Sirtuin 5 alleviates excessive mitochondrial fission via desuccinylation of ATPase inhibitory factor 1 in sepsis-induced acute kidney injury.

ABSTRACT: Sepsis-induced acute kidney injury (SAKI) poses a significant clinical challenge with high morbidity and mortality. Excessive mitochondrial fission has been identified as the central pathogenesis of sepsis-associated organ damage, which is also implicated in the early stages of SAKI. Sirtuin 5 (SIRT5) has emerged as a central regulator of cellular mitochondrial function; however, its role in the regulation of sepsis-induced excessive mitochondrial fission in kidney and the underlying mechanism remains unclear.In this study, SAKI was modeled in mice through cecal ligation and puncture (CLP), and in human renal tubular epithelial (HK-2) cells stimulated with lipopolysaccharide (LPS), to mimic the cell SAKI model. Our findings revealed that septic mice with a SIRT5 knockout (SIRT5 KO) exhibited shortened survival times and elevated levels of renal injury compared to wild-type (WT) mice, suggesting the significant involvement of SIRT5 in SAKI pathophysiology. Additionally, we observed that SIRT5 depletion led to increased renal mitochondrial fission, while the use of a mitochondrial fission inhibitor (Mdivi-1) reversed the detrimental effects caused by SIRT5 depletion, emphasizing the pivotal role of SIRT5 in preventing excessive mitochondrial fission. In vitro experiments demonstrated that the overexpression of SIRT5 effectively mitigated the adverse effects of LPS on HK-2 cells viability and mitochondrial fission. Conversely, downregulation of SIRT5 decreased HK-2 cells viability and exacerbated LPS-induced mitochondrial fission. Mechanistically, the protective function of SIRT5 may be in part, ascribed to its desuccinylating action on ATPase inhibitory factor 1 (ATPIF1).In conclusion, this study provides novel insights into the underlying mechanisms of SAKI, suggesting the possibility of identifying future drug targets in terms of improved mitochondrial dynamics by SIRT5.

microRNA-622 upregulates cell cycle process by targeting FOLR2 to promote CRC proliferation.

BACKGROUND: Epigenetic alterations contribute greatly to the development and progression of colorectal cancer, and effect of aberrant miR-622 expression is still controversial. This study aimed to discover miR-622 regulation in CRC proliferation. METHODS: miR-622 expression and prognosis were analyzed in clinical CRC samples from Nanfang Hospital. miR-622 regulation on cell cycle and tumor proliferation was discovered, and FOLR2 was screened as functional target of miR-622 using bioinformatics analysis, which was validated via dual luciferase assay and gain-of-function and loss-of-function experiments both in vitro and in vivo. RESULTS: miR-622 overexpression in CRC indicated unfavorable prognosis and it regulated cell cycle to promote tumor growth both in vitro and in vivo. FOLR2 is a specific, functional target of miR-622, which negatively correlates with signature genes in cell cycle process to promote CRC proliferation. CONCLUSIONS: miR-622 upregulates cell cycle process by targeting FOLR2 to promote CRC proliferation, proposing a novel mechanism and treatment target in CRC epigenetic regulation of miR-622.

Inhibition of SIRT6 aggravates p53-mediated ferroptosis in acute lung injury in mice.

Although studies have shown that protein 53 (p53)-mediated ferroptosis is involved in acute lung injury (ALI), the mechanism of its regulation remains unclear. The protective effects of Sirtuin 6 (SIRT6), a histone deacetylase, have been demonstrated in multiple diseases; however, further studies are needed to elucidate the role of SIRT6 in ALI. In the present study, we hypothesize that SIRT6 protects against lipopolysaccharide (LPS)-induced ALI by regulating p53-mediated ferroptosis. We observed that the inhibition of ferroptosis prevented LPS-induced ALI. The knockout of p53 blocked LPS-induced ferroptosis and ALI, suggesting that p53 facilitated ALI by promoting ferroptosis. In addition, the inhibition of SIRT6 aggravated LPS-induced ferroptosis and ALI, while the depression of ferroptosis blocked the exacerbation of lung injury induced by SIRT6 inhibition. The results suggest that SIRT6 protects against ALI by regulating ferroptosis. Furthermore, the inhibition of SIRT6 reinforced the p53 acetylation and the deletion of p53 rescued the exacerbation of ferroptosis induced by SIRT6 inhibition. The findings indicate that SIRT6 regulates the acetylation of p53 and prevents p53-mediated ferroptosis. In conclusion, our results indicate that SIRT6 protects against LPS-induced ALI by regulating p53-mediated ferroptosis, thereby demonstrating that SIRT6 holds great promise as a therapeutic target for ALI.

Discovery of Ibrutinib-based BTK PROTACs with in vivo anti-inflammatory efficacy by inhibiting NF-κB activation.

As a critical upstream regulator of nuclear factor-κB (NF-κB) activation, Bruton's tyrosine kinase (BTK) has been identified to be an effective therapeutic target for the treatment of acute or chronic inflammatory diseases. Herein, we describe the design, synthesis and structure-activity-relationship analysis of a novel series of Ibrutinib-based BTK PROTACs by recruiting Cereblon (CRBN) ligase. Among them, compound 15 was identified as the most potent degrader with a DC50 of 3.18 nM, significantly better than the positive control MT802 (DC50 of 63.31 nM). Compound 15 could also degrade BTK protein in Lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and suppress the mRNA expression and secretion of proinflammatory cytokines such as IL-1ß and IL-6 by inhibiting NF-κB activation. Furthermore, compound 15 reduced inflammatory responses in a mouse zymosan-induced peritonitis (ZIP) model. Our findings demonstrated for the first time that targeting BTK degradation by PROTACs might be an alternative option for the treatment of inflammatory disorders, and compound 15 represents one of the most efficient BTK PROTACs (DC50 = 3.18 nM; Dmax = 99.90%; near 100% degradation at 8 h) reported so far and could serve as a lead compound for further investigation as an anti-inflammatory agent.

Gut microbial metabolite hyodeoxycholic acid targets the TLR4/MD2 complex to attenuate inflammation and protect against sepsis.

Sepsis, a critical condition resulting from the systemic inflammatory response to a severe microbial infection, represents a global public health challenge. However, effective treatment or intervention to prevent and combat sepsis is still lacking. Here, we report that hyodeoxycholic acid (HDCA) has excellent anti-inflammatory properties in sepsis. We discovered that the plasma concentration of HDCA was remarkably lower in patients with sepsis and negatively correlated with the severity of the disease. Similar changes in HDCA levels in plasma and cecal content samples were observed in a mouse model of sepsis, and these changes were associated with a reduced abundance of HDCA-producing strains. Interestingly, HDCA administration significantly decreased systemic inflammatory responses, prevented organ injury, and prolonged the survival of septic mice. We demonstrated that HDCA suppressed excessive activation of inflammatory macrophages by competitively blocking lipopolysaccharide binding to the Toll-like receptor 4 (TLR4) and myeloid differentiation factor 2 receptor complex, a unique mechanism that characterizes HDCA as an endogenous inhibitor of inflammatory signaling. Additionally, we verified these findings in TLR4 knockout mice. Our study highlights the potential value of HDCA as a therapeutic molecule for sepsis.

Prognostic and therapeutic significance of microbial cell-free DNA in plasma of people with acute decompensation of cirrhosis.

BACKGROUND & AIMS: Although the effect of bacterial infection on cirrhosis has been well-described, the effect of non-hepatotropic virus (NHV) infection is unknown. This study evaluated the genome fragments of circulating microorganisms using metagenomic next-generation sequencing (mNGS) in individuals with acute decompensation (AD) of cirrhosis, focusing on NHVs, and related the findings to clinical outcomes. METHODS: Plasma mNGS was performed in 129 individuals with AD of cirrhosis in the study cohort. Ten healthy volunteers and 20, 39, and 81 individuals with stable cirrhosis, severe sepsis and hematological malignancies, respectively, were enrolled as controls. Validation assays for human cytomegalovirus (CMV) reactivation were performed in a validation cohort (n = 58) and exploratory treatment was instituted. RESULTS: In the study cohort, 188 microorganisms were detected in 74.4% (96/129) of patients, including viruses (58.0%), bacteria (34.1%), fungi (7.4%) and chlamydia (0.5%). A NHV signature was identified in individuals with AD, and CMV was the most frequent NHV, which correlated with the clinical effect of empirical antibiotic treatment, progression to acute-on-chronic liver failure, and 90-day mortality. The NHV signature in individuals with acute-on-chronic liver failure was similar to that in those with sepsis and hematological malignancies. CMV was detected in 24.1% (14/58) of patients in the validation cohort. Of the 14 cases with detectable CMV by mNGS, nine were further validated by real-time PCR or pp65 antigenemia testing. Three patients with CMV reactivation received ganciclovir therapy in an exploratory manner and experienced clinical resolutions. CONCLUSIONS: The results of this study suggest that NHVs may play a pathogenic role in complicating the course of AD. Further validation is needed to define whether this should be incorporated into the routine management of individuals with AD of cirrhosis. IMPACT AND IMPLICATIONS: A non-hepatotropic virus (NHV) signature, which was similar to that in individuals with sepsis and hematological malignancies, was identified in individuals with acute decompensation of cirrhosis. The detected viral signature had clinical correlates, including clinical efficacy of empirical antibiotic treatment, progression to acute-on-chronic liver failure and short-term mortality. Cytomegalovirus reactivation, which is treatable, may adversely affect clinical outcomes in some individuals with decompensated cirrhosis. Routine screening for NHVs, especially cytomegalovirus, may be useful for the management of individuals with acute decompensation of cirrhosis.

Administration of recombinant human thrombopoietin is associated with alleviated thrombocytopenia in adult intensive care unit patients with pneumonia: A single-center retrospective study.

Background: Recombinant human thrombopoietin (rhTPO) is reported to stimulate platelet production and increase peripheral platelet counts; it is primarily used to manage chemotherapy-induced thrombocytopenia and idiopathic thrombocytopenic purpura. However, the effect of rhTPO in patients with pneumonia and thrombocytopenia remains uncertain. Objective: To assess the association of rhTPO and platelet counts in ICU patients with pneumonia and thrombocytopenia. Materials and Methods: A retrospective cohort study was performed in the ICU department, Nanfang Hospital, Southern Medical University, Guangzhou, China. From January 2016 to April 2021, patients with pneumonia and thrombocytopenia were allocated to two groups-the rhTPO and no-rhTPO groups-according to whether they received rhTPO treatment or not during their ICU stay. Demographical and clinical data were collected and analyzed using statistical software; p < 0.05 was considered statistically significant. Results: Out of 327 patients, 149 were in the rhTPO group and 178 were in the no-rhTPO group. Within the first 7 days, platelet counts increased more for patients in the rhTPO group compared with those in the no-rhTPO group (99.21 ± 102.613 vs. 2.08 ± 43.877, p = 0.000). The clinical recovery rate of platelets increased within 7 days (65.8 vs. 18.5%, p = 0.000) and, after 7 days of enrollment, hemorrhagic scores decreased more apparently in the rhTPO group (2.81 ± 2.856 vs. 1.16 ± 2.123, p = 0.000). Further, bleeding events ceased in 66.7% of the patients in the rhTPO group compared with 37.3% of the patients in the no-rhTPO group (p = 0.000). Less red-blood-cells transfusions were needed in the rhTPO group (3.639 ± 4.630 vs. 5.818 ± 6.858, p = 0.009). Furthermore, through logistic regression, rhTPO administration was found to be an independent indicator that affected the platelet recovery rate within 7 days. Conclusion: This study finds that rhTPO administration is associated with increased platelet counts, alleviated bleeding, and reduced blood transfusion. For patients with pneumonia and thrombocytopenia, rhTPO may be an effective therapeutic drug; however, more RCT trails are needed to confirm our observation.

Empagliflozin activates Wnt/ß-catenin to stimulate FUNDC1-dependent mitochondrial quality surveillance against type-3 cardiorenal syndrome.

OBJECTIVES: Cardiorenal syndrome type-3 (CRS-3) is an abrupt worsening of cardiac function secondary to acute kidney injury. Mitochondrial dysfunction is a key pathological mechanism of CRS-3, and empagliflozin can improve mitochondrial biology by promoting mitophagy. Here, we assessed the effects of empagliflozin on mitochondrial quality surveillance in a mouse model of CRS-3. METHODS: Cardiomyocyte-specific FUNDC1-knockout (FUNDC1CKO) mice were subjected to CRS-3 prior to assessment of mitochondrial homeostasis in the presence or absence of empagliflozin. RESULTS: CRS-3 model mice exhibited lower heart function, increased inflammatory responses and exacerbated myocardial oxidative stress than sham-operated controls; however, empagliflozin attenuated these alterations. Empagliflozin stabilized the mitochondrial membrane potential, suppressed mitochondrial reactive oxygen species production, increased mitochondrial respiratory complex activity and restored the oxygen consumption rate in cardiomyocytes from CRS-3 model mice. Empagliflozin also normalized the mitochondrial morphology, mitochondrial dynamics and mitochondrial permeability transition pore opening rate in cardiomyocytes. Cardiomyocyte-specific ablation of FUN14 domain-containing protein 1 (FUNDC1) in mice abolished the protective effects of empagliflozin on mitochondrial homeostasis and myocardial performance. Empagliflozin activated ß-catenin and promoted its nuclear retention, thus increasing FUNDC1-induced mitophagy in heart tissues; however, a ß-catenin inhibitor reversed these effects. CONCLUSIONS: In summary, empagliflozin activated Wnt/ß-catenin to stimulate FUNDC1-dependent mitochondrial quality surveillance, ultimately improving mitochondrial function and cardiac performance during CRS-3. Thus, empagliflozin could be considered for the clinical management of heart function following acute kidney injury.

Cytosolic p53 Inhibits Parkin-Mediated Mitophagy and Promotes Acute Liver Injury Induced by Heat Stroke.

Heat stroke (HS) is a severe condition characterized by increased morbidity and high mortality. Acute liver injury (ALI) is a well-documented complication of HS. The tumor suppressor p53 plays an important role in regulation of mitochondrial integrity and mitophagy in several forms of ALI. However, the role of p53-regulated mitophagy in HS-ALI remains unclear. In our study, we discovered the dynamic changes of mitophagy in hepatocytes and demonstrated the protective effects of mitophagy activation on HS-ALI. Pretreatment with 3-MA or Mdivi-1 significantly exacerbated ALI by inhibiting mitophagy in HS-ALI mice. Consistent with the animal HS-ALI model results, silencing Parkin aggravated mitochondrial damage and apoptosis by inhibiting mitophagy in HS-treated normal human liver cell line (LO2 cells). Moreover, we described an increase in the translocation of p53 from the nucleus to the cytoplasm, and cytosolic p53 binds to Parkin in LO2 cells following HS. p53 overexpression using a specific adenovirus or Tenovin-6 exacerbated HS-ALI through Parkin-dependent mitophagy both in vivo and in vitro, whereas inhibition of p53 using siRNA or PFT-α effectively reversed this process. Our results demonstrate that cytosolic p53 binds to Parkin and inhibits mitophagy by preventing Parkin's translocation from the cytosol to the mitochondria, which decreases mitophagy activation and leads to hepatocyte apoptosis in HS-ALI. Overall, pharmacologic induction of mitophagy by inhibiting p53 may be a promising therapeutic approach for HS-ALI treatment.

NF­κB/IκBα signaling pathways are essential for resistance to heat stress­induced ROS production in pulmonary microvascular endothelial cells.

The results of a previous study demonstrated that heat stress (HS) triggered oxidative stress, which in turn induced the apoptosis of epithelial cells. These results uncovered a novel mechanism underlying the activation of NF­κB in primary human umbilical vein endothelial cells. The present study aimed to further investigate the role of NF­κB/IκBα signaling pathways in the inhibition of HS­induced reactive oxygen species (ROS) generation and cytotoxicity in endothelial cells. The results of the present study demonstrated that HS triggered a significant amount of NF­κB and IκBα nuclear translocation without IκBα degradation in a time­dependent manner. Mutant constructs of IκBα phosphorylation sites (Ser32, Ser36) were employed in rat pulmonary microvascular endothelial cells (PMVECs). Cell Counting Kit­8 assays demonstrated that both the small interfering (si)RNA­mediated knockdown of p65 and IκBα mutant constructs significantly decreased cell viability and aggravated ROS accumulation in HS­induced rat PMVECs compared with the control. Additionally, western blot analysis revealed that p65 siRNA attenuated the protein expression of IκBα. However, IκBα mutant constructs failed to attenuate NF­κB activation and nuclear translocation, indicating that IκBα­independent pathways contributed to NF­κB activity and nucleus translocation in a time­dependent manner following HS. Collectively, the results of the present study suggested that the NF­κB/IκBα pathway was essential for resistance to HS­induced ROS production and cytotoxicity in rat PMVECs, and that it could be a potential therapeutic target to reduce the mortality and morbidity of heat stroke.

Irisin Attenuates Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis in the H9C2 Cellular Model of Septic Cardiomyopathy through Augmenting Fundc1-Dependent Mitophagy.

In the present study, we used lipopolysaccharide- (LPS-) stimulated H9C2 cardiomyocytes to investigate whether irisin treatment attenuates septic cardiomyopathy via Fundc1-related mitophagy. Fundc1 levels and mitophagy were significantly reduced in LPS-stimulated H9C2 cardiomyocytes but were significantly increased by irisin treatment. Irisin significantly increased ATP production and the activities of mitochondrial complexes I and III in the LPS-stimulated cardiomyocytes. Irisin also improved glucose metabolism and significantly reduced LPS-induced levels of reactive oxygen species by increasing the activities of antioxidant enzymes, glutathione peroxidase (GPX), and superoxide dismutase (SOD), as well as levels of reduced glutathione (GSH). TUNEL assays showed that irisin significantly reduced LPS-stimulated cardiomyocyte apoptosis by suppressing the activation of caspase-3 and caspase-9. However, the beneficial effects of irisin on oxidative stress, mitochondrial metabolism, and viability of LPS-stimulated H9C2 cardiomyocytes were abolished by silencing Fundc1. These results demonstrate that irisin abrogates mitochondrial dysfunction, oxidative stress, and apoptosis through Fundc1-related mitophagy in LPS-stimulated H9C2 cardiomyocytes. This suggests irisin is a potentially useful treatment for septic cardiomyopathy, though further investigations are necessary to confirm our findings.

Risk Factors for Enterococcal Intra-Abdominal Infections and Outcomes in Intensive Care Unit Patients.

Background: To investigate the risk factors for enterococcal intra-abdominal infections (EIAIs) and the association between EIAIs and outcomes in intensive care unit (ICU) patients. Methods: We reviewed retrospectively the records of patients with intra-abdominal infections admitted to the Department of Critical Care Medicine at Nanfang Hospital, Southern Medical University, China, from January 2011 to December 2018. Patients with intra-abdominal infections were divided into enterococcal and non-enterococcal groups based on whether enterococci were isolated from intra-abdominal specimens. Results: A total of 431 patients with intra-abdominal infections were included, of whom 119 were infected with enterococci and 312 were infected with non-enterococci. Enterococci were isolated in 27.6% of patients, accounting for 24.5% (129/527) of all clinical bacterial isolates. Post-operative abdominal infection (adjusted odds ratio [OR], 2.361; p = 0.004), intestinal infection (adjusted OR, 2.703; p < 0.001), Mannheim Peritonitis Index score (MPI; adjusted OR, 1.052; p = 0.015), and use of antibiotic agents within the previous 90 days (adjusted OR, 1.880; p = 0.025) were associated with an increased risk of EIAIs. Compared with patients without enterococcal infection, ICU patients with enterococcal infection had a higher risk of failure of initial clinical therapy (49.6% vs. 24.2%; p < 0.001) and longer hospital stays (33 days [19, 48] vs. 18 days [12, 29]; p < 0.001). Enterococcal infection was associated with increased 28-day mortality, in-hospital mortality, and ICU mortality. However, no difference was found in length of ICU stay between the two groups. Additionally, there was no difference in ICU mortality, hospital mortality, or 28-day mortality in patients infected with enterococcus who did or did not receive empirical anti-enterococcal therapy. Conclusion: Post-operative abdominal infection, intestinal infection, MPI score, and use of antibiotic agents within the previous 90 days were independent risk factors for enterococcal infection. Enterococcal infection was associated with reduced short-term survival in ICU patients.

[Acute kidney injury in patients hospitalized with COVID-19 in Wuhan, China: a single-center retrospective observational study].

OBJECTIVE: To assess the predictors and outcomes of acute kidney injury (AKI) among patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: This retrospective observational study was conducted among patients with a confirmed diagnosis of COVID-19 admitted to Hankou Hospital between January, 5 and March 8, 2020. We evaluated the association of AKI with the demographic and biochemical parameters and clinical outcomes of the patients using univariate regression analysis. OBJECTIVE: Atotal of 287 COVID-19 patients, including 55 with AKI and 232 without AKI, were included in the analysis. Compared with the patients without AKI, the patients with AKI were older, predominantly male, and were more likely to have hypoxia and pre-existing hypertension and cerebrovascular diseases. The patients with AKI also had higher levels of white blood cells, D-dimer, aspartate aminotransferase, total bilirubin, creatine kinase, lactate dehydrogenase, procalcitonin, C-reactive protein, a higher prevalence of hyperkalemia, lower lymphocyte counts, and higher chest computed tomographic scores. The incidence of stage 1 AKI was 14.3% and that of stage 2 or 3 AKI was 4.9%. The patients with AKI had much higher mortality rate than those without AKI. OBJECTIVE: AKI is an important complication of COVID-19. An older age, a male gender, multiple pre- existing comorbidities, lymphopenia, increased infection indicators, elevated D-dimer, and impaired heart and liver functions are all potential risk factors ofAKI. COVID- 19 patients with AKI that progresses into stages 2 or 3 AKI have a high mortality rate. Prevention of AKI and monitoring kidney function is critical in the care of COVID-19 patients.

SIRT1 attenuates sepsis-induced acute kidney injury via Beclin1 deacetylation-mediated autophagy activation.

Our previous studies showed that silent mating-type information regulation 2 homologue-1 (SIRT1, a deacetylase) upregulation could attenuate sepsis-induced acute kidney injury (SAKI). Upregulated SIRT1 can deacetylate certain autophagy-related proteins (Beclin1, Atg5, Atg7 and LC3) in vitro. However, it remains unclear whether the beneficial effect of SIRT1 is related to autophagy induction and the underlying mechanism of this effect is also unknown. In the present study, caecal ligation and puncture (CLP)-induced mice, and an LPS-challenged HK-2 cell line were established to mimic a SAKI animal model and a SAKI cell model, respectively. Our results demonstrated that SIRT1 activation promoted autophagy and attenuated SAKI. SIRT1 deacetylated only Beclin1 but not the other autophagy-related proteins in SAKI. SIRT1-induced autophagy and its protective effect against SAKI were mediated by the deacetylation of Beclin1 at K430 and K437. Moreover, two SIRT1 activators, resveratrol and polydatin, attenuated SAKI in CLP-induced septic mice. Our study was the first to demonstrate the important role of SIRT1-induced Beclin1 deacetylation in autophagy and its protective effect against SAKI. These findings suggest that pharmacologic induction of autophagy via SIRT1-mediated Beclin1 deacetylation may be a promising therapeutic approach for future SAKI treatment.

The Value of Thromboelastography in the Diagnosis of Sepsis-Induced Coagulopathy.

Thromboelastography (TEG) is regularly used for monitoring abnormalities of the coagulation system in patients with sepsis. However, it is unclear whether TEG parameters are associated with sepsis-induced coagulopathy (SIC). Thus, we aimed to assess the diagnostic value of TEG for SIC. The medical records of patients who underwent TEG from January 2016 to December 2016 were analyzed retrospectively. The patients were divided into sepsis group and non-sepsis group. Baseline patient characteristics and coagulation function indexes were compared. Receiver-operating characteristic curve analysis was used to determine predictors of SIC. A total of 167 patients were included, of whom 84 had sepsis. The clot formation speed (K) was significantly higher(P < 0.001), and the maximum amplitude (MA) and angle were significantly lower (both P < 0.001) in the sepsis group than that in non-sepsis group. Patients with SIC had higher Sepsis-related Organ Failure Assessment scores than those patients without SIC (P < 0.001). The area under the curve of K for diagnosing SIC was 0.910. The area under the curve of angle and MA for excluding SIC was 0.895 and 0.882, respectively. Thus, TEG parameters have good diagnostic value for SIC.

Drp-1 as Potential Therapeutic Target for Lipopolysaccharide-Induced Vascular Hyperpermeability.

Mitochondria-dependent apoptotic signaling has a critical role in the pathogenesis of vascular hyperpermeability (VH). Dynamin-related protein-1- (Drp-1-) mediated mitochondrial fission plays an important role in mitochondrial homeostasis. In the present study, we studied the involvement of Drp-1 in resistance to VH induced by lipopolysaccharide (LPS). To establish the model of LPS-induced VH, LPS at 15 mg/kg was injected into rats in vivo and rat pulmonary microvascular endothelial cells were exposed to 500 ng/ml LPS in vitro. We found that depletion of Drp-1 remarkedly exacerbated the mitochondria-dependent apoptosis induced by LPS, as evidenced by reduced apoptosis, mitochondrial membrane potential (MMP) depolarization, and activation of caspase-3 and caspase-9. Increased FITC-dextran flux indicated endothelial barrier disruption. In addition, overexpression of Drp-1 prevented LPS-induced endothelial hyperpermeability and upregulated mitophagy, as evidenced by the loss of mitochondrial mass and increased PINK1 expression and mitochondrial Parkin. However, the mitophagy inhibitor, 3-Methyladenine, blocked these protective effects of Drp-1. Furthermore, inhibition of Drp-1 using mitochondrial division inhibitor 1 markedly inhibited LPS-induced mitophagy and aggravated LPS-induced VH, as shown by increased FITC-dextran extravasation. These findings implied that Drp-1 strengthens resistance to mitochondria-dependent apoptosis by regulating mitophagy, suggesting Drp-1 as a possible therapeutic target in LPS-induced VH.

Septic patients in the intensive care unit present different nasal microbiotas.

AIM: The primary objective of this study was to evaluate correlations among mortality, intensive care unit (ICU) length of stay and airway microbiotas in septic patients. MATERIALS & METHODS: A deep-sequencing analysis of the 16S rRNA gene V4 region was performed. RESULTS: The nasal microbiota in septic patients was dominated by three nasal bacterial types (Corynebacterium, Staphylococcus and Acinetobacter). The Acinetobacter type was associated with the lowest diversity and longest length of stay (median: 9 days), and the Corynebacterium type was associated with the shortest length of stay. We found that the Acinetobacter type in the >9-day group was associated with the highest mortality (33%). CONCLUSION: Septic patients have three nasal microbiota types, and the nasal microbiota is related to the length of stay and mortality.

SIRT1-mediated HMGB1 deacetylation suppresses sepsis-associated acute kidney injury.

Sepsis is the leading cause of death in the intensive care unit and continues to lack effective treatment. It is widely accepted that high-mobility group box 1 (HMGB1) is a key inflammatory mediator in the pathogenesis of sepsis. Moreover, some studies indicate that the functions of HMGB1 depend on its molecular localization and posttranslational modifications. Our previous study confirms that sirtuin 1, silent information regulator 2-related enzyme 1 (SIRT1), a type III deacetylase, can ameliorate sepsis-associated acute kidney injury (SA-AKI). We explored the effect and mechanism of SIRT1 on HMGB1 using a mouse model of cecal ligation and puncture-induced sepsis and LPS-treated human kidney (HK-2) cell line. We found that HMGB1 is elevated in the serum but is gradually reduced in kidney cells in the later stages of septic mice. The acetylation modification of HMGB1 is a key process before its nucleus-to-cytoplasm translocation and extracellular secretion in kidney cells, accelerating the development of SA-AKI. Moreover, SIRT1 can physically interact with HMGB1 at the deacetylated lysine sites K28, K29, and K30, subsequently suppressing downstream inflammatory signaling. Thus the SIRT1-HMGB1 signaling pathway is a crucial mechanism in the development of SA-AKI and presents a novel experimental perspective for future SA-AKI research.

Emerging Evidence concerning the Role of Sirtuins in Sepsis.

Sepsis, a dysregulated host response to infection, is a major public health concern. Though experimental and clinical studies relating to sepsis are increasing, the mechanism of sepsis is not completely understood. To date, numerous studies have shown that sirtuins (silent mating type information regulation 2 homolog), which belong to the class III histone deacetylases, may have a varied, or even opposite, effect in the pathogenesis of sepsis. Notably, downstream mechanisms of sirtuins are not fully understood. The sirtuin family consists of sirtuins 1-7; among them, sirtuin 1 (SIRT1) is the most studied one, during the development of sepsis. Furthermore, other sirtuin members are also confirmed to be involved in the regulation of inflammatory or metabolic signaling following sepsis. In addition, sirtuins may interact with each other to form a precise regulatory mechanism in different phases of sepsis. Therefore, in this review, by accumulating data from PubMed, we intend to explain the role of sirtuin in sepsis, which we hope will pave the way for further experimental study and the potential future clinical applications of sirtuins.

[A case of circulatory collapse during laparoscopic hepatectomy].

OBJECTIVE: We report a case of intractable circulatory failure event in a hypertensive patient during laparoscopy hepatectomy and analyze the diagnosis and treatment by multidisciplinary physicians. This case suggests that both surgeons and anesthesiologists should give attention to oral angiotensin II receptor antagonist during the preoperative period to avoid refractory hypotension. In addition, the use of EV1000 hemodynamic monitoring system in intensive care provides more convenience for clinical liquid management.