ASTRAGALOSIDE â £ MODULATES GUT MACROPHAGES M1/M2 POLARIZATION BY RESHAPING GUT MICROBIOTA AND SHORT CHAIN FATTY ACIDS IN SEPSIS.

ABSTRACT: M1 macrophage-mediated inflammation is critical in sepsis. We previously found the protective role of astragaloside intravenous (AS-IV) in sepsis-associated gut impairment, whose specific mechanism remains unknown. Gut microbiota modulates gut homeostatic balance to avoid excessive inflammation. Here, we aimed to investigate effects of AS-IV on gut macrophages polarization and potential roles of gut microbiota and short chain fatty acids (SCFAs) in septic gut damage. Mice were pretreated by AS-IV gavage for 7 days before cecal ligation and puncture. M1 polarization of gut lamina propria macrophages (LpMs) was promoted by cecal ligation and puncture, accompanied by abnormal cytokines release and intestinal barrier dysfunction. NLRP3 inflammasome was activated in M1 LpMs. 16S rRNA sequencing demonstrated gut microbiota imbalance. The levels of acetate, propionate, and butyrate in fecal samples decreased. Notably, AS-IV reversed LpMs M1/M2 polarization, lightened gut inflammation and barrier injury, reduced NLRP3 inflammasome expression in LpMs, restored the diversity of gut microbiome, and increased butyrate levels. Similarly, these benefits were mimicked by fecal microbiota transplantation or exogenous butyrate supplementation. In Caco-2 and THP-1 cocultured model, LPS and interferon γ caused THP-1 M1 polarization, Caco-2 barrier impairment, abnormal cytokines release, and high NLRP3 inflammasome expression in THP-1 cells, all of which were mitigated by butyrate administration. However, these protective effects of butyrate were abrogated by NLRP3 gene overexpression in THP-1. In conclusion, AS-IV can ameliorate sepsis-induced gut inflammation and barrier dysfunction by modulating M1/M2 polarization of gut macrophages, whose underlying mechanism may be restoring gut microbiome and SCFA to restrain NLRP3 inflammasome activation.

Astragaloside IV attenuates sepsis-induced intestinal barrier dysfunction via suppressing RhoA/NLRP3 inflammasome signaling.

Intestinal barrier dysfunction is a trigger for sepsis progression. NLRP3 inflammasome and RhoA contribute to sepsis and intestinal inflammation. The current study aimed to explore the effects of Astragaloside IV (AS-IV), a bioactive compound from Astragalus membranaceus, on sepsis-caused intestinal barrier dysfunction and whether NLRP3 inflammasome and RhoA are involved. Septic mice modeled by cecal ligation and puncture (CLP) operation were administered with 3 mg/kg AS-IV intravenously. AS-IV decreased mortality, cytokines release, I-FABP secretion, intestinal histological score and barrier permeability, and increased tight junction (TJ) expression in intestine in CLP model. Also, in Caco-2 cells subjected to lipopolysaccharide (LPS), 200 µg/mL AS-IV co-incubation reduced cytokines levels and enhanced in vitro gut barrier function without cytotoxicity. Subsequently, NLRP3 inflammasome and RhoA were highly activated both in intestinal tissue in vivo and in Caco-2 cells in vitro, both of which were significantly suppressed by AS-IV treatment. In addition, the benefits of AS-IV on Caco-2 monolayer barrier were largely counteracted by RhoA agonist CN03 and NLRP3 gene overexpression, respectively. Furthermore, LPS-induced NLRP3 inflammasome activation was abrogated by RhoA inhibitor C3 exoenzyme. However, NLRP3 knockdown by siRNA hardly affected RhoA activation in Caco-2 cells. These data suggest that AS-IV protects intestinal epithelium from sepsis-induced barrier dysfunction via inhibiting RhoA/NLRP3 inflammasome signal pathway.

Lidocaine-prilocaine cream reduces catheter-related bladder discomfort in male patients during the general anesthesia recovery period: A prospective, randomized, case-control STROBE study.

Urethral catheterization is a predictor of agitation during the general anesthesia recovery period. The aim of this study was to determine the effect of intraurethral 5% lidocaine and 25 mg/g prilocaine cream in reducing catheter-related bladder discomfort (CRBD) in male patients during the general anesthesia recovery period. Adult male patients undergoing elective operations that required urinary catheterization under general anesthesia were enrolled and assigned randomly to 2 groups. In the lidocaine-prilocaine cream group (n = 72), approximately 5 g of topical cream was spread in the preputial sac, the glans, the meatus, and on the urinary catheter surface before urinary catheterization. In the control group (n = 74), the urinary catheter was lubricated with lidocaine gel. The incidence and severity of CRBD were assessed 15, 30, 45, and 60 minutes postoperatively. We found that the incidence of CRBD in the lidocaine-prilocaine cream group was significantly lower than in the control group. Multivariate logistic regression analysis showed that lidocaine-prilocaine cream applications reduced moderate or severe CRBD. Thirty minutes postoperation was the most frequent time point for the incidence of CRBD. Application of lidocaine-prilocaine cream on the surface of the urinary catheter is an efficient and safe method to reduce the incidence and severity of CRBD.

Administration of HES in elderly patients undergoing hip arthroplasty under spinal anesthesia is not associated with an increase in renal injury.

BACKGROUND: Hydroxyethyl starch (HES) is applied to achieve volume expansion during surgery; however, nephrotoxicity may be induced in patients with sepsis. Simultaneously, neutrophil gelatinase-associated lipocalin (NGAL) and IL-18 have been illustrated as pivotal indicators to diagnose the acute kidney injury (AKI) early. This multi-center, randomized, double-blinded, placebo-controlled study aimed to investigate whether 6% HES 130/0.4 administration caused postoperative AKI, which can be revealed by urinary and plasma NGAL and IL-18 estimations in elderly patients with normal renal function undergoing hip arthroplasty under spinal anesthesia. METHODS: 120 ASA I-III, patients aged >65 y undergoing hip arthroplasty under spinal anesthesia randomly received 6% HES 130/0.4 or sodium lactate Ringer's solution 7.5 mL/kg during the first hour of surgery. 118 patients completed the study. Blood pressure, NGAL concentrations, IL18, ß2 micro-albumin and albumin in urine and creatinine, NGAL and IL-18 in plasma were repeatedly measured before, during, and after surgery. RESULTS: The groups were balanced in mean arterial pressure, urine and plasma NGAL, plasma IL-18 and creatinine, urine ß2 microalbumin and albumin (P > 0.05). Urine IL-18 was dramatically elevated in both groups after surgery (P < 0.05), but did not vary significantly between the groups (P > 0.05). CONCLUSION: Elderly patients undergoing surgery under spinal anesthesia are a high-risk population in AKI. These patients with normal renal function receiving a spinal anesthesia for a short duration surgery would not develop AKI when 500 mL (small volume) HES is infused. TRIAL REGISTRATION: Identifier: NCT02361736 . Registration date was 2 February 2015.

Preemptive submucosal infiltration with ropivacaine for uvulopalatopharyngoplasty.

OBJECTIVE: To evaluate the preemptive analgesic effect of submucosal infiltration of ropivacaine for uvulopalatopharyngoplasty. STUDY DESIGN: Randomized controlled trial. SETTING: Comprehensive clinical center and academic hospital. SUBJECTS AND METHODS: Fifty consecutive male patients scheduled for uvulopalatopharyngoplasty were divided randomly into group A and group B. In group A, 4 mL of 0.33% ropivacaine and normal saline with epinephrine was preincisionally injected under the mucosa on both sides of the tonsillar fossa, soft palate, and the lower part of palatoglossal arch, whereas the upper and middle parts of the palatoglossal arch and the upper part of the palatopharyngeal arch were infiltrated with 2 mL of the same mixture. In group B, an identical volume of normal saline with epinephrine was administered. In both groups, postoperative pain was initially controlled by intravenous morphine titration until patient-controlled analgesia with morphine could be used. Cumulative patient-controlled analgesic morphine consumption; visual analog scale scores at 4, 8, 12, 24, and 48 hours postoperatively at rest and during swallowing; and opioid-related adverse effects were recorded. RESULTS: The visual analog score was lower at rest during the 48-hour postoperative period and during swallowing within the first 12 hours for group A versus group B (P < .05). Patients in group A required 44.1%, 38.2%, and 41.1% less morphine during the first 24 hours, 24 hours to 48 hours, and 48 hours postoperatively, respectively, and fewer patients experienced nausea, vomiting, and pruritus (P < .05). CONCLUSION: Preemptive submucosal infiltration with 0.33% ropivacaine effectively controlled pain after uvulopalato-pharyngoplasty.

Prevention and reversal of morphine tolerance by the analgesic neuroactive steroid alphadolone.

OBJECTIVE: Alphadolone is a neuroactive steroid that causes antinociception in rats and analgesia in humans by interaction with spinal cord GABA(A) receptors. This study investigated whether alphadolone could affect morphine tolerance. METHODS: Morphine tolerance was induced in rats with subcutaneous sustained release morphine emulsion (M-SR; 125 mg/kg/day). Tolerance was assessed by a blinded observer using tail flick latency (TFL) response to intraperitoneal (ip) injection of immediate release morphine (M-IR 6.25 mg/kg). Fifty-five rats given M-SR were divided into three groups: group A received 1.0 mL subcutaneous emulsion containing vehicle; groups B and C had emulsions injected subcutaneously at the same time as the M-SR (B-250 mg/kg alphadolone; C-alphaxalone 80 mg/kg). RESULTS: Tail flick latency responses (percentage of maximum possible effect [% MPE]) to M-IR were reduced from 89.6 +/- 2.5 pretreatment to 20.3 +/- 4.8 after M-SR treatment (mean +/- SEM; P < 0.001, one-way anova). Coadministration of alphadolone emulsion with the M-SR caused no sedation and prevented the occurrence of morphine tolerance. TFL responses to M-IR (6.25 mg/kg) given to morphine tolerant rats were 29 +/- 8% MPE whereas the TFL was 78.6 +/- 9.8% MPE when immediate release alphadolone (10 mg/kg ip) was injected at the same time as M-IR to tolerant rats (P < 0.001 one-way anova). Alphaxalone treatment caused sedation and no effects on morphine tolerance. CONCLUSIONS: We conclude that the alphadolone can prevent morphine tolerance and it also restores normal morphine antinociception in rats with established morphine tolerance. The lack of sedation suggests clinical utility in human pain states requiring morphine.