Electrospun organic/inorganic hybrid nanofibers for accelerating wound healing: a review.

Electrospun nanofiber membranes hold great promise as scaffolds for tissue reconstruction, mirroring the natural extracellular matrix (ECM) in their structure. However, their limited bioactive functions have hindered their effectiveness in fostering wound healing. Inorganic nanoparticles possess commendable biocompatibility, which can expedite wound healing; nevertheless, deploying them in the particle form presents challenges associated with removal or collection. To capitalize on the strengths of both components, electrospun organic/inorganic hybrid nanofibers (HNFs) have emerged as a groundbreaking solution for accelerating wound healing and maintaining stability throughout the healing process. In this review, we provide an overview of recent advancements in the utilization of HNFs for wound treatment. The review begins by elucidating various fabrication methods for hybrid nanofibers, encompassing direct electrospinning, coaxial electrospinning, and electrospinning with subsequent loading. These techniques facilitate the construction of micro-nano structures and the controlled release of inorganic ions. Subsequently, we delve into the manifold applications of HNFs in promoting the wound regeneration process. These applications encompass hemostasis, antibacterial properties, anti-inflammatory effects, stimulation of cell proliferation, and facilitation of angiogenesis. Finally, we offer insights into the prospective trends in the utilization of hybrid nanofiber-based wound dressings, charting the path forward in this dynamic field of research.

Corrigendum to "Emulsifying Lipiodol with pH-Sensitive DOX@HmA nanoparticles for hepatocellular carcinoma TACE treatment eliminate metastasis" Mater. Today Bio, 23, 2023, 100873, ISSN 2590-0064.

[This corrects the article DOI: 10.1016/j.mtbio.2023.100873.].

Effects of donor age and reproductive history on developmental potential of ovum pickup oocytes in Japanese Black cattle (Wagyu).

The objectives of this study were to analyze the (1) effects of donor age and multiparity on development of in vitro fertilization (IVF) embryos after ovum pickup (OPU), (2) effects of repeated and consecutive OPU-IVF procedures on embryo development, and (3) embryo production from OPU-IVF in donors with differing embryo yields after multiple ovulation and embryo transfer technology (MOET) in Japanese Black cattle (Wagyu). Donors were pre-treated with low-dosage follicle-stimulating hormone (FSH; 200 IU total), and oocytes were collected via OPU and fertilized by IVF to generate blastocysts. The number of oocytes collected per OPU session per donor was lower in heifers (2-4 years old, 5.3 oocytes) than in primiparous and pluriparous cows (2-10 years old, 13.6-19.1 oocytes; P < 0.05). Rates of blastocyst development for oocytes from heifers (33.1%) were lower than for those from cows (2-10 years old, 44.1-54.3%; P < 0.05), and average blastocyst yield/OPU/animal was lower in heifers (3.7) than in 5-6 years old cows (10.1; P < 0.05). Donors undergoing five consecutive OPU-IVF sessions after low-dosage FSH showed similar oocyte retrieval (12.2-15.1 oocytes per OPU/animal), blastocyst development rates (35.6-45.0%), and embryo yield/OPU/animal (4.8-5.8; P > 0.05) across sessions. Additionally, embryo yield from OPU-IVF was significantly improved in animals with previous low embryo yield from MOET (5.9 vs. 2.6, respectively, P < 0.05). These results indicate that Wagyu cows with previous births can be more productive as OPU-IVF donors than heifers, and oocytes from donors undergoing to five consecutive OPU-IVF cycles are competent for embryo development without loss of embryo yield/OPU/animal. Moreover, OPU-IVF can be used for embryo production and breeding from all elite Japanese Black cattle, regardless of previous low embryo yield in routine MOET.

Mi-BMSCs alleviate inflammation and fibrosis in CCl4-and TAA-induced liver cirrhosis by inhibiting TGF-ß/Smad signaling.

Cirrhosis is an aggressive disease, and over 80 % of liver cancer patients are complicated by cirrhosis, which lacks effective therapies. Transplantation of mesenchymal stem cells (MSCs) is a promising option for treating liver cirrhosis. However, this therapeutic approach is often challenged by the low homing ability and short survival time of transplanted MSCs in vivo. Therefore, a novel and efficient cell delivery system for MSCs is urgently required. This new system can effectively extend the persistence and duration of MSCs in vivo. In this study, we present novel porous microspheres with microfluidic electrospray technology for the encapsulation of bone marrow-derived MSCs (BMSCs) in the treatment of liver cirrhosis. Porous microspheres loaded with BMSCs (Mi-BMSCs) exhibit good biocompatibility and demonstrate better anti-inflammatory properties than BMSCs alone. Mi-BMSCs significantly increase the duration of BMSCs and exert potent anti-inflammatory and anti-fibrosis effects against CCl4 and TAA-induced liver cirrhosis by targeting the TGF-ß/Smad signaling pathway to ameliorate cirrhosis, which highlight the potential of Mi-BMSCs as a promising therapeutic approach for early liver cirrhosis.

Ixekizumab-induced urticaria is associated with the short duration of remission in psoriasis by activation of mast cells.

BACKGROUND: Mast cell degranulation plays a pivotal role in urticaria and is also an early histologic characteristic of psoriasis. However, whether the activation of mast cells contributes to psoriasis recurrence after discontinuation of interleukin (IL)-17A blockers remains unclear. OBJECTIVE: To investigate the role of mast cells in ixekizumab treatment-associated urticaria (ITAUR) and assess the effect of urticaria eruption on psoriasis relapse. METHODS: A retrospective analysis was performed on biopsies of patients who experienced psoriasis relapse after discontinuation of ixekizumab. Transcriptomic and histopathologic features were assessed. Patterns were compared between patients with ITAUR and nonurticaria (NUR) as well as psoriasis-like mice with mast cell activation or inactivation. RESULTS: Patients with ITAUR experienced early relapse compared with NUR group after treatment withdrawal. Transcriptomic and histopathologic analyses revealed that patients with ITAUR had an elevated proportion of mast cells in resolved skin. Especially, the proportion of IL-17A+ mast cells was inversely correlated with the duration of remission. LIMITATIONS: The mechanism of mast cell activation in ITAUR has not been precisely elucidated. CONCLUSION: Ixekizumab treatment increases IL-17A+ mast cells in lesions of ITAUR, which is associated with early psoriasis relapse after ixekizumab withdrawal.

Overcoming the H4K20me3 epigenetic barrier improves somatic cell nuclear transfer reprogramming efficiency in mice.

Epigenetic reprogramming during fertilization and somatic cell nuclear transfer (NT) is required for cell plasticity and competent development. Here, we characterize the epigenetic modification pattern of H4K20me3, a repressive histone signature in heterochromatin, during fertilization and NT reprogramming. Importantly, the dynamic H4K20me3 signature identified during preimplantation development in fertilized embryos differed from NT and parthenogenetic activation (PA) embryos. In fertilized embryos, only maternal pronuclei carried the canonical H4K20me3 peripheral nucleolar ring-like signature. H4K20me3 disappeared at the 2-cell stage and reappeared in fertilized embryos at the 8-cell stage and in NT and PA embryos at the 4-cell stage. H4K20me3 intensity in 4-cell, 8-cell, and morula stages of fertilized embryos was significantly lower than in NT and PA embryos, suggesting aberrant regulation of H4K20me3 in PA and NT embryos. Indeed, RNA expression of the H4K20 methyltransferase Suv4-20h2 in 4-cell fertilized embryos was significantly lower than NT embryos. Knockdown of Suv4-20h2 in NT embryos rescued the H4K20me3 pattern similar to fertilized embryos. Compared to control NT embryos, knockdown of Suv4-20h2 in NT embryos improved blastocyst development ratios (11.1% vs. 30.5%) and full-term cloning efficiencies (0.8% vs. 5.9%). Upregulation of reprogramming factors, including Kdm4b, Kdm4d, Kdm6a, and Kdm6b, as well as ZGA-related factors, including Dux, Zscan4, and Hmgpi, was observed with Suv4-20h2 knockdown in NT embryos. Collectively, these are the first findings to demonstrate that H4K20me3 is an epigenetic barrier of NT reprogramming and begin to unravel the epigenetic mechanisms of H4K20 trimethylation in cell plasticity during natural reproduction and NT reprogramming in mice.

Emulsifying Lipiodol with pH-sensitive DOX@HmA nanoparticles for hepatocellular carcinoma TACE treatment eliminate metastasis.

Lipiodol-based transcatheter arterial chemoembolization (TACE) is currently the predominant and first-line treatment option recommended by the global standard for unresectable hepatocellular carcinoma (HCC). However, the unstable emulsion of Lipiodol causes a substantial proportion of chemotherapy drugs to enter the circulation system, leading to poor accumulation in cancer tissues and unexpected side effects of chemotherapy drugs. Herein, we emulsified Lipiodol with a pH-sensitive drug delivery system assembled from hexahistidine and zinc ions (HmA) with a super-high loading capacity of doxorubicin (DOX) and a promising ability to penetrate bio-barriers for the effective treatment of HCC by TACE. In vitro tests showed that DOX@HmA was comparable to free DOX in killing HCC cells. Impressively, during the in vivo TACE treatment, the anti-tumor efficacy of DOX@HmA was significantly greater than that of free DOX, indicating that DOX@HmA increased the accumulation of DOX in tumor. Emulsifying Lipiodol with pH-sensitive DOX@HmA significantly inhibited cell regeneration and tumor angiogenesis and decreased the systemic side effects of chemotherapy, especially by suppressing pulmonary metastasis in liver VX2 tumors in rabbits by inhibiting epithelial-mesenchymal transition (EMT). Emulsifying tumor microenvironment-responsive drug delivery systems (DDSs) with Lipiodol could be a new strategy for clinical TACE chemotherapy with potentially enhanced HCC treatment.

Advances in Stimuli-Responsive Chitosan Hydrogels for Drug Delivery Systems.

Sustainable and controllable drug transport is one of the most efficient ways of disease treatment. Due to high biocompatibility, good biodegradability, and low costs, chitosan and its derivatives are widely used in biomedical fields. Specifically, chitosan hydrogel enables drugs to pass through biological barriers because of their abundant amino and hydroxyl groups that can interact with human tissues. Moreover, the multi-responsive nature (pH, temperature, ions strength, and magnetic field, etc.) of chitosan hydrogels makes precise drug release a possibility. Here, the synthesis methods, modification strategies, stimuli-responsive mechanisms of chitosan-based hydrogels, and their recent progress in drug delivery are summarized. Chitosan hydrogels that carry and release drugs through subcutaneous (dealing with wound dressing), oral (dealing with gastrointestinal tract), and facial (dealing with ophthalmic, ear, and brain) are reviewed. Finally, challenges toward clinic application and the future prospects of stimuli-responsive chitosan-based hydrogels are indicated.

Jagged1 Acts as an RBP-J Target and Feedback Suppresses TNF-Mediated Inflammatory Osteoclastogenesis.

TNF plays a crucial role in inflammation and bone resorption in various inflammatory diseases, including rheumatoid arthritis (RA). However, its direct ability to drive macrophages to differentiate into osteoclasts is limited. Although RBP-J is recognized as a key inhibitor of TNF-mediated osteoclastogenesis, the precise mechanisms that restrain TNF-induced differentiation of macrophages into osteoclasts are not fully elucidated. In this study, we identified that the Notch ligand Jagged1 is a previously unrecognized RBP-J target. The expression of Jagged1 is significantly induced by TNF mainly through RBP-J. The TNF-induced Jagged1 in turn functions as a feedback inhibitory regulator of TNF-mediated osteoclastogenesis. This feedback inhibition of osteoclastogenesis by Jagged1 does not exist in RANKL-induced mouse osteoclast differentiation, as RANKL does not induce Jagged1 expression. The Jagged1 level in peripheral blood monocytes/osteoclast precursors is decreased in RA compared with the nonerosive inflammatory disease systemic lupus erythematosus, suggesting a mechanism that contributes to increased osteoclast formation in RA. Moreover, recombinant Jagged1 suppresses human inflammatory osteoclastogenesis. Our findings identify Jagged1 as an RBP-J direct target that links TNF and Notch signaling pathways and restrains TNF-mediated osteoclastogenesis. Given that Jagged1 has no effect on TNF-induced expression of inflammatory genes, its use may present a new complementary therapeutic approach to mitigate inflammatory bone loss with little impact on the immune response in disease conditions.

Probiotic powder ameliorates colorectal cancer by regulating Bifidobacterium animalis, Clostridium cocleatum, and immune cell composition.

Based on the relationship between the gut microbiota and colorectal cancer, we developed a new probiotic powder for treatment of colorectal cancer. Initially, we evaluated the effect of the probiotic powder on CRC using hematoxylin and eosin staining, and evaluated mouse survival rate and tumor size. We then investigated the effects of the probiotic powder on the gut microbiota, immune cells, and apoptotic proteins using 16S rDNA sequencing, flow cytometry, and western blot, respectively. The results showed that the probiotic powder improved the intestinal barrier integrity, survival rate, and reduced tumor size in CRC mice. This effect was associated with changes in the gut microbiota. Specifically, the probiotic powder increased the abundance of Bifidobacterium animalis and reduced the abundance of Clostridium cocleatum. In addition, the probiotic powder resulted in decreased numbers of CD4+ Foxp3+ Treg cells, increased numbers of IFN-γ+ CD8+ T cells and CD4+ IL-4+ Th2 cells, decreased expression of the TIGIT in CD4+ IL-4+ Th2 cells, and increased numbers of CD19+ GL-7+ B cells. Furthermore, the expression of the pro-apoptotic protein BAX was significantly increased in tumor tissues in response to the probiotic powder. In summary, the probiotic powder ameliorated CRC by regulating the gut microbiota, reducing Treg cell abundance, promoting the number of IFN-γ+ CD8+ T cells, increasing Th2 cell abundance, inhibiting the expression of TIGIT in Th2 cells, and increasing B cell abundance in the immune microenvironment of CRC, thereby increasing the expression of BAX in CRC.

Bone marrow Adipoq-lineage progenitors are a major cellular source of M-CSF that dominates bone marrow macrophage development, osteoclastogenesis, and bone mass.

M-CSF is a critical growth factor for myeloid lineage cells, including monocytes, macrophages, and osteoclasts. Tissue-resident macrophages in most organs rely on local M-CSF. However, it is unclear what specific cells in the bone marrow produce M-CSF to maintain myeloid homeostasis. Here, we found that Adipoq-lineage progenitors but not mature adipocytes in bone marrow or in peripheral adipose tissue, are a major cellular source of M-CSF, with these Adipoq-lineage progenitors producing M-CSF at levels much higher than those produced by osteoblast lineage cells. The Adipoq-lineage progenitors with high CSF1 expression also exist in human bone marrow. Deficiency of M-CSF in bone marrow Adipoq-lineage progenitors drastically reduces the generation of bone marrow macrophages and osteoclasts, leading to severe osteopetrosis in mice. Furthermore, the osteoporosis in ovariectomized mice can be significantly alleviated by the absence of M-CSF in bone marrow Adipoq-lineage progenitors. Our findings identify bone marrow Adipoq-lineage progenitors as a major cellular source of M-CSF in bone marrow and reveal their crucial contribution to bone marrow macrophage development, osteoclastogenesis, bone homeostasis, and pathological bone loss.

SIGIRR-caspase-8 signaling mediates endothelial apoptosis in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a kind of vasculitis with unidentified etiology. Given that the current diagnosis and therapeutic strategy of KD are mainly dependent on clinical experiences, further research to explore its pathological mechanisms is warranted. METHODS: Enzyme linked immunosorbent assay (ELISA) was used to measure the serum levels of SIGIRR, TLR4 and caspase-8. Western blotting was applied to determine protein levels, and flow cytometry was utilized to analyze cell apoptosis. Hematoxylin eosin (HE) staining and TUNEL staining were respectively used to observe coronary artery inflammation and DNA fragmentation. RESULTS: In this study, we found the level of SIGIRR was downregulated in KD serum and KD serum-treated endothelial cells. However, the level of caspase-8 was increased in serum from KD patients compared with healthy control (HC). Therefore, we hypothesized that SIGIRR-caspase-8 signaling may play an essential role in KD pathophysiology. In vitro experiments demonstrated that endothelial cell apoptosis in the setting of KD was associated with caspase-8 activation, and SIGIRR overexpression alleviated endothelial cell apoptosis via inhibiting caspase-8 activation. These findings were also recapitulated in the Candida albicans cell wall extracts (CAWS)-induced KD mouse model. CONCLUSION: Our data suggest that endothelial cell apoptosis mediated by SIGIRR-caspase-8 signaling plays a crucial role in coronary endothelial damage, providing potential targets to treat KD.

Albumin level and progression of coronary artery lesions in Kawasaki disease: A retrospective cohort study.

Background: Albumin (ALB) level is closely associated with the occurrence of intravenous immunoglobulin (IVIG) resistance and coronary artery lesions (CALs) in Kawasaki disease (KD). The association between ALB level and CALs progression, is critical to the prognosis of KD patients. But little is known about it. This study aims to investigate the effect of the ALB level on CALs progression in KD patients. Methods: A total of 3,479 KD patients from 1 January 2005 to 30 November 2020, in Wenzhou, China were recruited. A total of 319 KD patients who had CALs and ALB data, and finish the follow-up as requested were enrolled in this study. They were classified into the low ALB group and the normal ALB group, divided by 30 g/L. CALs outcomes were classified into two categories according to the CALs changes from the time that CALs were detected within 48 h before or after IVIG treatment to 1 month after disease onset: progressed and no progressed. Multiple logistic regression models were used to assess the independent effect of ALB level on CALs progression among KD patients. Stratified analysis was performed to verify the ALB level on CALs progression among patients in different subgroups. Results: Higher proportion of IVIG resistance (P < 0.001), receiving non-standard therapy (P < 0.001), and receiving delayed IVIG treatment (P = 0.020) were detected in patients with lower ALB level. Patients with lower ALB level had higher C-reactive protein (CRP) level (P = 0.097) and white blood cell count (WBC) (P = 0.036). After adjustment for confounders, patients with lower ALB level had higher odds of CALs progression; the adjusted odds ratio (OR) was 3.89 (95% CI: 1.68, 9.02). Similar results were found using stratification analysis and sensitivity analysis. Male gender and age over 36 months, as covariates in multiple logistic regression models, were also associated with CALs progression. Conclusion: Low ALB level is identified as an independent risk factor for CALs progression in KD patients. Male gender and age over 36 months are also proved to be risk factors for CALs progression. Further investments are required to explore its mechanisms.

Anion-templated silver thiolated clusters affected by carboxylate ligands.

Under the guidance of anion templates V10O286- and SO42-, the novelty of cluster assembly can be increased by using different carboxylate ligands. Herein, the synthesis, crystal structure and electrochemical properties of three anion-templated silver thiolated clusters are reported, namely V10O28@Ag46(iPrS)28(CF3CO2)12(DMF)2 (1), V10O28@Ag46(iPrS)30(CF3CO2)8(PhCO2)2(DMF)4 (2), and [SO4@Ag20(iPrS)10(PTA)3(HPTA)2]n (3, H2PTA = phthalic acid). Single-crystal X-ray diffraction analysis showed that 1 and 2 are discrete clusters V10O28@Ag46. The addition of PhCO2H in the second step of 1 leads to obtaining 2 with different organic shells. If the addition of H2PTA is made, 3 with a three-dimensional (3D) structure containing the SO42- template can be obtained. Both V10O286- and SO42- templates were generated in situ under solvothermal conditions. This work is the first where heterogeneous silver clusters containing the V10O286- anion template protected by an isopropyl thiolate ligand and a Ag20 cluster with a 3D structure are obtained. The assembly process influenced by carboxylic acid deserves to be continuously explored in the future.

TGFß reprograms TNF stimulation of macrophages towards a non-canonical pathway driving inflammatory osteoclastogenesis.

It is well-established that receptor activator of NF-κB ligand (RANKL) is the inducer of physiological osteoclast differentiation. However, the specific drivers and mechanisms driving inflammatory osteoclast differentiation under pathological conditions remain obscure. This is especially true given that inflammatory cytokines such as tumor necrosis factor (TNF) demonstrate little to no ability to directly drive osteoclast differentiation. Here, we found that transforming growth factor ß (TGFß) priming enables TNF to effectively induce osteoclastogenesis, independently of the canonical RANKL pathway. Lack of TGFß signaling in macrophages suppresses inflammatory, but not basal, osteoclastogenesis and bone resorption in vivo. Mechanistically, TGFß priming reprograms the macrophage response to TNF by remodeling chromatin accessibility and histone modifications, and enables TNF to induce a previously unrecognized non-canonical osteoclastogenic program, which includes suppression of the TNF-induced IRF1-IFNß-IFN-stimulated-gene axis, IRF8 degradation and B-Myb induction. These mechanisms are active in rheumatoid arthritis, in which TGFß level is elevated and correlates with osteoclast activity. Our findings identify a TGFß/TNF-driven inflammatory osteoclastogenic program, and may lead to development of selective treatments for inflammatory osteolysis.

Claudin-1 Mediated Tight Junction Dysfunction as a Contributor to Atopic March.

Atopic march refers to the phenomenon wherein the occurrence of asthma and food allergy tends to increase after atopic dermatitis. The mechanism underlying the progression of allergic inflammation from the skin to gastrointestinal (GI) tract and airways has still remained elusive. Impaired skin barrier was proposed as a risk factor for allergic sensitization. Claudin-1 protein forms tight junctions and is highly expressed in the epithelium of the skin, airways, and GI tract, thus, the downregulation of claudin-1 expression level caused by CLDN-1 gene polymorphism can mediate common dysregulation of epithelial barrier function in these organs, potentially leading to allergic sensitization at various sites. Importantly, in patients with atopic dermatitis, asthma, and food allergy, claudin-1 expression level was significantly downregulated in the skin, bronchial and intestinal epithelium, respectively. Knockdown of claudin-1 expression level in mouse models of atopic dermatitis and allergic asthma exacerbated allergic inflammation, proving that downregulation of claudin-1 expression level contributes to the pathogenesis of allergic diseases. Therefore, we hypothesized that the tight junction dysfunction mediated by downregulation of claudin-1 expression level contributes to atopic march. Further validation with clinical data from patients with atopic march or mouse models of atopic march is needed. If this hypothesis can be fully confirmed, impaired claudin-1 expression level may be a risk factor and likely a diagnostic marker for atopic march. Claudin-1 may serve as a valuable target to slowdown or block the progression of atopic march.

The C-Reactive Protein to Albumin Ratio Is an Independent Prognostic Factor in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization: A Large Cohort Study.

BACKGROUND: This study aimed to investigate the prognostic value of C-reactive protein to albumin ratio (CAR) in hepatocellular carcinoma (HCC) patients after transcatheter chemoembolization (TACE). METHODS: Totally, 958 HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage B were incorporated into the secondary analysis. X-Tile software was applied to determine the optimal cutoff point for CAR, and the total patients were divided into two groups. Cox proportional hazard regression models and Kaplan-Meier analyses were used to estimate the relationship between CAR and overall survival (OS). Stratified analyses were performed to evaluate the prognostic role of CAR in subgroups of major confounding factors, such as alpha-fetoprotein (AFP), diameter of the main tumor, Glasgow prognostic score (GPS) and modified GPS (mGPS). RESULTS: The optimal cutoff level for the CAR was 0.06. There was a direct correlation between an elevated CAR (≥ 0.06) and shorter OS after adjustment (HR:1.580; 95%CI:1.193-2.092). Kaplan-Meier analysis and log-rank test showed a significant difference in OS curves between the two groups (P < 0.001). CAR showed the distinct value of prognostic stratification in most subgroups, especially in the subgroup of GPS-0 (HR:1.966; 95%CI:1.453-2.660), mGPS-0 (HR:1.984; 95%CI:1.509-2.608) and AFP ≤ 400 ng/ml (HR:1.925; 95%CI:1.393-2.659). CONCLUSION: The CAR was one of the prognostic factors for HCC patients undergoing TACE treatment. CAR could also provide further prognostic stratification for HCC patients who appear to have a good prognosis, such as patients with AFP-negative, GPS-0 or mGPS-0 to identify patients at a higher risk of death for closer follow-up or more aggressive treatment. LEVEL OF EVIDENCE: Level 3, Cohort Study.

Characteristics of Kawasaki Disease Before and After the COVID-19 Pandemic in a Large Pediatric Heart Disease Center.

Background: Kawasaki disease (KD) is an acute febrile systemic vasculitis of unknown etiology. After the pandemic of coronavirus disease 2019 (COVID-19), some children infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) showed clinical symptoms similar to KD, indicating a close relationship between KD and SARS-CoV-2. Therefore, we designed this retrospective study to analyze the characteristics of KD patients before and after the COVID-19 pandemic. Methods: We retrospectively collected demographic and laboratory data of KD patients in Yuying Children's Hospital of Wenzhou Medical University from 1 January 2015 to 31 December 2020. Yuying Children's Hospital of Wenzhou Medical University is located in eastern China and is the largest pediatric heart disease center in the region, which includes a population of nearly 10 million. We studied the characteristics of KD patients and analyzed the changes in these characteristics before and after the emergence of SARS-CoV-2 in this area. Results: The analysis revealed the following novel features: (1) Under the influence of the COVID-19 pandemic, the onset age of Kawasaki disease became younger. (2) After the occurrence of COVID-19, the hospitalization days of KD patients were shorter than before the pandemic. (3) After the occurrence of COVID-19, the albumin of KD patients was higher than before the pandemic. (4) The COVID-19 pandemic did not have a significant effect on the incidence of coronary artery lesions (CALs) in Kawasaki disease. Conclusion: After the COVID-19 outbreak, the characteristics of KD patients showed a younger trend of age, shorter hospitalization days and higher levels of albumin, but the incidence of CALs did not change significantly.

Natural Killer Cells in Hepatic Ischemia-Reperfusion Injury.

Ischemia-reperfusion injury can be divided into two phases, including insufficient supply of oxygen and nutrients in the first stage and then organ injury caused by immune inflammation after blood flow recovery. Hepatic ischemia-reperfusion is an important cause of liver injury post-surgery, consisting of partial hepatectomy and liver transplantation, and a central driver of graft dysfunction, which greatly leads to complications and mortality after liver transplantation. Natural killer (NK) cells are the lymphocyte population mainly involved in innate immune response in the human liver. In addition to their well-known role in anti-virus and anti-tumor defense, NK cells are also considered to regulate the pathogenesis of liver ischemia-reperfusion injury under the support of more and more evidence recently. The infiltration of NK cells into the liver exacerbates the hepatic ischemia-reperfusion injury, which could be significantly alleviated after depletion of NK cells. Interestingly, NK cells may contribute to both liver graft rejection and tolerance according to their origins. In this article, we discussed the development of liver NK cells, their role in ischemia-reperfusion injury, and strategies of inhibiting NK cell activation in order to provide potential possibilities for translation application in future clinical practice.

C-C motif chemokine ligand 5 confines liver regeneration by down-regulating reparative macrophage-derived hepatocyte growth factor in a forkhead box O 3a-dependent manner.

BACKGROUND AND AIMS: Liver regeneration (LR) is vital for the recovery of liver function after hepatectomy. Limited regeneration capacity, together with insufficient remnant liver volume, is a risk factor for posthepatectomy liver failure (PHLF) resulting from small-for-size syndrome. Although inflammation plays an important role in controlling LR, the underlying mechanisms still remain obscure. APPROACH AND RESULTS: We identified C-C motif chemokine ligand (CCL) 5 as an important negative regulator for LR. CCL5 levels were elevated after partial hepatectomy (PHx), both in healthy donors of living donor liver transplantation (LT) and PHx mouse models. Ccl5 knockout mice displayed improved survival after 90% PHx and enhanced LR 36 h after 70% PHx. However, primary hepatocytes from Ccl5-/- mice exposed to growth factors in vitro showed no proliferation advantage compared to those from wild-type (WT) mice. Flow cytometry analysis showed that proportions of Ly6Clo macrophages were significantly increased in Ccl5-/- mice after 70% PHx. RNA-sequencing analysis revealed that sorted macrophages (CD11b+ Ly6Clo&hi ) manifested enhanced expression of reparative genes in Ccl5-/- mice compared to WT mice. Mechanistically, CCL5 induced macrophages toward proinflammatory Ly6Chi phenotype, thereby inhibiting the production of hepatocyte growth factor (HGF) through the C-C motif chemokine receptor (CCR) 1- and CCR5-mediated forkhead box O (FoxO) 3a pathways. Finally, blockade of CCL5 greatly optimized survival and boosted LR in the mouse PHx model. CONCLUSIONS: Our findings suggest that inhibition of CCL5 is a promising strategy to improve regeneration restoration by enhancing HGF secretion from reparative macrophages through the FoxO3a pathway, which may potentially reduce the mortality of PHLF.