Organ Injury Research Articles

Abstract P188: Prevalence of AHA Pediatric Risk Categories in Youth with Hypertension Disorders: a SUPERHERO Analysis

Background: Cardiovascular (CV) risk factors in childhood contribute to the development of CV disease (CVD) later in life. In higher risk groups of youth, increased risk of CV events begins early in adulthood. The American Heart Association (AHA) 2019 CV Risk Reduction in High-Risk Pediatric Patients scientific statement uses medical diagnoses and CV health factors to classify patients into High, Moderate, and At-risk categories. The prevalence of these risk categories in youth with hypertension (HTN) disorders is unknown. Methods: Cross-sectional analysis of baseline electronic health record data from youth referred for HTN disorders in the multisite retrospective SUPERHERO Registry. Inclusion criteria were age <19 years and index subspecialty clinic visit for a HTN disorder by ICD-10 codes from 1/1/2015–12/31/2023. Exclusion criteria were kidney failure on dialysis, kidney transplantation, or pregnancy by ICD-10 codes. We report prevalence of AHA Pediatric Risk Category (High, Moderate, At-risk). We used clinic BP and 2017 AAP Clinical Practice Guidelines to define HTN, clinic BMI percentile to define obesity, and ICD-10 codes to define other risk category medical diagnoses. We report frequencies and proportions in this descriptive analysis. Results: Of 9356 participants, 3544 (37.9%) were female and 5464 (58.4%) were ≥13 years. At the index visit, 5563 participants (63.5%) were hypertensive. A total of 634 participants (6.8%) were classified as High risk, 6100 participants (65.2%) as Moderate risk, and 1034 participants (11.1%) were in the At-risk group. There were 1588 participants (17.0%) not classified into a risk category with available data. Conclusions: In a large cohort of youth with HTN disorders, we found that over 80% of participants were in an AHA pediatric risk category with 63.5% of participants having either primary or secondary HTN. Our findings suggest that if only HTN is used to identify youth at early CV risk, we will miss youth who may benefit from early CV health factor intervention. Next steps include confirming our findings using laboratory and prescription data in defining risk categories and investigating the association of AHA pediatric risk category with target organ injury using laboratory and echocardiogram data.

Abstract P409: Cardiovascular Health Assessment and Intervention by AHA Pediatric Risk Category in Youth with Hypertension Disorders: a SUPERHERO Analysis

Background: Early intervention for modifiable cardiovascular (CV) health factors may decrease incidence of CV disease later in life, though whether youth at higher risk are more likely to have CV assessment and intervention is unknown. Our objective was to determine CV health initial assessment and intervention including echocardiogram (ECHO) order, anti-hypertensive medication prescription, and dietician referral by participant risk category from the 2019 American Heart Association (AHA) CV Risk Reduction in High-Risk Pediatric Patients scientific statement in a large cohort of youth with hypertension (HTN) disorders. Methods: Cross-sectional analysis of baseline data from the SUPERHERO Registry, a multisite retrospective cohort of youth referred for HTN disorders. Inclusion criteria were age <19 years and HTN disorder identified by ICD-10 codes from 1/1/2015–12/31/2023 at index visit to a subspecialty clinic. Exclusion criteria were kidney replacement therapy by dialysis or transplant or pregnancy by ICD-10 codes. Exposure was AHA Pediatric Risk Category (High, Moderate, At-risk). We used clinic BP by U.S. guidelines, clinic BMI percentile to define obesity, and ICD-10 codes to define other risk category medical diagnoses. Outcomes were ECHO order, anti-hypertensive medication prescription, and dietician referral. We used unadjusted generalized linear models. Results: Of 9356 participants, 1034 (11.1%), 6100 (65.2%), and 634 (6.8%) participants were categorized as High, Moderate, and At-risk groups. Overall, 3053 (32.6%) of participants had an ECHO order, 943 (16.4%) had anti-hypertensive medication prescribed, and 661 (7.1%) had a dietician referral. With At-risk group as reference, participants in High or Moderate risk groups were more likely to have an anti-hypertensive medication prescription (RR 3.12; 95% CL 2.23 to 4.36, RR 1.38; 95% CL 1.02 to 1.85). Participants in the Moderate risk group were more likely to have an ECHO order (RR 1.24; 95% CL 1.06 to 1.44). No difference between risk groups was seen for dietician referral. Conclusions: Among a large cohort of youth with HTN disorders, we found that higher risk groups were more likely to have an anti-hypertensive medication prescribed compared to lower risk group. The overall proportion of participants with medication prescriptions, ECHO orders, or dietician referrals were low. Next steps include investigating the association of risk category with target organ injury.

Contemporary management and outcomes of blunt traumatic American Association for the Surgery of Trauma Organ Injury Scale grades III and IV pancreatic injuries in children: A Trauma Quality Improvement Program analysis.

The Trauma Quality Improvement Program (TQIP) database has delineated management strategies and outcomes for adults with American Association for the Surgery of Trauma Organ Injury Scale grades III and IV pancreatic injuries and suggests that nonoperative management (NOM) is a viable option for these injuries. However, management strategies vary for children following significant pancreatic injuries and outcomes for these intermediate/high-grade injuries have not been sufficiently studied. Our aim was to describe the management and outcomes for grades III and IV pancreatic injuries using TQIP. We hypothesize that pediatric patients with intermediate/high-grade injuries can be safely managed with NOM. All pediatric patients (younger than 18 years) registered in TQIP between 2013 and 2021 who suffered a grade III or IV pancreatic injury due to blunt trauma were included in the current study. Patient demographics, clinical characteristics, complications, and in-hospital mortality were compared between the different treatment strategies for pancreatic injury: NOM versus drainage and/or pancreatic resection. A total of 580 patients meeting the inclusion criteria were identified. A total of 416 pediatric patients suffered a grade III pancreatic injury; 79% (n = 332) were NOM, 7% (n = 27) received a drain, and 14% (n = 57) underwent a pancreatic resection. A further 164 patients suffered a grade IV pancreatic injury; 77% (n = 126) were NOM, 11% (n = 18) received a drain, and 12% (n = 20) underwent a pancreatic resection. No differences in overall injury severity or demographical data were observed between the treatment groups. No difference in in-hospital mortality was detected between the different management strategies. Patients who received a drain had a longer hospital length of stay. The majority of children with American Association for the Surgery of Trauma Organ Injury Scale grades III and IV pancreatic injuries are managed nonoperatively. Nonoperative management is a reasonable strategy for these injuries and results in equivalent in-hospital adverse outcome profiles as pancreatic drainage or resection with a shorter hospital length of stay. Therapeutic/Care Management; Level IV.

Recovering skin-nerve interaction by nanoscale metal-organic framework for diabetic ulcers healing

Skin-nerve interaction plays an important role in promoting wound healing. However, in diabetic ulcers (DUs), the diabetic periphery neuropathy and excessive levels of reactive oxygen species (ROS) block skin-nerve interaction and further impede the DUs healing. Herein, we developed a nanoscale metal-organic framework loaded with nerve growth factor (NGF/Ce-UiO-66, denoted NGF/CU) for the treatment of DUs. The Ce-UiO-66 (CU) was applied as an antioxidant to scavenge ROS and reduce the inflammatory response while the NGF aided in the recovery of cutaneous nerves to further promote DUs healing. Both in vitro and in vivo experiments revealed the effective ability of NGF/CU for DUs healing. Subsequent RNA sequencing analysis revealed the mechanism that NGF/CU can improve wound healing by inhibiting the NF-κB signaling pathway and recovering the neuroendocrine system of the skin. This strategy of nerve regulation will provide more ideas for the treatment of DUs and other organ injuries.

FBXW7-Mediated Downregulation of GPX4 Aggravates Acute Kidney Injury Following Ischemia‒Reperfusion.

Acute kidney injury (AKI) is a prevalent and potentially life-threatening complication characterized by a high incidence and mortality. A large number of studies have emphasized the role of ferroptosis in AKI. Moreover, FBXW7, a ubiquitin ligase, has been implicated in acute organ injury. Analysis of the GEO database (GSE98622) revealed increased FBXW7 mRNA levels in the kidney following ischemia‒reperfusion (IR). However, the role of FBXW7 in AKI has not been elucidated. Therefore, this study aimed to investigate the role of FBXW7 in IR-AKI and its underlying mechanisms. Here, we found that IR could induce AKI and increase FBXW7 expression, while the ferroptosis inhibitor Fer-1 alleviated AKI and decreased FBXW7 expression. Furthermore, we treated HK-2 cells with hypoxia for 12h and reoxygenation for 4h (H12R4) to simulate IR-AKI and investigated the impact of modulating FBXW7 expression on ferroptosis by employing ferroptosis-related agonists or inhibitors. Our findings revealed that H12R4 induced HK2 ferroptosis and increased the expression of FBXW7. FBXW7 overexpression in control cells exacerbated erastin-induced ferroptosis, and FBXW7 knockdown inhibited ferroptosis in H12R4-treated cells. Mechanistically, we confirmed that FBXW7 can bind to GPX4, a key molecule that inhibits ferroptosis. The half-life of the GPX4 protein decreased after FBXW7 overexpression, GPX4 ubiquitination increased after H12R4, and GPX4 degradation decreased after FBXW7 knockdown. In conclusion, our results indicated that FBXW7 plays an important role in the development of IR-AKI by promoting ferroptosis through the downregulation of GPX4 expression. This study provides new insight into FBXW7 as a potential target for treating AKI.

Systemic organoprotection with inhaled nitric oxide (literature review)

Sufficient levels of nitric oxide (NO) ensure adequate blood flow to all organs and tissues. Despite the contradictory data on the role of endogenous NO as an organоprotector, NO insufflation is a promising direction, which is supported by evidence of modeling the protective effect on the myocardium, kidneys, and liver with exogenous NO in experimental and clinical studies. The largest number of studies have been conducted on models of ischemia-reperfusion injury in cardiovascular surgery. There are very few studies in abdominal and other non-cardiac surgery and they are mostly experimental. This review describes possible ways of implementing the organоprotective effect of NO, however, the exact mechanism remains not fully understood. One of the main links in the development of abdominal organ injury is intra-abdominal hypertension (IAH), which always accompanies laparoscopic surgeries and can last up to several hours. IAH causes ischemia of the kidneys and gastrointestinal mucosa with possible subsequent development of organ dysfunction. The degree of damage will depend not only on the duration of IAH but also on the patient’s premorbid background. The prognosis will be especially aggravated by the presence of atherosclerotic vascular lesions, which creates a preoperative background for hypoperfusion of visceral organs, which, due to the characteristics of vascularization, anatomical structure, and functioning, are very sensitive to the slightest disturbances in perfusion pressure and to the systemic inflammatory reaction, which will subsequently lead to an increase in vascular permeability, the formation of transcapillary leakage and interstitial edema, which is the beginning of organ dysfunction. Dysregulation of the mechanisms involved in NO production may be a link in the pathogenesis of the development of organ’s dysfunction, so maintaining adequate NO levels may be a target for therapy.

Intraoperative surgical complications of open surgery for congenital diaphragmatic hernia: a multicenter, observational study in Japan.

This study aimed to clarify surgical complications associated with open surgery for congenital diaphragmatic hernia (CDH). We performed an exploratory data analysis of the clinical characteristics of surgical complications of neonates with CDH who underwent laparotomy or thoracotomy between 2006 and 2021. Data of these patients were obtained from the database of the Japanese CDH Study Group. Among 1,111 neonates with left or right CDH, 852 underwent open surgery (laparotomy or thoracotomy). Of these 852 neonates, 51 had the following surgical complications: organ injury (n = 48; 6% of open surgeries); circulatory failure caused by changes in the organ location (n = 2); and skin burns (n = 1). Injured organs included the spleen (n = 30; 62% of organ injuries), liver (n = 7), lungs (n = 4), intestine (n = 4), adrenal gland (n = 2), and thoracic wall (n = 2). Fourteen of the patients who experienced organ injury required a blood transfusion (2% of open surgeries). The adjusted odds ratio of splenic injury for patients with non-direct closure of the diaphragm was 2.2 (95% confidence interval, 1.1-4.9). Of the patients who underwent open surgery for CDH, 2% experienced organ injury that required a blood transfusion. Non-direct closure of the diaphragmatic defect was a risk factor for splenic injury.

Plexin C1 influences immune response to intracellular LPS and survival in murine sepsis

BackgroundIntracellular sensing of lipopolysaccharide (LPS) is essential for the immune response against gram-negative bacteria and results in activation of caspase-11 and pyroptotic cell death with fatal consequences in sepsis. We found the neuronal guidance receptor plexin C1 (PLXNC1) influences the intracellular response to LPS.MethodsWe employed a murine model of sepsis via cecal ligation and binding (CLP), using PLXNC1-/- mice and littermate controls, and additionally transfected murine bone-marrow-derived macrophages (BMDMs) from both genotypes with LPS to achieve activation of the noncanonical inflammasome ex vivo. Additionally, we transfected the PLXNC1 ligand SL4c-d in vivo and ex vivo to examine its effect on intracellular LPS response.ResultsWe found the neuronal guidance receptor PLXNC1 dampens the intracellular response to LPS by interacting with adenylate cyclase 4 (ADCY4) and protein kinase A activity, which in turn diminishes caspase-11 expression. The absence of PLXNC1 results in excessive inflammation marked by increased cytokine release, increased secondary organ injury and reduced sepsis survival in a murine sepsis model induced by CLP. Notably, administration of SL4c-d—peptide ligand of PLXNC1—reduces the inflammatory response during CLP-induced sepsis and improves survival.ConclusionsThese results elucidate a previously unknown mechanism for PLXNC1 suppressing excessive noncanonical inflammasome activity and offer a new potential target for treatment of sepsis with its detrimental effects.

Elevation of Donor-derived Cell-free DNA Before Biopsy-proven Rejection in Kidney Transplant.

Standard-of-care biomarkers for renal allograft rejection are lagging indicators, signaling existing organ injury. This precludes early intervention, when immunological cascades leading to rejection are most susceptible. Donor-derived cell-free DNA (dd-cfDNA) shows promise as an early indicator of rejection, allowing earlier and possibly more effective treatment. This analysis was designed to assess this promise using real-world dd-cfDNA testing evidence. This retrospective analysis of the prospective, observational ProActive registry study (NCT04091984) assessed dd-cfDNA and serum creatinine levels before biopsy in 424 patients with ≥1 dd-cfDNA test (n = 1013) in the 6 mo before biopsy. Of 4667 enrolled patients, 1631 patients had ≥18 mo of follow-up data, of which 424 had a biopsy and were included in this analysis. Twenty-six biopsies showed antibody-mediated rejection (ABMR), 62 showed T cell-mediated rejection, and 336 showed nonrejection; each from a unique patient. dd-cfDNA fractions were significantly elevated 5 mo before ABMR biopsies, and 2 mo before T cell-mediated rejection biopsies, compared with nonrejection biopsies. In contrast, serum creatinine did not discriminate between rejection and nonrejection in advance, or concurrent with biopsy. Among patients with nonrejection biopsies, estimated glomerular filtration rate was significantly lower in cases with ≥2 increased dd-cfDNA results (≥1%), compared with those with 0 or 1 increased dd-cfDNA result. These data indicate that dd-cfDNA is an early indicator of biopsy-proven rejection, especially ABMR, suggesting a greater role for dd-cfDNA in surveillance to identify patients at high risk of ongoing or future rejection, thus requiring closer monitoring, biopsy, or other management changes.

Identification of Isoliensinine as a Ferroptosis Suppressor with Iron-Chelating Activity.

Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of lipid peroxides. The high involvement of ferroptosis in diverse human diseases highlights the need for the identification of new chemotypes with anti-ferroptotic activity. Here, we performed a natural product library screening in HT1080 fibrosarcoma cells and identified licochalcone A (LA), isoeugenyl acetate (ISA), and isoliensinine (ISL) as suppressors of either RSL3- or IKE-induced ferroptosis. Mechanistically, ferroptosis resistance conferred by these compounds is mainly through GPX4/NRF2-independent mechanisms. Among them, only ISL could effectively rescue ferroptosis induced by FINO2, which is a stable oxidant of ferrous iron, suggesting that ISL may have the properties of an iron chelator. Consistent with the hypothesis, both computational tools and X-ray photoelectron spectroscopy supported the binding between ISL and iron ions. And ISL greatly inhibited excessive iron-dependent ferroptotic cell death through limiting intracellular iron accumulation. Furthermore, its iron chelator activity also protected mice from organ injury in an acute iron overload model. In conclusion, this study provided valuable insights for developing effective anti-ferroptosis agents from natural products, which represent a potential therapeutic strategy for treating ferroptosis-associated organ damage.

Protective Effect of a Isothiazolinone Derivative on Acute Lung Injury by Regulating PI3K-AKT Signaling Pathway.

Acute lung injury (ALI) is a prevalent organ injury in sepsis, characterized by an inflammatory reactive disorder. Both the incidence and mortality rates of ALI have been steadily increasing. Isothiazolinone derivatives have displayed anti-inflammatory activity and have shown effectiveness in treating pneumonia. The objective of the study is to assess the effects and mechanisms of the isothiazolinone derivative 4-benzoyl-2-butyl-5-(ethylsulfinyl)isothiazol-3(2H)-one (C6) on sepsis-induced ALI.The analysis of biological function and signal pathway enrichment demonstrated that C6 primarily exhibited anti-inflammatory effects. Administration of different doses of C6 through intraperitoneal injection significantly improved the survival rate, body temperature, and body mass of mice with ALI induced by cecal ligation and puncture (CLP). Additionally, it mitigated lung tissue injury, pulmonary edema, lung permeability, inflammatory cell infiltration, apoptosis, and the expression of inflammatory cytokines. Network targeting analysis and experimental validation in mouse leukemia cells of monocyte macrophage (RAW264.7) cells and CLP-induced ALI mice revealed that the anti-inflammatory effect of C6 was mediated by the inhibition of the phosphatidylinositol 3 kinase -protein kinase B (PI3K-AKT) signaling pathway. The research suggest that C6 has protective effects against ALI by inhibiting the PI3K-AKT signaling pathway. This information could be valuable in developing potential treatments for ALI.

Biomarkers in cardiorenal syndrome, a potential use in precision medicine.

Cardiorenal syndrome refers to the interrelated dysfunction of the heart or kidney resulting in a cascade of feedback mechanisms, hemodynamic, neurohormonal, and immunological and/or biochemical feedback pathways causing damage in the other organ. Cardiorenal syndrome is categorized into five clinical subtypes depending on the perceived primary precipitant of organ injury and is associated with high morbidity and mortality. Therefore, the development of tools for the earliest identification of cardiorenal syndrome in hospitalized patients is of extremely high significance to ameliorate the prognosis and outcome of these patients. There is increasing interest in identifying molecules serving as biomarkers, reflecting hemodynamic changes, heart and kidney damage and/or dysfunction and oxidative stress-induced cell damage or changes in the extracellular matrix of both the heart and kidneys. Biomarkers provide important insights into the pathophysiology of cardiorenal syndrome and are invaluable tools to predict the decrease in renal function during cardiac dysfunction and vice versa. Based on the pathophysiological mechanisms of cardiorenal syndrome, we reviewed and evaluated the available literature on serum and urinary biomarkers as predictors of kidney and/or heart injury. In addition, heart- and kidney-specific biomarkers were also evaluated based ontheir reference to kidney and cardiac (dys)function respectively, and whether they would provide any prediction and prognostication of cardiorenal syndrome. In this article, we discuss the current knowledge on the pathophysiology of different types ofcardiorenal syndrome, examine the clinical utility of candidate biomarkers in the early diagnosis of cardiorenalsyndrome, and guide treatment by evaluating the respective roles of the involved pathophysiological pathways.

Ferroptosis in Obstetrical and Gynecological Diseases: A Mini Review.

Ferroptosis is an iron-dependent form of non-apoptotic cell programmed death, characterized by the disturbance of iron metabolism, accumulation of lipid peroxides and disruption of cellular antioxidant system. Ferroptosis induces oxidative cell death through decrease of antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells. In recent years, studies have confirmed that ferroptosis is closely related to numerous organ injuries, degenerative pathologies and even the tumorigenesis and therapeutic resistance of tumors. While the effect of ferroptosis in obstetrical and gynecological diseases remains unclear and the relevant researches are still limited. In this review, we summarize the current understanding of the molecular mechanisms and regulatory networks of ferroptosis, together with the potential physiological functions and pathological roles of ferroptosis in clinical obstetrical and gynecological diseases. Importantly, our review also aims to provide references for further understanding of its pathogenesis and explore potential therapeutic strategies for targeting ferroptosis in clinical obstetrical and gynecological diseases.

Juxtahepatic venous injuries are not AAST Grade V injuries if there is no contrast extravasation

Abstract Background: The organ injury scale (OIS) for liver trauma by the American Association of the Surgery of Trauma (AAST) was last updated in 2018 with new “imaging criteria” that continued to grade juxtahepatic venous (JHV) injuries, regardless of presence or absence of active bleeding, as Grade V. We hypothesized that JHV injury found on imaging, in the absence of active bleeding, should not be considered Grade V based on location alone. The aim of the study was to compare the outcomes of patients classified as AAST-OIS Grade V liver injuries based purely on JHV location, with patients who had AAST-OIS Grade I–III liver injuries. Materials and Methods: A retrospective analysis of 121 patients with liver injury from the TReCS database (June 2020–May 2023) was conducted. Patients underwent contrast-enhanced dual-phase computed tomography scans on admission were reviewed by both radiologists and surgeons. Patients diagnosed with JHV injuries (JHV – with no contrast extravasation [CE]) and patients with low-grade injuries (OIS I–III) were compared for baseline data on age, gender, injury severity score (ISS) scoring, injury mechanism, length of hospital stay, and liver-related complications. Results: Of 121 patients identified, 66 had Grade I–III injuries and 21 had Grade V injuries due to JHV location alone. Three of the latter group had CE and were excluded. Heterogeneity was compared between the two groups for age (P = 0.634), gender (P = 0.964), mechanisms (P = 0.346), and ISS (P = 0.068). The median length of stay for the JHV (with no CE) group was 4.5 days and 6.00 days for the OIS Grade I–III group (P = 0.233). One patient in the JHV group had hemobilia, and there were no other liver-related complications in the cohort. Conclusion: Our findings suggest that the “imaging” criterion of “JHV” injuries, in the absence of extravasation or significant disruption, may be safely revised to a lower grade on the AAST-OIS for liver injuries.

GDF15 attenuates sepsis-induced myocardial dysfunction by inhibiting cardiomyocytes ferroptosis via the SOCS1/GPX4 signaling pathway

Sepsis is a systemic inflammatory response syndrome triggered by infection, presenting with symptoms such as fever, increased heart rate, and low blood pressure. In severe cases, it can lead to multiple organ dysfunction, posing a life-threatening risk. Sepsis-induced cardiomyopathy (SIC) is a critical factor in the poor prognosis of septic patients, leading to myocardial dysfunction characterized by cell death, inflammation, and diminished cardiac function. Ferroptosis, an iron-dependent form of programmed cell death, is a key mechanism causing cardiomyocyte damage in SIC. Growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily, is associated with various cardiovascular diseases and can inhibit oxidative stress, reduce reactive oxygen species (ROS), and suppress ferroptosis. Elevated serum GDF15 levels in sepsis are correlated with organ injuries, suggesting its potential as a therapeutic target. However, its role and mechanisms in SIC remain unclear. Glutathione peroxidase 4 (GPX4), the only enzyme capable of reducing lipid peroxides within cells, protects cells by reducing lipid peroxidation levels and inhibiting ferroptosis. Investigating the regulatory factors of GPX4 may provide a theoretical basis for SIC treatment. In this study, a mouse SIC model revealed that elevated GDF15 exerts a protective effect. Antagonizing GDF15 exacerbates myocardial damage. Through transcriptomic analysis and other methods, we confirmed that GDF15 inhibits the expression of SOCS1 by activating the ALK5-SMAD2/3 pathway, thereby activates the JAK2/STAT3 pathway, promotes the transcription of GPX4, inhibits ferroptosis in cardiomyocytes, and plays a myocardial protective role in SIC.

Systematic establishment of the relationship between skin absorption and toxicity of furanoids via in silico, in vitro, and in vivo assessments

Furanoids are a class of contaminants prevalent in both airborne and occupational environments, with potential health implications through inhalation, oral ingestion, and skin penetration. Given their diminutive molecular size, there is a presumption that furanoids can readily permeate the skin. To systematically explore this presumption, we investigated the skin absorption and toxicity of a series of furans (furfuryl alcohol, furfuryl acetate, furfural, methyl 2-furoate, and 5-methylfurfural) using in silico, in vitro, and in vivo models. The in vitro permeation test (IVPT) from neat and aqueous suspension (5 mM) of furans demonstrated a facile absorption through pig and nude mouse skins. The lipophilicity of furans significantly influenced skin deposition, with higher lipophilicity displaying greater deposition. However, an opposing trend emerged in the receptor compartment accumulation. In barrier-defective skin simulating atopic dermatitis (AD) and psoriasis, enhanced deposition occurred with more hydrophilic furans but not with the more lipophilic ones. In the cell-based study, furanoids induced the proliferation of keratinocytes and skin fibroblasts except for the compounds with the aldehyde group (furfural and 5-methylfurfural). Both furfuryl acetate and 5-methylfurfural activated keratinocytes via the overexpression of COX-2 and PGE2 by 1.5‒2-fold. This stimulation involved the mitogen-activated protein kinase (MAPK) signaling pathway. For the in vivo mouse skin treatment, we selected furfuryl acetate (hydrophilic) and 5-methylfurfural (lipophilic). Both furans showed different patterns of skin lesions, where repeated application of furfuryl acetate caused epidermal hyperplasia and scaling, while 5-methylfurfural predominantly evoked skin inflammation and barrier disintegration. Toxicokinetics analysis revealed a higher plasma concentration of topically applied furfuryl acetate than that of the 5-methylfurfural (5.04 versus 2.34 nmol/ml), resulting in the mild injury of furfuryl acetate-treated peripheral organs. Conversely, no notable adverse effects on organs were observed for the 5-methylfurfural. This study established the relationship between cutaneous absorption and the toxicity of furans following skin exposure.

Nanorepair medicine for treatment of organ injury.

Organ injuries, such as acute kidney injury, ischemic stroke, and spinal cord injury, often result in complications that can be life-threatening or even fatal. Recently, many nanomaterials have emerged as promising agents for repairing various organ injuries. In this review, we present the important developments in the field of nanomaterial-based repair medicine, herein referred to as 'nanorepair medicine'. We first introduce the disease characteristics associated with different types of organ injuries and highlight key examples of relevant nanorepair medicine. We then provide a summary of existing strategies in nanorepair medicine, including organ-targeting methodologies and potential countermeasures against exogenous and endogenous pathologic risk factors. Finally, we offer our perspectives on current challenges and future expectations for the advancement of nanomedicine designed for organ injury repair.

The Myofibroblast Fate of Therapeutic Mesenchymal Stromal Cells: Regeneration, Repair, or Despair?

Mesenchymal stromal cells (MSCs) can be isolated from various tissues of healthy or patient donors to be retransplanted in cell therapies. Because the number of MSCs obtained from biopsies is typically too low for direct clinical application, MSC expansion in cell culture is required. However, ex vivo amplification often reduces the desired MSC regenerative potential and enhances undesired traits, such as activation into fibrogenic myofibroblasts. Transiently activated myofibroblasts restore tissue integrity after organ injury by producing and contracting extracellular matrix into scar tissue. In contrast, persistent myofibroblasts cause excessive scarring-called fibrosis-that destroys organ function. In this review, we focus on the relevance and molecular mechanisms of myofibroblast activation upon contact with stiff cell culture plastic or recipient scar tissue, such as hypertrophic scars of large skin burns. We discuss cell mechanoperception mechanisms such as integrins and stretch-activated channels, mechanotransduction through the contractile actin cytoskeleton, and conversion of mechanical signals into transcriptional programs via mechanosensitive co-transcription factors, such as YAP, TAZ, and MRTF. We further elaborate how prolonged mechanical stress can create persistent myofibroblast memory by direct mechanotransduction to the nucleus that can evoke lasting epigenetic modifications at the DNA level, such as histone methylation and acetylation. We conclude by projecting how cell culture mechanics can be modulated to generate MSCs, which epigenetically protected against myofibroblast activation and transport desired regeneration potential to the recipient tissue environment in clinical therapies.

Heat acclimation alleviates the heat stress-induced impairment of vascular endothelial cells

Heat acclimation (HA) is found to help decrease the incidence of heat-related illnesses such as heat syncope and exertional heat stroke. However, the response of vascular endothelial cells to HA remain to be elucidated. In this study, mouse brain microvascular endothelial cells (bEnd.3), human umbilical vein endothelial cells (HUVEC), and human aortic endothelial cells (HAEC) were selected. The cells were first subjected to HA at 40 ℃ for 2 h per day for 3 days, and then subjected to heat stress at 43 ℃ for 2 h or 4 h. After heat stress, HA-pretreated cells showed a significant increase in cell viability, cell integrity, a decrease in the proportion of S phase cells, cell apoptosis, and cytoskeletal shrinkage compared with the cells without HA pretreatment. Additionally, the expression of VEGF, ICAM-1, iNOS and EPO in HA-pretreated cells significantly increased. We also presented evidence that HA upregulated HSP70 and bcl-2, while downregulated p-p53 and bax. Notably, the suppression of HSP70 expression attenuated the protective role of heat acclimation. Furthermore, HA mitigated injuries in vital organs of mice exposed to heat stress. Conclusively, these findings indicated the HA can increase the vitality of vascular endothelial cells after heat stress, partially restore the function of vascular endothelial cells, and this protective effect may be related to the upregulation of HSP70 expression.

Intraoperative Oxygen Treatment, Oxidative Stress, and Organ Injury Following Cardiac Surgery

Liberal oxygen (hyperoxia) is commonly administered to patients during surgery, and oxygenation is known to impact mechanisms of perioperative organ injury. To evaluate the effect of intraoperative hyperoxia compared to maintaining normoxia on oxidative stress, kidney injury, and other organ dysfunctions after cardiac surgery. This was a participant- and assessor-blinded, randomized clinical trial conducted from April 2016 to October 2020 with 1 year of follow-up at a single tertiary care medical center. Adult patients (>18 years) presenting for elective open cardiac surgery without preoperative oxygen requirement, acute coronary syndrome, carotid stenosis, or dialysis were included. Of 3919 patients assessed, 2501 were considered eligible and 213 provided consent. Of these, 12 were excluded prior to randomization and 1 following randomization whose surgery was cancelled, leaving 100 participants in each group. Participants were randomly assigned to hyperoxia (1.00 fraction of inspired oxygen [FiO2]) or normoxia (minimum FiO2 to maintain oxygen saturation 95%-97%) throughout surgery. Participants were assessed for oxidative stress by measuring F2-isoprostanes and isofurans, for acute kidney injury (AKI), and for delirium, myocardial injury, atrial fibrillation, and additional secondary outcomes. Participants were monitored for 1 year following surgery. Two hundred participants were studied (median [IQR] age, 66 [59-72] years; 140 male and 60 female; 82 [41.0%] with diabetes). F2-isoprostanes and isofurans (primary mechanistic end point) increased on average throughout surgery, from a median (IQR) of 73.3 (53.1-101.1) pg/mL at baseline to a peak of 85.5 (64.0-109.8) pg/mL at admission to the intensive care unit and were 9.2 pg/mL (95% CI, 1.0-17.4; P = .03) higher during surgery in patients assigned to hyperoxia. Median (IQR) change in serum creatinine (primary clinical end point) from baseline to postoperative day 2 was 0.01 mg/dL (-0.12 to 0.19) in participants assigned hyperoxia and -0.01 mg/dL (-0.16 to 0.19) in those assigned normoxia (median difference, 0.03; 95% CI, -0.04 to 0.10; P = .45). AKI occurred in 21 participants (21%) in each group. Intraoperative oxygen treatment did not affect additional acute organ injuries, safety events, or kidney, neuropsychological, and functional outcomes at 1 year. Among adults receiving cardiac surgery, intraoperative hyperoxia increased intraoperative oxidative stress compared to normoxia but did not affect kidney injury or additional measurements of organ injury including delirium, myocardial injury, and atrial fibrillation. ClinicalTrials.gov Identifier: NCT02361944.