Preparation of polyvinyl alcohol/chitosan nanofibrous films incorporating graphene oxide and lanthanum chloride by electrospinning method for potential photothermal and chemical synergistic antibacterial applications in wound dressings.

Electrospun fibres have been widely used as skin dressings due to their unique structur. However, due to the lack of intrinsic antimicrobial activity, it is easy for the wound to become infected. Bacterial infection, which leads to chronic inflammation, severely hinders the normal process of skin regeneration. In this study, a polyvinyl alcohol/chitosan (PVA/CS) composite films with chemical sterilization and near-infrared (NIR) photothermal antibacterial activity was fabricated by electrospinning. Graphene oxide (GO), a photosensitiser, was incorporated into the films, and lanthanum chloride (Lacl3) as a chemical antibacterial agent was also doped in the electrospun films. The structure, morphology, mechanical properties, wettability, and antimicrobial and photothermal antibacterial activity of the PVA/CS-based fibre films were investigated. The results showed that the addition of Lacl3 to the PVA/CS/GO nanofibres (PVA/CS/GO-La) improved the hydrophilicity, tensile strength and resistance to elastic deformation of the nanofibres. The PVA/CS/GO-La12.5 mM sample exhibited the best antibacterial performance, showing high inhibition against Staphylococcus aureus (82% antibacterial efficacy) and Escherichia coli (99.7% antibacterial efficacy). Furthermore, the antibacterial efficacy of the films surface was further enhanced after exposure to NIR light (808 nm, 0.01 W) for 20 min. In addition, the nanofibre films showed no cytotoxicity against human skin fibroblasts (HSFs), indicating its potential application in the field of broad-spectrum antibacterial materials.

The Morel-Lavallée Lesion: Review and Update on Diagnosis and Management.

Morel-Lavallée lesion is a closed soft tissue degloving injury usually associated with high-velocity trauma. It most commonly occurs in the thigh, hip, and pelvis. Because such lesions are prone to a missed or delayed diagnosis, it may present a potential risk of infection at the fracture site once it progresses. Therefore, timely identification and management of Morel-Lavallée lesion is crucial. Moreover, there are no relevant guidelines for the treatment of Morel-Lavallée lesion. Based on the above facts, we reviewed the etiology, epidemiology, pathophysiology, clinical presentation, imaging features, treatment, prognosis, and complications of Morel-Lavallée lesion with the aim of providing a comprehensive overview of Morel-Lavallée lesion, increasing awareness of this injury among orthopaedic surgeons, and thus providing a management algorithm that can be applied to this injury.

Identification of Flavonoids from Scutellaria barbata D. Don as Inhibitors of HIV-1 and Cathepsin L Proteases and Their Structure-Activity Relationships.

Scutellaria barbata D. Don (SB, Chinese: Ban Zhi Lian), a well-known medicinal plant used in traditional Chinese medicine, is rich in flavonoids. It possesses antitumor, anti-inflammatory, and antiviral activities. In this study, we evaluated the inhibitory activities of SB extracts and its active components against HIV-1 protease (HIV-1 PR) and SARS-CoV2 viral cathepsin L protease (Cat L PR). UPLC/HRMS was used to identify and quantify the major active flavonoids in different SB extracts, and fluorescence resonance energy transfer (FRET) assays were used to determine HIV-1 PR and Cat L PR inhibitions and identify structure-activity relationships. Molecular docking was also performed, to explore the diversification in bonding patterns of the active flavonoids upon binding to the two PRs. Three SB extracts (SBW, SB30, and SB60) and nine flavonoids inhibited HIV-1 PR with an IC50 range from 0.006 to 0.83 mg/mL. Six of the flavonoids showed 10~37.6% inhibition of Cat L PR at a concentration of 0.1 mg/mL. The results showed that the introduction of the 4'-hydroxyl and 6-hydroxyl/methoxy groups was essential in the 5,6,7-trihydroxyl and 5,7,4'-trihydroxyl flavones, respectively, to enhance their dual anti-PR activities. Hence, the 5,6,7,4'-tetrahydroxyl flavone scutellarein (HIV-1 PR, IC50 = 0.068 mg/mL; Cat L PR, IC50 = 0.43 mg/mL) may serve as a lead compound to develop more effective dual protease inhibitors. The 5,7,3',4'-tetrahydroxyl flavone luteolin also showed a potent and selective inhibition of HIV-1 PR (IC50 = 0.039 mg/mL).

T lymphocyte characteristics and immune repertoires in the epicardial adipose tissue of heart failure patients.

Background: Epicardial adipose tissue (EAT) acts as an active immune organ and plays a critical role in the pathogenesis of heart failure (HF). However, the characteristics of immune cells in EAT of HF patients have rarely been elucidated. Methods: To identify key immune cells in EAT, an integrated bioinformatics analysis was performed on public datasets. EAT samples with paired subcutaneous adipose tissue (SAT), heart, and peripheral blood samples from HF patients were collected in validation experiments. T cell receptor (TCR) repertoire was assessed by high-throughput sequencing. The phenotypic characteristics and key effector molecules of T lymphocytes in EAT were assessed by flow cytometry and histological staining. Results: Compared with SAT, EAT was enriched for immune activation-related genes and T lymphocytes. Compared with EAT from the controls, activation of T lymphocytes was more pronounced in EAT from HF patients. T lymphocytes in EAT of HF patients were enriched by highly expanded clonotypes and had greater TCR clonotype sharing with cardiac tissue relative to SAT. Experiments confirmed the abundance of IFN-γ+ effector memory T lymphocytes (TEM) in EAT of HF patients. CCL5 and GZMK were confirmed to be associated with T lymphocytes in EAT of HF patients. Conclusion: EAT of HF patients was characterized by pronounced immune activation of clonally expanded IFN-γ+ TEM and a generally higher degree of TCR clonotypes sharing with paired cardiac tissue.

Quinpirole ameliorates nigral dopaminergic neuron damage in Parkinson's disease mouse model through activating GHS-R1a/D2R heterodimers.

Growth hormone secretagogue receptor 1a (GHS-R1a) is an important G protein-coupled receptor (GPCR) that regulates a variety of functions by binding to ghrelin. It has been shown that the dimerization of GHS-R1a with other receptors also affects ingestion, energy metabolism, learning and memory. Dopamine type 2 receptor (D2R) is a GPCR mainly distributed in the ventral tegmental area (VTA), substantia nigra (SN), striatum and other brain regions. In this study we investigated the existence and function of GHS-R1a/D2R heterodimers in nigral dopaminergic neurons in Parkinson's disease (PD) models in vitro and in vivo. By conducting immunofluorescence staining, FRET and BRET analyses, we confirmed that GHS-R1a and D2R could form heterodimers in PC-12 cells and in the nigral dopaminergic neurons of wild-type mice. This process was inhibited by MPP+ or MPTP treatment. Application of QNP (10 µM) alone significantly increased the viability of MPP+-treated PC-12 cells, and administration of quinpirole (QNP, 1 mg/kg, i.p. once before and twice after MPTP injection) significantly alleviated motor deficits in MPTP-induced PD mice model; the beneficial effects of QNP were abolished by GHS-R1a knockdown. We revealed that the GHS-R1a/D2R heterodimers could increase the protein levels of tyrosine hydroxylase in the SN of MPTP-induced PD mice model through the cAMP response element binding protein (CREB) signaling pathway, ultimately promoting dopamine synthesis and release. These results demonstrate a protective role for GHS-R1a/D2R heterodimers in dopaminergic neurons, providing evidence for the involvement of GHS-R1a in PD pathogenesis independent of ghrelin.

Clinical Outcomes of the Modified Stoppa Combined with Iliac Fossa Approach for Complex Acetabular Fractures: A Medium- and Long-term Retrospective Study.

OBJECTIVE: The modified Stoppa combined with iliac fossa approach has gained increasing popularity. Although early clinical outcomes have been satisfactory, extensive long-term clinical outcomes are relatively scarce. The purpose of this study was to evaluate the medium- and long-term outcomes of this approach for complex acetabular fractures. METHODS: This was a retrospective study involving 57 patients with complex acetabular fractures from January 2009 to January 2016. All fractures were treated with the modified Stoppa combined with iliac fossa approach. Follow-up was at least 5 years. Primary outcome measures, including quality of reduction and clinical outcomes, were recorded by an independent observer. Secondary outcome measures included time to surgery, surgical time, intraoperative blood loss, and perioperative complications. RESULTS: Fifty-seven patients (range, 18-80 years) included 46 males and 11 females. There were 32 cases on the left side and 25 cases on the right side. The most common associated injury was pulmonary contusion. According to the Judet-Letournel classification, there were 27 both-column fractures, 16 anterior column with posterior hemitransverse fractures and 14 T-type fractures. The average time from injury to surgery was 7.3 days. The average intraoperative blood loss and transfusion were 750.9 ml and 564.3 ml, respectively. All fractures healed within 6 months after surgery. The average follow-up time was 7.7 years, and there was no loss of follow-up. The quality of reduction was graded as anatomical in 23 cases (40.4%), imperfect in 22 cases (38.6%), and poor in 12 cases (21.0%). According to grading system of Merle d' Aubigne and Postel, clinical outcomes at 1 year follow-up were excellent in 17 cases (29.8%), good in 25 cases (43.9%), fair in four cases (7.0%), and poor in 11 cases (19.3%). The excellent and good rate was 73.7% and the difference was not statistically significant compared with the clinical outcomes at the last follow-up. Intraoperative complications included four cases of obturator nerve injury and two cases of vascular injury. Postoperative complications included one case of wound delayed healing, two cases of deep vein thrombosis, two cases of avascular necrosis of femoral head, three cases of heterotopic ossification and five cases of post-traumatic arthritis. Only one of these patients underwent reoperation for femoral head necrosis. CONCLUSIONS: The modified Stoppa combined with iliac fossa approach can achieve satisfactory reduction quality and hip function. It might be a valuable alternative to the ilioinguinal approach for the surgical management of acetabular fractures.

The effect of a full-time infection control nursing service in the prevention of multidrug-resistant organism in the orthopedic ward.

BACKGROUND: Our aim was to evaluate the effect of setting up a full-time infection control nursing service on reducing the prevalence of multidrug-resistant organism (MDRO) in the orthopedic ward. METHODS: From January 2015 to March 2019, routine prevention and control measures were taken for patients infected/colonized with MDRO in this ward, which was set as the pre-intervention period. The intervention period was from April 2019 to June 2021. The study was designed to evaluate whether the establishment of a full-time infection control nursing service could reduce the positive density of MDRO in the hospital by using an interrupted time-series model of a quasi experimental study. RESULTS: There were 11,759 patients during pre-intervention period and 8142 patients during intervention period. The total number of MDRO isolated before intervention was 177, of which 145 were obtained in hospital and 32 were brought in from outside hospital. The total number of MDRO isolated after intervention was 47, of which 29 were obtained in hospital and 18 were brought in from outside hospital. Before intervention, the positive density of MDRO in the orthopedic ward showed an increasing trend (ß1 = 0.02, P = 0.003). After intervention, the positive density of MDRO showed a downward trend (ß3 = - 0.05, P = 0.018). CONCLUSIONS: The establishment of the full-time infection control nursing service in the orthopedic ward can effectively reduce the nosocomial prevalence of MDRO.

Cancer-related fatigue in hospitalised patients treated for lymphoma and its burden on family caregivers.

OBJECTIVE: To investigate the prevalence of cancer-related fatigue (CRF) in patients with lymphoma and to explore the burden of CRF on the family caregivers (FCs). METHODS: A cross-sectional study was conducted in a university-affiliated tertiary care hospital in China. Patients with lymphoma who received treatment in the in-patient ward of the Haematology Department were consecutively recruited. Face-to-face interviews were conducted to gather information related to the patients' sociodemographic characteristics and perceived CRF and its burden on the FCs. Cochran-Armitage trend analysis and Multivariable logistic regression analyses were employed to determine the association between CRF and the FCs' burden. RESULTS: Of the 116 cancer patient-FC dyads, about 70% of patients experienced some level of fatigue, while 51% of unpaid family members suffered some degree of depression. The Cochran-Armitage trend analysis showed that the FCs' burden significantly increased with the severity of CRF. Logistic regression indicated that the FCs of the patients reporting fatigue experienced a higher burden in both the unadjusted and adjusted models. CONCLUSION: The prevalence of CRF appeared to be high among patients with lymphoma. It might be important to design innovative health-promoting practices for ameliorating or preventing the impact of fatigue.

Bioinformatics and Immune Infiltration Analyses Reveal the Key Pathway and Immune Cells in the Pathogenesis of Hypertrophic Cardiomyopathy.

Objective: This study was designed to identify the key pathway and immune cells for hypertrophic cardiomyopathy (HCM) via bioinformatics analyses of public datasets and evaluate the significance of immune infiltration in the pathogenesis of HCM. Methods: Expressional profiling from two public datasets (GSE36961 and GSE141910) of human HCM and healthy control cardiac tissues was obtained from the GEO database. After data preprocessing, differentially expressed genes (DEGs) were then screened between HCM and healthy control cardiac tissues in parallel. Gene Ontology, pathway functional enrichment, and gene set enrichment analysis were performed using DAVID and GSEA application. The compositional patterns of immune and stromal cells in HCM and control cardiac tissues were estimated based on the merged data using xCell. Protein-protein interaction (PPI) network and module analyses were constructed by STRING and Cytoscape applications. Gender-based expressional differences analyses were also conducted to explore gender differences in HCM. GSE130036 and clinical samples were used for verification analyses. Results: A total of 310 DEGs were identified. Upregulated DEGs were mainly enriched in "adhesion" and "apoptotic process" in the biological process. As for the downregulated DEGs, "inflammatory response," "innate immune response," "phagosome," and "JAK-STAT signaling pathway" were highly enriched. Immune infiltration analyses suggested that the scores of macrophages, monocytes, DC, Th1, Treg, and plasma cells in the HCM group were significantly decreased, while CD8+ T cells, basophils, fibroblasts, and platelets were significantly enriched. Module analyses revealed that STAT3, as the hub genes in HCM together with LYVE1+CD163+ macrophages, may play a key role in the pathogenesis of HCM while there were no obvious gender differences in the HCM samples from selected datasets. Verification analyses performed on GSE130036 and clinical samples showed a strong positive correlation (Spearman correlation = 0.7646) and a good co-localization relationship between LYVE1 and CD163, suggesting the potential function of LYVE1+CD163+ macrophages in maintaining the homeostasis of cardiac tissue. Conclusion: STAT3-related pathway and CD163+LYVE1+ macrophages were identified as the potential key pathway and immune cells in HCM and may serve as interesting targets for further in-depth research.

Prevalence and association of anxiety and depression among orthopaedic trauma inpatients: a retrospective analysis of 1994 cases.

BACKGROUND: Patients with traumatic injuries are often accompanied by emotional disorders, which seriously impede functional gains. The objective of this study was to identify the prevalence and risk factors associated with underlying anxiety and depression in orthopaedic trauma patients. METHODS: From July 2015 to December 2017, all orthopaedic trauma patients were included in the retrospective study. Patients with conditions that might affect cognitive impairment were excluded from the study. Basic demographic data were collected. All patients were screened for emotional disorders on admission using a simple questionnaire called "Huaxi Emotional-Distress Index" (HEI). Bivariate analyses and logistic regression were used to identify the factors associated with a HEI score of > 8. RESULTS: One hundred and sixty-two patients (8.1%) had a HEI score of > 8. About 1.0% of enrolled patients had severe emotional disorders (HEI score ≥ 17). The reasons caused by emotional disorders in patients with orthopaedic trauma were a higher Injury Severity Score (ISS), a higher visual analogue score (VAS) and type of surgery. On logistic regression, marital status was a protective factor for emotional disorders, while VAS and ISS were the risk factors for emotional disorders. CONCLUSIONS: Although a significantly low percentage of orthopaedic trauma patients in our setting have emotional disorders, traumatic orthopaedic surgeons still need to pay attention to the risk of emotional disorders and integrate effective screening tools into clinical practice to screen for these factors and stratify emotional disorders. Appropriate targeted psychological intervention and treatment should be adopted according to the stratification of emotional disorders.

Author Correction: Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of mice.

During re-read of our previously article Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of micepublished in Acta Pharmacologica Sinica, we were regretted to point out a mistake shown in Fig. 2a. The representative figure chosen to indicate the inhibitory effect of 4 mg/kg of plumbagin treatment at 1 week against MDA-MB-231SArfp cells localization within bone environment was incorrect due to the mishandling in manuscript preparation. Although this correction does not affect the results and conclusion of the paper, all the authors agree on the correction of our negligence as providing the corrected Fig. 2a presented below. We feel sorry and apologize for all the inconvenience it caused.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Reduction patterns of Japanese encephalitis incidence following vaccine introduction into long-term expanded program on immunization in Yunnan Province, China.

BACKGROUND: Japanese encephalitis (JE) is a leading cause of childhood viral encephalitis both at global level and in China. Vaccination is recommended as a key strategy to control JE. In China most JE cases have been reported in southwest provinces, which include Yunnan. In this study, we quantify the epidemiological shift of JE in Yunnan Province from 2005 to 2017, covering before and after the introduction of JE vaccination into routine Expanded Program on Immunization (EPI) in 2007. METHODS: We used routinely collected data in the case-based JE surveillance system from 2005 through 2017 in Yunnan. Cases were reported from hospital and county-level Centers for Disease Control in line with the National JE Surveillance Guideline. Epidemiological data were extracted, analysed and presented in appropriate ways. Immunization coverage was estimated from actual JE doses administered and new births for each year. RESULTS: A total 4780 JE cases (3077 laboratory-confirmed, 1266 clinical and 437 suspected) were reported in the study period. Incidence of JE (per 100 000 population) increased from 0.95 in 2005 to 1.69 in 2007. With increase in vaccination coverage, incidence rates decreased steadily from 1.16 in 2009 to 0.17 in 2017. However, seasonality remained similar across the years, peaking in June-September. Banna (bordering Myanmar and Laos), Dehong (bordering Myanmar), and Zhaotong (an inland prefecture) had the highest incidence rates of 2.3, 1.9, and 1.6, respectively. 97% of all cases were among local residents. As vaccination coverage increased (and incidence decreased), proportion of JE cases among children < 10 years old decreased from 70% in 2005 to 32% in 2017, while that among adults ≥20 years old increased from 12 to 48%. There were a large number of JE cases with unknown treatment outcomes, especially in the earlier years of the surveillance system. CONCLUSIONS: The 13-year JE surveillance data in Yunnan Province showed dramatic decrease of total incidence and a shift from children to adults. Improving vaccination coverage, including access to adults at risk, and strengthening the JE surveillance system is needed to further control or eliminate JE in the province.

Pathologic T-cell response in ischaemic failing hearts elucidated by T-cell receptor sequencing and phenotypic characterization.

AIMS: A persistent cardiac T-cell response initiated by myocardial infarction is linked to subsequent adverse ventricular remodelling and progression of heart failure. No data exist on T-cell receptor (TCR) repertoire changes in combination with phenotypic characterization of T cells in ischaemic failing human hearts. METHODS AND RESULTS: Analysis of TCR repertoire with high-throughput sequencing revealed that compared with T cells in control hearts, those in ischaemic failing hearts showed a clonally expanded TCR repertoire but similar usage patterns of TRBV-J rearrangements and V gene segments; compared with T cells in peripheral blood, those in ischaemic failing hearts exhibited a restricted and clonally expanded TCR repertoire and different usage patterns of TRBV-J rearrangements and V gene segments, suggesting the occurrence of tissue-specific T-cell expansion in ischaemic failing hearts. Consistently, TCR clonotype sharing was prominent in ischaemic failing hearts, especially in hearts of patients who shared human leucocyte antigen (HLA) alleles. Furthermore, ischaemia heart failure (IHF) heart-associated clonotypes were more frequent in peripheral blood of IHF patients than in that of controls. Heart-infiltrating T cells displayed memory- and effector-like characteristics. Th1 cells were the predominant phenotype among CD4+ T cells; CD8+ T cells were equally as abundant as CD4+ T cells and produced high levels of interferon-γ, granzyme B, and perforin. CONCLUSION: We provide novel evidence for a tissue-specific T-cell response predominated by Th1 cells and cytotoxic CD8+ T cells in ischaemic failing human hearts that may contribute to the progression of heart failure.

High selective reduction of nitrate into nitrogen by novel Fe-Cu/D407 composite with excellent stability and activity.

In this study, we develop a new composite material of Fe-Cu/D407 composite via using nanoscale zero-valent iron (nZVI) with copper deposited on chelating resin (D407) to remove nitrate from the water. The experimental results show that a remarkable nitrate removal and the selectivity of N2 are 99.9% and 89.7%, respectively, under the anaerobic conditions of Cu/Fe molar ratio of 1:2, pH = 3.0. Even without of inert gas and adjusting the initial pH of the solution, the removal rate of nitrate by Fe-Cu/D407 reached to 85% and the selectivity of nitrogen reached to 55%. Meanwhile, the Fe-Cu/D407 maintained preferable removal efficiency of nitrate (100% - 92%) over a wide pH range of 3-11. In addition, the removal rate of the drinking water, lake water and wastewater from the Fe-Cu/D407 is still very high and the reactivity of Fe-Cu/D407 was relatively unaffected by the presence of dissolved ions in the waters tested. Moreover, the synergetic effect of Fe, Cu and D407 in the composite Fe-Cu/D407 were well investigated for the first time according to the analyses of TPR, XPS and EIS. The catalytic mechanism and denitrification routes were also proposed.

Author Correction: Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid in vitro.

The authors regretted to find the mis-representative images in Fig. 3a, c and Fig. 4a, c when re-read our previously published article Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid In vitro (DOI: 10.1038/aps.2015.42) in the journal of Acta Pharmacologica Sinica. This mistake occurred due to the careless compilation when the authors tried to show the synergistic effect against tumor apoptosis during figure presentation process. The right Fig. 3a, c and Fig. 4a, c were provided below. Despite that this correction does not affect the results and conclusions of the aforementioned paper, all the authors still consent on the correction of this negligence. We apologize to the Editor and the readership of the journal for any inconvenience caused. Your thoughtful understanding is highly appreciated.

Correction to: Suppressive effects of plumbagin on invasion and migration of breast cancer cells via the inhibition of STAT3 signaling and down-regulation of inflammatory cytokine expressions.

[This corrects the article DOI: 10.4248/BR201304007.].

Dihydromyricetin Inhibits Inflammation of Fibroblast-Like Synoviocytes through Regulation of Nuclear Factor-κB Signaling in Rats with Collagen-Induced Arthritis.

Dihydromyricetin (DMY), the main flavonoid of Ampelopsis grossedentata, has potent anti-inflammatory activity. However, the effect of DMY on chronic autoimmune arthritis remains undefined. In this study, we investigated the therapeutic effects of DMY on collagen-induced arthritis (CIA). Wistar rats were immunized with bovine type II collagen to establish CIA and were then administered DMY intraperitoneally (5, 25, and 50 mg/kg) every other day for 5 weeks. Paw swelling, clinical scoring, and histologic analysis were assessed to determine the therapeutic effects of DMY on the development of arthritis in CIA rats. The results showed that treatment with DMY significantly reduced erythema and swelling in the paws of CIA rats. Pathologic analysis of the knee joints and peripheral blood cytokine assay results confirmed the antiarthritic effects of DMY on synovitis and inflammation. Fibroblast-like synoviocytes (FLSs) were isolated from the synovium of CIA rats and treated with 10 ng/ml interleukin (IL)-1ß DMY significantly inhibited the proliferation, migration, and inflammation of IL-1ß-induced FLSs, whereas it significantly increased IL-1ß-induced FLS apoptosis in a dose-dependent manner (6.25-25 µM). Moreover, DMY suppressed phosphorylation of IκB kinase (IKK) and inhibitor of NF-κB α and subsequently reduced the IL-1ß-induced nucleus translocation of NF-κB in FLSs. Through a molecular docking assay, we demonstrated that DMY could directly bind to the Thr9 and Asp88 residues in IKKα and the Asp95, Asn142, and Gln167 residues in IKKß These findings demonstrate that DMY could alleviate inflammation in CIA rats and attenuate IL-1ß-induced activities in FLSs through suppression of NF-κB signaling.

Liver-heart crosstalk controls IL-22 activity in cardiac protection after myocardial infarction.

Interleukin (IL)-22 regulates tissue inflammation and repair. Here we report participation of the liver in IL-22-mediated cardiac repair after acute myocardial infarction (MI). Methods: We induced experimental MI in mice by ligation of the left ascending artery and evaluated the effect of IL-22 on post-MI cardiac function and ventricular remodeling. Results: Daily subcutaneous injection of 100 µg/kg mouse recombinant IL-22 for seven days attenuated adverse ventricular remodeling and improved cardiac function in mice at 28 days after left anterior descending coronary artery ligation-induced MI. Pharmacological inhibition of signal transducer and activator of transcription (STAT3) muted these IL-22 activities. While cardiomyocyte-selective depletion of STAT3 did not affect IL-22 activities in protecting post-MI cardiac injury, hepatocyte-specific depletion of STAT3 fully muted these IL-22 cardioprotective activities. Hepatocyte-derived fibroblast growth factor (FGF21) was markedly increased in a STAT3-dependent manner following IL-22 administration and accounted for the cardioprotective benefit of IL-22. Microarray analyses revealed that FGF21 controlled the expression of cardiomyocyte genes that are involved in cholesterol homeostasis, DNA repair, peroxisome, oxidative phosphorylation, glycolysis, apoptosis, and steroid responses, all of which are responsible for cardiomyocyte survival. Conclusions: Supplementation of IL-22 in the first week after acute MI effectively prevented left ventricular dysfunction and heart failure. This activity of IL-22 involved crosstalk between the liver and heart after demonstrating a role of the hepatic STAT3-FGF21 axis in IL-22-induced post-MI cardiac protection.

Genetic Regulation of the Thymic Stromal Lymphopoietin (TSLP)/TSLP Receptor (TSLPR) Gene Expression and Influence of Epistatic Interactions Between IL-33 and the TSLP/TSLPR Axis on Risk of Coronary Artery Disease.

The thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) axis is involved in multiple inflammatory immune diseases, including coronary artery disease (CAD). To explore the causal relationship between this axis and CAD, we performed a three-stage case-control association analysis with 3,628 CAD cases and 3,776 controls using common variants in the genes TSLP, interleukin 7 receptor (IL7R), and TSLPR. Three common variants in the TSLP/TSLPR axis were significantly associated with CAD in a Chinese Han population [rs3806933T in TSLP, Padj = 4.35 × 10-5, odds ratio (OR) = 1.18; rs6897932T in IL7R, Padj = 1.13 × 10-7, OR = 1.31; g.19646A>GA in TSLPR, Padj = 2.04 × 10-6, OR = 1.20]. Reporter gene analysis demonstrated that rs3806933 and rs6897932 could influence TSLP and IL7R expression, respectively. Furthermore, the "T" allele of rs3806933 might increase plasma TSLP levels (R2 = 0.175, P < 0.01). In a stepwise procedure, the risk for CAD increased by nearly fivefold compared with the maximum effect of any single variant (Padj = 6.99 × 10-4, OR = 4.85). In addition, the epistatic interaction between TSLP and IL33 produced a nearly threefold increase in the risk of CAD in the combined model of rs3806933TT-rs7025417TT (Padj = 3.67 × 10-4, OR = 2.98). Our study illustrates that the TSLP/TSLPR axis might be involved in the pathogenesis of CAD through upregulation of mRNA or protein expression of the referenced genes and might have additive effects on the CAD risk when combined with IL-33 signaling.