Comparative Analysis of Gut Bacterial Community Composition in Two Tropical Economic Sea Cucumbers under Different Seasons of Artificial Environment.

With the continuous rise of the sea cucumber aquaculture industry in China, the tropical sea cucumber aquaculture industry is also improving. However, research on the gut microorganisms of tropical sea cucumbers in captivity is scarce. In this study, high-throughput sequencing methods were used to analyze the gut microbial composition of Stichopus monotuberculatus and Holothuria scabra in the dry season and wet season of artificial environments. The results showed that 66 phyla were obtained in all samples, of which 59 phyla were obtained in the dry season, and 45 phyla were obtained in the wet season. The Tax4Fun analysis showed that certain gut bacterial communities affect the daily metabolism of two sea cucumber species and are involved in maintaining gut microecological balance in the gut of two sea cucumber species. In addition, compared with differences between species, PCoA and UPGMA clustering analysis showed the gut prokaryotes of the same sea cucumber species varied more in different seasons, indicating that the influence of environment was higher than the feeding choices of sea cucumbers under relatively closed conditions. These results revealed the gut bacterial community composition of S. monotuberculatus and H. scabra and the differences in gut bacterial structure between two sea cucumber species in different seasons were compared, which would provide the foundation for tropical sea cucumber aquaculture in the future.

Peroxiredoxin 3 has a crucial role in the macrophage polarization by regulating mitochondrial homeostasis.

Acute lung injury (ALI) is one of the life-threatening complications of sepsis, and macrophage polarization plays a crucial role in the sepsis-associated ALI. However, the regulatory mechanisms of macrophage polarization in ALI and in the development of inflammation are largely unknown. In this study, we demonstrated that macrophage polarization occurs in sepsis-associated ALI and is accompanied by mitochondrial dysfunction and inflammation, and a decrease of PRDX3 promotes the initiation of macrophage polarization and mitochondrial dysfunction. Mechanistically, PRDX3 overexpression promotes M1 macrophages to differentiate into M2 macrophages, and enhances mitochondrial functional recovery after injury by reducing the level of glycolysis and increasing TCA cycle activity. In conclusion, we identified PRDX3 as a critical hub integrating oxidative stress, inflammation, and metabolic reprogramming in macrophage polarization. The findings illustrate an adaptive mechanism underlying the link between macrophage polarization and sepsis-associated ALI.

GBP2 upregulated in LPS-stimulated macrophages-derived exosomes accelerates septic lung injury by activating epithelial cell NLRP3 signaling.

Macrophages infiltration is a crucial factor causing Sepsis-associated acute lung injury (ALI). Accumulating evidence suggests macrophages-alveolar epithelial cells communication is proven to be critical in ALI. However, little is known regarding how activated macrophages regulated sepsis-associated ALI. To explore the role of macrophages-alveolar epithelial cells communication in the ALI process, our data revealed that Lipopolysaccharides-induced macrophages-derived exosomes (L-Exo) induced sepsis-associated ALI and caused alveolar epithelial cells damage. Moreover, Guanylate-binding protein 2 (GBP2) was significantly upregulated in L-Exo, and NLRP3 inflammasomes was the direct target of GBP2. Further experimentation showed that GBP2 inhibition in vitro and in vivo reserves L-Exo effects, while GBP2 overexpression in vitro and in vivo promotes L-Exo effects. These results demonstrated that L-Exo contains excessive GBP2 and promotes inflammation through targeting NLRP3 inflammasomes, which induced alveolar epithelial cells dysfunction and pyroptosis. These findings demonstrate that L-Exo exerted a deleterious effect on ALI by regulating the GBP2/NLRP3 axis, which might provide new insight on ALI prevention and treatment.

Effect of different feeding methods on gastrointestinal function in critical patients (DFM-GFC): study protocol for a randomized controlled trial.

BACKGROUND: Enteral nutrition is a major pathway of nutrition for patients requiring critical care. However, it remains unclear whether intermittent or continuous feeding is the better approach, especially after nasogastric enteral nutrition via a gastric tube. Therefore, this randomized controlled clinical study was designed to observe the effects of different methods on critically ill patients. METHODS: Different Feeding Methods on Gastrointestinal Function of Critical patients (DFM-GFC) is a randomized clinical study that will be performed to assess the effects of three feeding methods on critically ill patients. A total of 90 critically ill patients will be equally randomized into three groups: continuous feeding, cyclic feeding, and intermittent feeding. The patients will be administered a gastrointestinal nutrition preparation over 24 h via a gastric tube or over 16 h via an intermittent pump. The primary outcome is the mean duration (days) to reach the caloric goal in each group. Secondary outcomes include the rate of onset of gastric residual, abdominal pressure, the rate of onset pneumonia, and the proportion of individuals achieving the caloric goal. Additionally, the length of intensive care unit (ICU) stay and mortality rate at 28 days post-enrolment will be evaluated. DISCUSSION: This study will observe the effects of different feeding methods on various parameters, such as the energy target and gastrointestinal motility, in critically ill patients to improve quality of life and reduce the case fatality rate. The purpose of this study is to explore whether there is a more effective, safer and cost-efficient feeding method for the clinical treatment of critically ill patients. TRIAL REGISTRATION: ID: NCT04224883, ClinicalTrials.gov , registered January 9, 2020.

Electroacupuncture at Zusanli (ST36), Guanyuan (CV4), and Qihai (CV6) Acupoints Regulates Immune Function in Patients with Sepsis via the PD-1 Pathway.

Objective: The present study is aimed at investigating the biochemical and clinical effects of electroacupuncture in patients with sepsis. Methods: Patients with sepsis treated at Guangdong Provincial Hospital of Chinese Medicine from July 2019 to December 2020 were included. Patients were randomly assigned to treatment with routine Western medicine (WM group) or treatment with Western medicine plus electroacupuncture based on Western medicine (EA group). Indices associated with immune function and clinical efficacy were determined before and at 3 and 5 days after treatment. Indicators of immune function included the percentage of T lymphocyte subsets, natural killer (NK) cells, and soluble programmed death protein 1 (sPD-1) levels. Indicators of clinical efficacy included infection-related indicators in whole blood; levels of tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and interferon-γ (INF-γ); and assessments using acute physiology and chronic health evaluation-II (APACHE-II) and sequential organ failure assessment (SOFA) scores. Results: Baseline data were not different between WM (N = 30) and EA groups (N = 30). At day 5 following treatment, the level of sPD-1 in the EA group was lower than that in the WM group. Proportions of CD3 + T lymphocytes, CD4 + T lymphocytes, and NK cells, the percentage of lymphocytes, and INF-γ levels in the EA group were significantly higher than those in the WM group. Compared with the WM group, the white blood cell count (WBC), percentage and count of neutrophils, ratio of neutrophils to lymphocytes, and levels of CRP and TNF-α were significantly decreased in the EA group 5 days after treatment. The APACHE-II score of the EA group was significantly lower than that of the WM group 5 days after treatment. Conclusion: Electroacupuncture may regulate the immune function of patients with sepsis through the PD-1 pathway to achieve an anti-inflammatory state and improve clinical symptoms.

Designer Functional Nanomedicine for Myocardial Repair by Regulating the Inflammatory Microenvironment.

Acute myocardial infarction is a major global health problem, and the repair of damaged myocardium is still a major challenge. Myocardial injury triggers an inflammatory response: immune cells infiltrate into the myocardium while activating myofibroblasts and vascular endothelial cells, promoting tissue repair and scar formation. Fragments released by cardiomyocytes become endogenous "danger signals", which are recognized by cardiac pattern recognition receptors, activate resident cardiac immune cells, release thrombin factors and inflammatory mediators, and trigger severe inflammatory responses. Inflammatory signaling plays an important role in the dilation and fibrosis remodeling of the infarcted heart, and is a key event driving the pathogenesis of post-infarct heart failure. At present, there is no effective way to reverse the inflammatory microenvironment in injured myocardium, so it is urgent to find new therapeutic and diagnostic strategies. Nanomedicine, the application of nanoparticles for the prevention, treatment, and imaging of disease, has produced a number of promising applications. This review discusses the treatment and challenges of myocardial injury and describes the advantages of functional nanoparticles in regulating the myocardial inflammatory microenvironment and overcoming side effects. In addition, the role of inflammatory signals in regulating the repair and remodeling of infarcted hearts is discussed, and specific therapeutic targets are identified to provide new therapeutic ideas for the treatment of myocardial injury.

Effects of Chengqi Decoction on Complications and Prognosis of Patients with Pneumonia-Derived Sepsis: Retrospective Cohort Study.

PURPOSE: A specific and efficacious method for treatment of pneumonia-derived sepsis is lacking. Chengqi decoction has been used for treatment of pneumonia-derived sepsis, but a clinical trial on patients with pneumonia-derived sepsis is lacking, a gap in the literature that we sought to fill. Patients and Methods. 282 patients with pneumonia-derived sepsis admitted to the intensive care unit of our hospital were selected. They were divided into the treatment group (141 cases) and control group (141 cases). Both groups underwent conventional treatment, but Chengqi decoction (in the form of enema) was given to the treatment group. Mortality, morbidity (abdominal distension and gastrointestinal bleeding), duration of antibiotic use, and use of vasoactive agents were documented 28 days after the drug was used. RESULTS: The treatment group reduced mortality and morbidity (abdominal distension) (P < 0.05). After adjustment for significant covariates, 28-day survival was similar for the whole group (hazard ratio (HR): 0.48; 95% confidence interval (CI): 0.23-0.97; P=0.037), for the subgroup (n = 120) with Acute Physiology and Chronic Health Evaluation II score ≥25 (HR: 0.180; 95% CI: 0.032-0.332; P=0.039) and for the subgroup (n = 66) with N-terminal B-type natriuretic peptide <1800 (0.059, 0.004-0.979, and 0.019). There was no difference between the two groups for the duration of antibiotic use, major bleeding, or use of vasoactive drugs. CONCLUSIONS: Chengqi decoction improved 28-day survival and reduced the prevalence of abdominal distension in patients with pneumonia-derived sepsis.

Macrophage exosomes transfer angiotensin II type 1 receptor to lung fibroblasts mediating bleomycin-induced pulmonary fibrosis.

BACKGROUND: Macrophages are involved in the pathogenesis of idiopathic pulmonary fibrosis, partially by activating lung fibroblasts. However, how macrophages communicate with lung fibroblasts is largely unexplored. Exosomes can mediate intercellular communication, whereas its role in lung fibrogenesis is unclear. Here we aim to investigate whether exosomes can mediate the crosstalk between macrophages and lung fibroblasts and subsequently induce fibrosis. METHODS: In vivo, bleomycin (BLM)-induced lung fibrosis model was established and macrophages infiltration was examined. The effects of GW4869, an exosomes inhibitor, on lung fibrosis were assessed. Moreover, macrophage exosomes were injected into mice to observe its pro-fibrotic effects. In vitro, exosomes derived from angiotensin II (Ang II)-stimulated macrophages were collected. Then, lung fibroblasts were treated with the exosomes. Twenty-four hours later, protein levels of α-collagen I, angiotensin II type 1 receptor (AT1R), transforming growth factor-ß (TGF-ß), and phospho-Smad2/3 (p-Smad2/3) in lung fibroblasts were examined. The Student's t test or analysis of variance were used for statistical analysis. RESULTS: In vivo, BLM-treated mice showed enhanced infiltration of macrophages, increased fibrotic alterations, and higher levels of Ang II and AT1R. GW4869 attenuated BLM-induced pulmonary fibrosis. Mice with exosomes injection showed fibrotic features with higher levels of Ang II and AT1R, which was reversed by irbesartan. In vitro, we found that macrophages secreted a great number of exosomes. The exosomes were taken by fibroblasts and resulted in higher levels of AT1R (0.22 ±â€Š0.02 vs. 0.07 ±â€Š0.02, t = 8.66, P = 0.001), TGF-ß (0.54 ±â€Š0.05 vs. 0.09 ±â€Š0.06, t = 10.00, P < 0.001), p-Smad2/3 (0.58 ±â€Š0.06 vs. 0.07 ±â€Š0.03, t = 12.86, P < 0.001) and α-collagen I (0.27 ±â€Š0.02 vs. 0.16 ±â€Š0.01, t = 7.01, P = 0.002), and increased Ang II secretion (62.27 ±â€Š7.32 vs. 9.56 ±â€Š1.68, t = 12.16, P < 0.001). Interestingly, Ang II increased the number of macrophage exosomes, and the protein levels of Alix (1.45 ±â€Š0.15 vs. 1.00 ±â€Š0.10, t = 4.32, P = 0.012), AT1R (4.05 ±â€Š0.64 vs. 1.00 ±â€Š0.09, t = 8.17, P = 0.001), and glyceraldehyde-3-phosphate dehydrogenase (2.13 ±â€Š0.36 vs. 1.00 ±â€Š0.10, t = 5.28, P = 0.006) were increased in exosomes secreted by the same number of macrophages, indicating a positive loop between Ang II and exosomes production. CONCLUSIONS: Exosomes mediate intercellular communication between macrophages and fibroblasts plays an important role in BLM-induced pulmonary fibrosis.

Alamandine via MrgD receptor attenuates pulmonary fibrosis via NOX4 and autophagy pathway.

Alamandine (ALA) and its receptor MrgD were recently identified as components of the renin-angiotensin system, which confer protection against cardio-fibrosis and renal-fibrosis; however, the effects of ALA on pulmonary fibrosis are unknown. This study was designed to serve two goals: (i) to evaluate the ALA/MrgD axis ability in the prevention of angiotensin II (Ang II) - induced pulmonary fibrosis in fibroblasts, and (ii) to determine the effect of ALA in bleomycin (BLM) - treated C57B/6 mice. In vivo experiments revealed that the treatment of C57B/6 mice with ALA prevented BLM-induced fibrosis, and these findings were similar to those reported for pirfenidone. The antifibrosis actions of ALA were mediated via alleviation of oxidative injury and autophagy induction. In addition, in vitro studies revealed that ALA treatment attenuated Ang II-induced α-collagen I, CTGF, and α-SMA production in fibroblast which was blocked by D-Pro7-Ang-(1-7), a MrgD antagonist. This led to alleviation of oxidative injury and induction of autophagy similar to that reported for rapamycin. This study demonstrated that ALA via MrgD receptor reduced pulmonary fibrosis through attenuation of oxidative injury and induction of autophagy.

Risk Assessment of Intermittent and Continuous Nasogastric Enteral Feeding Methods in Adult Inpatients: A Meta-Analysis.

Diarrhea and pneumonia are common and serious complications in hospitalized patients requiring nasogastric enteral feeding. Our study aimed to compare the risk of diarrhea and pneumonia between intermittent nasogastric enteral feeding (IEF) and continuous nasogastric enteral feeding (CEF). We systematically searched PubMed, Web of Science, and Cochrane for relevant articles published from August 9, 1992, to September 1, 2019. A total of 637 IEF and CEF patients were included in our meta-analysis. Odds ratios (ORs) with associated 95% confidence intervals (CIs) were calculated to estimate the effects of diarrhea and pneumonia. We showed that hospital patients that required IEF had an increased risk of diarrhea compared with CEF. In the subgroup analyses, similar conclusions were identified in the non-China group and small sample size group (size < 100). However, our results showed no significant differences in the China group or large sample size group (size ≥ 100). Furthermore, our analysis showed that no significant association was observed for the risk of pneumonia between IEF and CEF patients. For inpatients requiring nasogastric enteral feeding, CEF is a better method of enteral nutrition compared with IEF, of which patients experience a significantly increased risk of diarrhea.

Author Correction: Mir-21 Mediates the Inhibitory Effect of Ang (1-7) on AngII-induced NLRP3 Inflammasome Activation by Targeting Spry1 in lung fibroblasts.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Case report on a 32-year-old female with elevated serum creatinine levels and primary Sjögren's syndrome-chronic interstitial nephritis.

Primary Sjögren's syndrome (PSS) is a chronic autoimmune disease characterized by lymphoplasmacytic infiltration of the exocrine glands, which results in multiple organs damage. Renal injury affects 0.3-27.0% of PSS patients, and tubulointerstitial nephritis is the most frequent form of nephropathy in PSS. The present study reports on the case of a 32-year-old female with a 1-year history of elevated serum creatinine levels, and a 6-month history of mild pain in the waist and leg. Blood biochemistry tests indicated a creatinine level of 221.3 µmol/l and estimated glomerular filtration rate of 24.6 ml/min/1.73 m2 [Chronic Kidney Disease Epidemiology (CKD-EPI) formula]. Accordingly, the patient was diagnosed with stage IV chronic kidney disease. To clarify the underlying cause of the disease, a kidney biopsy was performed, which revealed tubular epithelial cells with multiple focal and lamellar atrophy (~60%), as well as extensive renal interstitial fibrosis with scattered inflammatory cell infiltration. Based on these results, the patient was finally diagnosed with severe chronic interstitial nephritis, chronic kidney disease stage IV, PSS and anemia due to chronic kidney disease. The patient was treated with half-dose glucocorticoid (prednisone, 25 mg oral qd maintained up to 12 months). The patient's serum creatinine levels had decreased to 172.4 µmol/l after 1 month and to 178.7 µmol/l after 12 months. The present case concluded that young patients with chronic renal failure should first be assessed for rheumatic immune system diseases. PSS may involve several organs and the clinical manifestations may be varied. Although chronic renal failure is frequently the first manifestation of renal disorder due to PSS, it may be overlooked by clinicians. The present results suggest that further attention should be paid to determine the association between symptoms in the clinical setting.

Autophagy Attenuates Angiotensin II-Induced Pulmonary Fibrosis by Inhibiting Redox Imbalance-Mediated NOD-Like Receptor Family Pyrin Domain Containing 3 Inflammasome Activation.

AIMS: The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is activated by reactive oxygen species (ROS) and repressed by autophagy, has been identified as a novel agent of pulmonary fibrosis. Angiotensin II (AngII), the bioactive pro-oxidant in the renin-angiotensin system, aggravates lung fibrosis. However, the effect of AngII on NLRP3 inflammasome and autophagy in lung fibrosis remains unknown. This study investigates the potential link between AngII-induced autophagy in the regulation of NLRP3 inflammasome/IL-1ß axis in lung fibrosis. RESULTS: In vivo, autophagy and the NLRP3 inflammasome were activated in fibrotic patients and positively correlated with oxidation. Treatment with rapamycin promoted autophagy but inhibited oxidation, NLRP3 inflammasome, and lung fibrosis after bleomycin (BLM) infusion. The autophagy inhibitor 3-methyladenine reduced BLM-induced lung fibrosis and concurrently facilitated NLRP3 inflammasome activation and oxidation in fibroblasts. In vitro, AngII promoted intercellular ROS, hydrogen peroxide, and NADPH oxidase 4 (NOX4) protein levels and reduced the glutathione concentration, thereby leading to NLRP3 inflammasome activation and consequent collagen synthesis. AngII induced autophagy, while VAS2870, NOX4, small-interfering RNA (siRNA), and compound C eliminated AngII-induced LC3B augmentation. Moreover, blocking autophagy with bafilomycin A1 or LC3B siRNA resulted in oxidant accumulation, NLRP3 inflammasome hyperactivation, and collagen deposition. Finally, AngII induced P62/SQSTM1, targeting ubiquitinated apoptosis-associated speck-like protein containing a CARD for degradation, thereby contributing to NLRP3 inflammasome inactivation. Innovation and Conclusion: Autophagy attenuates pulmonary fibrosis by regulating NLRP3 inflammasome activation induced by AngII-mediated ROS via redox balance modulation.

Angiotensin-(1-7) Attenuated Cigarette Smoking-related Pulmonary Fibrosis via Improving the Impaired Autophagy Caused by Nicotinamide Adenine Dinucleotide Phosphate Reduced Oxidase 4-Dependent Reactive Oxygen Species.

Cigarette smoking is acknowledged as the major risk factor of pulmonary fibrosis. Angiotensin (Ang) II has been reported to aggravate smoking-induced lung fibrosis, whereas the effect of Ang-(1-7) on smoking-related lung fibrosis remains unknown. The autophagy, being activated by reactive oxygen species (ROS), is identified as a novel mechanism of pulmonary fibrosis. However, whether autophagy is involved in regulation of smoking-induced lung fibrosis still needs investigation. Here, we aim to investigate the effect of Ang-(1-7) on smoking-related lung fibrosis by the regulation of autophagy and ROS. In vivo, Ang-(1-7) was constantly infused into passive smoking rats for 8 weeks. In vitro, primary lung fibroblasts were pretreated with antioxidant, nicotinamide adenine dinucleotide phosphate reduced oxidase (NOX) 4 siRNA, or light chain (LC) 3B siRNA before exposure to cigarette smoke extract (CSE). GFP-mCherry red fluorescent protein-LC3 advenovirus was introduced to evaluate the autophagic flux in cells. We found that Ang-(1-7) reduced hydrogen peroxide (H2O2) concentration, protein levels of NOX4, and autophagy impairment, as well as improving lung fibrosis induced by smoking stimulation in vivo. In vitro, CSE treatment elevated NOX4 protein expression and ROS production, resulting in the accumulation of impaired autophagosomes in fibroblasts. LC3B depletion enhanced CSE-induced collagen synthesis. Treatment with antioxidants or NOX4 siRNA inhibited CSE-induced insufficient autophagic flux and collagen production. In contrast, the action of Ang-(1-7) opposed the effects of CSE. In conclusion, Ang-(1-7) improves smoking-induced pulmonary fibrosis via attenuating the impaired autophagy caused by NOX4-dependent ROS in vivo and in vitro.

Mir-21 Mediates the Inhibitory Effect of Ang (1-7) on AngII-induced NLRP3 Inflammasome Activation by Targeting Spry1 in lung fibroblasts.

MicroRNA-21 (mir-21) induced by angiotensin II (AngII) plays a vital role in the development of pulmonary fibrosis, and the NLRP3 inflammasome is known to be involved in fibrogenesis. However, whether there is a link between mir-21 and the NLRP3 inflammasome in pulmonary fibrosis is unknown. Angiotensin-converting enzyme 2/angiotensin(1-7) [ACE2/Ang(1-7)] has been shown to attenuate AngII-induced pulmonary fibrosis, but it is not clear whether ACE2/Ang(1-7) protects against pulmonary fibrosis by inhibiting AngII-induced mir-21 expression. This study's aim was to investigate whether mir-21 activates the NLRP3 inflammasome and mediates the different effects of AngII and ACE2/Ang(1-7) on lung fibroblast apoptosis and collagen synthesis. In vivo, AngII exacerbated bleomycin (BLM)-induced lung fibrosis in rats, and elevated mir-21 and the NLRP3 inflammasome. In contrast, ACE2/Ang(1-7) attenuated BLM-induced lung fibrosis, and decreased mir-21 and the NLRP3 inflammasome. In vitro, AngII activated the NLRP3 inflammasome by up-regulating mir-21, and ACE2/Ang(1-7) inhibited NLRP3 inflammasome activation by down-regulating AngII-induced mir-21. Over-expression of mir-21 activated the NLRP3 inflammasome via the ERK/NF-κB pathway by targeting Spry1, resulting in apoptosis resistance and collagen synthesis in lung fibroblasts. These results indicate that mir-21 mediates the inhibitory effect of ACE2/Ang(1-7) on AngII-induced activation of the NLRP3 inflammasome by targeting Spry1 in lung fibroblasts.