Pharmacologically significant constituents collectively responsible for anti-sepsis action of XueBiJing, a Chinese herb-based intravenous formulation.

Sepsis, a life-threatening health issue, lacks effective medicine targeting the septic response. In China, treatment combining the intravenous herbal medicine XueBiJing with conventional procedures reduces the 28-day mortality of critically ill patients by modulating septic response. In this study, we identified the combined active constituents that are responsible for the XueBiJing's anti-sepsis action. Sepsis was induced in rats by cecal ligation and puncture (CLP). The compounds were identified based on their systemic exposure levels and anti-sepsis activities in CLP rats that were given an intravenous bolus dose of XueBiJing. Furthermore, the identified compounds in combination were assessed, by comparing with XueBiJing, for levels of primary therapeutic outcome, pharmacokinetic equivalence, and pharmacokinetic compatibility. We showed that a total of 12 XueBiJing compounds, unchanged or metabolized, circulated with significant systemic exposure in CLP rats that received XueBiJing. Among these compounds, hydroxysafflor yellow A, paeoniflorin, oxypaeoniflorin, albiflorin, senkyunolide I, and tanshinol displayed significant anti-sepsis activities, which involved regulating immune responses, inhibiting excessive inflammation, modulating hemostasis, and improving organ function. A combination of the six compounds, with the same respective doses as in XueBiJing, displayed percentage survival and systemic exposure in CLP rats similar to those by XueBiJing. Both the combination and XueBiJing showed high degrees of pharmacokinetic compatibility regarding interactions among the six active compounds and influences of other circulating XueBiJing compounds. The identification of XueBiJing's pharmacologically significant constituents supports the medicine's anti-sepsis use and provides insights into a polypharmacology-based approach to develop medicines for effective sepsis management.

Sestrin2 protects against lethal sepsis by suppressing the pyroptosis of dendritic cells.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sestrin2 (SESN2), a highly evolutionarily conserved protein, is critically involved in the cellular response to various stresses and has been confirmed to maintain the homeostasis of the internal environment. However, the potential effects of SESN2 in regulating dendritic cells (DCs) pyroptosis in the context of sepsis and the related mechanisms are poorly characterized. In this study, we found that SESN2 was capable of decreasing gasdermin D (GSDMD)-dependent pyroptosis of splenic DCs by inhibiting endoplasmic reticulum (ER) stress (ERS)-related nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated ASC pyroptosome formation and caspase-1 (CASP-1) activation. Furthermore, SESN2 deficiency induced NLRP3/ASC/CASP-1-dependent pyroptosis and the production of proinflammatory cytokines by exacerbating the PERK-ATF4-CHOP signaling pathway, resulting in an increase in the mortality of septic mice, which was reversed by inhibiting ERS. These findings suggest that SESN2 appears to be essential for inhibiting NLRP3 inflammasome hyperactivation, reducing CASP-1-dependent pyroptosis, and improving sepsis outcomes through stabilization of the ER. The present study might have important implications for exploration of novel potential therapeutic targets for the treatment of sepsis complications.

Hierarchical integrated processing of reward-related regions in obese males: A graph-theoretical-based study.

Abnormal activities in reward-related regions are associated with overeating or obesity. Preliminary studies have shown that changes in neural activity in obesity include not only regional reward regions abnormalities but also impairments in the communication between reward-related regions and multiple functional areas. A recent study has shown that the transitions between different neural networks are nonrandom and hierarchical, and that activation of particular brain networks is more likely to occur after other brain networks. The aims of this study were to investigate the key nodes of reward-related regions in obese males and explore the hierarchical integrated processing of key nodes. Twenty-four obese males and 24 normal-weight male controls of similar ages were recruited. The fMRI data were acquired using 3.0 T MRI. The fMRI data preprocessing was performed in DPABI and SPM 12. Degree centrality analyses were conducted using GRETNA toolkit, and Granger causality analyses were calculated using DynamicBC toolbox. Decreased degree centrality was observed in left ventral medial prefrontal cortex (vmPFC) and right parahippocampal/hippocampal gyrus in group with obesity. The group with obesity demonstrated increased effective connectivity between left vmPFC and several regions (left inferior temporal gyrus, left supplementary motor area, right insular cortex, right postcentral gyrus, right paracentral lobule and bilateral fusiform gyrus). Increased effective connectivity was observed between right parahippocampal/hippocampal gyrus and left precentral/postcentral gyrus. Decreased effective connectivity was found between right parahippocampal/hippocampal gyrus and left inferior parietal lobule. This study identified the features of hierarchical interactions between the key reward nodes and multiple function networks. These findings may provide more evidence for the existing view of hierarchical organization in reward processing.

Comparative evaluation of epidural bupivacaine alone and bupivacaine combined with magnesium sulfate in providing postoperative analgesia: a meta-analysis of randomized controlled trials.

BACKGROUND: The comparative efficacy of epidural bupivacaine alone and bupivacaine combined with magnesium sulfate in providing postoperative analgesia remains controversial. METHODS: We searched Mediline (OvidSP), EMBASE (OvidSP) and Cochrane Central Register of Controlled Trials (CENTRAL) to identify trials that compared epidural bupivacaine and magnesium sulfate combination (intervention) with bupivacaine alone (control). Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework was used to assess the quality of evidence. RESULTS: Eleven studies fulfilled our inclusion criteria after screening. We found that epidural bupivacaine combined with magnesium sulfate could prolong the time for first rescue analgesics (SMD 4.96; 95% CI [2.75, 7.17], P < 0.00001, I2 = 98%), reduce the number of patients who need rescue analgesics (RR 0.38; 95% CI [0.20, 0.74], P = 0.004, I2 = 75%) and requirement for rescue analgesics (SMD -2.65; 95% CI [- 4.23, - 1.06], P = 0.001, I2 = 96%). CONCLUSIONS: Magnesium suifate as an adjuvant of epidural bupivacaine improved postoperative analgesia. However, we rated the quality of evidence to be very low because of high heterogeneity, imprecise of results and small sample sizes. Furthermore, further large high-quality trials are still needed to confirm the effects of magnesium sulfate on postoperative analgesia.

[Study on antipyretic effect of rhubarb on rats and its antipyretic ingredients].

A combination of LC-MS technology and activity evaluation was used to identify the antipyretic ingredients in rhubarb. The rat model of fever was established with dried yeast and then was administered ethanol extract and different polar fractions of rhubarb. Next, the anal temperature of these rats was measured and recorded at 0.5, 1, 2, 3, 4 and 5 h after administration, and the inhibition rate of each part on the rise of body temperature was calculated. The inhibition rate is higher and the antipyretic effect is better. The chemical composition of the effective fraction was analyzed with UPLC-ESI-Orbitrap-MS/MS technology. Compared with the model group, the increase of body temperature of ethanol extract group all reduced at each measurement time especially after 3 h, and the inhibition rate were 38.7%(P<0.05), 78.2%(P<0.01) and 72.4%(P<0.01) at 3 h, 4 h, and 5 h after administration, respectively. Both n-butanol and water fraction showed some antipyretic activity in the early stage, with the inhibition rate of 28.1%(P<0.01) and 24.9%(P<0.05) at 1 h after administration, respectively, while other fractions were not active. Thirty-three and twelve compounds were identified from n-butanol and water fraction by LC-MS/MS analysis, respectively, including ten tannins, fifteen anthraquinone glycosides, four anthrone glycosides, one phenolic glycoside, one naphthaline derivative, one anthraquinone and one sucrose. These results revealed that rhubarb had antipyretic activity on rats, and tannin and anthraquinone glycosides were the main active ingredients inside.

Integration of Neural Reward Processing and Appetite-Related Signaling in Obese Females: Evidence From Resting-State fMRI.

BACKGROUND: The reward-related regions have been considered a crucial component in the regulation of eating behavior. Furthermore, appetite-related regions associated with reward can influence eating behaviors through altered functional activity related to food in brain areas associated with emotion, memory, sensory processing, motor function, and cognitive control. PURPOSE: To investigate the key nodes in obese females of reward-related regions and, based on key nodes, to evaluate the directionality of functional connectivity between key nodes and appetite-related regions. STUDY TYPE: Prospective. POPULATION: Twenty-eight obese and 28 normal-weight female controls of similar age. FIELD STRENGTH/SEQUENCE: 3.0 T MRI and echo planar imaging (EPI) sequence, 3D BRAVO sequence. ASSESSMENT: The fMRI data preprocessing was based on the Data Processing & Analysis of Brain Imaging and Statistical Parametric Mapping 12. Degree centrality calculation was based on the GRETNA toolkit and granger causality analysis were based on the DynamicBC toolbox. Statistical Tests: Independent two-sample t-tests were used to assess the differences in demographic and clinical data between two groups. Two-sample t-tests were conducted to test the difference in degree centrality and effective connectivity of key nodes between two groups. RESULTS: Compared with normal-weight controls, obese females showed an increased degree centrality in the left ventral striatum/caudate (t = 2.96808, P < 0.05) and decreased degree centrality in right orbitofrontal cortex (OFC) (t = -3.3558, P < 0.05). The obese females showed directional effective connectivity between left ventral striatum/caudate and several regions (left inferior temporal gyrus, fusiform gyrus, postcentral gyrus, and right precentral gyrus) (P < 0.05). Directional effective connectivity was also observed between the right OFC and several regions (left middle temporal gyrus, cuneus, OFC, superior temporal gyrus, middle frontal gyrus, and right inferior parietal lobule) (P < 0.05). DATA CONCLUSION: The left ventral striatum/caudate and right OFC are key nodes in reward-related regions. The key nodes with reward processing mainly enhance visual processing of information and further participate in cognitive, attention, and sensorimotor processing. LEVEL OF EVIDENCE: 1. Technical Efficacy: Stage 4. J. Magn. Reson. Imaging 2019;50:541-551.

Synthesis of novel galactose functionalized gold nanoparticles and its radiosensitizing mechanism.

BACKGROUND: Biocompatible gold nanoparticles (GNPs) are potentially practical and efficient agents in cancer radiotherapy applications. In this study, we demonstrated that GNPs can significantly modulate irradiation response of hepatocellular carcinoma cells in vitro and investigated the underlying mechanisms. We co-grafted galactose (GAL) targeting hepatocyte specific asialoglycoprotein receptor and Polyethylene Glycol (PEG) onto GNPs surfaces to increase GNPs targeting specificity and stability. RESULTS: This novel GAL-PEG-GNPs and bare GNPs show similar appearance and cytotoxicity profiles, while more GAL-PEG-GNPs can be effectively uptaken and could enhance cancer cell killing. CONCLUSION: GAL-PEG-GNPs have better radiosensitization to HepG2. The sensitization mechanism of GAL-PEG-GNPs is related to the apoptotic gene process activated by generation of a large amount of free radicals induced by GNPs.

[Comparative Study on Photosynthetic Characteristics and Medicinal Ingredients in Different Months of Inula nervosa].

OBJECTIVE: To compare the photosynthetic characteristics and medicinal ingredients in different months in order to provide a theoretical basis for cultivation and harvest of Inula nervosa. METHODS: The photosynthetic characteristics was measured by using LI-6400 and morphological characteristics were compared in different months, and the contents of total flavonoids and total phenols were determined by UV spectrophotometry. RESULTS: Net photosynthetic rate of Inula nervosa was the highest in June, which showed a single peak curve, and the average of daily change reached to 8.50 µmol/(m2 x s). Light response curve data showed the ability of using the strongest light was in June. Chlorophyll fluorescence parameters values also displayed that, openness of reflect center and photochemical efficiency of leaves' photosystem II were the highest, which also had the fastest rate of electron transfer in June. Morphological indicators showed that the single leaf area and leaf area of Inula nervosa were significantly higher in June than those in other months. The content of total phenols were much higher than that of total flavonoids in Inula nervosa. And the medicinal ingredient content of the underground part was higher than that in the aerial part. CONCLUSION: The best harvest time of underground part of Inula nervosa should be after autumn, when the weight and active ingredients are accumulated to a considerable level.

[Meta Analysis on Yield Effect of Biochar for Staple Crops in China].

In order to quantitatively evaluate the impact of biochar on the yield of staple crops in China, a total of 866 pairs of data from 116 published studies were collected. Meta analysis was used to quantitatively analyze the impact of biochar on the yield of staple crops in China and its influencing factors. Meanwhile, a structural equation model (SEM) was constructed to further explain the interaction among the factors. The results showed that compared with no biochar application, biochar application could improve the physical and chemical properties of the soil in the main grain fields and increase the yield of the main grain crops, with an average yield increase rate of 8.77%. Among them, when the pH of biochar was 7-8, the average yield increase rate was the highest, reaching 26.49%. When C/N<60, the average yield increase rate was 13.73%, which was significantly higher than that of C/N≥60. Applying biochar to acidic or neutral soil could give full play to its yield-increasing effect. When the amount of carbon applied was 10-20 t·hm-2, the average yield increase rate of wheat and corn was the highest. The average yield of rice was the highest when the amount of carbon was 15-25 t·hm-2. However, the yield-increasing rates of rice with different carbon application levels were similar, so it is possible to consider losing part of the yield and give consideration to the economic benefits by appropriate reduction. In addition, the yield-increasing effect of biochar decreased with the increase in application years, and generally the yield-increasing effect was not significant after three years. The SEM showed that the application amount of biochar not only directly affected the yield of staple crops but also indirectly affected the yield of staple crops by improving soil fertility, whereas biochar C/N and pH only affected the yield of staple crops by improving soil fertility. Therefore, in the future application of biochar, priority should be given to applying it to acidic or neutral soil with low fertility, and its C/N and pH should be controlled below 60 and 7-8, respectively. Soil conditions, biochar characteristics, and field management measures should be comprehensively considered to maximize the yield of staple crops. This research can provide scientific basis and theoretical basis for the popularization and rational application of biochar.

Characteristics of circRNAs expression profiles in the piglets intestine induced by oxidative stress.

BACKGROUD: Oxidative stress (OS) can affect the expression of key genes and destroy the intestinal structure. However, it is unclear how OS regulates the expression of circular RNAs (circRNAs), microRNAs (miRNAs) and mRNAs. OBJECTIVE: The aim of this study was to examine the expression of circRNAs, miRNAs and mRNAs exposed to OS. METHODS: Piglets were exposed to diquat (DQ), a herbicide, and the activity of antioxidant enzymes and the morphology of the intestine were investigated. We utilized whole transcriptome sequencing to examine the global expression of circRNAs, miRNAs and mRNAs in the jejunum. RESULTS: Compared to controls, 751 circRNAs, 731 miRNAs and 164 mRNAs were differentially expressed in diquat-treated piglets. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that oxidative phosphorylation, RNA degradation and ubiquitin-mediated proteolysis were closely associated with OS. CONCLUSIONS: Our results indicated that diquat-induced OS alters the intestinal structure, resulting in the differential expression of circRNAs, miRNAs and mRNAs in the jejunum of piglets. Meanwhile, OS weakened the enzyme antioxidant system in serum of piglets. Our results provide a foundation for further studies on the mechanisms involved in the response to OS in the jejunum.

Single-cell transcriptome profiling of the immune space-time landscape reveals dendritic cell regulatory program in polymicrobial sepsis.

Rationale: Evident immunosuppression has been commonly seen among septic patients, and it is demonstrated to be a major driver of morbidity. Nevertheless, a comprehensive view of the host immune response to sepsis is lacking as the majority of studies on immunosuppression have focused on a specific type of immune cells. Methods: We applied multi-compartment, single-cell RNA sequencing (scRNA-seq) to dissect heterogeneity within immune cell subsets during sepsis progression on cecal ligation and puncture (CLP) mouse model. Flow cytometry and multiplex immunofluorescence tissue staining were adopted to identify the presence of 'mature DCs enriched in immunoregulatory molecules' (mregDC) upon septic challenge. To explore the function of mregDC, sorted mregDC were co-cultured with naïve CD4+ T cells. Intracellular signaling pathways that drove mregDC program were determined by integrating scRNA-seq and bulk-seq data, combined with inhibitory experiments. Results: ScRNA-seq analysis revealed that sepsis induction was associated with substantial alterations and heterogeneity of canonical immune cell types, including T, B, natural killer (NK), and myeloid cells, across three immune-relevant tissue sites. We found a unique subcluster of conventional dendritic cells (cDCs) that was characterized by specific expression of maturation- and migration-related genes, along with upregulation of immunoregulatory molecules, corresponding to the previously described 'mregDCs' in cancer. Flow cytometry and in stiu immunofluorescence staining confirmed the presence of sepsis-induced mregDC at protein level. Functional experiments showed that sepsis-induced mregDCs potently activated naive CD4+ T cells, while promoted CD4+ T cell conversion to regulatory T cells. Further observations indicated that the mregDC program was initiated via TNFRSF-NF-κB- and IFNGR2-JAK-STAT3-dependent pathways within 24 h of septic challenge. Additionally, we confirmed the detection of mregDC in human sepsis using publicly available data from a recently published single-cell study of COVID-19 patients. Conclusions: Our study generates a comprehensive single-cell immune landscape for polymicrobial sepsis, in which we identify the significant alterations and heterogeneity in immune cell subsets that take place during sepsis. Moreover, we find a conserved and potentially targetable immunoregulatory program within DCs that associates with hyperinflammation and organ dysfunction early following sepsis induction.

circGLI3 Inhibits Oxidative Stress by Regulating the miR-339-5p/VEGFA Axis in IPEC-J2 Cells.

As a new type of noncoding RNA, circular RNA (circRNA) is stable in cells and not easily degraded. This type of RNA can also competitively bind miRNAs to regulate the expression of their target genes. The role of circRNA in the mechanism of intestinal oxidative stress (OS) in weaned piglets is still unclear. In our research, diquat (DQ) was used to induce OS in small intestinal epithelial cells (IPEC-J2) to construct an OS cell model. Mechanistically, dual luciferase reporter assays, fluorescence in situ hybridization (FISH), and western blotting were performed to confirm that circGLI3 directly sponged miR-339-5p and regulated the expression of VEGFA. Overexpression of circGLI3 promoted IPEC-J2 cell proliferation, increased the proportion of S-phase cells (P < 0.01), and reduced reactive oxygen species (ROS) generation when IPEC-J2 cells were subjected to OS. circGLI3 can increase the activity of glutathione peroxidase (GSH-Px) and the total antioxidant capacity (T-AOC) in IPEC-J2 cells and reduce the malondialdehyde (MDA) content and levels of inflammatory factors. Therefore, overexpression of circGLI3 reduced oxidative damage, whereas miR-339-5p mimic counteracted these effects. We identified a regulatory network composed of circGLI3, miR-339-5p, and VEGFA and verified that circGLI3 regulates VEGFA by directly binding miR-339-5p. The expression of VEGFA affects IPEC-J2 cell proliferation, cell cycle progression, and ROS content and changes the levels of antioxidant enzymes and inflammatory factors. This study reveals the molecular mechanism by which circGLI3 inhibits OS in the intestine of piglets and provides a theoretical basis for further research on the effect of OS on intestinal function.

Effect of carrier solvent in 1,2-indanedione formulation on the development of fingermarks on porous substrates.

As an important technique for the detection of fingermarks on porous surfaces, 1,2-indanedione is widely used due to its excellent detection performance. In order to optimize the effectiveness of 1,2-indanedione, several institutions have modified the original formulation. In this study, four different 1,2-indanedione formulations were used to treat fingermarks deposited on different porous substrates to determine the most suitable formulation and whether Solstice-PF can be an alternative carrier solvent for the currently used HFE7100. It was found that the Solstice-PF-based formulation performed similarly to the HFE7100-based formulation on copy paper, but when treating fingermarks deposited on brown paper and newspaper, Solstice-PF was superior to HFE7100 by developing up to 10% more marks graded 3 and 4 regardless of the ageing period. The results confirm that Solstice-PF can be used as an alternative carrier solvent for 1,2-indanedione formulations with good detection rates and lower costs.

Sestrin2 protects dendrite cells against ferroptosis induced by sepsis.

Ferroptosis is a nonapoptotic form of programmed cell death triggered by the accumulation of reactive oxygen species (ROS) depended on iron overload. Although most investigations focus on the relationship between ferroptosis and cancer, neurodegenerative diseases, and ischemia/reperfusion injury, research on ferroptosis induced by immune-related inflammatory diseases, especially sepsis, is scarce. Sestrin2 (Sesn2), a highly evolutionary and stress-responsive protein, is critically involved in defense against oxidative stress challenges. Upregulated expression of Sesn2 has been observed in preliminary experiments to have an antioxidative function in the context of an inflammatory response. Nevertheless, the underlying function of Sesn2 in inflammation-mediated ferroptosis in the immune system remains uncertain. The current study aimed to demonstrate the protective effect of Sesn2 on ferroptosis and even correlations with ferroptosis and the functions of ferroptotic-dendritic cells (DCs) stimulated with lipopolysaccharide (LPS). The mechanism underlying DCs protection from LPS-induced ferroptosis by Sesn2 was further explored in this study. We found that the immune response of DCs assessed by co-stimulatory phenotypes was gradually enhanced at the peak time of 12 h upon 1 µg/ml LPS stimulation while ferroptosis in DCs treated with LPS at 24 h was significantly detected. LPS-induced ferroptosis showed a suppressive impact on DCs in phenotypic maturation, which was conversely relieved by the ferroptotic inhibitor. Compared with wild-type (WT) mice, DCs in genetic defective mice of Sesn2 (Sesn2-/-) exhibited exacerbated ferroptosis. Furthermore, the protective effect of Sesn2 on ferroptosis was noticed to be associated with the ATF4-CHOP-CHAC1 pathway, eventually exacerbating ferroptosis by degrading of glutathione. These results indicate that Sesn2 can suppress the ferroptosis of DCs in sepsis by downregulating the ATF4-CHOP-CHAC1 signaling pathway, and it might play an antioxidative role.

Antagonism of Cerebral High Mobility Group Box 1 Ameliorates Dendritic Cell Dysfunction in Sepsis.

Sepsis has emerged as a global health issue, and accounts for millions of deaths in intensive care units. Dysregulation of the immune response reportedly contributes to the pathogenesis and progression of this lethal condition, which involves both the dysfunction of immune cells and incompetent immunomodulatory mechanisms. High mobility group box 1 (HMGB1) is known as a later inflammatory mediator and is critically involved in the severity and prognosis of sepsis by inducing intractable inflammation and dysfunction of various immune cells. In the present study, we found that intracerebroventricular (ICV) injection of Box A, a specific antagonist of HMGB1, restored the dysregulated response of splenic dendritic cells (DCs) in septic mice by enhancing the expression of surface molecules, including CD80, CD86, and MHC-II, as well as improving DC priming of T lymphocytes. Cerebral HMGB1 was also confirmed to have potent inhibitory effects on DC functions when administrated by ICV injection in normal mice. The brain cholinergic system was found to mediate the immunomodulatory effects of central HMGB1, as it exhibited enhanced activity with persistent HMGB1 exposure. Furthermore, the inhibitory effects of cerebral HMGB1 on the response of peripheral DCs were also blocked by α7nAchR gene knockout. These findings provide novel insight into the relationship between cerebral HMGB1 and splenic DC dysfunction during sepsis, which is, at least in part, dependent on cholinergic system activity.

Sestrin2 protects dendritic cells against endoplasmic reticulum stress-related apoptosis induced by high mobility group box-1 protein.

Sestrin2 (SESN2) is a highly evolutionary conserved protein and involved in different cellular responses to various stresses. However, the potential function of SESN2 in immune system remains unclear. The present study was designed to test whether dendritic cells (DCs) could express SESN2, and investigate the underlying molecular mechanism as well as its potential significance. Herein, we firstly reported that SESN2 was expressed in DCs after high mobility group box-1 protein (HMGB1) stimulation and the apoptosis of DCs was obviously increased when SESN2 gene silenced by siRNA. Cells undergone SESN2-knockdown promoted endoplasmic reticulum (ER) stress (ERS)-related cell death, markedly exacerbated ER disruption as well as the formation of dilated and aggregated structures, and they significantly aggravated the extent of ERS response. Conversely, overexpressing SESN2 DCs markedly decreased apoptotic rates and attenuated HMGB1-induced ER morphology fragment together with inhibition of ERS-related protein translation. Furthermore, sesn2-/--deficient mice manifested increased DC apoptosis and aggravated ERS extent in septic model. These results indicate that SESN2 appears to be a potential regulator to inhibit apoptotic ERS signaling that exerts a protective effect on apoptosis of DCs in the setting of septic challenge.

Clinical Efficiency of Vasopressin or Its Analogs in Comparison With Catecholamines Alone on Patients With Septic Shock: A Systematic Review and Meta-Analysis.

BACKGROUND: Vasopressin is an efficient remedy for septic shock patients as its great capacity in promoting hemodynamic stabilization. The aim of current systematic review and meta-analysis is to compare the clinical efficiency of vasopressin or its analogs with sole catecholamines on patients with septic shock. METHODS: A systematic search of Cochrane Library, EMBASE, and PubMed online databases was performed up to 30 Oct 2019 to identify randomized controlled trials comparing use of vasopressin or its analogs (e.g., terlipressin, selepressin) with administration of catecholamines alone. RESULTS: We included 23 RCTs with 4,225 patients in the current study. Compared with solely use of catecholamines, administration of vasopressin or its analogs was not associated with reduced 28-day or 30-day mortality among patients with septic shock [RR=0.94 (95% CI, 0.87-1.01), P=0.08, I2 = 0%]. The result of primary endpoint remained unchanged after conducting sensitivity analysis. Despite a significantly higher risk of digital ischemia in patients receiving vasopressin or its analogs [RR=2.65 (95% CI, 1.26-5.56), P < 0.01, I2 = 48%], there was no statistical significance in the pooled estimate for other secondary outcomes, including total adverse events, arrhythmia, acute myocardial infarction (AMI) and cardiac arrest, acute mesenteric ischemia, ICU/hospital length of stay, and mechanical ventilation (MV) duration. CONCLUSIONS: The administration of vasopressin or its analogs was not associated with reduced 28-day or 30-day mortality among patients with septic shock, while an increased incidence of digital ischemia should be noted in patients receiving agonists for vasopressin receptors.

Sestrin2: Its Potential Role and Regulatory Mechanism in Host Immune Response in Diseases.

Sestrin2 (SESN2), a highly evolutionarily conserved protein, is critically involved in cellular responses to various stresses. SESN2 has a protective effect on physiological and pathological states mainly via regulating oxidative stress, endoplasmic reticulum stress, autophagy, metabolism, and inflammation. In recent years, breakthrough investigations with regard to the regulation and signaling mechanisms of SESN2 have markedly deepened our understanding of its potential role as well as its significance in host response. However, the functions of SESN2 in the immune system and inflammation remain elusive. It has been documented that many immune cells positively express SESN2 and, in turn, that SESN2 might modulate cellular activities. This review incorporates recent progress and aims to provide novel insight into the protective role and regulatory pathway of SESN2, which acts as a potential biomarker and therapeutic target in the context of various diseases.

Activation of Central Alpha 7 Nicotinic Acetylcholine Receptor Reverses Suppressed Immune Function of T Lymphocytes and Protects Against Sepsis Lethality.

Sepsis remains the leading cause of high mortality and huge financial burden in intensive care units (ICU), but with scarce effective treatments due to refractory multiple organ dysfunction and persistent immunosuppression. Treatments that aim at modulating immune function and attenuating multiple organ injury will certainly benefit septic cases. Alpha 7 nicotinic acetylcholine receptor (α7nAchR) has been reported with potent immunomodulatory properties in various diseases as the essential mediator of the cholinergic anti-inflammatory pathway (CAP). Few studies have demonstrated the potential effect of central α7nAchR on the progression and prognosis of septic response, while its expression was first discovered on neurons and most abundant in the central nervous system. In the present study, it was found severe damage of multiple organs under the operation of cecal ligation and puncture (CLP) in rats, including heart, liver, kidneys, and lungs, as evidenced by abnormal histomorphology and notable elevation of injury markers. Concurrently, the function of spleen CD4+ T cells was disrupted under septic challenge, accompanied by polarization of helper T cell (Th)2, which exhibited outward signs of immunosuppression. Intracerebroventricular injection of PNU282987, a selective agonist of α7nAchR, significantly alleviated multiple organ injury, reversed immunosuppressive state, and improved the outcome of septic rats, while they were exacerbated by treatment with methyllycaconitine, a selective antagonist of α7nAchR. This study provides the first evidence that activation of central α7nAchR is beneficial for attenuating multiple organ dysfunction as well as abnormal immune response, and improving the prognosis of rats when exposed with sepsis.

Glutamate Transporters/Na(+), K(+)-ATPase Involving in the Neuroprotective Effect as a Potential Regulatory Target of Glutamate Uptake.

The glutamate (Glu) transporters GLAST and GLT-1, as the two most important transporters in brain tissue, transport Glu from the extracellular space into the cell protecting against Glu toxicity. Furthermore, GLAST and GLT-1 are sodium-dependent Glu transporters (GluTs) that rely on sodium and potassium gradients generated principally by Na(+), K(+)-ATPase to generate ion gradients that drive Glu uptake. There is an interaction between Na(+), K(+)-ATPase and GluTs to modulate Glu uptake, and Na(+), K(+)-ATPase α, ß or γ subunit can be directly coupled to GluTs, co-localizing with GLAST or GLT-1 in vivo to form a macromolecular complex and operate as a functional unit to regulate glutamatergic neurotransmission. Therefore, GluTs/Na(+), K(+)-ATPase may be involved in the neuroprotective effect as a potential regulatory target of Glu uptake in neurodegenerative diseases induced by Glu-mediated neurotoxicity as the final common pathway.