An Innovation Technique in East Asia Rhinoplasty.

OBJECTIVE: To investigate the application and therapeutic efficacy of a novel cartilage framework: the external septa framework in East Asian rhinoplasty. METHODS: From November 2021 to April 2023, Department of Plastic and Aesthetic (Burn) Surgery, the Second Xiangya Hospital, Central South University, treated 41 patients with autologous costal cartilage rhinoplasty using an innovation external septal framework. The surgical open approach used an inverted V-shaped trans-columellar incision and marginal incision. The sixth or seventh costal cartilage was harvested to form the nasal columella support grafts (strut), external nasal septal graft, cap grafts, and shield grafts, in which the nasal column support graft and external nasal septal graft are connected in a way of tongue in groove to form a external septum framework to support and lengthen the tip. A cap graft is used to shape the tip of the nose, the rectus abdominis fascia is used to cover the tip of the nose, and the shield grafts are used to augment the inferior lobules. ePTFE was sculpted according to the degree of augment of the nasal dorsum and implanted on the dorsal to augment the nasal dorsum. Clinical outcomes were assessed through standard facial photographs taken during the preoperative and follow-up periods, and a postoperative satisfaction survey was completed with regular follow-up using the rhinoplasty outcome evaluation scale (ROE) and visual analogue scale (VAS). Results of objective and subjective measurements before and after surgery were compared utilizing paired-sample t tests. Values of P < 0.05 were considered significant. Nasal framework's objective evaluation outcomes were assessed by measuring the patients' preoperative and postoperative nasolabial angle, nasal length, and nasal tip projection. (The distance between the pronasale and the alar-cheek junction was calculated as the tip projection.) The comparison of preoperative and postoperative nasolabial angle and nasal length was performed using the paired-sample t test, and the comparison of nasal tip projection was performed using the Wilcoxon signed rank-sum test for the comparison of paired samples. Values of P < 0 .05 were considered significant. RESULTS: A total of 41 patients were treated, including 9 males and 32 females, ranging in age from 17 to 48 years(32.8 ± 1.5 years old), In the study, an average follow-up period of 19.85 ± 4.88 months was observed (range 12-29 months). There was no long-term or short-term complication observed. The aesthetic outcome of all cases such as saddle nose, deviated nasal columella, bilateral asymmetry of the nose, bilateral nasal base depression, and bulbous tip was satisfactory. Patient satisfaction evaluation: The ROE scale was (11.85 ± 2.46) preoperatively and (17.43 ± 2.15) postoperatively. The VAS scores were (4.86 ± 1.60) preoperatively and (8.48 ± 1.25) postoperatively. The difference of ROE scale and VAS scores among the patients was statistically significant (P < 0. 05), and 88.9% of patients were satisfied following those procedures. In terms of nasolabial angle, preoperative and postoperative measurements of 41 patients were (86.11 ± 2.25)° and (98.66 ± 1.90)°, respectively, and the difference of nasolabial angle was statistically significant (P < 0.05); nasal length measurements were 39.43 ± 1.55 mm (37.95-43.51 mm) preoperatively and 42.17 ± 1.46 mm (40.23-45.62 mm) postoperatively; in terms of nasal tip projection, preoperative and postoperative measurements of median values were 1.84(1.73,2.01) cm and 2.15(2.02,2.32) cm, respectively; and the difference between preoperative and postoperative values was statistically significant (P < 0.05). CONCLUSIONS: The innovative cartilage framework-external septal framework, avoids the dissection of septa and absorption of septal cartilage with compression of ESG, it is easy to be performed, and it is also stable and strong to achieve in good aesthetic result. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors  www.springer.com/00266 .

Radiographic Study of the Nasal Valve in Different CT Evaluation Method in Asian Patients with Unilateral Cleft Lip Nose.

OBJECTIVE(S): It was the first study to apply and compare two CT methods to assess the validity and clinical significance of structural alterations of the nasal valve in patients with cleft lip nose for assessing nasal ventilation disturbance. METHODS: The study collected data from the NOSE score, as well as internal nasal valve area, internal nasal valve angle, external nasal valve area, and septal deviation angle, to evaluate the differences and correlations between those factors in patients with cleft lip and nose. RESULTS: There were significant differences among INV transverse and coronal area and INV angle on different axial standardized planes between clefted side and non-clefted side. There were statistically significant negative correlations between NOSE scores and those indicators of standard plane and acoustic-axis standardized coronal plane. NOSE score and NSD angle were the indicators of significant differences in the measured data of different complications groups (p = 0.002, p = 0.017). The correlation comparison showed that two standardized CT imaging transverse planes have similar correlations in NOSE score, NSD angle, and complications. CONCLUSION: The results of the two CT evaluation methods showed that there was a significant difference in nasal valve area on the cleft and non-cleft sides, which was significantly associated with nasal ventilation disturbance. The CT evaluation method based on standard axial 3D reconstruction is more convenient to use in the clinic, can be used for pre-surgical evaluation of nasal repair in patients with secondary nasal deformities of unilateral cleft lip, and is valuable for treatment. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A New Definition for Alar Flare Based on "Alar Flare Angle".

BACKGROUND: An accurate diagnosis and an appropriate treatment are important parts of successful rhinoplasty. We proposed a new definition for alar flares to guide our clinical work. METHODS: A retrospective study was conducted on patients with alar flares from July 2017 to July 2021, and the follow-up time ranged from 12 to 27 months, mean of 16 months. We defined the alar flare angle by the formation of two lines: the line that connects the alar to the alar root point and line that connects the alar to the pronasale. The alar flare angle, interalar distance and nasal base width were measured, and alar wedge excision or alar base excision and tip elevation were performed. Scars, complications and satisfaction scales were evaluated after surgery. Through an analysis of the database, we found that the ideal alar flare angle was between 130 degrees and 140 degrees. If it was less than 130 degrees, it represented alar flares, and patients asked for alar surgery. RESULTS: A total of 33 patients were included. All patients underwent tip elevation, 12 patients underwent external alar wedge excision, and 5 patients underwent external alar wedge excision and alar base excision. External alar wedge excision can be used to completely correct alar flares, and in our study, the alar flare angles were more than 130 degrees after surgery. One patient complained of an acceptable scar, and there was no infection or alar deformity. All patients were satisfied. CONCLUSIONS: We proposed a new definition in which an alar flare angle less than 130 degrees can be diagnosed as an alar flare. This new definition is valuable for the clinical diagnosis and treatment of alar flares. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Psychological evaluation of Asian female patients with rhinoplasty.

BACKGROUND: Patients requiring plastic surgery exhibit more abnormal psychological trends (e.g., body dysmorphic disorder [BDD], depression, and anxiety) than those requiring other surgeries. However, there are only a few domestic studies on the psychological aspects of the population requiring plastic surgery. Therefore, we analyzed the psychological characteristics and psychological impact of rhinoplasty in female patients. METHODS: In this study, patients were classified into 2 groups: 151 males and 60 females. The self-rating scale of body image (SSBI), self-rating anxiety scale, self-rating depression scale, and postoperative satisfaction questionnaire were used to examine the patients before and after surgery. The results were analyzed using t-test, analysis of variance, chi-square test, paired rank sum test, and Pearson correlation analysis. RESULTS: The total prevalence of BDD in female patients who underwent rhinoplasty was 7.3%. The prevalence of anxiety disorders was 31.8% and that of depression was 45.0%. Female patients with BDD were more likely to exhibit depression (55.5%) and anxiety (36.4%). The SSBI score was related to marital status (p = 0.001) and history of rhinoplasty (p = 0.000). Moreover, there was a significant negative correlation between preoperative BDD score and postoperative satisfaction (r = -0.392, p = 0.002) as well as between the previous history of rhinoplasty and postoperative satisfaction (r = -0.603, p = 0.000). CONCLUSION: Pathological psychologies such as anxiety, depression, and BDD are common in patients scheduled to undergo rhinoplasty, and BDD is more likely to be associated with depression. Rhinoplasty has little psychological impact on patients, i.e., it neither causes improvement nor deterioration. Female patients who have undergone rhinoplasty should be considered to a have high risk of BDD. Although the outcomes of surgery are generally quite positive, patients diagnosed with BDD are more likely to be dissatisfied.

A New Algorithm for Secondary Repair of Unilateral Cleft Lip Nasal Deformity.

OBJECTIVES: Following primary surgery for unilateral cleft lip palate (UCLP), cleft lip nasal deformities (CLNDs) (nasal asymmetry, collapsed nasal alae, and a widened alar base) are generally inevitable and often require secondary rhinoplasty. However, reconstructing a cleft nose with an alar tissue deficiency remains challenging for rhinoplasty surgeons. METHODS: The manifestations of common deformities are described herein, and a secondary rhinoplasty technique for unilateral CLNDs using a nasolabial flap (NLF) has been proposed for patients with alar tissue deficiency. Secondary rhinoplasties were performed in 12 patients with unilateral CLNDs between 2020 and 2021 using a NLF. Photogrammetric measurements were performed preoperatively and postoperatively. A total of 12 flaps were successfully transferred. Ten patients were followed up for >1 year. RESULTS: Significant postoperative decreases in nasal alar width were measured in both the base view (p < 0.050) and the frontal view (p < 0.050). Despite the additional facial scars that occurred in some cases, all patients were satisfied with the aesthetic effects. CONCLUSIONS: The NLF achieved satisfactory results in secondary rhinoplasty of unilateral CLND for patients with nasal tissue deficiencies in whom the surgeon weighed the potential benefits over postoperative scarring. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1648-1655, 2024.

New classification system of contracted nose and its treatment algorithm.

BACKGROUND: The nasal contracture after rhinoplasty is one of the most severe complications in East Asian patients. The classification and treatment algorithm of nasal contracture have not yet been established. This study aimed to develop a new classification system and treatment algorithm of contracted noses in East Asian patients to improve treatment outcomes. METHODS: A retrospective study was conducted with 62 patients with nasal contracture who underwent a revision rhinoplasty between March 2017 and March 2021. The authors classified the 62 patients into 3 groups based on the classification system. All patients underwent rhinoplasty designed according to the corresponding classification. The patients were followed up after surgery, and the rhinoplasty outcomes evaluation (ROE) was used to evaluate their satisfaction rate. RESULTS: A total of 59 female patients and 3 male patients (mean age, 29.45 ± 7.73 years) were included in this study. Forty-five cases presented mild nasal contracture (72.58%), 11 presented moderate nasal contracture (17.74%), and 6 presented severe nasal contracture (9.68%). There were statistically significant differences in the number of prior rhinoplasty procedures, infection history, and preoperative ROE scores among the three groups, with no differences in sex ratio, age, kinds of initial implant materials, and postoperative ROE scores. Almost all patients achieved satisfactory outcomes after the revision surgery designed by different classifications. CONCLUSION: The authors have established a new classification system and treatment algorithm for contracted noses based on the change in pathological anatomy of nose, which is effective for guiding the treatment of contracted noses with good results.

Hypoxia-induced CCL2/CCR2 axis in adipose-derived stem cells (ADSCs) promotes angiogenesis by human dermal microvascular endothelial cells (HDMECs) in flap tissues.

Flap expansion has become an important method widely used in wound repair and organ reconstruction. However, distal skin flap ischemic necrosis remains a problematic complication. In this study, integrative bioinformatics analyses indicated the upregulation of C-C motif chemokine ligand 2 (CCL2) and C-C motif chemokine receptor 2 (CCR2) in reperfusion-exposed skin flap tissues. In adipose-derived stem cells (ADSCs, CD90-positive, CD29-positive, CD34-negative, and CD106-negative) exposed to hypoxia, HIF-1α and CCL2 levels were significantly elevated. Conditioned medium (CM) from hypoxia-stimulated ADSCs promoted HDMEC proliferation, migration, and tube formation, partially inhibited by sh-CCL2-induced CCL2 knockdown or neutralized antibody-induced CCL2 depletion in ADSCs. Consistently, CCL2, CCR2, TNF-α, TLR2, and TLR4 protein levels in HDMECs were significantly increased by hypoxia-treated ADSCs CM, and partially decreased by sh-CCL2-induced CCL2 knockdown or neutralizing antibody-induced CCL2 knockdown in ADSCs. In the flap expansion model, ADSCs transplantation significantly improved flap survival and angiogenesis by endothelial cells in flap tissues, whereas CCL2 knockdown in ADSCs partially eliminated the improvement by ADSCs transplantation; overexpression of CCL2 in ADSCs further promoted the effects of ADSCs transplantation on skin flap. In conclusion, the CCL2/CCR2 axis in ADSCs could be induced by hypoxia, promoting HDMEC proliferation, migration, and tube formation and improving flap survival and angiogenesis in flap tissues.

Clinical Application of Pre-Expanded Perforator Flaps.

Background: Challenging large soft tissue defects are typically treated with microvascular free tissue transfer; however, success has been noted with pre-expanded perforator flaps. Objective: To report outcomes and complications from pre-expanded perforator flaps. Methods: A retrospective chart review of patients undergoing tissue reconstruction with pre-expanded perforator flaps between 2014 and 2020. Data collection included flap type, defect characteristics, and complications. Results: All 29 patients had successful flap reconstruction without major complication. The median area of tissue defect was 17 × 13 cm2 (range 7 × 4 to 27 × 24 cm2). Mean tissue expansion period was 15.2 weeks (range 9-26 weeks). The most common flap was the pre-expanded internal mammary artery perforator flaps. Conclusion: The findings of this study suggest that combining tissue expansion with a perforator flap for large tissue reconstruction can be successful with limited complications. This technique may allow a larger pliable skin flap that deserves further investigation.

A novel classification of alar retraction based on nostril exposure in Asian rhinoplasty.

OBJECTIVE: Alar retraction is considered a challenge in rhinoplasty. The classification of alar retraction remains poorly defined, especially in Asia. Patients with alar retraction are associated with excessive exposure to the nostrils in Asia. This study aimed to introduce a classification method of alar retraction based on nostril exposure. MATERIALS AND METHODS: Medical records of patients who had undergone rhinoplasty with alar retraction based on nostril exposure between January 2015 and December 2020 were retrospectively reviewed. The corrections of alar retraction were categorized into three groups according to a classification method of alar retraction based on nostril exposure: mild alar retraction, moderate alar retraction, and severe alar retraction. The visual analog scale (VAS) and rhinoplasty outcomes evaluation (ROE) were used to evaluate the satisfaction rate. RESULTS: Within a median period of 13.3 months, 45 patients (51.14%) with mild alar retraction were corrected by alar contour graft. 23 patients (26.14%) with moderate alar retraction were treated with the alar contour graft(n=10), the lateral crural strut graft (n = 6), and the alar projection graft (n = 7). 20 patients (22.73%) with severe alar retraction were corrected by lateral crural strut graft combined with composite graft (n = 6), lateral crural strut graft (n = 10), and composite graft (n = 4). The severe alar retraction group had a higher satisfaction rate in ROE(P<0.05) and VAS (P<0.05) than moderate alar retraction and mild alar retraction at a follow-up of 12 months after surgery. CONCLUSIONS: The classification of alar retraction based on nostril exposure is more practical for rhinoplasty in Asia.

The impact of COVID-19 on plastic and reconstructive surgery in China: A single-centre retrospective study.

BACKGROUND: This study aimed to investigate the volume of plastic surgery operations in a large public hospital and figure out the changes in the related factors associated with Coronavirus Disease 2019 (COVID-19) and identify the potential problems. METHODS: We created a survey and collected clinical data from 1 January 2018 to 31 December 2020. Information on procedure time, patient gender, patient age, and procedure type was collected from the database. The data were analysed using IBM SPSS Statistics for Windows, version 25.0. RESULTS: A total of 10,827 patients were admitted to our department. The total number of patients decreased by 21.53% in 2020 (3057 cases) than the same period in 2019 (3896 cases). The total number of aesthetic procedures decreased by 34.17% in 2020 than that in 2019. However, restorative procedures in 2020 (2013 cases) only decreased by 12.86% than that in 2019 (2310 cases). The percentages of women amongst patients who underwent aesthetic procedures were 91.75%, 92.18%, and 90.71% in 2018, 2019, and 2020, respectively. Most of the patients in these three years were aged 20-29 years. CONCLUSIONS: The plastic surgery industry is experiencing the effects of the unprecedented COVID-19 pandemic worldwide. COVID-19 was quickly brought under control, and the plastic surgery industry developed rapidly in China because of the active, timely, and accurate implementation of epidemic prevention strategies.

MiR-590-3p affects the function of adipose-derived stem cells (ADSCs) on the survival of skin flaps by targeting VEGFA.

Introduction: Partial necrosis of skin flaps is still a substantial problem in plastic and reconstructive surgery. In this study, the role of miR-590-3p in adipose-derived stem cells (ADSCs) transplantation in improving the survival of skin flap in a mouse model was delved into. Method: An abdominal perforator flap model was established in mice. The histopathological examination of mice skin tissues after ADSCs transplantation was implemented using Hematoxylin & eosin (H&E) staining. Immunohistochemistry (IHC) or immunofluorescence (IF) staining was utilized to assess the PCNA or CD31 levels. The concentrations of VEGFA in the culture medium were quantified using a VEGFA ELISA kit. Result: The damage of tissue in the skin flap was dramatically relieved by ADSCs transplantation. MiR-590-3p overexpression notably suppressed, while miR-590-3p knockdown facilitated skin flap survival by regulating PCNA, VCAM-1, and VEGFA levels. MiR-590-3p targeted VEGFA to regulate its expression. The knockdown of VEGFA significantly inhibited, while overexpression of VEGFA notably promoted the survival of skin flap. Conclusion: ADSCs transplantation promotes skin flap survival by boosting angiogenesis. The miR-590-3p/VEGFA axis modulates skin flap angiogenesis and survival in ADSCs. These results reveal that interfering with miR-590-3p in ADSCs could potentially be a novel therapeutic target for the improvement of skin flap survival.

MAPK inhibitors protect against early­stage osteoarthritis by activating autophagy.

Osteoarthritis (OA) is a chronic, age­related osteoarthropathy that causes a considerable decline in quality of life, as well as economic losses due to its high incidence and poor prognosis. Mitogen­activated protein kinases (MAPKs) regulate multiple cellular processes, including proliferation, differentiation and apoptosis, in certain diseases, such as cancer, diabetes and Alzheimer's disease. The present study aimed to investigate the regulatory role of the MAPK signaling pathway in early­stage OA. A rabbit model of early­stage OA was induced by treatment with the enzyme papain. U0126 [an extracellular signal­regulated kinase (ERK) inhibitor], SP600125 [a Jun NH2­terminal kinase (JNK) inhibitor] and SB203580 (a p38 inhibitor) were administered to the rabbits via intra­articular injection. The severity of OA was assessed by histological examination using H&E, toluidine blue and safranin­O/fast green staining, as well by analyzing the glycosaminoglycan (GAG) content and determining the OA Research Society International (OARSI) score. Western blotting was used to detect the protein expression levels of matrix metalloproteinase­3 (MMP3), ERK, phosphorylated (p)­ERK, p38, p­p38, JNK, p­JNK, Beclin1, UNC­51­like kinase 1 (ULK1) and microtubule­associated protein 1 light chain 3 (LC3)II/I. U0126, SP600125 or SB203580 treatment significantly decreased the OARSI scores and significantly increased the GAG levels in the cartilaginous tissues of OA model rabbits. These results indicated that the MAPK inhibitors reduced the severity of OA­induced injury at the early stage. Western blotting results demonstrated that MAPK inhibition significantly decreased the protein expression levels of MMP3 in OA cartilage. The protective effect of MAPK inhibitors in OA was mediated via the activation of autophagy, as demonstrated by the increased protein expression levels of LC3II/I, ULK1 and Beclin1. Overall, the data indicated that MAPK inhibitors may exert a protective effect against OA by restoring compromised autophagy. Furthermore, the present study suggested that MAPK inhibitors may represent a potential pharmacological strategy for treating OA in the future.

Application of Three-Dimensional Imaging in Asian Rhinoplasty with Costal Cartilage.

BACKGROUND: 3D computer-simulated technology is becoming popular in China. Rhinoplasty with costal cartilage is a good option for Asians. However, the application of 3D imaging in Asian rhinoplasty with costal cartilage has not been systematically assessed. OBJECTIVE: To analyze the effect of 3D imaging in Asian rhinoplasty with costal cartilage. METHODS: In this study, 44 patients were included and randomly divided into 3D and non-3D imaging groups. We performed a prospective survey on the aesthetic scores for preoperative, simulated, and postoperative images and calculated the relative nasal index scores of patients in both groups. Additionally, surveys on satisfactions with surgical outcomes and doctor-patient communication in both groups were conducted. RESULTS: The actual postoperative result was well consistent with the preoperative simulation result. The 3D computer simulation did not impact the satisfaction with surgical outcomes but increased that with doctor-patient communication. The 3D computer-simulated technology was an effective tool for doctor-patient communication and surgery planning in Asian rhinoplasty with costal cartilage. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Piperlongumine Is an NLRP3 Inhibitor With Anti-inflammatory Activity.

Piperlongumine (PL) is an alkaloid from Piper longum L. with anti-inflammatory and antitumor properties. Numerous studies have focused on its antitumor effect. However, the underlying mechanisms of its anti-inflammation remain elusive. In this study, we have found that PL is a natural inhibitor of Nod-like receptor family pyrin domain-containing protein-3 (NLRP3) inflammasome, an intracellular multi-protein complex that orchestrates host immune responses to infections or sterile inflammations. PL blocks NLRP3 activity by disrupting the assembly of NLRP3 inflammasome including the association between NLRP3 and NEK7 and subsequent NLRP3 oligomerization. Furthermore, PL suppressed lipopolysaccharide-induced endotoxemia and MSU-induced peritonitis in vivo, which are NLRP3-dependent inflammation. Thus, our study identified PL as an inhibitor of NLRP3 inflammasome and indicated the potential application of PL in NLRP3-relevant diseases.

Endothelial cell-specific deficiency of the adenosine deaminase ADAR1 aggravates LPS-induced lung injury in mice via an MDA5-independent pathway.

Adenosine deaminase acting on RNA 1 (ADAR1) has been shown to participate in the regulation of endothelial cells (ECs), as well as local and systemic inflammatory responses. Here, we find that bacterial lipopolysaccharide (LPS)-induced upregulation of ADAR1 in lung ECs is impaired in aged mice, an animal model with high rates of sepsis and mortality. Endothelial cell-specific ADAR1 knockout (ADAR1ECKO ) mice suffer from higher mortality rates, aggravated lung injury, and increased vascular permeability under LPS challenge. In primary ADAR1 knockout ECs, expression of the melanoma differentiation-associated gene 5 (MDA5), a downstream effector of ADAR1, is significantly elevated. MDA5 knockout completely rescues the postnatal offspring death of ADAR1ECKO mice. However, there is no reduction in mortality or apoptosis in lung cells of ADAR1ECKO /MDA5-/- mice challenged with LPS, indicating the involvement of an MDA5-independent mechanism in this process.

Immune-Responsive Gene 1/Itaconate Activates Nuclear Factor Erythroid 2-Related Factor 2 in Hepatocytes to Protect Against Liver Ischemia-Reperfusion Injury.

BACKGROUND AND AIMS: Itaconate, a metabolite of the tricarboxylic acid cycle, plays anti-inflammatory roles in macrophages during endotoxemia. The mechanisms underlying its anti-inflammatory roles have been shown to be mediated by the modulation of oxidative stress, an important mechanism of hepatic ischemia-reperfusion (I/R) injury. However, the role of itaconate in liver I/R injury is unknown. APPROACH AND RESULTS: We found that deletion of immune-responsive gene 1 (IRG1), encoding for the enzyme producing itaconate, exacerbated liver injury and systemic inflammation. Furthermore, bone marrow adoptive transfer experiments indicated that deletion of IRG1 in both hematopoietic and nonhematopoietic compartments contributes to the protection mediated by IRG1 after I/R. Interestingly, the expression of IRG1 was up-regulated in hepatocytes after I/R and hypoxia/reoxygenation-induced oxidative stress. Modulation of the IRG1 expression levels in hepatocytes regulated hepatocyte cell death. Importantly, addition of 4-octyl itaconate significantly improved liver injury and hepatocyte cell death after I/R. Furthermore, our data indicated that nuclear factor erythroid 2-related factor 2 (Nrf2) is required for the protective effect of IRG1 on mouse and human hepatocytes against oxidative stress-induced injury. Our studies document the important role of IRG1 in the acute setting of sterile injury induced by I/R. Specifically, we provide evidence that the IRG1/itaconate pathway activates Nrf2-mediated antioxidative response in hepatocytes to protect liver from I/R injury. CONCLUSIONS: Our data expand on the importance of IRG1/itaconate in nonimmune cells and identify itaconate as a potential therapeutic strategy for this unfavorable postsurgical complication.

TSLP protects against liver I/R injury via activation of the PI3K/Akt pathway.

Thymic stromal lymphopoietin (TSLP) is a cytokine mainly released by epithelial cells that plays important roles in inflammation, autoimmune disease, and cancer. While TSLP is expressed in the liver at high levels, the role of TSLP in liver ischemia/reperfusion (I/R) injury remains unknown. Experiments were carried out to determine the role of TSLP in liver I/R injury. Wild-type (WT) and TSLP receptor-knockout (TSLPR-/-) mice were subjected to liver partial warm I/R injury. Liver injury was assessed by measuring serum alanine aminotransferase (ALT) level, necrotic areas by liver histology, hepatocyte death, and local hepatic inflammatory responses. Signal pathways were explored in vivo and in vitro to identify possible mechanisms for TSLP in I/R injury. TSLP and TSLPR protein expression increased during liver I/R in vivo and following hepatocyte hypoxia/reoxygenation in vitro. Deletion of TSLPR or neutralization of TSLP with anti-TSLP antibody exacerbated liver injury in terms of serum ALT levels as well as necrotic areas in liver histology. Administration of exogenous recombinant mouse TSLP to WT mice significantly reduced liver damage compared with controls, but failed to prevent I/R injury in TSLPR-/- mice. TSLP induced autophagy in hepatocytes during liver I/R injury. Mechanistically, Akt was activated in WT mice during liver I/R injury. The opposite results were observed in TSLPR-/- mice. In addition, TSLP could directly induce Akt activation in hepatocytes independent of nonparenchymal cells in vitro. Furthermore, the Akt agonist, insulin-like growth factor-1 (IGF-1), prevented I/R injury in TSLPR-/- mice and an Akt inhibitor, LY294002, blocked the protective effects of TSLP in WT mice subjected to I/R. Our data indicate that TSLP protects against liver I/R injury via activation of the PI3K/Akt pathway. Through this pathway, TSLP induces autophagy in hepatocytes. Thus, TSLP is a potent inhibitor of stress-induced hepatocyte necrosis.

Gasdermin D protects against noninfectious liver injury by regulating apoptosis and necroptosis.

Gasdermin D (GsdmD) was recently identified as the executioner of pyroptotic inflammatory cell death, and is a substrate for caspases-1 and 11. GsdmD is detrimental in lethal endotoxemia but protective in bacterial sepsis. However, little is known about its role during noninfectious/sterile injuries. In this study, we examined the contribution of GsdmD using WT and GsdmD-/- mice in two models of noninfectious liver injury: hemorrhagic shock with resuscitation (HS/R) and acetaminophen (APAP) overdose. GsdmD-/- mice had significantly increased liver damage at 6 h after HS/R or APAP vs WT, shown by significantly elevated ALT level and extended areas of cell death in liver. Caspase-8, a mediator of multiple cell death pathways, was highly elevated in GsdmD-/- mice after injury. Significantly increased cleavage of caspase-8 and subsequent high levels of apoptosis were found in livers of GsdmD-/- mice after HS/R, a relatively mild ROS-induced liver injury. However, during more severe APAP-mediated ROS-induced liver injury, caspase-8 cleavage in GsdmD-/- liver was inhibited compared with WT, resulting in accumulation of pro-caspase-8 and increased levels of necroptosis. Our findings indicate a novel hepatoprotective role for GsdmD in noninfectious inflammation models via regulation of caspase-8 expression and downstream cell death pathways. The effects of GsdmD protection are likely injury specific and may also depend on injury severity and levels of ROS produced. These data suggest modulation of GsdmD/caspase-8 may be a novel therapeutic option in ROS-mediated liver injury.

RELA/NEAT1/miR-302a-3p/RELA feedback loop modulates pancreatic ductal adenocarcinoma cell proliferation and migration.

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy due to distant metastasis. RELA, a major component of the NF-κB pathway, could serve as an oncogene through activating proliferation or migration-related gene expression, including NEAT1, a well-known oncogenic long noncoding RNA. In the current study, the expression and function of RELA and NEAT1 in PDAC were examined. The potential upstream regulatory microRNAs of RELA were screened and verified for their correlation with RELA and NEAT1. The expression and function of the selected miR-302a-3p were evaluated. RELA and NEAT1 expression were upregulated in PDAC tissues, particularly in PDAC tissues with lymph node metastasis, and their expression correlated with clinical parameters. RELA overexpression promoted PDAC cell proliferation and migration, which could be partially attenuated by the NEAT1 knockdown. By binding to RELA, miR-302a-3p inhibited RELA expression, as well as PDAC cell proliferation and migration. RELA downstream NEAT1 expression was negatively regulated by miR-302a-3p; the suppressive effect of NEAT1 knockdown on PDAC cell proliferation and migration was partially attenuated by miR-302a-3p inhibition. Moreover, through direct binding, the expression of miR-302a-3p was also negatively regulated by NEAT1. The expression of miR-302a-3p was downregulated and negatively correlated with RELA or NEAT1 in tissue samples, indicating that rescuing miR-302a-3p expression may inhibit PDAC cell proliferation and migration through RELA/NEAT1. In summary, RELA, NEAT1, and miR-302a-3p form a feedback loop in PDAC to modulate PDAC cell proliferation and migration.

cGAS-mediated autophagy protects the liver from ischemia-reperfusion injury independently of STING.

Liver ischemia-reperfusion (I/R) injury occurs through induction of oxidative stress and release of damage-associated molecular patterns (DAMPs), including cytosolic DNA released from dysfunctional mitochondria or from the nucleus. Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is a cytosolic DNA sensor known to trigger stimulator of interferon genes (STING) and downstream type 1 interferon (IFN-I) pathways, which are pivotal innate immune system responses to pathogen. However, little is known about the role of cGAS/STING in liver I/R injury. We subjected C57BL/6 (WT), cGAS knockout (cGAS-/-), and STING-deficient (STINGgt/gt) mice to warm liver I/R injury and that found cGAS-/- mice had significantly increased liver injury compared with WT or STINGgt/gt mice, suggesting a protective effect of cGAS independent of STING. Liver I/R upregulated cGAS in vivo and also in vitro in hepatocytes subjected to anoxia/reoxygenation (A/R). We confirmed a previously published finding that hepatocytes do not express STING under normoxic conditions or after A/R. Hepatocytes and liver from cGAS-/- mice had increased cell death and reduced induction of autophagy under hypoxic conditions as well as increased apoptosis. Protection could be restored in cGAS-/- hepatocytes by overexpression of cGAS or by pretreatment of mice with autophagy inducer rapamycin. Our findings indicate a novel protective role for cGAS in the regulation of autophagy during liver I/R injury that occurs independently of STING. NEW & NOTEWORTHY Our studies are the first to document the important role of cGAS in the acute setting of sterile injury induced by I/R. Specifically, we provide evidence that cGAS protects liver from I/R injury in a STING-independent manner.