Immunosuppressive leucosceptrane-type sesterterpenoids with antipodal cyclopentenones isolated from Leucosceptrum canum.

Ten undescribed leucosceptrane-type sesterterpenoids with antipodal cyclopentenone moieties were isolated from the leaves of Leucosceptrum canum. Their structures including absolute configurations were elucidated by comprehensive spectroscopic analyses (including 1D and 2D NMR, and HRMS) and ECD calculations. In vitro immunosuppressive effects of these sesterterpenoids against the proliferation of T cells and the secretion of cytokine IFN-γ were evaluated. Among them, 11α-H-leucosceptroid C, 5,13-dehydro-11α-H-leucosceptroid C, 5,13-dehydro-11ß-hydroxy-leucosceptroid C, and 5,13-dehydro-11α-hydroxy-leucosceptroid C significantly inhibited IFN-γ secretion with IC50 values of 12.55-23.62 µM. More remarkable inhibitory effects against IFN-γ secretion were observed for 5,13-dehydro-11ß-hydroxy-leucosceptroid D, leucosceptroid U, 14-epi-leucosceptroid U, leucosceptroid V, and 14-epi-leucosceptroid V, with IC50 values of 4.32-9.47 µM.

Association between serum pyridoxal 5'-phosphate levels and all-cause, cardiovascular mortality, and cardiovascular disease in adults: a population-based cohort study.

Background: The association between pyridoxal 5'-phosphate (PLP) and cardiovascular disease (CVD) remains a topic of discussion. Objectives: This study aimed to explore the relationship between serum PLP levels and the incidence of all-cause mortality, cardiovascular mortality, and the risk of CVD among the US population. Design: A population-based cohort study. Methods: This study analyzed data from the National Health and Nutrition Examination Survey. Adjusted hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated using weighted Cox proportional hazards regression models to assess the risk associated with all-cause and cardiovascular mortality. Weighted binary logistic regression was utilized to assess the relationship between serum PLP levels and the risk of CVD. Nonlinear associations were evaluated using multivariable-adjusted restricted cubic splines. Results: There were 2546 cases of all-cause mortality and 867 cases of cardiovascular mortality over a mean follow-up of 11.36 years. In the fully adjusted model, the adjusted HRs with 95% CIs for all-cause mortality associated with increases in serum PLP levels corresponding to the interquartile ranges were 0.83 (0.74-0.93), 0.71 (0.63-0.80), and 0.64 (0.56-0.74), respectively. Similarly, cardiovascular mortality decreased by 0.78 (0.62-0.97), 0.63 (0.49-0.81), and 0.62 (0.50-0.77) with each quartile increase in serum PLP levels. Higher serum PLP levels confer protection against CVD risk (odds ratio: 0.87, 95% CI: 0.79-0.96). Serum PLP levels showed nonlinear relationships with risk of all-cause mortality, cardiovascular mortality, and CVD. Conclusion: The results of this study provide evidence that serum PLP serves as a protective factor against all-cause mortality, cardiovascular mortality, and CVD in US adults, with dose-response relationships.

Association between serum pyridoxal 5'-phosphate levels and all-cause, cardiovascular mortality, and cardiovascular disease in US adults Why was the study done? The association between pyridoxal 5'-phosphate (PLP) and cardiovascular disease (CVD) remains a topic of discussion. This study aimed to explore the relationship between serum PLP levels and the incidence of all-cause mortality, cardiovascular mortality, and the risk of CVD among the US population. What did the researchers do? This study used data from National Health and Nutrition Examination Survey (NHANES), applying statistical methods to see if there's a connection between the amount of PLP in the blood and health outcomes. What did the researchers find? The findings showed that over an average of 11 years, people with higher levels of PLP in their blood were less likely to die for any reason. They were also less likely to die from heart-related problems or to develop heart disease. The protection seemed to increase as PLP levels got higher. What do the findings mean? The results of this study provide evidence that serum PLP serves as a protective factor against all-cause mortality, cardiovascular mortality, and cardiovascular disease in US adults, with dose­response relationships.

Primary Sjogren's Syndrome Associated with Lung Adenocarcinoma: Probing the Potential Common Pathogenic Mechanisms and Experimental Verification.

This study aimed to probe the potential common pathogenic mechanisms linking primary Sjogren's syndrome (pSS) and lung adenocarcinoma (LUAD) through bioinformatics analysis and experimental verification. The relevant genes associated with pSS and LUAD were retrieved from the Gene Expression Omnibus (GEO) database and Genecard database. Subsequently, differentially expressed genes (DEGs) associated with pSS and LUAD were screened as pSS-LUAD-DEGs. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were performed to elucidate the significant biological functions of pSS-LUAD-DEGs. Core targets were identified by constructing the protein-protein interaction (PPI) network, further assessing hub gene diagnostic accuracy through Receiver Operating Characteristic (ROC) curve analyses. In this study, NOD/Ltj mice served as pSS animal models and were stimulated with particulate matter 2.5 (PM2.5) to generate an inflammatory reaction. Quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and western blotting were employed for relevant molecular biology experiment verification. The results revealed through KEGG and GO enrichment analyses indicate that inflammation plays a critical role in linking pSS and LUAD. IL6, CCNA2, JAK2, IL1B, ASPM, CCNB2, NUSAP1, and CEP55 were determined as key targets of pSS-LUAD. BALB/c mice and NOD/Ltj mice exhibited enhanced expression of inflammatory cytokines IL-6 and IL-1ß in lung tissues following 21 days of stimulation with PM2.5, activating the JAK2/STAT3 signaling pathway and up-regulating the expression of tumor-associated genes CCNA2, CCNB2, and CEP55, with NOD/Ltj mice exhibiting more pronounced changes than BALB/c mice. This protocol demonstrates that carcinogenesis induced by the pulmonary inflammatory microenvironment may be a key reason for the high incidence of LUAD in pSS patients. Additionally, blocking-related mechanisms may help prevent the occurrence of LUAD in pSS patients.

Associations of urinary phytoestrogens with all-cause and cardiovascular mortality in adults: a population-based cohort study.

Background: The overall understanding of the correlations between mortality risk and phytoestrogens in general population remains limited. We examined the association between urinary phytoestrogen levels and all-cause and cardiovascular mortality based on the National Health and Nutrition Examination Survey (NHANES). Methods: Weighted Cox proportional hazard regression models were employed to calculate adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). Nonlinear relationships were assessed using multivariable-adjusted restricted cubic splines (RCS). Results: In the fully adjusted model, the highest quartiles of urinary genistein levels were correlated with significantly elevated all-cause (HR = 1.36, 95%CI: 1.16-1.59) and cardiovascular (HR = 1.58, 95%CI: 1.20-2.09) mortality. Urinary enterolactone levels in the third quartile were associated with reduced all-cause (HR = 0.77, 95%CI: 0.65-0.90) and cardiovascular (HR = 0.74, 95%CI: 0.55-0.99) mortality. In the highest quartiles of urinary daidzein levels, the cardiovascular mortality was significantly increased (HR = 1.44, 95%CI: 1.09-1.90). RCS showed an non-linear relationship between urinary daidzein levels and all-cause mortality (P = 0.04). Conclusion: In the context of a nationally representative sample, genistein exhibited associations with elevated all-cause and cardiovascular mortality, whereas enterolactone showed an association with reduced mortality. The dose-response relationship between urinary daidzein levels and all-cause mortality as well as sex-specific disparities in the impact of phytoestrogen levels should be considered.

Selenium dioxide promoted selenylation/cyclization of leucosceptrane sesterterpenoids.

A novel selenium dioxide promoted selenylation/cyclization of leucosceptrane sesterterpenoids was reported. Two types of leucosceptrane derivatives with different valence states of selenium atoms (Se2+ and Se4+) were obtained. The mechanisms of these two processes were proposed, and the selenium-containing derivates may serve as intermediates of Riley oxidation that could be trapped with appropriate substrates. Immunosuppressive activity screening revealed that 10 and 11 had obvious inhibitory effects on IFN-γ production, with IC50 values of 5.29 and 17.60 µM, respectively, which were more active than their precursor leucosceptroid A.

Excessive hydrogen sulfide-induced activation of NMDA receptors in the colon participates in anxiety- and compulsive-like behaviors in a rodent model of hemorrhagic shock and resuscitation.

OBJECTIVE: Hemorrhagic shock and resuscitation (HSR) cause inflammatory responses in the gastrointestinal tract and is associated with substantial morbidity and mortality rates. Hydrogen sulfide (H2S), a gasotransmitter with pleiotropic activity, exhibits anti-inflammatory benefits at physiological levels. However, deleterious effects are observed when its concentration increases. In this investigation, we employed a mouse model of HSR to examine the effects of an H2S scavenger on the gastrointestinal tract and brain, with emphasis on N-Methyl-d-Aspartate (NMDA) receptor function. METHODS: Mice were immediately administered dl-propargylglycine (PAG) intragastrically as an H2S scavenger after HSR exposure. The O-maze and buried beads tests were used to assess compulsive- and anxiety-like behaviors. Pathological changes in the intestine were evaluated at 24 and 30 days after HSR. Subsequently, at 30 days after HSR, we examined electrophysiological and pathological changes in the amygdala. RESULTS: Within 24 h of HSR exposure, animals treated with PAG showed significantly lower colonic injury. Additionally, compared to the HSR-treated mice 30 days after HSR, the PAG-treated mice displayed reduced buried beads, increased open-arm time, lower blood levels of Diamine Oxidase (DAO) and considerably improved ZO-1 intensity, a stronger association between the delta rhythm phase and beta activity amplitude, and lower neuroinflammatory response in the amygdala. MK-801, an NMDA receptor inhibitor, significantly reversed H2S-induced intestinal and cerebral injury. CONCLUSION: This experimental data suggests that H2S-induced excessive activation of NMDA receptors contributes to anxiety- and compulsive-like behaviors caused by HSR.

[Nitrogen Flow Characteristics of Agricultural Production and Consumption System in the Yangtze River Delta Region and Its Driving Factors].

To assess the impact of human activities on regional nitrogen （N） flow, based on the statistical data of 27 cities in the Yangtze River Delta Region （YRD）, N flow characteristics of the agricultural production and consumption system （APC） in the YRD from 2011 to 2020 were analyzed using substance flow analysis, and driving factors for N flow were analyzed using scenario analysis. The results showed that from 2011 to 2020, the mean N input intensity of the APC in the YRD was 194.6 kg·ï¼ˆhm2·a）-1, which was more than five times the national average value； thus, the YRD was a hotspot of N input intensity in China. Chemical N fertilizer was the largest component of N input, and the YRD changed from a net export area of grain and animal products to a net import area due to the rapid growth of food consumption demand. The N output of the system was mainly N loss to the environment, accounting for 53.2% on average. The N use efficiency （NUE） of cropland and the N recycling ratio of the APC ranged from 38.7-42.2% and 15.8-21.5%, respectively, which were both at a low level. In addition, the total amount of N input and output of the APC both showed a parabolic decline trend, decreasing by 11.3% and 10.0%, respectively. Spatially, the overall N input intensity showed a pattern of "high in the north and low in the south," and the spatial heterogeneity of N input intensity among cities was significant. Cities with high input intensity were mainly located in the north and east of Jiangsu, Shanghai, and northeast of Zhejiang. A significant positive spatial autocorrelation of the distribution of mean N input intensity was observed. The uncertainty of N flows was estimated using the error propagation equation. The uncertainty interval of N input and output ranged from 4.5% to 34.6%, which was roughly equivalent to the results of related studies, indicating that the model results were reliable. Based on the scenario analysis method, the decrease of the livestock scale led to a decrease of -0.27%-7.53% in the N input, making it the main reason for the decrease of total N input in the APC. Improving the NUE of cropland and re-establishing the linkage between cropland and livestock will help reduce N loss to the environment.

Leucosceptrane sesterterpenoids from Tibetan Leucosceptrum canum and their immunosuppressive activity.

Phytochemical investigation on the leaves of Tibetan Leucosceptrum canum, a Chinese medicinal herb, led to the isolation of seven new leucosceptrane sesterterpenoids (1-7) and five known analogs (8-12). Comprehensive spectroscopic analysis (including 1D and 2D NMR, and HRMS), quantum chemistry computations, and single crystal X-ray crystallographic analysis were applied to elucidate their structures. Compounds 1-3 and 6 were the first examples of the leucosceptrane sesterterpenoids with rare C-2 oxidation. Compound 2 exhibited immunosuppressive activities via suppressing the secretion of cytokines IL-6 and TNF-α in LPS-induced macrophages RAW264.7 with IC50 values of 13.39 and 19.34 µM, respectively.

Inhibition of the P38 MAPK/NLRP3 pathway mitigates cognitive dysfunction and mood alterations in aged mice after abdominal surgery plus sevoflurane.

BACKGROUND: Cognitive dysfunction, encompassing perioperative psychological distress and cognitive impairment, is a prevalent postoperative complication within the elderly population, and in severe cases, it may lead to dementia. Building upon our prior research that unveiled a connection between postoperative mood fluctuations and cognitive dysfunction with the phosphorylation of P38, this present investigation aims to delve deeper into the involvement of the P38 MAPK/NLRP3 pathway in perioperative neurocognitive disorders (PND) in an abdominal exploratory laparotomy (AEL) aged mice model. METHODS: C57BL/6 mice (male, 18-month-old) underwent AEL with 3 % anesthesia. Then, inhibitors targeting P38 MAPK (SB202190, 1 mg/kg) and GSK3ß (TWS119, 10 mg/kg) were administered multiple times daily for 7 days post-surgery. The NLRP3-cKO AEL and WT AEL groups only underwent the AEL procedure. Behavioral assessments, including the open field test (OFT), novel object recognition (NOR), force swimming test (FST), and fear conditioning (FC), were initiated on postoperative day 14. Additionally, mice designated for neuroelectrophysiological monitoring had electrodes implanted on day 14 before surgery and underwent novel object recognition while their local field potential (LFP) was concurrently recorded on postoperative day 14. Lastly, after they were euthanasized, pathological analysis and western blot were performed. RESULTS: SB202190, TWS119, and astrocyte-conditional knockout NLRP3 all ameliorated the cognitive impairment behaviors induced by AEL in mice and increased mean theta power during novel location exploration. However, it is worth noting that SB202190 may exacerbate postoperative depressive and anxiety-like behaviors in mice, while TWS119 may induce impulsive behaviors. CONCLUSIONS: Our study suggests that anesthesia and surgical procedures induce alterations in mood and cognition, which may be intricately linked to the P38 MAPK/NLRP3 pathway.

A comprehensive review and meta-analysis comparing robot-assisted and laparoscopic adrenalectomy in individuals with obesity.

This meta-analysis aimed to compare the efficacy of robot-assisted vs. laparoscopic adrenalectomy in individuals with obesity. We performed an extensive review of the PubMed, Embase, and Cochrane Library databases for research on adrenalectomy in individuals with obesity up to August 2024. Only studies comparing robot-assisted surgery with laparoscopic surgery were included. Only articles written in English were included. We utilized established criteria for inclusion and exclusion, concentrating on randomized controlled trials and cohort studies. The ROBINS-I instrument was employed to assess the bias risk in non-randomized control studies. Review Manager 5.4.1 was utilized to conduct the meta-analysis. The final analysis incorporated four retrospective cohort studies with a total of 492 individuals with obesity (261 receiving RA and 231 undergoing LA). The results showed that RA was linked to a shorter duration of hospitalization and less estimated blood loss in comparison to LA. Nonetheless, there were no notable distinctions between the two surgical methods in terms of OT, laparotomy conversion rates, overall postoperative complications, or death rates after surgery. In conclusion, RA is a reliable and safe choice for individuals with obesity. It offers notable advantages over LA in terms of LOHS and EBL.

Immunosuppressive leucosesterterpane and penta-nor-leucosesterterpane sesterterpenoids from Leucosceptrum canum.

Five undescribed leucosesterterpane sesterterpenoids, leucosceptrines A-E, two undescribed penta-nor-leucosesterterpane (C20) sesterterpenoids, nor-leucosceptrines A and B, and three known analogues, were obtained from the aerial parts of Leucosceptrum canum of Chinese origin. Leucosceptrines A-C are the first examples of leucosesterterpane-type sesterterpenoids with unclosed dihydropyran rings and reverse configurations at chiral centers C-4 and/or C-12. Nor-leucosceptrines A and B possesses an unusual penta-nor-leucosesterterpane skeleton. Their structures were unambiguously elucidated through comprehensive spectroscopic analyses and single-crystal X-ray diffraction. A plausible biogenetic pathway for these sesterterpenoids was proposed. The immunosuppressive effects of these isolates on the secretion of the cytokine IFN-γ by T cells stimulated with anti-CD3/CD28 monoclonal antibodies were observed with different potencies.

NBR1-p62-Nrf2 mediates the anti-pulmonary fibrosis effects of protodioscin.

BACKGROUND: Idiopathic pulmonary fibrosis is a persistent disease of the lung interstitium for which there is no efficacious pharmacological therapy. Protodioscin, a steroidal saponin, possesses diverse pharmacological properties; however, its function in pulmonary fibrosis is yet to be established. Hence, in this investigation, it was attempted to figure out the anti-pulmonary fibrosis influences of protodioscin and its pharmacological properties related to oxidative stress. METHODS: A mouse lung fibrosis model was generated using tracheal injections of bleomycin, followed by intraperitoneal injection of different concentrations of protodioscin, and the levels of oxidative stress and fibrosis were detected in the lungs. Multiple fibroblasts were treated with TGF-ß to induce their transition to myofibroblasts. It was attempted to quantify myofibroblast markers' expression levels and reactive oxygen species levels as well as Nrf2 activation after co-incubation of TGF-ß with fibroblasts and different concentrations of protodioscin. The influence of protodioscin on the expression and phosphorylation of p62, which is associated with Nrf2 activation, were detected, and p62 related genes were predicted by STRING database. The effects of Nrf2 inhibitor or silencing of the Nrf2, p62 and NBR1 genes, respectively, on the activation of Nrf2 by protodioscin were examined. The associations between p62, NBR1, and Keap1 in the activation of Nrf2 by protodioscin was demonstrated using a co-IP assay. Nrf2 inhibitor were used when protodioscin was treated in mice with pulmonary fibrosis and lung tissue fibrosis and oxidative stress levels were detected. RESULTS: In vivo, protodioscin decreased the levels of fibrosis markers and oxidative stress markers and activated Nrf2 in mice with pulmonary fibrosis, and these effects were inhibited by Nrf2 inhibitor. In vitro, protodioscin decreased the levels of myofibroblast markers and oxidative stress markers during myofibroblast transition and promoted Nrf2 downstream gene expression, with reversal of these effects after Nrf2, p62 and NBR1 genes were silenced or Nrf2 inhibitors were used, respectively. Protodioscin promoted the binding of NBR1 to p62 and Keap1, thereby reducing Keap1-Nrf2 binding. CONCLUSION: The NBR1-p62-Nrf2 axis is targeted by protodioscin to reduce oxidative stress and inhibit pulmonary fibrosis.

Hydrogen sulfide mitigates memory impairments via the restoration of glutamatergic neurons in a mouse model of hemorrhage shock and resuscitation.

Impaired long-term memory, a complication of traumatic stress including hemorrhage shock and resuscitation (HSR), has been reported to be associated with multiple neurodegenerations. The ventral tegmental area (VTA) participates in both learned appetitive and aversive behaviors. In addition to being prospective targets for the therapy of addiction, depression, and other stress-related diseases, VTA glutamatergic neurons are becoming more widely acknowledged as powerful regulators of reward and aversion. This study revealed that HSR exposure induces memory impairments and decreases the activation in glutamatergic neurons, and decreased ß power in the VTA. We also found that optogenetic activation of glutamatergic neurons in the VTA mitigated HSR-induced memory impairments, and restored ß power. Moreover, hydrogen sulfide (H2S), a gasotransmitter with pleiotropic roles, has neuroprotective functions at physiological concentrations. In vivo, H2S administration improved HSR-induced memory deficits, elevated c-fos-positive vesicular glutamate transporters (Vglut2) neurons, increased ß power, and restored the balance of γ-aminobutyric acid (GABA) and glutamate in the VTA. This work suggests that glutamatergic neuron stimulation via optogenetic assay and exogenous H2S may be useful therapeutic approaches for improving memory deficits following HSR.

Eldecalcitol protected osteocytes against ferroptosis of D-gal-induced senescent MLO-Y4 cells and ovariectomized mice.

BACKGROUND: Active vitamin D analog eldecalcitol is clinically applied in treatment of postmenopausal osteoporosis. This study aims to determine the role of eldecalcitol in the protection of osteocytes from senescence and the associated ferroptosis. METHODS: The MLO-Y4 osteocytes were exposed to D-gal inducing senescence. The ovariectomized (OVX) mice treated with D-gal using as an aging inducer were intraperitoneally injected with eldecalcitol. The multiplexed confocal imaging, fluorescence in situ hybridization and transmission electron microscopy were applied in assessing osteocytic properties. Immunochemical staining and immunoblotting were carried out to detect abundance and expression of molecules. RESULTS: The ablation of vitamin D receptor led to a reduction in amounts of osteocytes, a loss of dendrites, an increase in mRNA expression of SASP factors and in protein expression of senescent factors, as well as changes in mRNA expression of ferroptosis-related genes (PTGS2 & RGS4). Eldecalcitol reversed senescent phenotypes of MLO-Y4 cells shown by improving cell morphology and density, decreasing ß-gal-positive cell accumulation, and down-regulating protein expression (P16, P21 & P53). Eldecalcitol reduced intracellular ROS and MDA productions, elevated JC-1 aggregates, and up-regulated expression of Nrf2 and GPX4. Eldecalcitol exhibited osteopreserve effects in D-gal-induced aging OVX mice. The confocal imaging displayed its improvement on osteocytic network organization. Eldecalcitol decreased the numbers of senescent osteocytes at tibial diaphysis by SADS assay and attenuated mRNA expression of SASP factors as well as down-regulated protein expression of senescence-related factors and restored levels of ferroptotic biomarkers in osteocytes-enriched bone fraction. It reduced 4-HNE staining area, stimulated Nrf2-positive staining, and promoted nuclear translocation of Nrf2 in osteocytes of mice as well as inhibited and promoted protein expression of 4-HNE and Nrf2, respectively, in osteocytes-enriched bone fraction. CONCLUSIONS: The present study revealed the ameliorative effects of eldecalcitol on senescence and the associated ferroptosis of osteocytes, contributing to its preservation against osteoporosis of D-gal-induced senescent ovariectomized mice.

Unusual immunosuppressive pyridine-containing bisnor- (c23), tetranor- (c21) and pentanor- (c20) sesterterpenoids from Tibetan Leucosceptrum canum.

An unusual pyridine-containing sesterterpenoid, leucosceptrodine (1), and five new nor-leucosceptrane sesterterpenoids, including bisnor- (C23, 2), tetranor- (C21, 3) and pentanor- (C20, 4-6) skeletons, were isolated from the leaves of Tibetan Leucosceptrum canum. Their structures including their absolute configurations were determined by extensive spectroscopic analyses and quantum chemical calculations. A single crystal of one epimer (5) was crystallized from a pair of inseparable epimers, and its structure including its absolute configuration was determined by X-ray crystallographic analysis. The immunosuppressive activities of compounds 1-4 with different potencies were evaluated by inhibiting the secretion of cytokines TNF-α and IL-6 in LPS-induced RAW264.7 macrophages.

Icariin mitigates anxiety-like behaviors induced by hemorrhagic shock and resuscitation via inhibiting of astrocytic activation.

BACKGROUND: Abnormal activation of astrocytes in the amygdala contributes to anxiety after hemorrhagic shock and resuscitation (HSR). Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)-associated epigenetic reprogramming of astrocytic activation is crucial to anxiety. A bioactive monomer derived from Epimedium icariin (ICA) has been reported to modulate NF-κB signaling and astrocytic activation. PURPOSE: The present study aimed to investigate the effects of ICA on post-HSR anxiety disorders and its potential mechanism of action. METHODS: We first induced HSR in mice through a bleeding and re-transfusion model and selectively inhibited and activated astrocytes in the amygdala using chemogenetics. Then, ICA (40 mg/kg) was administered by oral gavage once daily for 21 days. Behavioral, electrophysiological, and pathological changes were assessed after HSR using the light-dark transition test, elevated plus maze, recording of local field potential (LFP), and immunofluorescence assays. RESULTS: Exposure to HSR reduced the duration of the light chamber and attenuated open-arm entries. Moreover, HSR exposure increased the theta oscillation power in the amygdala and upregulated NF-κB p65, H3K27ac, and H3K4me3 expression. Contrarily, chemogenetic inhibition of astrocytes significantly reversed these changes. Chemogenetic inhibition in astrocytes was simulated by ICA, but chemogenetic activation of astrocytes blocked the neuroprotective effects of ICA. CONCLUSION: ICA mitigated anxiety-like behaviors induced by HSR in mice via inhibiting astrocytic activation, which is possibly associated with NF-κB-induced epigenetic reprogramming.

Syntheses of Linear Biosynthetic C25-Precursors of Leucosceptroids.

An efficient synthetic approach was developed and applied to the syntheses of four linear biosynthetic C25-precursors of leucosceptroids. The synthesis features a Julia-Kocienski olefination and a late-stage bioinspired photo-oxidation as key steps. The immunosuppressive effects of all synthetic compounds on mouse T cells and macrophage RAW264.7 were determined.

Leucosceptrane Sesterterpenoids as a New Type of Natural Immunosuppressive Agents in Treating Sepsis.

Intragastric administration of the total sesterterpenoid extract (TSE) of medicinal plant Leucosceptrum canum at 2.5 g/kg dose protected mice from LPS-induced sepsis. Phytochemical investigation led to the isolation and identification of 47 leucosceptrane sesterterpenoids (1-47) including 30 new compounds (1-30) with complicated oxygenation patterns. Biological screening indicated their immunosuppressive activity via inhibiting IFN-γ secretion and/or proliferation of T cells with different potencies. Mechanism study of compounds 9, 25, and 32 revealed that they inhibited the activations of AKT-mTOR, JNK, p38 MAPK or ERK pathway in T cells and macrophages. In addition, compounds 9 and 25 induced G0/G1 cell arrest of T cells. The major component, leucosceptroid N (32), significantly lowered the levels of IL-6 and TNF-α in peripheral blood serum, and ameliorated the multiorgan damages of LPS-induced sepsis mice at 25 mg/kg dose. These findings suggest that leucosceptrane sesterterpenoids are a new type of potential immunosuppressive agents for sepsis treatment.