Restoration of the Mucosal IgA Response by Improving CD4+ T Pyroptosis Fails to Attenuate Gut Bacterial Translocation and Organ Damage After LPS Attack.

BACKGROUND: Currently, the mechanisms of impaired gut mucosal immunity in sepsis remain unclear. Gut immunoglobulin A (IgA) is an important defense mechanism against invasive pathogens, and CD4+ T cells regulate the IgA response. AIM: We aimed to verify the hypothesis indicating that CD4+ T pyroptosis induced by lipopolysaccharide (LPS) leads to an impaired gut IgA response and subsequent bacterial translocation and organ damage. METHODS: Cultured CD4+ T cells and mice were manipulated with LPS, and pyroptosis was improved by A438079 or adoptive CD4+ T cell transfer. The changes demonstrated in pyroptosis-related molecules, cytotoxicity and CD4+ T cells were examined to determine CD4+ T pyroptosis. The changes demonstrated in IgA+ B cells, AID (key enzyme for immunoglobulins) and IgA production and function were examined to evaluate the IgA response. Serum biomarkers, bacterial colonies and survival analysis were detected for bacterial translocation and organ damage. RESULTS: LPS attack induced CD4+ T pyroptosis, as evidenced by increased expression of P2X7, Caspase-11 and cleaved GSDMD, which elevated cytotoxicity and decreased CD4+ T cells. Decreased CD4+ T subsets (Foxp3+ T and Tfh cells) influenced the IgA response, as evidenced by lower AID expression, which decreased IgA+ B cells and IgA production and function. A438079 or cell transfer improved the IgA response but failed to reduce the translocation of gut pathogens, damage to the liver and kidney, and mortality of mice. CONCLUSION: LPS attack results in CD4+ T pyroptosis. Improvement of pyroptosis restores the mucosal IgA response but fails to ameliorate bacterial translocation and organ damage.

UPLC-QTOF-MS-based lipidomic study of wedelolactone in acute colitis mice induced by dextran sulfate sodium.

Inflammatory bowel disease is a relapsing inflammatory disease seriously endanger human health. Wedelolactone (WED) is a major active ingredient from Eclipta prostrata (L.) L. and has shown anti-inflammatory effects. However, the mechanism of WED in treating inflammatory colitis remains unknown. We aimed to investigate the mechanisms of WED in treating ulcerative colitis through lipidomic study. Sixty male C57BL/6 mice were exposed to DSS to induce acute colitis. Disease progression was judged by the disease activity index (DAI) and pathological changes of colon tissue. An ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) method was performed for colon and plasma lipidomics analyses. Differential metabolites in the three groups were distinguished by univariate and multivariate analysis. WED exerted anti-inflammatory effects representing by body weight and DAI score. Three metabolites were identified in plasma and 20 in colon. According to pathway analysis, the effects of WED on colitis were associated with seven pathways. The glycerophospholipid metabolism and ether lipid metabolism were the primary pathways. The findings provide important insight of the mechanism of WED in treating DSS induced colitis through lipidomic perspective.

A Mini Review on Fluid Topology Optimization.

Topology optimization holds great potential to achieve the best performance for various fluid-related applications like aircraft components and microfluidic mixers. This paper reviews comprehensively the technical progress of this field over the last decade from the viewpoint of structural expression. The density-based approach has been widely adopted to design structures due to its simple concept, ease of implementation, and robustness. Different designs using such a pointwise method for systems under Stokes, laminar Navier-Stokes, turbulent, non-Newtonian, and steady-state/unsteady-state fluid flows are reviewed and discussed in depth. Both isogeometric analysis and the moving morphable components/voids methods will demonstrate their advantages regarding integration with computer-aided design. The moving morphable components/voids method also significantly reduces computing costs. From the viewpoint of boundary smoothness, we are most concerned about whether smoother boundaries can reduce objective functions such as energy dissipation even lower. Therefore, this work also concentrates on level set and spline expression methods. Furthermore, we identify isogeometric analysis and machine learning in shaping the field's future. In addition, the review highlights the following two challenges: achieving accurate fluid model construction and the relatively limited experimental validation of fluid topology optimization outcomes.

Concurrent chemoradiotherapy versus radiotherapy alone after induction chemoimmunotherapy for stage III NSCLC patients who did not undergo surgery: a single institution retrospective study.

BACKGROUND: With remarkable success and few side effects, induction chemoimmunotherapy has been used to improve the prognosis of patients with resectable or potentially resectable non-small cell lung cancer (NSCLC), even in stage III disease. However, for patients who are medically inoperable, unresectable or refuse surgery after induction chemoimmunotherapy, it is unclear whether patients should be treated with concurrent chemoradiotherapy (cCRT) or radiotherapy (RT) alone considering patient safety and tolerability. This study aimed to determine whether cCRT is safe and superior to RT alone after chemoimmunotherapy for stage III NSCLC. METHODS: Patients diagnosed with stage III NSCLC who received chemoimmunotherapy followed by cCRT/RT alone without surgery at Tianjin Cancer Hospital between November 2018 to December 2021 were retrospectively collected. Patients were divided into two groups: induction chemoimmunotherapy followed by cCRT (cCRT cohort) or RT alone (RT alone cohort). Kaplan-Meier method was used to estimate survival. Univariate and multivariate Cox regression models were adopted to estimate risk factors for PFS. RESULTS: Sixty-five patients were included, with 44 (67.7%) received RT alone and 21 (32.3%) received cCRT. Patients in the cCRT group had significantly prolonged PFS (HR = 0.155, p = 0.004), LPFS (HR = 0.225, p = 0.029) and DMFS (HR = 0.028, p = 0.006) than those in the RT alone group. Albeit nonsignificant, a trend toward improved OS (HR = 0.030, p = 0.069) was also observed in the cCRT group. The multivariate analysis further confirmed that cCRT (HR = 0.141, p = 0.008) was the independent factor for promoting a favorable PFS. Treatment-related adverse events were similar between groups (p > 0.05). Patients with consolidation immunotherapy exhibited a trend of improved PFS (HR = 0.398, p = 0.274) and numerically better OS (HR = 0.018, p = 0.209) compared with those without. CONCLUSIONS: For patients with unresectable stage III NSCLC, cCRT following chemoimmunotherapy appears to be safe and may prolong survival compared with radiotherapy alone. Further investigations on the combination of chemoimmunotherapy and CRT are warranted.

Path sampling and integration method to calculate speckle patterns.

A stable speckle pattern is generated when a coherent beam illuminates a stationary scattering medium that contains numerous scatterers with fixed positions. To date, there has been no valid method to the best of our knowledge for calculating the speckle pattern of a macro medium with a large number of scatterers. Here, a new method based on possible path sampling with corresponding weights and coherent superposition is presented for the simulation of optical field propagation in a scattering medium and output speckle patterns. In this method, a photon is launched onto a medium with fixed scatterers. It propagates in one direction; upon collision with a scatterer, its direction is updated. The procedure is repeated until it exits the medium. A sampled path is obtained in this manner. By repeatedly launching photons, numerous independent optical paths can be sampled. A speckle pattern, corresponding to the probability density of the photon, is formed by the coherent superposition of sufficiently sampled path lengths ending on a receiving screen. This method can be used in sophisticated studies of the influences of medium parameters, motion of scatterers, sample distortions on speckle distributions, and morphological appearances. It can be used for micro-examination of optical fields in scattering media and may inspire new methods and techniques for non-invasive precision detection and diagnosis of scattering media.

Imaging and positioning through scattering media with double-helix point spread function engineering.

Significance: Double-helix point spread function (DH-PSF) microscopy has been developed for three-dimensional (3D) localization and imaging at super-resolution but usually in environments with no or weak scattering. To date, super-resolution imaging through turbid media has not been reported. Aim: We aim to explore the potential of DH-PSF microscopy in the imaging and localization of targets in scattering environments for improved 3D localization accuracy and imaging quality. Approach: The conventional DH-PSF method was modified to accommodate the scanning strategy combined with a deconvolution algorithm. The localization of a fluorescent microsphere is determined by the center of the corresponding double spot, and the image is reconstructed from the scanned data by deconvoluting the DH-PSF. Results: The resolution, i.e., the localization accuracy, was calibrated to 13 nm in the transverse plane and 51 nm in the axial direction. Penetration thickness could reach an optical thickness (OT) of 5. Proof-of-concept imaging and the 3D localization of fluorescent microspheres through an eggshell membrane and an inner epidermal membrane of an onion are presented to demonstrate the super-resolution and optical sectioning capabilities. Conclusions: Modified DH-PSF microscopy can image and localize targets buried in scattering media using super-resolution. Combining fluorescent dyes, nanoparticles, and quantum dots, among other fluorescent probes, the proposed method may provide a simple solution for visualizing deeper and clearer in/through scattering media, making in situ super-resolution microscopy possible for various demanding applications.

Lipidomics Study of Sepsis-Induced Liver and Lung Injury under Anti-HMGB1 Intervention.

Sepsis usually leads to lethal multiorgan dysfunction including acute liver failure (ALF) and acute lung injury (ALI). This research sought to reveal the lipid alteration of anti-high mobility group box 1 (HMGB1) treatment in sepsis-induced ALF and ALI by lipidomics. The cecal ligation and puncture-induced mouse model was established and the anti-HMGB1 neutralizing antibody was administrated. The histopathological characteristics and inflammatory factors were determined to assess the efficacy of the antibody. Utraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used to determine lipid metabolism profiles in the liver and lung. The underlying biomarkers were identified through multivariate statistical analysis and correlation analysis with traditional physiological indicators. The pathological and biochemical results demonstrated that anti-HMGB1 neutralizing antibodies mitigated ALF and ALI in mice. Three differential metabolites in the liver and six various metabolites in the lung were significantly reversed by anti-HMGB1 treatment, mainly involved in arachidonic acid metabolism, glycerophospholipid metabolism, and sphingolipid metabolism. Additionally, we investigated several traditional signaling pathways associated with HMGB1. However, the correlation between these traditional pathways and anti-HMGB1 intervention was not significant in the current study. In conclusion, our finding provided some scientific basis for targeting HMGB1 in sepsis-induced liver and lung injury. Mass spectrometry data with identifier no. MTBLS6466 have been uploaded to MetaboLights (http://www.ebi.ac.uk/metabolights/login).

Second generation androgen receptor antagonist, TQB3720 abrogates prostate cancer growth via AR/GPX4 axis activated ferroptosis.

Purpose: Prostate cancer (PCa) poses a great threat to humans. The study aimed to evaluate the potential of TQB3720 in promoting ferroptosis to suppress prostate cancer, providing a theoretical basis for PCa therapy. Methods: PCa cells and nude mice models were divided into TQB3720, enzalutamide (ENZ), and control groups. Sulforhodamine B assay, colony formation assessment, organoids culture system, and the CCK8 assay were used for detecting proliferation. Western blot assay was processed to detect the expression of androgen receptor (AR), ferroptosis, and apoptosis-related genes. Flow cytometry was applied to measure the intracellular ROS levels. ELISA was performed to determine the cellular oxidized glutathione (GSSG) and malondialdehyde (MDA) levels. RT-qPCR was conducted to detect the mRNA expression of genes in AR signaling. BODIPYTM™ 581/591 was processed for detection of intracellular lipid peroxidation levels. The interaction of AR with other translational factor complex proteins was explored using Co-immunoprecipitation (Co-IP), and the chromatin immunoprecipitation (ChIP) assay was performed to detect the binding of AR-involved translational complex to downstream genes promoter. Luciferase reporter assay was conducted to examine the translation activity of GPX4 promoter, and immunohistochemistry (IHC) was conducted to analyze the levels of c-MYC, Ki-67 and AR in TQB3720-treated cancer tissues. Results: Here, we found TQB3720 inhibits the growth of prostate cancer in vitro and in vivo. TQB3720 treatment induced intracellular levels of GSSG and MDA significantly, by which hints AR antagonist caused ferroptosis-related cell death. Moreover, molecular evidence shown TQB3720 regulates downstream of AR signaling by binding AR resulting in inhibition of AR entry into the nucleus. Additional, we also proved that TQB3720 abrogates the interaction between AR and SP1 and leads to decrease GPX4 transcription. Conclusion: TQB3720 promotes ferroptosis in prostate cancer cells by reducing the AR/SP1 transcriptional complex binding to GPX4 promoter. As a result, it is suggested to be a potential drug for clinic prostate cancer treatment.

Improvement of gut-vascular barrier by terlipressin reduces bacterial translocation and remote organ injuries in gut-derived sepsis.

Gut-vascular barrier (GVB) serves as the last barrier to limit the migration of intestinal toxins into the blood circulation. The efficacy of terlipressin (a vasopressin V1 receptor agonist) in reducing GVB and multiple organ damage in gut-derived sepsis is unknown. In this study, we hypothesized that, besides other intestinal barriers, GVB play a key role in gut-derived sepsis and terlipressin improve GVB damage and then reduce bacterial translocation and organ injuries. In vivo, a cecal ligation and puncture mouse model was established. The mice were subjected to examine the damage of GVB determined by intestinal plasmalemma vesicle-associated protein-1(PV-1) and vascular endothelial-cadherin. And the intestinal permeability was assessed by translocation of intestinal bacteria and macromolecules. In vitro, transendothelial electrical resistance (TER) during interleukin (IL)-1ß stimulation was measured on endothelial cells with or without small interfering RNA targeting ß-catenin (si ß-catenin). Terlipressin significantly improved GVB damage and reduced translocation of intestinal macromolecules and bacteria by activating PI3K signaling. Of note, intestinal PV-1 expression was significantly correlated with translocation of macromolecules, and dramatic increase of macromolecules was observed in intestinal tissues whereas fewer macromolecules and bacteria were observed in blood, liver and lung following terlipressin treatment. In vitro, terlipressin restored TER during IL-1ß stimulation and si ß-catenin transfection blocked the changes delivered by terlipressin. Collectively, terlipressin alleviated GVB damage and subsequent bacterial translocation via blood vessels after sepsis challenge, resulting in reduced distant organ injuries and the responsible mechanisms may involve the activation of PI3K/ß-catenin pathway.

UPLC-Q-TOF/MS-Based Plasma and Urine Metabolomics Contribute to the Diagnosis of Sepsis.

In this study, we aimed to identify potential metabolic biomarkers that can improve the diagnostic accuracy of sepsis. Sixty-six patients including 30 septic and 36 nonsepsis patients from an intensive care unit were recruited. The global plasma and urine metabolomic profiles were determined by ultraperformance liquid chromatography coupled with a quadrupole time-of-flight mass spectrometry-based methodology. The risk factors, including both traditional physiological indicators and metabolic biomarkers, were investigated by binary logistic regression analysis and used to build a least absolute shrinkage and selection operator (Lasso) regression model to evaluate the ability of diagnosis. Fifty-five metabolites in plasma and 11 metabolites in urine were identified through orthogonal projections to latent structures discriminant analysis (OPLS-DA). Among them, ten (PE (20:4(5Z, 8Z, 11Z, 14Z)/P-18:0), harderoporphyrinogen, chloropanaxydiol, (Z)-2-octenal, N1,N8-diacetylspermidine, 1-nitroheptane, venoterpine, α-CEHC, LysoPE (20:0/0:0), corticrocin) metabolites were identified as risk factors. The Lasso regression model incorporating these ten metabolic biomarkers and five traditional physiological indicators displayed better differentiation than the traditional model, represented by the elevated area under receiver operating characteristic curve (AUROC) from 96.80 to 100.0%. Furthermore, patients with septic shock presented a significantly lower level of PE-Cer (d16:1(4E)/19:0). This study suggests that metabolomic profiling could be an effective tool for sepsis diagnosis.

Dexmedetomidine Alleviates Gut-Vascular Barrier Damage and Distant Hepatic Injury Following Intestinal Ischemia/Reperfusion Injury in Mice.

BACKGROUND: Intestinal ischemia/reperfusion (I/R) challenge often results in gut barrier dysfunction and induces distant organ injury. Dexmedetomidine has been shown to protect intestinal epithelial barrier against I/R attack. The present study aims to investigate the degree to which intestinal I/R attack will contribute to gut-vascular barrier (GVB) damage, and to examine the ability of dexmedetomidine to minimize GVB and liver injuries in mice. METHODS: In vivo, intestinal ischemic challenge was induced in mice by clamping the superior mesenteric artery for 45 minutes. After clamping, the mice were subjected to reperfusion for either 2, 4, 6, or 12 hours. Intraperitoneal injection of dexmedetomidine 15, 20, or 25 µg·kg-1 was performed intermittently at the phase of reperfusion. For the in vitro experiments, the challenge of oxygen-glucose deprivation/reoxygenation (OGD/R) was established in cultured vascular endothelial cells, and dexmedetomidine (1 nM) was used to treat the cells for 24 hours. Moreover, in vivo and in vitro, SKL2001 (a specific agonist of ß-catenin) or XAV939 (a specific inhibitor of ß-catenin) was applied to determine the role of ß-catenin in the impacts provided by dexmedetomidine. RESULTS: The attack of intestinal I/R induced GVB damage. The greatest level of damage was observed at 4 hours after intestinal reperfusion. There was a significant increase in plasmalemma vesicle-associated protein-1 (PV1, a specific biomarker for endothelial permeability) expression (5.477 ± 0.718 vs 1.000 ± 0.149; P < .001), and increased translocation of intestinal macromolecules and bacteria to blood and liver tissues was detected (all P < .001). Liver damages were observed. There were significant increases in histopathological scores, serum parameters, and inflammatory factors (all P < .001). Dexmedetomidine 20 µg·kg-1 reduced PV1 expression (0.466 ± 0.072 vs 1.000 ± 0.098; P < .001) and subsequent liver damages (all P < .01). In vitro, dexmedetomidine significantly improved vascular endothelial cell survival (79.387 ± 6.447% vs 50.535 ± 1.766%; P < .001) and increased the productions of tight junction protein and adherent junction protein (all P < .01) following OGD/R. Importantly, in cultured cells and in mice, ß-catenin expression significantly decreased (both P < .001) following challenge. Dexmedetomidine or SKL2001 upregulated ß-catenin expression and produced protective effects (all P < .01). However, XAV939 completely eliminated the protective effects of dexmedetomidine on GVB (all P < .001). CONCLUSIONS: The disruption of GVB occurred following intestinal I/R. Dexmedetomidine alleviated I/R-induced GVB impairment and subsequent liver damage.

Structure characteristics and immunomodulatory activities of a polysaccharide RGRP-1b from radix ginseng Rubra.

The present study was undertaken to explore the structure characteristics, immune regulation, and anti-cancer abilities of polysaccharides in radix ginseng Rubra (RGR). For this purpose, RGR polysaccharides (RGRP) were purified through DEAE and S-300 chromatography. Monosaccharide composition, methylation, and GC-MS analyses, as well as field emission scanning electron microscope (FESEM), atomic force microscope (AFM), Fourier-transformed infrared resonance (FT-IR), and nuclear magnetic resonance (NMR) spectra, were used to establish the structure of RGRP-1b. Our results revealed that RGRP-1a and RGRP-1b possess different molecular weights (21.3 kDa and 10.2 kDa, respectively). RGRP-1a was found to be composed of glucose, while RGRP-1b was composed of glucose, galactose, and arabinose. The main chain structure of RGRP-1b was composed of 1,4-α-Glcp, with a 1,4,6-α-Glcp branch unit. Its side chains were branched at the O-4 position of 1,4,6-α-Glcp, namely 1)-ß-Galp-(4 â†’ 1)-α-Araf-(5 â†’ α-Araf and 1)-ß-Galp-(6 â†’ α-Glcp. The changes in the nitric oxide (NO) levels and cytotoxicity revealed that macrophages probably get activated by RGRP-1b. The expressions of IL-6, IL-12, and TNF-α were found to be upregulated after treatment with RGRP-1b. RGRP-1b thus possesses the potential to arrest the growth of Huh7 through immunoregulation. Our cumulative findings indicate that RGRP-1b obtained from radix ginseng Rubra can function as a strong immune modulator.

UPLC-MS-Based Serum Metabolic Profiling Reveals Potential Biomarkers for Predicting Propofol Responsiveness in Females.

Although previous studies have shown that certain factors interfere with the sensitivity of propofol, the mechanisms for interindividual variability in response to propofol remain unclear. This study aimed to screen the metabolites to predict patients' sensitivity to propofol and to identify metabolic pathways to explore possible mechanisms associated with propofol resistance. Sera from 40 female patients undergoing elective hysteroscopic surgery in a prospective cohort propofol study were obtained before the administration of propofol. The patients' responsiveness to propofol was differentiated based on propofol effect-site concentration. Serum samples from two sets, a discovery set (n = 24) and an independent validation set (n = 16), were analyzed using ultraperformance liquid chromatography coupled with mass spectrometry based untargeted metabolomics. In the discovery set, 494 differential metabolites were screened out, and then 391 potential candidate biomarkers with the area under receiver operating characteristic curve >0.80 were selected. Pathway analysis showed that the pathway of glycerophospholipid metabolism was the most influential pathway. In the independent validation set, six potential biomarkers enabled the discrimination of poor responders from good and intermediate responders, which might be applied to predict propofol sensitivity. The mass spectrometry data are available via MetaboLights (http://www.ebi.ac.uk/metabolights/login) with the identifier MTBLS2311.

Green synthesis of gold nanoparticles from Dendrobium officinale and its anticancer effect on liver cancer.

A novel gold nanoparticle (Do-AuNP) was successfully synthesized from water extracts of traditional Chinese medicine Dendrobium officinale (DO) without using any extra chemicals regents. The physicochemical properties of Do-AuNPs were analyzed by transmission electron microscopy, dynamic light scattering, energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, and atomic force microscopy. The amount of DO extract on the AuNPs was about 13%. In order to evaluate the anti-tumor efficiency and biosafety, the inhibitory rate of HepG2 cells and survival rate of L02 cells were performed in vitro, and the immunohistochemical analysis of H&E, Ki-67, and TUNEL staining were conducted in vivo. Our results demonstrated that Do-AuNP had better anti-tumor efficiency compared with DO extraction alone without increasing toxicity in vivo and in vitro. The present study provides useful information for Do-AuNP as a new nanomedicine for liver cancer.

HMGB1 signaling-regulated endoplasmic reticulum stress mediates intestinal ischemia/reperfusion-induced acute renal damage.

BACKGROUND: Ischemia/reperfusion of the intestine often leads to distant organ injury, but the mechanism of intestinal ischemia/reperfusion-induced renal dysfunction is still not clear. The present study aimed to investigate the mechanisms of acute renal damage after intestinal ischemia/reperfusion challenge and explore the role of released high-mobility group box-1 in this process. METHODS: Intestinal ischemia/reperfusion was induced in male Sprague-Dawley rats by clamping the superior mesenteric artery for 1.5 hours. At different reperfusion time points, anti-high-mobility group box-1 neutralizing antibodies or ethyl pyruvate were administered to neutralize or inhibit circulating high-mobility group box-1, respectively. RESULTS: Significant kidney injury was observed after 6 hours of intestinal reperfusion, as indicated by increased serum levels of urea nitrogen and creatinine, increased expression of neutrophil gelatinase-associated lipocalin, interleukin-6, and MIP-2, and enhanced cell apoptosis, as indicated by cleaved caspase 3 levels in renal tissues. The levels of phosphorylated eIF2ɑ, activating transcription factor 4, and C/EBP-homologous protein (CHOP) were markedly elevated, indicating the activation of endoplasmic reticulum stress in the impaired kidney. High-mobility group box-1 translocated to cytoplasm in the intestine and serum concentrations of high-mobility group box-1 increased notably during the reperfusion phase. Both anti-high-mobility group box-1 antibodies and ethyl pyruvate treatment significantly reduced serum high-mobility group box-1 concentrations, attenuated endoplasmic reticulum stress in renal tissue and inhibited the development of renal damage. Moreover, the elevated expression of receptor for advanced glycation end products in the kidneys after intestinal ischemia/reperfusion was abrogated after high-mobility group box-1 inhibition. CONCLUSION: These results suggested that high-mobility group box-1 signaling regulated endoplasmic reticulum stress and promoted intestinal ischemia/reperfusion-induced acute kidney injury. High-mobility group box-1 neutralization/inhibition might serve as a pharmacological intervention strategy for these pathophysiological processes.

Erratum: Antitumor activity of gambogic acid on NCI-H1993 xenografts via MET signaling pathway downregulation.

[This corrects the article DOI: 10.3892/ol.2015.3719.].

Physicochemical properties of polysaccharides from Ligusticum chuanxiong and analysis of their anti-tumor potential through immunoregulation.

We investigated the extraction, purification, physicochemical properties and biological activity of Ligusticum chuanxiong polysaccharides (LCXPs). Two polysaccharide fractions (Ligusticum chuanxiong [LCX]P-1a and LCXP-3a) were obtained by DEAE Sepharose™ Fast Flow and Sephacryl™S-300 high resolution column chromatography. The results showed that the molecular weight of LCXP-1a and LCXP-3a was 11.159 kDa and 203.486 kDa, respectively. LCXP-1a is composed of rhamnose, glucuronic acid, galacturonic acid, and glucose at a molar percentage of 0.52 : 1.88 : 1.06 : 95.36, But LCXP-3a has another molar percentage of mannose, rhamnose, glucuronic acid, galacturonic acid, glucose, galactose, xylose, arabinose, and fucose of 0.64 : 6.69 : 1.03 : 43.74 : 2.20 : 26.90 : 0.82 : 15.94 : 1.80. Both LCXP-1a and LCXP-3a could stimulate macrophages to produce NO, TNF-α, IL-6, and IL-12p70. Co-culturing macrophages and hepatocellular carcinoma cells showed that LCXP-1a and LCXP-3a inhibited the growth of HepG2 and Hep3B through immunoregulation. They arrested the cell cycle at the G0/G1 phase and promoted apoptosis. Moreover, there was no cytotoxicity to the hepatocyte cell line, LO2. We also noted that the immunomodulatory activity and anti-tumor activity of LCXP-3a were significantly better than those of LCXP-1a. Our data demonstrate that LCXP-3a is potentially a well-tolerated and effective immunomodulatory adjuvant cancer treatment.

Terlipressin relieves intestinal and renal injuries induced by acute mesenteric ischemia via PI3K/Akt pathway.

Background: To date, the effect of vasopressin on organ damages after acute mesenteric ischemia (MI) remains poorly understood. Aims: To investigate the effect of terlipressin, a selective vasopressin V1 receptor agonist, versus norepinephrine on the intestinal and renal injuries after acute MI, and to explore the underlying mechanism of terlipressin. Methods: Acute MI model was produced by clamping the superior mesenteric artery for 1 hour. Immediately after unclamping, terlipressin or norepinephrine was intravenously administered for 2 hours. Meanwhile, in vitro, RAW264.7 cells were treated with lipopolysaccharide or lipopolysaccharide+terlipressin. In addition, wortmannin was used to determine the role of phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) pathway in the potential impacts of terlipressin. Results: MI led to severe hypotension, caused notable intestinal and renal impairments and resulted in high mortality, which were markedly improved by terlipressin or norepinephrine. Terlipressin increased mean arterial pressure, decreased intestinal epithelial cell apoptosis, inhibited the generation of M1 macrophage in intestinal and renal tissues, and hindered the release of inflammatory cytokines after MI. Moreover, in cultured macrophages, terlipressin reduced the mRNA level of specific M1 markers and the release of inflammatory cytokines caused by lipopolysaccharide challenge. Wortmannin decreased the expression of PI3K and Akt induced by terlipressin in cells and in tissues, and abolished the above protective effects conferred by terlipressin. Conclusions: Terlipressin or norepinephrine could effectively improve organ damages and mortality after acute MI. Terlipressin elevates blood pressure and inhibits intestinal epithelial apoptosis and macrophage M1 polarization via the PI3K/Akt pathway.

Immunomodulatory effects of a polysaccharide from Solanum nigrum Linne through TLR4-MyD88 signaling pathway.

Solanum nigrum Linne polysaccharide (SNLP), an active ingredient from Solanum nigrum Linne, has been proposed to inhibit tumor growth and display immunomodulatory activity. However, the molecular mechanism related to immune regulation remains unclear. In the present study, a homogeneous polysaccharide (SNLP-1) was extracted, the immune effects and the underlying molecular mechanisms were investigated. The immunomodulatory activity assay in vitro showed that SNLP-1 promoted the release of NO and TNF-α and IL-6 secretion in macrophages. In tumor-bearing mice, SNLP-1 could improve immune function including increasing the spleen index, thymus index and inducing Th1 responses mediated by IL-2, IFN-γ, and TNF, as well as decreasing the tumor weight. Furthermore, SNLP-1 elevated the expression of the critical nodes in the TLR4-Myd88 signaling pathways in vitro and in vivo. These results indicated that TLR4-MyD88 signal pathway may be one of the signal pathways of immune regulation of SNLP-1.

Impact of Anxiety or Depression Symptoms on Propofol Requirements for Sedation in Females: A Prospective Cohort Study.

Mental disorders are thought to affect various clinical outcomes during the perioperative period. Among them, anxiety and depression are 2 of the most common types. However, the impacts of anxiety or depression on propofol requirements remain unclear. This study aimed to investigate the effects of anxiety or depression symptoms on the propofol requirements for sedation in females. This study recruited female patients aged 18 to 65 years, with American Society of Anesthesiologists physical status classification of 1 to 2, who were scheduled for hysteroscopic surgery under propofol-based intravenous anesthesia. The day before surgery, the Hospital Anxiety and Depression Scale (HADS) was used to assess the symptoms of anxiety and depression within the past 6 months. Target-controlled propofol was gradually titrated to achieve 3 desired levels of sedation: Modified Observer's Assessment of Alertness/Sedation scale (MOAA/S) score 3, MOAA/S score 1, and MOAA/S score 1 and Narcotrend Index <65. The effect-site concentration of propofol correlated with HADS-Anxiety scores for the sedation levels of MOAA/S 3 and 1 (r = .249, P = .008; and r = .190, P = .045, respectively). However, the propofol requirements did not correlate with HADS-Depression scores at any sedation level. In conclusion, female patients with anxiety symptoms, but not depression symptoms, required a higher dose of propofol for sedation in hysteroscopy.