In Vitro Lactic Acid Bacteria Anti-Hepatitis B Virus (HBV) Effect and Modulation of the Intestinal Microbiota in Fecal Cultures from HBV-Associated Hepatocellular Carcinoma Patients.

Hepatocellular carcinoma (HCC), being ranked as the top fifth most prevalent cancer globally, poses a significant health challenge, with a considerable mortality rate. Hepatitis B virus (HBV) infection stands as the primary factor contributing to HCC, presenting substantial challenges in its treatment. This study aimed to identify lactic acid bacteria (LAB) with anti-HBV properties and evaluate their impact on the intestinal flora in HBV-associated HCC. Initially, two LAB strains, Levilactobacillus brevis SR52-2 (L. brevis SR52-2) and LeviLactobacillus delbrueckii subsp. bulgaicus Q80 (L. delbrueckii Q80), exhibiting anti-HBV effects, were screened in vitro from a pool of 498 LAB strains through cell experiments, with extracellular expression levels of 0.58 ± 0.05 and 0.65 ± 0.03, respectively. These strains exhibited the capability of inhibiting the expression of HBeAg and HBsAg. Subsequent in vitro fermentation, conducted under simulated anaerobic conditions mimicking the colon environment, revealed a decrease in pH levels in both the health control (HC) and HCC groups influenced by LAB, with a more pronounced effect observed in the HC group. Additionally, the density of total short-chain fatty acids (SCFAs) significantly increased (p < 0.05) in the HCC group. Analysis of 16S rRNA highlighted differences in the gut microbiota (GM) community structure in cultures treated with L. brevis SR52-2 and L. delbrueckii Q80. Fecal microflora in normal samples exhibited greater diversity compared to HBV-HCC samples. The HCC group treated with LAB showed a significant increase in the abundance of the phyla Firmicutes, Bacteroidetes and Actinobacteria, while Proteobacteria significantly decreased compared to the untreated HCC group after 48 h. In conclusion, the findings indicate that LAB, specifically L. brevis SR52-2 and L. delbrueckii Q80, possessing antiviral properties, contribute to an improvement in gastrointestinal health.

M-type pyruvate kinase 2 (PKM2) tetramerization alleviates the progression of right ventricle failure by regulating oxidative stress and mitochondrial dynamics.

BACKGROUND: Right ventricle failure (RVF) is a progressive heart disease that has yet to be fully understood at the molecular level. Elevated M-type pyruvate kinase 2 (PKM2) tetramerization alleviates heart failure, but detailed molecular mechanisms remain unclear. OBJECTIVE: We observed changes in PKM2 tetramerization levels during the progression of right heart failure and in vitro cardiomyocyte hypertrophy and explored the causal relationship between altered PKM2 tetramerization and the imbalance of redox homeostasis in cardiomyocytes, as well as its underlying mechanisms. Ultimately, our goal was to propose rational intervention strategies for the treatment of RVF. METHOD: We established RVF in Sprague Dawley (SD) rats by intraperitoneal injection of monocrotaline (MCT). The pulmonary artery pressure and right heart function of rats were assessed using transthoracic echocardiography combined with right heart catheterization. TEPP-46 was used both in vivo and in vitro to promote PKM2 tetramerization. RESULTS: We observed that oxidative stress and mitochondrial disorganization were associated with increased apoptosis in the right ventricular tissue of RVF rats. Quantitative proteomics revealed that PKM2 was upregulated during RVF and negatively correlated with the cardiac function. Facilitating PKM2 tetramerization promoted mitochondrial network formation and alleviated oxidative stress and apoptosis during cardiomyocyte hypertrophy. Moreover, enhancing PKM2 tetramer formation improved cardiac mitochondrial morphology, mitigated oxidative stress and alleviated heart failure. CONCLUSION: Disruption of PKM2 tetramerization contributed to RVF by inducing mitochondrial fragmentation, accumulating ROS, and finally promoted the progression of cardiomyocyte apoptosis. Facilitating PKM2 tetramerization holds potential as a promising therapeutic approach for RVF.

Supplementation with high-GABA-producing Lactobacillus plantarum L5 ameliorates essential tremor triggered by decreased gut bacteria-derived GABA.

BACKGROUND: The γ-aminobutyric acid (GABA) hypothesis posits a role of GABA deficiency in the central nervous system in the pathogenesis and progression of essential tremor (ET). However, the specific causative factor for GABA deficiency is not clear. The gut microbiota in mammals has recently been considered as a significant source of GABA. Furthermore, the GABA-based signals originating from the intestine can be transmitted to the brain through the "enteric nervous system-vagus nerve-brain" axis. However, the plausible contribution of gut microbiota to ET seems inspiring but remains obscure. METHODS: Fecal samples from patients with ET and healthy controls were examined by metagenomic sequencing to compare the composition of gut microbiota and the expression of genes involved in GABA biosynthesis. The impact of gut microbiota on ET was explored through transplantation of fecal microbiota from patients with ET into the murine ET model. Lactic acid bacteria producing high amounts of GABA were identified through whole-genome sequencing and ultra-performance liquid chromatography-tandem mass spectrometry. Subsequently, mice were treated with the high-GABA-producing strain Lactobacillus plantarum L5. Tremor severity, behavioral tests, pro-inflammatory cytokines, GABA concentration, and gut microbiota composition were examined in these mice. RESULTS: The gut microbiota of patients with ET demonstrated an impaired GABA-producing capacity and a reduced fecal GABA concentration. Transplantation of the gut microbiota from patients with ET induced an extension of tremor duration and impaired mobility in the murine model of ET. L5 exhibited an augmented GABA-producing capacity, with the De Man-Rogosa-Sharpe culture broth containing 262 mg/l of GABA. In addition, administration of L5 significantly decreased the tremor severity and enhanced the movement capability and grasping ability of ET mice. In vivo mechanistic experiments indicated that L5 reshaped the gut microbial composition, supplemented the mucosa-associated microbiota with GABA-producing capacity, increased the GABA concentrations in the cerebellum, and diminished inflammation in the central nervous system. CONCLUSIONS: These findings highlight that deficiency of GABA-producing gut microbes plays an essential role in the pathogenesis of ET and that L5 is a promising candidate for treating ET.

Interplay of sleep patterns and oxidative balance score on total cardiovascular disease risk: Insights from the National Health and Nutrition Examination Survey 2005-2018.

Background: Unhealthy lifestyle and diet may contribute to the development of cardiovascular disease (CVD), but limited evidence exists regarding the association between sleep patterns, oxidative stress-related exposures to diet and lifestyle, and CVD risk. Methods: We analysed data from 10 212 adults in the National Health and Nutrition Examination Survey (NHANES) database (2005-2018). Self-report questionnaires were used to collect data on sleep duration, sleepiness, and trouble sleeping, classified into three categories: healthy, intermediate, and poor sleep patterns. Healthy sleep was defined as sleeping seven to nine hours per night with no self-reported sleepiness or trouble sleeping, while intermediate and poor sleep patterns indicated one and two to three sleep problems, respectively. The oxidative balance score (OBS) was calculated based on twenty oxidative stress-related exposures to dietary and lifestyle factors, with a higher score indicating greater antioxidant exposure. Survey-based multivariable-adjusted regression analysis was conducted to examine the association of sleep patterns or OBS alone and combined with the total and specific CVD risk. Results: Participants with poor sleep patterns had a higher likelihood of developing CVD (odds ratio (OR) = 1.76; 95% confidence interval (CI) = 1.26-2.45, P < 0.05), while an inverse association was found between OBS and CVD risk (quartile (Q) 4 vs Q1: OR = 0.67; 95% CI = 0.47-0.94, P = 0.02, P for trend <0.05). There was an interaction between sleep patterns and OBS (P for interaction = 0.03). Participants with unhealthy (intermediate and poor) sleep patterns and pro-oxidant OBS (Q1 and Q2) were significantly associated with increased risk of total CVD (OR = 2.31; 95% CI = 1.42-3.74, P < 0.05), as well as angina and congestive heart failure, but not coronary heart disease (CHD). Stratified analysis showed that among individuals without hyperlipidaemia, participants with both unhealthy sleep patterns and pro-oxidant OBS exhibited a higher risk of CHD compared to those with healthy sleep patterns and antioxidative OBS. Conclusions: Unhealthy sleep patterns and reduced oxidative balance are positively associated with an increased risk of overall and specific CVD. Interventions that target healthy sleep habits and antioxidant-rich diets and lifestyles may be important for reducing the risk of CVD.

Lactiplantibacillus plantarum 124 Modulates Sleep Deprivation-Associated Markers of Intestinal Barrier Dysfunction in Mice in Conjunction with the Regulation of Gut Microbiota.

Intestinal diseases caused by sleep deprivation (SD) are severe public health threats worldwide. However, whether or not probiotics attenuate the intestinal damage associated with SD remains unclear. In this study, we used antibiotic pretreatment and fecal microbiota transplantation to investigate the protective role of Lactiplantibacillus plantarum (L. plantarum) 124 against SD-related intestinal barrier damage in C57BL/6 mice. Compared with those of a normal sleeping mouse, we observed that intestinal antioxidant capacity and anti-inflammatory cytokine levels were decreased, while pro-inflammatory cytokines were increased in sleep deprivation mice with an increasing duration of sleep deprivation. This resulted in decreased tight junction protein expression and increased intestinal barrier permeability. In contrast, intragastric administration with L. plantarum 124 reversed SD-associated intestinal oxidative stress, inflammation, colonic barrier damage, and the dysbiosis of the microbiota in the colon. In addition, L. plantarum 124 restored gut microbiota homeostasis via restoring abundance, including that of Dubosiella, Faecalibaculum, Bacillus, Lachnoclostridium, and Bifidobacterium. Further studies showed that gut microbiota mediated SD-associated intestinal damage and the treatment L. plantarum 124 in SD-associated colonic barrier damage. L. plantarum 124 is a potential candidate for alleviating SD-associated intestinal barrier damage. Overall, L. plantarum 124 consumption attenuates intestinal oxidative stress, inflammation, and intestinal barrier damage in SD-associated mice via the modulation of gut microbes.

Gut microbiota: Candidates for a novel strategy for ameliorating sleep disorders.

The aim of this review was to evaluate the feasibility of treating sleep disorders using novel gut microbiota intervention strategies. Multiple factors can cause sleep disorders, including an imbalance in the gut microbiota. Studies of the microbiome-gut-brain axis have revealed bidirectional communication between the central nervous system and gut microbes, providing a more comprehensive understanding of mood and behavioral regulatory patterns. Changes in the gut microbiota and its metabolites can stimulate the endocrine, nervous, and immune systems, which regulate the release of neurotransmitters and alter the activity of the central nervous system, ultimately leading to sleep disorders. Here, we review the main factors affecting sleep, discuss possible pathways and molecular mechanisms of the interaction between sleep and the gut microbiota, and compare common gut microbiota intervention strategies aimed at improving sleep physiology.

Metabolism of resistant starch RS3 administered in combination with Lactiplantibacillus plantarum strain 84-3 by human gut microbiota in simulated fermentation experiments in vitro and in a rat model.

This study aimed to investigate the metabolic and population responses of gut microbiota to resistant starch (RS3) in the presence of exogenous Lactiplantibacillus plantarum strain 84-3 (Lp84-3) in vitro and in vivo. Lp84-3 promoted acetate, propionate, and butyrate production from RS3 by gut microbiota and increased Lactobacillus and Blautia contents in vitro. Furthermore, in the presence of Lp84-3, starch granules presented a "dot-by-hole" fermentation pattern. Administration of Lp84-3 with RS3 increased the level of SCFA-producing Faecalibaculum, Parabacteroides, Alistipes, and Anaeroplasma in the faeces of rates, with Lactobacillus and Akkermansia representing the key genera that significantly promoted SCFAs, especially propionate and butyrate. Lp84-3 with RS3 promoted genes related to tryptophan synthase (EC 4.2.1.20) and beta-glucosidase (EC 3.2.1.21) in faecal bacteria. Our findings highlight the ability of Lp84-3 to enhance RS3 degradation, possibly by promoting SCFA-producing bacteria, and indicate that Lp84-3 could be a potential probiotic with a beneficial effect on gut microbiota.

Dexmedetomidine exerts an anti-inflammatory effect via α2 adrenoceptors to alleviate cognitive dysfunction in 5xFAD mice.

Background: Inflammation promotes the progression of Alzheimer's disease (AD). In this study, we explored the effect of dexmedetomidine on inflammation and cognitive function in a mouse model of AD. Methods: 5xFAD mice were intragastrically administered saline, dexmedetomidine, or dexmedetomidine and yohimbine for 14 days. The effects of dexmedetomidine on the acquisition and retention of memory in the Morris water-maze test and Y maze were evaluated. The deposition of amyloid beta protein (Abeta) and cytokine levels in the hippocampus were assessed. The expression of Bace1 protein and NFκB-p65 protein was assessed by Western blotting. Results: Compared with WT mice, 5xFAD mice exhibited cognitive impairment in the Morris water maze test and Y maze test. Cognitive decline was alleviated by dexmedetomidine and this was reversed by the α2 adrenoceptor antagonist yohimbine. Compared with saline treatment, dexmedetomidine led to a reduction in the Abeta deposition area (p < 0.05) and in the mean gray value (p < 0.01) in the hippocampus of 5xFAD mice. Compared with saline treatment, dexmedetomidine inhibited the activation of astrocytes and microglia in the hippocampal DG of 5xFAD mice and reduced the area of GFAP (p < 0.01) and IBA1 (p < 0.01). The level of IL-1ß in the hippocampus decreased significantly after dexmedetomidine treatment compared with saline treatment in 5xFAD mice (p < 0.01). Yohimbine neutralized the effects of dexmedetomidine. Dexmedetomidine inhibited the expression of BACE1 and NF-κB p65 (p < 0.01), and these changes were reversed by yohimbine treatment. Conclusion: Dexmedetomidine alleviates cognitive decline, inhibits neuroinflammation, and prevents the deposition of Abeta in 5xFAD mice. The effect is mediated by the α2 adrenoceptor-mediated anti-inflammatory pathway. Dexmedetomidine may be effective for the treatment of AD and a better choice for the sedation of AD.

Bifidobacterium longum 070103 Fermented Milk Improve Glucose and Lipid Metabolism Disorders by Regulating Gut Microbiota in Mice.

BACKGROUND: Fermented milk is beneficial for metabolic disorders, while the underlying mechanisms of action remain unclear. This study explored the benefits and underlying mechanisms of Bifidobacterium longum 070103 fermented milk (BLFM) in thirteen-week high-fat and high-sugar (HFHS) fed mice using omics techniques. METHODS AND RESULTS: BLFM with activated glucokinase (GK) was screened by a double-enzyme coupling method. After supplementing BLFM with 10 mL/kg BW per day, fasting blood glucose, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and leptin were significantly reduced compared with the HFHS group. Among them, the final body weight (BW), epididymal fat, perirenal fat, and brown fat in BLFM group had better change trends than Lacticaseibacillus rhamnosus GG fermented milk (LGGFM) group. The amplicon and metabolomic data analysis identified Bifibacterium as a key gut microbiota at regulating glycolipid metabolism. BLFM reverses HFHS-induced reduction in bifidobacteria abundance. Further studies showed that BLFM significantly reduces the content of 3-indoxyl sulofphate associated with intestinal barrier damage. In addition, mice treated with BLFM improved BW, glucose tolerance, insulin resistance, and hepatic steatosis. CONCLUSION: BLFM consumption attenuates obesity and related symptoms in HFHS-fed mice probably via the modulation of gut microbes and metabolites.

Comparative analysis of the efficacies of probiotic supplementation and glucose-lowering drugs for the treatment of type 2 diabetes: A systematic review and meta-analysis.

The aim of this systematic review and meta-analysis was to evaluate the effects of probiotics and glucose-lowering drugs (thiazolidinedione [TZD], glucagon-like pep-tide-1 receptor agonists [GLP-1 RA], dipeptidyl peptidase IV inhibitors, and sodium glucose co-transporter 2 inhibitors [SGLT-2i]) in patients with type 2 diabetes from randomized con-trolled trials (RCTs). The PubMed, Web of science, Embase, and Cochrane Library databases were searched on the treatment effects of probiotics and glucose-lowering drugs on glycemia, lipids, and blood pressure metabolism published between Jan 2015 and April 2021. We performed meta-analyses using the random-effects model. We included 25 RCTs (2,843 participants). Overall, GLP-1RA, SGLT-2i, and TZD significantly reduce fasting blood sugar (FBS) and glycated hemoglobin (HbA1c), whereas GLP-1 RA increased the risk of hypoglycaemia. Multispecies probiotics decrease FBS, total cholesterol (TC), and systolic and diastolic blood pressure (SBP, DBP). Moreover, subgroup analyses indicated that participants aged >55 years, BMI ≥30 kg/m2, longer duration of intervention, and subjects from Eastern countries, showed significantly higher reduction in FBS and HbA1c, TC, TG and SBP. This meta-analysis revealed that including multiple probiotic rather than glucose-lowering drugs might be more beneficial regarding T2D prevention who suffering from simultaneously hyperglycemia, hypercholesterolemia, and hypertension.

LncRNA-MEG3 attenuates hyperglycemia-induced damage by enhancing mitochondrial translocation of HSP90A in the primary hippocampal neurons.

The diabetic cognitive impairments are associated with high-glucose (HG)-induced mitochondrial dysfunctions in the brain. Our previous studies demonstrated that long non-coding RNA (lncRNA)-MEG3 alleviates diabetic cognitive impairments. However, the underlying mechanism has still remained elusive. Therefore, this study was designed to investigate whether the mitochondrial translocation of HSP90A and its phosphorylation are involved in lncRNA-MEG3-mediated neuroprotective effects of mitochondrial functions in HG-treated primary hippocampal neurons and diabetic rats. The primary hippocampal neurons were exposed to 75 mM glucose for 72 h to establish a HG model in vitro. Firstly, the RNA pull-down and RNA immunoprecipitation (RIP) assays clearly indicated that lncRNA-MEG3-associated mitochondrial proteins were Annexin A2, HSP90A, and Plectin. Although HG promoted the mitochondrial translocation of HSP90A and Annexin A2, lncRNA-MEG3 over-expression only enhanced the mitochondrial translocation of HSP90A, rather than Annexin A2, in the primary hippocampal neurons treated with or without HG. Meanwhile, Plectin mediated the mitochondrial localization of lncRNA-MEG3 and HSP90A. Furthermore, HSP90A threonine phosphorylation participated in regulating mitochondrial translocation of HSP90A, and lncRNA-MEG3 also enhanced mitochondrial translocation of HSP90A through suppressing HSP90A threonine phosphorylation. Finally, the anti-apoptotic role of mitochondrial translocation of HSP90A was found to be associated with inhibiting death receptor 5 (DR5) in HG-treated primary hippocampal neurons and diabetic rats. Taken together, lncRNA-MEG3 could improve mitochondrial functions in HG-exposed primary hippocampal neurons, and the underlying mechanisms were involved in enhanced mitochondrial translocation of HSP90A via suppressing HSP90A threonine phosphorylation, which may reveal a potential therapeutic target for diabetic cognitive impairments.

Propofol Rescued Astrocytes from LPS-induced Inflammatory Response via Blocking LncRNA-MEG3/NF-κB Axis.

OBJECTIVE: Evidences demonstrate that propofol attenuates neuro-inflammation following brain ischemia. Moreover, LncRNA-MEG3 has been identified as an independent prognostic marker for ischemic stroke patients, and found to correlate to cerebral ischemia in animal models. Therefore, the current study explored the role of propofol in lipopolysaccharide (LPS)-mediated inflammation in cultured astrocytes, along with the molecular mechanism involved in LncRNAMEG3/ NF-κB axis. METHODS: The primary cultured astrocytes isolated from rats were used to establish an inflammatory model, which were treated with LPS. Propofol was administrated to the primary cultured astrocytes during LPS treatment. The effects of propofol on pro-inflammatory cytokines and the LncRNAMEG3/ NF-κB pathway were detected by ELISA, qRT-PCR and Western Blot assay, respectively. Then, dual-luciferase assay, chromatin immunoprecipitation and RNA immunoprecipitation were used to determine the interaction between LncRNA-MEG3 and NF-κB. RESULTS: Our study found propofol to significantly reduce LncRNA-MEG3 expression, which was elevated in LPS-stimulated astrocytes. Moreover, both propofol and LncRNA-MEG3 knockdown remarkably alleviated LPS-induced cytotoxicity by suppressing expressions and release of proinflammatory cytokines. Loss of LncRNA-MEG3 notably suppressed the NF-κB activity and its phosphorylated activation. Additionally, it was also observed that LncRNA-MEG3 could bind nuclear p65/p50, and promote the binding of NF-κB to IL-6 and TNF-α promoters in the nucleus, subsequently stimulating the production of inflammatory cytokines in LPS-treated astrocytes. Furthermore, a specific inhibitor of NF-κB, PDTC, rescued astrocytes from LPS exposure without affecting the LncRNA-MEG3 expression. CONCLUSION: These findings demonstrate that LncRNA-MEG3 acts as a positive regulator of NF-κB, mediating the neuroprotection of propofol in LPS-triggered astrocytes injury.

Analysis of the long non-coding RNA and mRNA expression profiles associated with lidocaine-induced neurotoxicity in the spinal cord of a rat model.

Neurotoxicity is thought to be one of the causes of lidocaine-associated neurological complications; however, the mechanisms underlying lidocaine-related neurotoxicity are still unclear. Long non-coding RNAs (lncRNAs) are novel mediators of neurotoxicity, and their role in lidocaine-induced neurotoxicity needs to be explored. Here, we established a rat model of lidocaine-induced neurotoxicity via the repetitive intrathecal administration of 10% lidocaine. Thereafter, microarray and bioinformatics analyses were performed to evaluate the changes in lncRNA and mRNA expression profiles in the lumbar spinal cord of the treated rats. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was also employed for verification. The lidocaine-treated rats (group L) showed elevated paw withdrawal threshold (PWT) as well as histopathological injuries in the lumbar spinal cord compared with the control saline-treated rats (group N). Further, relative to group N, microarray analysis showed 179 and 675 differentially expressed lncRNAs (DElncRNAs) and DEmRNAs in the lumbar spinal cord of rats in the group L, respectively. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the DEmRNAs showed that the most significantly enriched functions and pathways were those associated with cell cycle and immuno-inflammatory processes. Furthermore, coding-noncoding co-expression analysis showed multiple lncRNAs that were co-expressed with factors that regulate inflammation. Additionally, by constructing a preliminary competitive endogenous RNA (ceRNA) network analysis, we established a regulatory network of the lncRNAs and mRNAs that are potentially involved in lidocaine-induced neurotoxicity. In conclusion, our findings provide new insights into the molecular mechanisms of lidocaine-induced neurotoxicity; this has significance with respect to the identification of novel therapeutic targets.

Development of novel polymeric nanoagents and their potential in cancer diagnosis and therapy runing title: Polymeric nanoagents for cancer theranostics.

Cancer has been one of the leading factors of death around the world. Cancer patients usually have low 5-year survival rates and poor life quality requiring substantial improvement. In clinic, the presenting diagnostic strategies lack sensitivity with only a small proportion of patients can be accurately identified. For diagnosed patients, most of them are at the advanced stages thus being delayed to receive treatment. Therefore, it is eager to investigate and develop highly effective and accurate techniques for cancer early diagnosis and individualized therapy. Various nanoplatforms are emerging as imaging agents and drug carriers for cancer theranostics recently. Novel polymeric nanoagents, as a potent exemplar, have extraordinary merits, such as good stability, high biosafety and high drug loading efficacy, showing the great prospect for cancer early diagnosis and precise treatment. Herein, we review the recent advances in novel polymeric nanoagents and elucidate their synthesis procedures. We further introduce the applications of novel polymeric nanoagents in cancer diagnosis, treatment, and theranostics, as well as associated challenges and prospects in this field.

The Impact on 30-Day Mortality From a Brief Focused Ultrasound-Guided Management Protocol Immediately Before Emergency Noncardiac Surgery in Critically Ill Patients: A Multicenter Randomized Controlled Trial.

OBJECTIVE: To determine whether brief ultrasound-guided treatment of hemodynamic shock and respiratory failure immediately before emergency noncardiac surgery reduced 30-day mortality. DESIGN: Parallel, nonblinded, randomized trial with 1:1 allocation to control and intervention groups. SETTING: Twenty-eight major hospitals within China. PARTICIPANTS: Six-hundred sixty patients ≥14 years of age, scheduled for emergency noncardiac surgery with evidence of shock (heart rate >120 beat/min, systolic blood pressure< 90 mmHg or requiring inotrope infusion), or respiratory failure (Pulse Oxygen Saturation <92%, respiratory rate >20 beat/min, or requiring mechanical ventilation). INTERVENTIONS: A brief (<15 minutes) focused ultrasound of ventricular filling and function, lung, and peritoneal spaces, with predefined treatment recommendation based on the ultrasound was performed before surgery or standard care. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 30-day mortality. Secondary outcomes included changes in medical or surgical diagnosis and management due to ultrasound, intensive care unit, and hospital stay and cost, and Short Form-8 quality-of-life scores. Although there were frequent changes in diagnosis (82%) and management (49%) after the ultrasound, mortality at 30 days was not different between groups (50 [15.7%] v 53 [16.3%]; odds ratio 1.05, 0.69-1.6, p = 0.826). There were no differences in the secondary outcomes of the days spent in the hospital (mean 13.8 days, 95% confidence interval [CI] 12.1-15.6 v 14.4 d, 11.8-17.1, p = 0.718) or intensive care unit (mean 9.3 days, 95% CI 7.7-11.0 v 8.7 d, 7.2-10.2, p = 0.562), hospital cost (USD$14.5K, 12.2-16.7 v 13.7, 11.5-15.9, p = 0.611) or Short Form-8 scores at one year (mean 80.9, 95% CI 78.4-83.3 v 79.7, 76.9-82.5, p = 0.54) between participants allocated to the ultrasound and control groups. CONCLUSIONS: In critically ill patients with hemodynamic shock or respiratory failure, a focused ultrasound-guided management did not reduce 30-day mortality but led to frequent changes in diagnosis and patient management.

Effect of Electroencephalography Spectral Edge Frequency (SEF) and Patient State Index (PSI)-Guided Propofol-Remifentanil Anesthesia on Delirium After Laparoscopic Surgery: The eMODIPOD Randomized Controlled Trial.

BACKGROUND: The effect of SedLine electroencephalography (EEG)-guided anesthetic care on postoperative delirium (POD) has not been studied. METHODS: This single-center randomized EEG Monitoring tO Decrease the Incidence of Post-Operative Delirium (eMODIPOD) trial involved 1560 patients aged 50 years or above undergoing laparoscopic surgery. Propofol-remifentanil anesthesia was guided either by SedLine (EEG-guided care, n=779) or not (usual care, n=781). The goal of EEG-guided care was to maintain spectral edge frequency between 10 and 15 and patient state index (PSI) between 25 and 50. The primary outcome was the incidence of POD on postoperative days 1 to 5. The secondary outcomes included emergence delirium, composite moderate-to-severe complications, length of hospital stay, intensive care unit admission, 30-day hospital readmission and all-cause mortality, and intraoperative awareness. RESULTS: Of the 1560 randomized patients, 1545 were included in the modified intention-to-treat analysis. The median propofol administered for anesthesia maintenance was 900 mg and 1000 mg in the EEG-guided and usual care groups, respectively (P=0.21). POD occurred in 1.0% (8/771) and 1.2% (9/774) of patients in the EEG-guided and usual care groups, respectively (risk ratio: 0.89; 95% confidence interval: 0.35-2.30). There were no between-group differences in all secondary outcome measures. Emergence delirium occurred in 11.8% (91/771) and 13.2% (102/774) of the EEG-guided care and usual care groups, respectively (risk ratio: 0.90; 95% confidence interval: 0.69-1.17; P=0.41). Three patients from each group reported intraoperative awareness. CONCLUSIONS: Compared with usual care, SedLine spectral edge frequency-guided and patient state index-guided propofol-remifentanil anesthetic care neither alters anesthetic delivery nor decreases the unexpected low incidence of POD in relatively young Chinese patients undergoing laparoscopic surgery.

Lysozyme-like Protein Produced by Bifidobacterium longum Regulates Human Gut Microbiota Using In Vitro Models.

The extracellular secreted protein of Bifidobacterium longum (B. longum) plays an important role in maintaining the homeostasis of the human intestinal microenvironment. However, the mechanism(s) of interaction remain unclear. Lysozyme is a kind of antibacterial peptide. In this study, the amino acid sequence of a lysozyme-like protein of B. longum based on whole-genome data of an isolate from human gut feces was found. We further predicted functional domains from the amino acid sequence, purified the protein, and verified its bioactivity. The growth of some bacteria were significantly delayed by the 020402_LYZ M1 protein. In addition, the gut microbiota was analyzed via high-throughput sequencing of 16S rRNA genes and an in vitro fermentation model, and the fluctuations in the gut microbiota under the treatment of 020402_LYZ M1 protein were characterized. The 020402_LYZ M1 protein affected the composition of human gut microbiota significantly, implying that the protein is able to communicate with intestinal microbes as a regulatory factor.

Long noncoding RNA Meg3 mediates ferroptosis induced by oxygen and glucose deprivation combined with hyperglycemia in rat brain microvascular endothelial cells, through modulating the p53/GPX4 axis.

Individuals with diabetes are exposed to a higher risk of perioperative stroke than non-diabetics mainly due to persistent hyperglycemia. LncRNA Meg3 has been considered as an important mediator in regulating ischemic stroke. However, the functional and regulatory roles of Meg3 in diabetic brain ischemic injury remain unclear. In this study, rat brain microvascular endothelial cells (RBMVECs) were exposed to 6 h of oxygen and glucose deprivation (OGD), and subsequent reperfusion via incubating cells with glucose of various high concentrations for 24 h to imitate in vitro diabetic brain ischemic injury. It was shown that the marker events of ferroptosis and increased Meg3 expression occurred after the injury induced by OGD combined with hyperglycemia. However, all ferroptotic events were reversed with the treatment of Meg3-siRNA. Moreover, in this in vitro model, p53 was also characterized as a downstream target of Meg3. Furthermore, p53 knockdown protected RBMVECs against OGD + hyperglycemic reperfusion-induced ferroptosis, while the overexpression of p53 exerted opposite effects, implying that p53 served as a positive regulator of ferroptosis. Additionally, the overexpression or knockdown of p53 significantly modulated GPX4 expression in RBMVECs exposed to the injury induced by OGD combined with hyperglycemic treatment. Furthermore, GPX4 expression was suppressed again after the reintroduction of p53 into cells silenced by Meg3. Finally, chromatin immunoprecipitation assay uncovered that p53 was bound to GPX4 promoter. Altogether, these data revealed that, by modulating GPX4 transcription and expression, the Meg3-p53 signaling pathway mediated the ferroptosis of RBMVECs upon injury induced by OGD combined with hyperglycemic reperfusion.

Microbial Communities and Physicochemical Characteristics of Traditional Dajiang and Sufu in North China Revealed by High-Throughput Sequencing of 16S rRNA.

The process of soybean fermentation has been practiced for more than 3,000 years. Although Dajiang and Sufu are two popular fermented soybean products consumed in North China, limited information is available regarding their microbial composition. Hence, the current study sought to investigate, and compare, the physicochemical indicators and microbial communities of traditional Dajiang and Sufu. Results showed that the titratable acidity (TA), and salinity, as well as the lactic acid, and malic acid contents were significantly higher in Sufu samples compared to Dajiang. Furthermore, Sufu samples contain abundant sucrose and fructose, while the acetic acid content was lower in Sufu compared to Dajiang samples. Moreover, the predominant bacterial phyla in Dajiang and Sufu samples were Firmicutes and Proteobacteria, while the major genera comprise Bacillus, Lactobacillus, Tetragenococcus, and Weissella. Moreover, Dajiang samples also contained abundant Pseudomonas, and Brevundimonas spp., while Halomonas, Staphylococcus, Lysinibacillus, Enterobacter, Streptococcus, Acinetobacter, and Halanaerobium spp. were abundant in Sufu samples. At the species level, Bacillus velezensis, Tetragenococcus halophilus, Lactobacillus rennini, Weissella cibaria, Weissella viridescens, Pseudomonas brenneri, and Lactobacillus acidipiscis represented the major species in Dajiang, while Halomonas sp., Staphylococcus equorum, and Halanaerobium praevalens were the predominant species in Sufu. Acetic acid and sucrose were found to be the primary major physicochemical factor influencing the bacterial communities in Dajiang and Sufu, respectively. Furthermore, Bacillus subtilis is strongly correlated with lactic acid levels, L. acidipiscis is positively correlated with acetic acid levels, while Staphylococcus sciuri and S. equorum are strongly, and positively, correlated with malic acid. Following analysis of carbohydrate and amino acid metabolism in all samples, cysteine and methionine metabolism, as well as fatty acid biosynthesis-related genes are upregulated in Dajiang compared to Sufu samples. However, such as the Staphylococcus, W. viridescens, and P. brenneri, as potentially foodborne pathogens, existed in Dajang and Sufu samples. Cumulatively, these results suggested that Dajiang and Sufu have unique bacterial communities that influence their specific characteristics. Hence, the current study provides insights into the microbial community composition in Dajiang and Sufu samples, which may facilitate the isolation of functional bacterial species suitable for Dajiang and Sufu production, thus improving their production efficiency.

Metagenomics-Based Analysis of the Age-Related Cumulative Effect of Antibiotic Resistance Genes in Gut Microbiota.

Antibiotic resistance in bacteria has become a major global health problem. One of the main reservoirs of antibiotic resistance genes is the human gut microbiota. To characterise these genes, a metagenomic approach was used. In this study, a comprehensive antibiotic resistome catalog was established using fecal samples from 246 healthy individuals from world's longevity township in Jiaoling, China. In total, 606 antibiotic resistance genes were detected. Our results indicated that antibiotic resistance genes in the human gut microbiota accumulate and become more complex with age as older groups harbour the highest abundance of these genes. Tetracycline resistance gene type tetQ was the most abundant group of antibiotic resistance genes in gut microbiota, and the main carrier of antibiotic resistance genes was Bacteroides. Antibiotic efflux, inactivation, and target alteration were found to be the dominant antimicrobial resistance mechanisms. This research may help to establish a comprehensive antibiotic resistance catalog that includes extremely long-lived healthy people such as centenarians, and may provide potential recommendations for controlling the use of antibiotics.