Iron Overload-Dependent Ferroptosis Aggravates LPS-Induced Acute Lung Injury by Impairing Mitochondrial Function.

Ferroptosis is a newly proposed form of programmed cell death that is iron-dependent and closely linked to oxidative stress. Its specific morphological changes include shrunken mitochondria, increased density of mitochondrial membrane, and rupture or disappearance of mitochondrial cristae. The main mechanism of ferroptosis involves excessive free iron reacting with membrane phospholipids, known as the Fenton reaction, resulting in lipid peroxidation. However, the role of iron in acute lung injury (ALI) remains largely unknown. In this study, LPS was instilled into the airway to induce ALI in mice. We observed a significant increase in iron concentration during ALI, accompanied by elevated levels of lipid peroxidation markers such as malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE). Treatment with the iron chelator deferoxamine (DFO) or ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed lipid peroxidation and significantly attenuates lung injury. Similarly, DFO or Fer-1 treatment improved the cell survival significantly in vitro. These results demonstrated that ferroptosis occurs during ALI and that targeting ferroptosis is an effective treatment strategy. Interestingly, we found that the increased iron was primarily concentrated in mitochondria and DFO treatment effectively restored normal mitochondria morphology. To further confirm the damaging effect of iron on mitochondria, we performed mitochondrial stress tests in vitro, which revealed that iron stimulation led to mitochondrial dysfunction, characterized by impaired basal respiratory capacity, ATP production capacity, and maximum respiratory capacity. MitoTEMPO, an antioxidant targeting mitochondria, exhibited superior efficacy in improving iron-induced mitochondrial dysfunction compared to the broad-spectrum antioxidant NAC. Treatment with MitoTEMPO more effectively alleviated ALI. In conclusion, ferroptosis contributes to the pathogenesis of ALI and aggravates ALI by impairing mitochondrial function.

Glutathione S-Transferase α4 Alleviates Hyperlipidemia- Induced Vascular Neointimal Hyperplasia in Arteriovenous Grafts via Inhibiting Endoplasmic Reticulum Stress.

Neointimal hyperplasia causes the failure of coronary artery bypass grafting (CABG). Our previous studies have found that endothelial dysfunction is one candidate for triggering neointimal hyperplasia, but which factors are involved in this process is unclear. Glutathione S-transferase α4 (GSTA4) play an important role in metabolizing 4-hydroxynonenal (4-HNE), a highly reactive lipid peroxidation product, which causes endothelial dysfunction or death. Here, we investigated the role of GSTA4 in neointima formation after arteriovenous grafts (AVGs) with or without high-fat diet (HFD). Compared with normal diet (ND), HFD caused endothelial dysfunction and increased neointima formation, concomitantly accompanied by downregulated expression of GSTA4 at the mRNA and protein levels. In vitro, overexpression of GSTA4 attenuated 4-HNE-induced endothelial dysfunction and knockdown of GSTA4 aggravated endothelial dysfunction. Furthermore, silencing GSTA4 expression facilitated the activation of 4-HNE induced endoplasmic reticulum stress (ERS) and inhibition of ERS pathway alleviated 4-HNE-induced endothelial dysfunction. Additionally, compared with wild-type (WT) mice, mice with knockout of endothelial-specific GSTA4 (GSTA4 EC KO) exhibited exacerbated vascular endothelial dysfunction and increased neointima formation caused by HFD. Together, these results demonstrate the critical role of GSTA4 in protecting the function of endothelial cells and in alleviating hyperlipidemia-induced vascular neointimal hyperplasia in arteriovenous grafts.

Protective role of pretreatment with Anisodamine against sepsis-induced diaphragm atrophy via inhibiting JAK2/STAT3 pathway.

There is an increasing tendency for sepsis patients to suffer from diaphragm atrophy as well as mortality. Therefore, reducing diaphragm atrophy could benefit sepsis patients' prognoses. Studies have shown that Anisodamine (Anis) can exert antioxidant effects when blows occur. However, the role of Anisodamine in diaphragm atrophy in sepsis patients has not been reported. Therefore, this study investigated the antioxidant effect of Anisodamine in sepsis-induced diaphragm atrophy and its mechanism. We used cecal ligation aspiration (CLP) to establish a mouse septic mode and stimulated the C2C12 myotube model with lipopolysaccharide (LPS). After treatment with Anisodamine, we measured the mice's bodyweight, diaphragm weight, fiber cross-sectional area and the diameter of C2C12 myotubes. The malondialdehyde (MDA) levels in the diaphragm were detected using the oxidative stress kit. The expression of MuRF1, Atrogin1 and JAK2/STAT3 signaling pathway components in the diaphragm and C2C12 myotubes was measured by RT-qPCR and Western blot. The mean fluorescence intensity of ROS in C2C12 myotubes was measured by flow cytometry. Meanwhile, we also measured the levels of Drp1 and Cytochrome C (Cyt-C) in vivo and in vitro by Western blot. Our study revealed that Anisodamine alleviated the reduction in diaphragmatic mass and the loss of diaphragmatic fiber cross-sectional area and attenuated the atrophy of the C2C12 myotubes by inhibiting the expression of E3 ubiquitin ligases. In addition, we observed that Anisodamine inhibited the JAK2/STAT3 signaling pathway and protects mitochondrial function. In conclusion, Anisodamine alleviates sepsis-induced diaphragm atrophy, and the mechanism may be related to inhibiting the JAK2/STAT3 signaling pathway.

N-Acetylcysteine Attenuates Sepsis-Induced Muscle Atrophy by Downregulating Endoplasmic Reticulum Stress.

(1) Background: Sepsis-induced muscle atrophy is characterized by a loss of muscle mass and function which leads to decreased quality of life and worsens the long-term prognosis of patients. N-acetylcysteine (NAC) has powerful antioxidant and anti-inflammatory properties, and it relieves muscle wasting caused by several diseases, whereas its effect on sepsis-induced muscle atrophy has not been reported. The present study investigated the effect of NAC on sepsis-induced muscle atrophy and its possible mechanisms. (2) Methods: The effect of NAC on sepsis-induced muscle atrophy was assessed in vivo and in vitro using cecal ligation and puncture-operated (CLP) C57BL/6 mice and LPS-treated C2C12 myotubes. We used immunofluorescence staining to analyze changes in the cross-sectional area (CSA) of myofibers in mice and the myotube diameter of C2C12. Protein expressions were analyzed by Western blotting. (3) Results: In the septic mice, the atrophic response manifested as a reduction in skeletal muscle weight and myofiber cross-sectional area, which is mediated by muscle-specific ubiquitin ligases-muscle atrophy F-box (MAFbx)/Atrogin-1 and muscle ring finger 1 (MuRF1). NAC alleviated sepsis-induced skeletal muscle wasting and LPS-induced C2C12 myotube atrophy. Meanwhile, NAC inhibited the sepsis-induced activation of the endoplasmic reticulum (ER) stress signaling pathway. Furthermore, using 4-Phenylbutyric acid (4-PBA) to inhibit ER stress in LPS-treated C2C12 myotubes could partly abrogate the anti-muscle-atrophy effect of NAC. Finally, NAC alleviated myotube atrophy induced by the ER stress agonist Thapsigargin (Thap). (4) Conclusions: NAC can attenuate sepsis-induced muscle atrophy, which may be related to downregulating ER stress.

Injectable Self-Expanding/Self-Propelling Hydrogel Adhesive with Procoagulant Activity and Rapid Gelation for Lethal Massive Hemorrhage Management.

Developing hydrogels that can quickly reach deep bleeding sites, adhere to wounds, and expand to stop lethal and/or noncompressible bleeding in civil and battlefield environments remains a challenge. Herein, an injectable, antibacterial, self-expanding, and self-propelling hydrogel bioadhesive with procoagulant activity and rapid gelation is reported. This hydrogel combines spontaneous gas foaming and rapid Schiff base crosslinking for lethal massive hemorrhage. Hydrogels have rapid gelation and expansion rate, high self-expanding ratio, excellent antibacterial activity, antioxidant efficiency, and tissue adhesion capacity. In addition, hydrogels have good cytocompatibility, procoagulant ability, and higher blood cell/platelet adhesion activity than commercial combat gauze and gelatin sponge. The optimized hydrogel (OD-C/QGQL-A30) exhibits better hemostatic ability than combat gauze and gelatin sponge in rat liver and femoral artery bleeding models, rabbit volumetric liver loss massive bleeding models with/without anticoagulant, and rabbit liver and kidney incision bleeding models with bleeding site not visible. Especially, OD-C/QGQL-A30 rapidly stops the bleedings from pelvic area of rabbit, and swine subclavian artery vein transection. Furthermore, OD-C/QGQL-A30 has biodegradability and biocompatibility, and accelerates Methicillin-resistant S. aureus (MRSA)-infected skin wound healing. This injectable, antibacterial, self-expanding, and self-propelling hydrogel opens up a new avenue to develop hemostats for lethal massive bleeding, abdominal organ bleeding, and bleeding from coagulation lesions.

Injectable Antiswelling and High-Strength Bioactive Hydrogels with a Wet Adhesion and Rapid Gelling Process to Promote Sutureless Wound Closure and Scar-free Repair of Infectious Wounds.

Developing injectable antiswelling and high-strength bioactive hydrogels with wet tissue adhesiveness and a rapid gelling process to meet the requirements for rapid hemostasis, sutureless wound closure, and scar-free repair of infected skin wounds continues to have ongoing challenges. Herein, injectable, antibacterial, and antioxidant hydrogel adhesives based on poly(citric acid-co-polyethylene glycol)-g-dopamine and amino-terminated Pluronic F127 (APF) micelles loaded with astragaloside IV (AS) are prepared. The H2O2/horseradish peroxidase (HRP) system is used to cause cross-linking of the hydrogel network through oxidative coupling between catechol groups and chemical cross-linking between the catechol group and the amino group. The hydrogels exhibit a rapid gelling process, high mechanical strength, an antiswelling effect, good antioxidant property, H2O2 release behavior, and degradability. In addition, the hydrogels present good wet tissue adhesiveness, high bursting pressure, excellent antibacterial activity, long-term sustained release of AS, and good biocompatibility. The hydrogels perform good hemostasis on mouse liver, rat liver, and rabbit femoral vein bleeding models and achieve much better closure and healing of skin incisions than biomedical glue and surgical sutures. Furthermore, the hydrogel dressing significantly improved the scar-free repair of MRSA-infected full thickness skin defect wounds by modulating inflammation, regulating the ratio of collagen I/III, and improving the vascularization and granulation tissue formation. Thus, AS-loaded hydrogels show huge potential as multifunctional dressings for in vivo hemostasis, sutureless wound closure, and scar-free repair of infected skin wounds.

Peroxinredoxin 6 reduction accelerates cigarette smoke extract­induced senescence by regulating autophagy in BEAS­2B cells.

Cigarette smoke (CS)-induced accelerated senescence and insufficient autophagy has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Peroxiredoxin (PRDX) 6 is a protein with prevalent antioxidant capacity. Previous studies indicate that PRDX6 could activate autophagy and alleviate senescence in other diseases. The present study investigated whether PRDX6-regulated autophagy was involved in the regulation of CS extract (CSE)-induced BEAS-2B cell senescence via the knockdown of PRDX6 expression. Furthermore, the present study evaluated the mRNA levels of PRDX6, autophagy and senescence-associated genes in the small airway epithelium from patients with COPD by analyzing the GSE20257 dataset from the Gene Expression Omnibus database. The results demonstrated that CSE reduced PRDX6 expression levels and transiently induced the activation of autophagy, followed by the accelerated senescence of BEAS-2B cells. Knockdown of PRDX6 induced autophagy degradation and accelerated senescence in CSE-treated BEAS-2B cells. Furthermore, autophagy inhibition by 3-Methyladenine increased P16 and P21 expression levels, while autophagy activation by rapamycin reduced P16 and P21 expression levels in CSE-treated BEAS-2B cells. The GSE20257 dataset revealed that patients with COPD had lower PRDX6, sirtuin (SIRT) 1 and SIRT6 mRNA levels, and higher P62 and P16 mRNA levels compared with non-smokers. P62 mRNA was significantly correlated with P16, P21 and SIRT1, which indicated that insufficient autophagic clearance of damaged proteins could be involved in accelerated cell senescence in COPD. In conclusion, the present study demonstrated a novel protective role for PRDX6 in COPD. Furthermore, a reduction in PRDX6 could accelerate senescence by inducing autophagy impairment in CSE-treated BEAS-2B cells.

Preparation, thermal response mechanisms and biomedical applications of thermosensitive hydrogels for drug delivery.

INTRODUCTION: Drug treatment is one of the main ways of coping with disease today. For the disadvantages of drug management, thermosensitive hydrogel is used as a countermeasure, which can realize the simple sustained release of drugs and the controlled release of drugs in complex physiological environments. AREAS COVERED: This paper talks about thermosensitive hydrogels that can be used as drug carriers. The common preparation materials, material forms, thermal response mechanisms, characteristics of thermosensitive hydrogels for drug release and main disease treatment applications are reviewed. EXPERT OPINION: When thermosensitive hydrogels are used as drug loading and delivery platforms, desired drug release patterns and release profiles can be tailored by selecting raw materials, thermal response mechanisms, and material forms. The properties of hydrogels prepared from synthetic polymers will be more stable than natural polymers. Integrating multiple thermosensitive mechanisms or different kinds of thermosensitive mechanisms on the same hydrogel is expected to realize the spatiotemporal differential delivery of multiple drugs under temperature stimulation. The industrial transformation of thermosensitive hydrogels as drug delivery platforms needs to meet some important conditions.

Recent progress of antibacterial hydrogels in wound dressings.

Hydrogels are essential biomaterials due to their favorable biocompatibility, mechanical properties similar to human soft tissue extracellular matrix, and tissue repair properties. In skin wound repair, hydrogels with antibacterial functions are especially suitable for dressing applications, so novel antibacterial hydrogel wound dressings have attracted widespread attention, including the design of components, optimization of preparation methods, strategies to reduce bacterial resistance, etc. In this review, we discuss the fabrication of antibacterial hydrogel wound dressings and the challenges associated with the crosslinking methods and chemistry of the materials. We have investigated the advantages and limitations (antibacterial effects and antibacterial mechanisms) of different antibacterial components in the hydrogels to achieve good antibacterial properties, and the response of hydrogels to stimuli such as light, sound, and electricity to reduce bacterial resistance. Conclusively, we provide a systematic summary of antibacterial hydrogel wound dressings findings (crosslinking methods, antibacterial components, antibacterial methods) and an outlook on long-lasting antibacterial effects, a broader antibacterial spectrum, diversified hydrogel forms, and the future development prospects of the field.

Endoplasmic reticulum stress promotes sepsis-induced muscle atrophy via activation of STAT3 and Smad3.

Endoplasmic reticulum (ER) stress is involved in skeletal muscle atrophy in various conditions, but the role of ER stress in sepsis-induced muscle atrophy is not well understood. In this study, we conducted experiments in wild-type (WT) mice and C/EBP homologous protein knockout (CHOP KO) mice to explore the role and mechanism of ER stress in sepsis-induced muscle atrophy. Cecal ligation and puncture (CLP) was used to establish a mouse model of sepsis. In WT mice, the body weight, muscle mass, and cross-sectional area of muscle fibers in CLP group both decreased significantly compared with sham group, which revealed that sepsis-induced dramatic muscle atrophy. Additionally, sepsis activated the ubiquitin-proteasome system (UPS), accompanied by the activation of ER stress. In vitro, inhibition of ER stress suppressed the activity of E3 ubiquitin ligases and alleviated the myotube atrophy. In vivo, CHOP KO also reduced the expression of E3 ubiquitin ligases and UPS-mediated protein degradation, and significantly attenuated sepsis-induced muscle atrophy. Deletion of CHOP also decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and Smad3, and inhibition of STAT3 and Smad3 partly reduced proteolysis caused by ER stress in vitro. These findings confirm that ER stress activates UPS-mediated proteolysis and promotes sepsis-induced muscle atrophy, which is partly achieved by activating STAT3 and Smad3.

Endoplasmic Reticulum Stress-induced Endothelial Dysfunction Promotes Neointima Formation after Arteriovenous Grafts in Mice on High-fat Diet.

OBJECTIVE: Endothelial dysfunction is one candidate for triggering neointima formation after arteriovenous grafts (AVGs), but the factors mediating this process are unclear. The purpose of this study was to investigate the role of endoplasmic reticulum stress (ERS)-induced endothelial dysfunction in neointima formation following AVGs in high-fat diet (HFD) mice. METHODS: CCAAT-enhancer-binding protein-homologous protein (CHOP) knockout (KO) mice were created. Mice were fed with HFD to produce HFD model. AVGs model were applied in the groups of WT ND, WT HFD, and CHOP KO HFD. Human umbilical vein endothelial cells (HUVECs) were cultured with oxidized low density lipoprotein (ox-LDL) (40 mg/L) for the indicated time lengths (0, 6, 12, 24 h). ERS inhibitor tauroursodeoxycholic acid (TUDCA) was used to block ERS. Immunohistochemical staining was used to observe the changes of ICAM1. Changes of ERS were detected by real-time RT-PCR. Protein expression levels and ERS activation were detected by Western blotting. Endothellial cell function was determined by endothelial permeability assay and transendothelial migration assay. RESULTS: HFD increased neointima formation in AVGs associated with endothelial dysfunction. At the same time, ERS was increased in endothelial cells (ECs) after AVGs in mice consuming the HFD. In vitro, ox-LDL was found to stimulate ERS, increase the permeability of the EC monolayer, and cause endothelial dysfunction. Blocking ERS with TUDCA or CHOP siRNA reversed the EC dysfunction caused by ox-LDL. In vivo, knockout of CHOP (CHOP KO) protected the function of ECs and decreased neointima formation after AVGs in HFD mice. CONCLUSION: Inhibiting ERS in ECs could improve the function of AVGs.

Astragaloside IV alleviates sepsis-induced muscle atrophy by inhibiting the TGF-ß1/Smad signaling pathway.

BACKGROUND: Muscle atrophy occurs in patients with sepsis and increases mortality and disability. Remission of muscle atrophy may improve the quality of life in patients with sepsis. Astragaloside IV (ASIV) has been shown to have excellent anti-inflammatory and anti-fibrotic effects and to reduce organ damage caused by sepsis. However, the effect of ASIV on sepsis-induced muscle atrophy has not been reported. Therefore, this study explored the pharmacological effects and mechanisms of ASIV in sepsis-induced muscle atrophy. METHODS: Cecal ligation and puncture (CLP) was used to establish a mouse model of sepsis and lipopolysaccharide (LPS)-stimulated C2C12 myotubes. After administration of ASIV, the body weight, tibialis anterior (TA) and gastrocnemius muscle weight and fiber cross-sectional area of the mice were measured. The diameter of myotubes was observed by immunofluorescence staining. ELISA was used to assess inflammatory factors in plasma and cell culture supernatants. RT-PCR and Western blotting were used to detect the expression of MuRF1, Atrogin-1 and TGF-ß1/Smad signaling pathway components in TA and C2C12 myotubes. RESULTS: Our study found that ASIV reduced serum inflammatory factors and improved survival in septic mice. ASIV alleviated muscle mass reduction, myofiber cross-sectional area reduction, and C2C12 myotube atrophy by inhibiting the expression of the E3 ubiquitin ligases MuRF1 and atrogin-1. In addition, we observed that ASIV inhibited TGF-ß1/Smad signaling. Inhibition of the TGF-ß1/Smad signaling pathway partly blocked the anti-muscle atrophy effect of ASIV. CONCLUSION: ASIV can alleviate sepsis-induced muscle atrophy, which may be related to the inhibition of the TGF-ß1/Smad signaling pathway.

Impact on Carbon Intensity of Carbon Emission Trading-Evidence from a Pilot Program in 281 Cities in China.

China's carbon emissions trading scheme (ETS) is an institutional arrangement that China intends to explore as a means of energy conservation and emission reduction. It is the core of China's goal of achieving carbon peaking and carbon neutrality. This paper regards the introduction of pilot carbon emission trading policies as a quasi-natural experiment. Propensity Score Matching (PSM), Differences-in-Differences (DID), and spatial Durbin methods were used to evaluate the policy effects of pilot carbon emission trading policies on the carbon intensity of Chinese cities. We empirically tested the impact mechanism using the panel data of 281 cities at the prefecture level and above in China from 2006 to 2019. The results show that (1) the pilot policy of carbon emission trading has significantly reduced the carbon intensity of Chinese cities and shows characteristics of heterogeneity; (2) the dynamic effect test shows that the mitigation effect of the pilot carbon emission trading policy has increased gradually with time; (3) the mediation effect shows that the pilot carbon emission trading policy alleviates urban pollution in the region by improving the level of environmental governance and jointly reduces urban carbon intensity by increasing the level of green technology innovation; (4) the Durbin test suggests that pilot carbon emissions trading policy enforcement can significantly improve the carbon intensity of the area surrounding the city. In summary, the national carbon emissions trading market appears to be a successful experiment that also can contribute to China's sustainable development. Its promise in achieving the "double carbon" target provides important policy implications.

Dysregulation of miR-204-5p/APLN axis affects malignant progression and cell stemness of esophageal cancer.

OBJECTIVE: This study attempted to investigate the mechanism of miR-204-5p and its downstream gene in regulating bio-functions of esophageal cancer (EC). METHODS: Bioinformatics analysis was performed to select the mature miRNAs, mRNAs, and clinical data of EC. The miRNA-mRNA regulatory axis was predicted through bioinformatics and used Dual-luciferase analysis to verify the interaction between miR-204-5p and APLN. qRT-PCR was applied to analyze expression of miR-204-5p and APLN mRNA. Western blot was utilized to detect APLN protein expression. Functional assays like CCK-8, wound healing, Transwell, and stem cell sphere formation assays were launched to confirm proliferative, migratory, invasive and stemness of cells in different treatment groups. RESULTS: MiR-204-5p was lowly expressed while its target gene APLN was highly expressed in tumor tissues. Besides, miR-204-5p overexpression hindered proliferation, invasion, migration, and stemness of EC cells. Additionally, dual-luciferase assay verified the interaction of miR-204-5p and APLN. MiR-204-5p could downregulate APLN level and its overexpression reduced the effect of APLN on EC cell functions. CONCLUSION: Dysregulation of miR-204-5p/APLN axis was linked with malignant progression of EC. MiR-204-5p/APLN may be an underlying candidate for the design of anticarcinogens.

Development and Validation of a Nomogram for Predicting 28-Day Mortality on Admission in Elderly Patients with Severe Community-Acquired Pneumonia.

Introduction: There were few studies on the mortality of severe community-acquired pneumonia (SCAP) in elderly people. Early prediction of 28-day mortality of hospitalized patients will help in the clinical management of elderly patients (age ≥65 years) with SCAP, but a prediction model that is reliable and valid is still lacking. Methods: The 292 elderly patients with SCAP met the criteria defined by the American Thoracic Society from 33 hospitals in China. Clinical parameters were analyzed by the use of univariable and multivariable logistic regression analysis. A nomogram to predict the 28-day mortality in elderly patients with SCAP was constructed and evaluated using the area under the receiver operating characteristic curve (AUC) and internally verified using the Bootstrap method. Results: A total of 292 elderly patients (227 surviving and 65 died within 28 days) were included in the analysis. Age, Glasgow score, blood platelet, and blood urea nitrogen values were found to be significantly associated with 28-day mortality in elderly patients with SCAP. The AUC of the nomogram was 0.713 and the calibration curve for 28-day mortality also showed high coherence between the predicted and actual probability of mortality. Conclusion: This study provides a nomogram containing age, Glasgow score, blood platelet, and blood urea nitrogen values that can be conveniently used to predict 28-day mortality in elderly patients with SCAP. This model has the potential to assist clinicians in evaluating prognosis of patients with SCAP.

Comparison of the extraperitoneal and transperitoneal routes for permanent colostomy: a meta-analysis with RCTs and systematic review.

AIM: To assess the efficacy of extraperitoneal colostomy (EPC) in preventing stoma-related complications. BACKGROUND: Transperitoneal colostomy (TPC) is a widely used surgical approach. However, TPCs have been reported to have increased risks of stoma-related complications, such as parastomal hernias, stomal retraction, and stomal prolapse. The purpose of EPC is to reduce these complications. However, there is still a lack of evidence-based studies. MATERIALS AND METHODS: MEDLINE, EMBASE, Web of Science, Scopus, MOOSE, PubMed, Google Scholar, Baidu Scholar, and the Cochrane Library were searched to conduct a systematic review and meta-analysis with RCTs. The meta-analysis was performed with RevMan 5.4 software. RESULTS: This study included 5 eligible RCTs. Compared with the TPC group, the EPC group had lower incidence rates of parastomal hernias (RR, 0.14; 95% CI, 0.04-0.52, P = 0.003, I2 = 0%) and stomatal prolapse (RR, 0.27; 95% CI, 0.08-0.95, P = 0.04, I2 = 0%), but a higher rate of defecation sensation (RR, 3.51; 95% CI, 2.47-5.0, P < 0.00001, I2 = 37%). No statistically significant differences were observed in stoma retraction, colostomy construction time, stoma ischemia, or stoma necrosis. CONCLUSION: Extraperitoneal colostomies are associated with lower rates of postoperative complications than transperitoneal colostomies. A randomized controlled trial meta-analysis found that permanent colostomies after abdominoperineal resection resulted in better outcomes.

Low Eosinophil Phenotype Predicts Noninvasive Mechanical Ventilation Use in Patients with Hospitalized Exacerbations of COPD.

RATIONALE: Eosinophilic inflammation is related to the progression and outcomes of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Till now, few studies have focused on low EOS in AECOPD. OBJECTIVE: To reveal the clinical characteristics, therapeutic responses and prognosis of patients hospitalized of AECOPD with low EOS. METHODS: The electronic database of Zhongshan Hospital, Fudan University was used. Cohort 1 included 608 patients with hospitalized AECOPD. Study population 2 consisted of 166 patients with AECOPD admission at least twice. Impact of low EOS on NIMV treatment, length of hospital stays and 12-month AECOPD-related readmission were analyzed with multivariable logistic regression model. Thirty-five hospitalized AECOPD patients were prospectively recruited as cohort 3 to explore the association between EOS and other immune cells using Spearman correlation coefficient for ranked data. RESULTS: EOS level was suppressed on admission in AECOPD patients, and significantly improved after hospitalized treatment (P < 0.05). For inflammatory markers, leucocytes, neutrophils and lactate dehydrogenase levels were higher, while lymphocytes, monocytes and interleukin-6 levels were lower in the low-EOS group than those in the non-low EOS group (P < 0.05). Low EOS (EOS < 50 cells/µL) was an independent risk factor of NIMV use (OR = 1.86, 95% CI = 1.26 ~ 2.73). The EOS percentage was positively correlated with the T cell percentage (r = 0.46, P < 0.05) and negatively correlated with the natural killer cell percentage (r = -0.39, P < 0.05). The patients with low EOS had lower level of CD4+ T cell (P < 0.05) than that of patients with non-low EOS. CONCLUSION: Low EOS might be a stable phenotype in patients with hospitalized AECOPD and could be used to inform NIMV management, hyperinflammatory state and impaired immunity situation.

Ameliorative Effects of Osthole on Experimental Renal Fibrosis in vivo and in vitro by Inhibiting IL-11/ERK1/2 Signaling.

Objectives: Natural product, osthole, has been proven to have a protective effect on organ fibrosis, including renal fibrosis. All of these studies are mainly focused on the regulation of TGF-ß/Smad signaling pathway. However, due to the pleiotropic roles of TGF-ß/Smad signaling, direct TGF-ß-targeted treatments are unlikely to be therapeutically feasible in clinic. Recently, the downstream IL-11/ERK1/2 signaling of TGF-ß has become an attractive therapeutic target without upstream disadvantages. Based on that, this study was designed to identify the potential effects of osthole on IL-11/ERK1/2 signaling pathway in renal fibrosis. Methods: The renal fibrosis model was established in vivo and in vitro, we investigated the effects of osthole on unilateral ureteral obstruction (UUO)-induced renal fibrosis and TGF-ß-induced HK-2 cells. After preliminarily confirming the antifibrogenic effects of osthole and the link between its antifibrogenic effects and the inhibition of IL-11/ERK1/2 signaling, we applied a direct IL-11-induced HK-2 cells fibrosis model to further explore the inhibitory effects of osthole on IL-11/ERK1/2 signaling pathway. Results: Our results confirmed that osthole can decrease the secretion of fibrosis proteins, such as α-smooth muscle actin (α-SMA), collagen I, and fibronectin, ameliorate experimental renal fibrosis in vivo and in vitro, and the effect was associated with suppressing TGF-ß1/Smad signaling. More importantly, we found that IL-11/ERK1/2 signaling in UUO-induced renal fibrosis and TGF-ß-induced HK-2 cell model was obviously upregulated, and osthole treatment also significantly inhibited the abnormal IL-11/ERK1/2 signaling activation. Given the direct link between TGF-ß/Smad signaling and IL-11/ERK1/2 signaling pathway, we have verified that osthole has a direct inhibitory effect on IL-11/ERK1/2 signaling independent of TGF-ß signaling by using an IL-11-induced HK-2 cells fibrosis model. Osthole treatment decreased the protein expression of α-SMA, collagen I and fibronectin without changing their mRNA levels in IL-11-induced HK-2 cells. Moreover, it was observed that the IL-11/ERK1/2 inhibitor, U0126, partly blocked the antifibrogenic effects of osthole. Conclusion: In this study, we found that osthole has a previously unrecognized role in inhibiting IL-11/ERK1/2 signaling pathway. Our work demonstrated that the antifibrogenic effect of osthole is not only mediated by TGF-ß/Smad2/3 signaling, but also directly mediated by IL-11/ERK1/2 signaling pathway independent of TGF-ß1 signaling.

Celastrol alleviates metabolic disturbance in high-fat diet-induced obese mice through increasing energy expenditure by ameliorating metabolic inflammation.

Celastrol, a natural triterpene, has been shown to treat obesity and its related metabolic disorders. In this study, we first assessed the relationship between the antiobesity effects of celastrol and its antiinflammatory activities. Our results showed that celastrol can reduce weight gain, ameliorate glucose intolerance, insulin resistance, and dyslipidemia without affecting food intake in high-fat diet-induced obese mice. A CLAMS was used to clarify the improvement of metabolic profiles was attribute to increased adipose thermogenesis after celastrol treatment. Further studies found that celastrol decreased the infiltration of macrophage as well as its inflammatory products (IL-1ß, IL-18, MCP-1α, and TNF-α) in liver and adipose tissues, which also displayed an obvious inhibition of TLR3/NLRP3 inflammasome molecules. This study demonstrated that celastrol could be a potential drug for treating metabolic disorders, the underlying mechanism is related to ameliorating metabolic inflammation, thus increasing body energy expenditure.