic ray pulses in thin hBN, we showed that their zigzag reflection trajectories bound within the hBN layer create an illusion of backward-moving and leaping behavior of pulse fringes. These rays result from the coherent beating of hyperbolic waveguide modes but could be mistakenly interpreted as negative group velocities and backward energy flow. Moreover, the zigzag reflections produce nanoscale (60 nm) and ultrafast (40 fs) spatiotemporal optical vortices along the trajectory, presenting opportunities to chiral spatiotemporal control of light-matter interactions. Supported by experimental evidence, our simulations highlight the potential of hyperbolic ray reflections for molecular vibrational absorption nanospectroscopy. The results pave the way for miniaturized, on-chip optical spectrometers, and ultrafast optical manipulation.

Natural product Kaji-ichigoside F1 exhibits rapid antidepression via activating the AMPA-BDNF-mTOR pathway and inhibiting the NMDAR-CaMKIIα pathway.

BACKGROUND: Depression is a common and recurrent neuropsychiatric disorder. Recent studies have shown that the N-methyl-d-aspartate (NMDA) receptor (NMDAR) is involved in the pathophysiology of depression. Previous studies have found that Kaji-ichigoside F1 (KF1) has a protective effect against NMDA-induced neurotoxicity. However, the antidepressant mechanism of KF1 has not been confirmed yet. PURPOSE: In the present study, we aimed to evaluate the rapid antidepressant activity of KF1 and explore the underlying mechanism. STUDY DESIGN: First, we explored the effect of KF1 on NMDA-induced hippocampal neurons and the underlying mechanism. Second, depression was induced in C57BL/6 mice via chronic unpredictable mild stress (CUMS), and the immediate and persistent depression-like behavior was evaluated using the forced swimming test (FST) after a single administration of KF1. Third, the contributions of NMDA signaling to the antidepressant effect of KF1 were investigated using pharmacological interventions. Fourth, CUMS mice were treated with KF1 for 21 days, and then their depression-like behaviors and the underlying mechanism were further explored. METHODS: The FST was used to evaluate immediate and persistent depression-like behavior after a single administration of KF1 with or without NMDA pretreatment. The effect of KF1 on depressive-like behavior was investigated in CUMS mice by treating them with KF1 once daily for 21 days through the sucrose preference test, FST, open field test, and tail suspension test. Then, the effects of KF1 on the morphology and molecular and functional phenotypes of primary neuronal cells and hippocampus of mice were investigated by hematoxylin-eosin staining, Nissl staining, propidium iodide staining, TUNEL staining, Ca2+ imaging, JC-1 staining, ELISA, immunofluorescence analysis, RT-PCR, and Western blot. RESULTS: KF1 could effectively improve cellular viability, reduce apoptosis, inhibit the release of LDH and Ca2+, and increase the mitochondrial membrane potential and the number of dendritic spines numbers in hippocampal neurons. Moreover, behavioral tests showed that KF1 exerted acute and sustained antidepressant-like effects by reducing Glu-levels and ameliorating neuronal damage in the hippocampus. Additionally, in vivo and in vitro experiments revealed that PSD95, Syn1, α-amino-3­hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and brain-derived neurotrophic factor (BDNF) were upregulated at the protein level, and BDNF and AMPA were upregulated at the mRNA level. NR1 and NR2A showed the opposite trend. CONCLUSION: These results confirm that KF1 exerts rapid antidepressant effects mainly by activating the AMPA-BDNF-mTOR pathway and inhibiting the NMDAR-CaMKIIα pathway. This study serves as a new reference for discovering rapid antidepressants.

Inhibitory effect of Incarvillea diffusa Royle extract in the formation of calcium oxalate nephrolithiasis by regulating ROS-induced Nrf2/HO-1 pathway in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Calcium oxalate (CaOx) kidney stones are widely acknowledged as the most prevalent type of urinary stones, with high incidence and recurrence rates. Incarvillea diffusa Royle (ID) is a traditionally used medicinal herb in the Miao Minzu of Guizhou province, China, for treating urolithiasis. However, the active components and the underlying mechanism of its pharmacodynamic effects remain unclear. AIM OF THE STUDY: This study aimed to investigate the potential inhibitory effect of the active component of ID on the formation of CaOx nephrolithiasis and elucidate the underlying mechanism. MATERIALS AND METHODS: In vivo, a CaOx kidney stone model was induced in Sprague-Dawley (SD) rats using an ethylene glycol and ammonium chloride protocol for four weeks. Forty-eight male SD rats were randomly assigned to 6 groups (n = 8): blank group, model group, apocynin group, and low, medium, and high dose of ID's active component (IDW) groups. After three weeks of administration, rat urine, serum, and kidney tissues were collected. Renal tissue damage and crystallization, Ox, BUN, Ca2+, CRE, GSH, MDA, SOD contents, and levels of IL-1ß, IL-18, MCP-1, caspase-1, IL-6, and TNF-α in urine, serum, and kidney tissue were assessed using HE staining and relevant assay kits, respectively. Protein expression of Nrf2, HO-1, p38, p65, and Toll-4 in kidney tissues was quantified via Western blot. The antioxidant capacities of major compounds were evaluated through DPPH, O2·-, and ·OH radical scavenging assays, along with their effects on intracellular ROS production in CaOx-induced HK-2 cells. RESULTS: We found that IDW could significantly reduce the levels of CRE, GSH, MDA, Ox, and BUN, and enhancing SOD activity. Moreover, it could inhibit the secretion of TNF-α, IL-1ß, IL-18, MCP-1, caspase-1, and decreased protein expression of Nrf2, HO-1, p38, p65, and Toll-4 in renal tissue. Three major compounds isolated from IDW exhibited promising antioxidant activities and inhibited intracellular ROS production in CaOx-induced HK-2 cells. CONCLUSIONS: IDW facilitated the excretion of supersaturated Ca2+ and decreased the production of Ox, BUN in SD rat urine, and mitigated renal tissue damage by regulating Nrf2/HO-1 signaling pathway. Importantly, the three major compounds identified as active components of IDW contributed to the inhibition of CaOx nephrolithiasis formation. Overall, IDW holds significant potential for treating CaOx nephrolithiasis.

KF-catalyzed direct thiomethylation of carboxylic acids with DMSO to access methyl thioesters.

With dimethyl sulfoxide (DMSO) as the methylthio source, a KF-catalyzed strategy was employed for the direct thiomethylation of carboxylic acids with DMSO for the preparation of methyl thioesters. In this process, a wide range of methyl thioesters were obtained in moderate to excellent yields. This novel strategy features the first use of DMSO as a methylthiolating agent for the construction of methyl thioesters, transition metal-free conditions, inexpensive reagents, easy workup, broad substrate scope and sustainability. Additionally, this procedure can be readily scaled up to a gram scale.

Venous Thrombosis Assay in a Mouse Model of Cancer.

This methodology paper highlights the surgical nuances of a rodent model of venous thrombosis, specifically in the context of cancer-associated thrombosis (CAT). Deep venous thrombosis is a common complication in cancer survivors and can be potentially fatal. The current murine venous thrombosis models typically involve a complete or partial mechanical occlusion of the inferior vena cava (IVC) using a suture. This procedure induces a total or partial stasis of blood and endothelial damage, triggering thrombogenesis. The current models have limitations such as higher variability in clot weights, significant mortality rate, and prolonged learning curve. This report introduces surgical refinements using vascular clips to address some of these limitations. Using a syngeneic colon cancer xenograft mouse model, we employed customized vascular clips to ligate the infrarenal vena cava. These clips allow residual lip space similar to a 5-0 polypropylene suture after IVC ligations. Mice with the suture method served as controls. The vascular clip method resulted in a consistent reproducible partial vascular occlusion and greater clot weights with less variability than the suture method. The larger clot weights, greater clot mass, and clot to the IVC luminal surface area were expected due to the higher pressure profile of the vascular clips compared to a 6-0 polypropylene suture. The approach was validated by gray scale ultrasonography, which revealed consistently greater clot mass in the infrarenal vena cava with vascular clips compared to the suture method. These observations were further substantiated with the immunofluorescence staining. This study offers an improved method to generate a venous thrombosis model in mice, which can be employed to deepen the mechanistic understanding of CAT and in translational research such as drug discovery.

Pharmacokinetics, absolute bioavailability, and tissue distribution of WJ-14, a novel N-methyl-d-aspartate receptor antagonist, in rats by liquid chromatography-tandem mass spectrometry.

To circumvent the limitations of current antidepressants, WJ-14, a novel N-methyl-d-aspartate receptor antagonist, was synthesized and demonstrated to have remarkable efficiency in the treatment of depression. To illustrate the pharmacokinetics, absolute bioavailability, and tissue distribution of WJ-14 in rats, a rapid and sensitive liquid chromatography-tandem mass spectrometry-based analytical method was developed and validated for the separation and detection of WJ-14 in both plasma and tissue samples. After oral administration, WJ-14 was rapidly absorbed into the blood with time to reach the maximum plasma concentration (Tmax ) within 0.28 h and quickly eliminated with clearance (Cl) exceeding 6.80 L/h/kg and elimination half-life (t1/2 ) within 2.69 h. No obvious accumulation was found with mean residencetime (MRT) within 4.10 h. Tissue distribution revealed that WJ-14 was extensively distributed in the main tissues of rats, and massive amounts of WJ-14 were distributed in the liver. Extensive distribution and quick elimination led to extremely low absolute bioavailability of WJ-14 (1.91% of 8.33 mg/kg and 3.30% of 24.99 mg/kg). WJ-14 was detected in the brain only 0.083 h after oral administration, which is crucial for a rapid-onset antidepressant candidate. In addition, WJ-14 likely exhibited a non-linear pharmacokinetic process at dosages of 8.33 and 24.99 mg/kg. The findings may provide valuable information for subsequent studies on WJ-14.

Association of concomitant continuous pain in trigeminal neuralgia with a narrow foramen ovale.

Background: The pathogenesis of concomitant continuous pain remains unclear and is worthy of further study. In this clinical study, we aimed to explore the potential role of a narrow foramen ovale in the development of concomitant continuous pain. Methods: A total of 108 patients with classical trigeminal neuralgia affecting the third branch of the trigeminal nerve and 46 healthy individuals were enrolled in this study. Three-dimensional reconstructed computerized tomography images of all participants were collected, and the morphometric features of the foramen ovale were examined by two investigators who were blinded to the clinical data of the patients. Results: In this cohort, patients with concomitant continuous pain suffered from more sensory abnormalities (18.4% vs. 2.9%, p = 0.015) and responded more poorly to medication (74.3% vs. 91.9%, p = 0.018) than patients without concomitant continuous pain. While no significant differences regarding the mean length (5.02 mm vs. 5.36 mm, p > 0.05) and area (22.14 mm2 vs. 23.80 mm2, p > 0.05) were observed between patients with and without concomitant continuous pain, the mean width of the foramen ovale on the affected side in patients with concomitant continuous pain was significantly narrower than that in patients without concomitant continuous pain (2.01 mm vs. 2.48 mm, p = 0.003). Conclusion: This neuroimaging and clinical study demonstrated that the development of concomitant continuous pain was caused by the compression of the trigeminal nerve owing to a narrow foramen ovale rather than responsible vessels in classical trigeminal neuralgia.