Vitamin D Supplementation during Intensive Care Unit Stay Is Associated with Improved Outcomes in Critically Ill Patients with Sepsis: A Cohort Study.

BACKGROUND: Vitamin D, as a common micronutrient, has been widely used in critically ill patients. However, whether supplementation of vitamin D in adult patients with sepsis can improve their prognosis remains controversial. METHODS: Data from the Mart for Intensive Care IV database was used in this retrospective cohort study, and adult patients with sepsis were enrolled. Critically ill patients, admitted to intensive care units (ICUs) between 2008 and 2019 at the Beth Israel Deaconess Medical Center (BIDMC), were divided into the vitamin D supplementation group and non-vitamin D supplementation group. The primary outcomes were defined as all-cause in-hospital, 28-day, and 90-day mortality rates after admission to the ICU. A 1:1 propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and overlap weighting (OW) analyses were used to minimize selection bias and balance the baseline demographic characteristics. Regression and survival analyses were performed to assess the association between vitamin D supplementation and clinical outcomes in patients with sepsis. RESULTS: In total, 3539 patients with sepsis were enrolled as study participants; of these, 315 were supplemented with vitamin D during their ICU stay. In-hospital, 28-day, and 90-day mortality rates were significantly lower in patients with sepsis supplemented with vitamin D. Multivariate regression analysis showed vitamin D supplementation as a potential protective factor for in-hospital mortality with an odds ratio (OR) = 0.70 (0.51-0.96) after adjusting for all confounders. The hazard ratios (HRs) for 28-day and 90-day mortality were 0.65 (0.50-0.85) and 0.70 (0.55-0.90), respectively. The survival analysis showed that the vitamin D supplementation group had a higher survival probability within 28 and 90 days (p-value < 0.05). These results remained relatively stable post PSM, IPTW, and OW. However, we found no evidence that vitamin D supplementation could shorten the length of stay in the ICU or hospital. CONCLUSIONS: Vitamin D supplementation during an ICU stay was associated with improved prognosis in patients with sepsis, as evidenced by lower in-hospital, 28-day, and 90-day mortality rates and lower disease severity-related scores, but showed no influence on the length of stay in the hospital or ICU.

Lactoferrin attenuates cardiac fibrosis and cardiac remodeling after myocardial infarction via inhibiting mTORC1/S6K signaling pathway.

Rationale: Myocardial infarction (MI) causes a severe injury response that eventually leads to adverse cardiac remodeling and heart failure. Lactoferrin (Ltf), as a secreted protein, bears multi-pharmacological properties. Present study aims to establish the cardioprotective function and corresponding mechanism of Ltf in MI process. Methods and results: We performed proteomic analysis in Tregs derived from MI heart, and identified Ltf as a remarkably upregulated secreted protein. However, Ltf was decreased in circulation and positively correlated with cardiac function both in mice and patients after MI. Ltf administration remarkably alleviated cardiac fibrosis and remodeling, improved cardiac function, and reduced incidence of heart failure in mice post-MI. In vitro, Ltf suppressed fibroblast to myofibroblast conversion induced by transforming growth factor-ß (TGF-ß). Mechanistically, phosphoproteomic landscape analysis revealed that Ltf repressed the activation of mTORC1/S6K/eIF-4B signaling pathway via interaction with CD74 receptor. Administration of mTORC1/S6K/eIF-4B axis agonist MHY1485 abolished the cardioprotective effects of Ltf. Besides, MHY1485 also markedly reversed the effects of Ltf on suppressing the transformation of fibroblast to myofibroblast mediated by TGF-ß. Conclusion: Our study established the cardiac protective role of Ltf in attenuating cardiac remodeling and improving cardiac function by inhibiting the activation of myofibroblasts through suppressing mTORC1/S6K/eIF-4B signaling pathway post-MI. Treatment with Ltf may serve as a potential novel therapeutic intervention in patients with MI.

Cthrc1 deficiency aggravates wound healing and promotes cardiac rupture after myocardial infarction via non-canonical WNT5A signaling pathway.

Cardiac fibroblasts are crucial for scar formation and cardiac repair after myocardial infarction (MI). Collagen triple helix repeat containing 1 (CTHRC1), an extracellular matrix protein, is involved in the pathogenesis of vascular remodeling, bone formation, and tumor progression. However, the role and underlying mechanism of CTHRC1 in post-MI wound repair are not fully clear. Bioinformatics analysis demonstrated CTHRC1 up-regulation in cardiac fibroblasts after ischemic cardiac injury. Serum levels of CTHRC1 were increased in MI mice and CTHRC1 expression was up-regulated in cardiac fibroblasts after MI. In vitro results showed that the induction of CTHRC1 expression in cardiac fibroblasts was mediated by canonical TGFß1-Smad2/3 signaling axis. Moreover, CTHRC1 improved wound healing and boosted cardiac fibroblast activation in vitro. Cthrc1 deficiency aggravated cardiac function and reduced collagen deposition as well as increased mortality attributable to cardiac rupture after MI. Consistent with above phenotypes, reduced the levels of myocardial CD31, α-smooth muscle actin, collagen I, and collagen III was observed, whereas myocardial expression of matrix metalloproteinase 2 and matrix metalloproteinase 9 were increased in Cthrc1 knockout mice post-MI. Above effects could be partly reversed by rCTHRC1 protein or rWNT5A protein. Our study indicates that cardiac fibroblast-derived, canonical TGFß1-Smad2/3-dependent CTHRC1 could improve wound repair and prevent cardiac rupture after MI via selectively activating non-canonical WNT5A-PCP signaling pathway.

Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation.

Rationale: Previous studies have suggested that myocardial inflammation plays a critical role after ischemic myocardial infarction (MI); however, the underlying mechanisms still need to be fully elucidated. WW domain-containing ubiquitin E3 ligase 1 (WWP1) is considered as an important therapeutic target for cardiovascular diseases due to its crucial function in non-ischemic cardiomyopathy, though it remains unknown whether targeting WWP1 can alleviate myocardial inflammation and ischemic injury post-MI. Methods: Recombinant adeno-associated virus 9 (rAAV9)-cTnT-mediated WWP1 or Kruppel-like factor 15 (KLF15) gene transfer and a natural WWP1 inhibitor Indole-3-carbinol (I3C) were used to determine the WWP1 function in cardiomyocytes. Cardiac function, tissue injury, myocardial inflammation, and signaling changes in the left ventricular tissues were analyzed after MI. The mechanisms underlying WWP1 regulation of cardiomyocyte phenotypes in vitro were determined using the adenovirus system. Results: We found that WWP1 expression was up-regulated in cardiomyocytes located in the infarct border at the early phase of MI and in hypoxia-treated neonatal rat cardiac myocytes (NRCMs). Cardiomyocyte-specific WWP1 overexpression augmented cardiomyocyte apoptosis, increased infarct size and deteriorated cardiac function. In contrast, inhibition of WWP1 in cardiomyocytes mitigated MI-induced cardiac ischemic injury. Mechanistically, WWP1 triggered excessive cardiomyocyte inflammation after MI by targeting KLF15 to catalyze K48-linked polyubiquitination and degradation. Ultimately, WWP1-mediated degradation of KLF15 contributed to the up-regulation of p65 acetylation, and activated the inflammatory signaling of MAPK in ischemic myocardium and hypoxia-treated cardiomyocytes. Thus, targeting of WWP1 by I3C protected against cardiac dysfunction and remodeling after MI. Conclusions: Our study provides new insights into the previously unrecognized role of WWP1 in cardiomyocyte inflammation and progression of ischemic injury induced by MI. Our findings afford new therapeutic options for patients with ischemic cardiomyopathy.

Cardiac Overexpression of Chil1 Improves Wound Healing to Prevent Cardiac Rupture After Myocardial Infarction.

Timely formation of collagen-rich-scar is of importance to prevent ventricular rupture after myocardial infarction (MI). Chil1 (Chitinase 3-like 1) is a secreted protein associated with tissue remodeling response. However, its function in MI progression remains elusive. Chil1 was downregulated in the injured area overall post-MI. Overexpression of Chil1 markedly reduced cardiac rupture, increased wall thickness, and improved cardiac function post-MI due to collagen-rich-scar formation and extracellular matrix remodeling. In vitro, Chil1 induced the transformation of fibroblasts to myofibroblasts. Mechanistically, a phosphoproteomics study revealed that Chil1 binded to the EGFR enhancing RAF/MEK1/ERK signaling pathway to exert cardiac protection function. The effects of Chil1 on fibroblasts transformation and cardiac protections after MI were partially abolished by co-treated with RAF inhibitor. Together, our findings identify Chil1 as a protection factor in MI progression through binding to EGFR which further activates RAF/MEK1/ERK signaling pathway.

Effects of ondansetron exposure during ICU stay on outcomes of critically ill patients with sepsis: a cohort study.

Background: Sepsis is a life-threatening disease with high morbidity and mortality, characterized by an inadequate systemic immune response to an initial stimulus. Whether the use of ondansetron (OND) during intensive care unit (ICU) stay is associated with the prognosis of sepsis patients remains unclear. Methods: Critically ill patients with sepsis were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Multivariate logistic regression and Cox regression analyses were used to explore the association between OND use and clinical outcomes after adjusting for confounders. Kaplan-Meier survival curve was used for survival analysis. Propensity score matching (PSM) and subgroup analysis were performed to further confirm the results. Results: The OND-medication group showed reduced in-hospital mortality, 28-day and 90-day mortalities. The OR for in-hospital mortality was 0.80 (0.64-0.99) and HRs for 28-day mortality and 90-day mortality were 0.77 (0.64-0.92) and 0.83 (0.70-0.98), respectively. After PSM, the clinical outcomes remained consistent. In-hospital mortality was lower in the OND-medication group (28.1% vs. 35.8%, P= 0.044), as well as 28-day mortality (23.4% vs. 32.1%, P=0.022) and 90-day mortality (27.4% vs. 35.8%, P=0.035). The protective effect of OND in sepsis patients was relatively robust, independent of age, septic shock, vasopressin and mechanical ventilation. Additionally, the OND users had longer lengths of stay in ICU (6.9(3.1-13.2) vs. 5.1(2.5-11.0), P = 0.026) while no statistical differences were found in lengths of stay in hospital (P = 0.333). Conclusion: OND exposure might be associated with lower in-hospital, 28-day, and 90-day mortality rates in critically ill patients with sepsis. This study indicated that OND might help improve the prognosis of patients with sepsis.

Porous Se@SiO2 nanocomposite promotes migration and osteogenic differentiation of rat bone marrow mesenchymal stem cell to accelerate bone fracture healing in a rat model.

Background: Delay or failure of bone union is a significant clinical challenge all over the world, and it has been reported that bone marrow mesenchymal stem cells (BMSCs) offer a promising approach to accelerate bone fracture healing. Se can modulate the proliferation and differentiation of BMSCs. Se-treatment enhances the osteoblastic differentiation of BMSCs and inhibiting the differentiation and formation of mature osteoclasts. The purpose of this study was to assess the effects of porous Se@SiO2 nanocomposite on bone regeneration and the underlying biological mechanisms. Methods: We oxidized Se2- to develop Se quantum dots, then we used the Se quantum dots to form a solid Se@SiO2 nanocomposite which was then coated with polyvinylpyrrolidone (PVP) and etched in hot water to synthesize porous Se@SiO2 nanocomposite. We used XRD pattern to assess the phase structure of the solid Se@SiO2 nanocomposite. The morphology of porous Se@SiO2 nanocomposite were evaluated by scanning electron microscope (SEM) and the biocompatibility of porous Se@SiO2 nanocomposite were investigated by cell counting kit-8 (CCK-8) assays. Then, a release assay was also performed. We used a Transwell assay to determine cell mobility in response to the porous Se@SiO2 nanocomposite. For in vitro experiments, BMSCs were divided into four groups to detect reactive oxygen species (ROS) generation, cell apoptosis, alkaline phosphatase activity, calcium deposition, gene activation and protein expression. For in vivo experiments, femur fracture model of rats was constructed to assess the osteogenic effects of porous Se@SiO2 nanocomposite. Results: In vitro, intervention with porous Se@SiO2 nanocomposite can promote migration and osteogenic differentiation of BMSCs, and protect BMSCs against H2O2-induced inhibition of osteogenic differentiation. In vivo, we demonstrated that the porous Se@SiO2 nanocomposite accelerated bone fracture healing using a rat femur fracture model. Conclusion: Porous Se@SiO2 nanocomposite promotes migration and osteogenesis differentiation of rat BMSCs and accelerates bone fracture healing, and porous Se@SiO2 nanocomposite may provide clinic benefit for bone tissue engineering.