Skeletal muscle TET3 promotes insulin resistance through destabilisation of PGC-1α.

AIM/HYPOTHESIS: The peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α) plays a critical role in the maintenance of glucose, lipid and energy homeostasis by orchestrating metabolic programs in multiple tissues in response to environmental cues. In skeletal muscles, PGC-1α dysregulation has been associated with insulin resistance and type 2 diabetes but the underlying mechanisms have remained elusive. This research aims to understand the role of TET3, a member of the ten-eleven translocation (TET) family dioxygenases, in PGC-1α dysregulation in skeletal muscles in obesity and diabetes. METHODS: TET expression levels in skeletal muscles were analysed in humans with or without type 2 diabetes, as well as in mouse models of high-fat diet (HFD)-induced or genetically induced (ob/ob) obesity/diabetes. Muscle-specific Tet3 knockout (mKD) mice were generated to study TET3's role in muscle insulin sensitivity. Genome-wide expression profiling (RNA-seq) of muscle tissues from wild-type (WT) and mKD mice was performed to mine deeper insights into TET3-mediated regulation of muscle insulin sensitivity. The correlation between PGC-1α and TET3 expression levels was investigated using muscle tissues and in vitro-derived myotubes. PGC-1α phosphorylation and degradation were analysed using in vitro assays. RESULTS: TET3 expression was elevated in skeletal muscles of humans with type 2 diabetes and in HFD-fed and ob/ob mice compared with healthy controls. mKD mice exhibited enhanced glucose tolerance, insulin sensitivity and resilience to HFD-induced insulin resistance. Pathway analysis of RNA-seq identified 'Mitochondrial Function' and 'PPARα Pathway' to be among the top biological processes regulated by TET3. We observed higher PGC-1α levels (~25%) in muscles of mKD mice vs WT mice, and lower PGC-1α protein levels (~25-60%) in HFD-fed or ob/ob mice compared with their control counterparts. In human and murine myotubes, increased PGC-1α levels following TET3 knockdown contributed to improved mitochondrial respiration and insulin sensitivity. TET3 formed a complex with PGC-1α and interfered with its phosphorylation, leading to its destabilisation. CONCLUSIONS/INTERPRETATION: Our results demonstrate an essential role for TET3 in the regulation of skeletal muscle insulin sensitivity and suggest that TET3 may be used as a potential therapeutic target for the metabolic syndrome. DATA AVAILABILITY: Sequences are available from the Gene Expression Omnibus ( https://www.ncbi.nlm.nih.gov/geo/ ) with accession number of GSE224042.

Challenges and recent advances in MOF-based gas separation membranes.

Membrane-based gas separation, characterized by a small footprint, low energy consumption and no pollution, has gained widespread attention as an environmentally friendly alternative to traditional gas separation. Metal-organic-frameworks (MOFs) are considered to be one of the most promising membrane-based gas separation materials because of their large specific surface area and high porosity. One of the hottest studies at the moment is how to utilize the characteristics of MOFs to prepare higher performance gas separation membranes. This paper provides a review of gas separation membranes used in recent years. Firstly, the synthesis methods of MOFs and MOF membranes are briefly introduced. Then, methods to improve the membrane properties of MOFs are described in detail, and include applications of lamellar MOFs, ionic liquid (IL) spin coating, functionalization of MOFs, defect engineering and mixed fillers. In addition, the challenges of MOF-based gas separation membranes are presented, including pore size, environmental disturbances, plasticization, interfacial compatibility, and so on. Finally, based on the current development status of the MOF membranes, the development prospects of MOF gas separation membranes are discussed. It is hoped to provide reliable and complete ideas for researchers to prepare high-performance gas separation membranes in the future.

Minimally invasive delivery of human umbilical cord-derived mesenchymal stem cells by an injectable hydrogel via Diels-Alder click reaction for the treatment of intrauterine adhesions.

Intrauterine adhesions (IUA) are the most common cause of uterine infertility, and conventional treatments have not consistently achieved satisfactory pregnancy rates. Stem cell therapy shows promising potential for the clinical treatment of IUA. Although various advanced biomaterials have been designed for delivering stem cells to the uterine cavity, there remain significant challenges, particularly in devising therapeutic strategies for clinical application that minimize surgical incisions and conform to the intricate structure of uterine cavity. Herein, an injectable hydrogel loaded with human umbilical cord-derived mesenchymal stem cells (UCMSCs) was synthesized via the Diels-Alder click reaction for endometrial regeneration and fertility restoration, exhibiting suitable mechanical properties, good biocompatibility, and desirable degradation properties. Notably, this hydrogel permitted minimally invasive administration and integrated seamlessly with surrounding tissue. Our study revealed that the UCMSCs-laden injectable hydrogel enhanced cell proliferation, migration, angiogenesis, and exhibited anti-fibrotic effects in vitro. The implantation of this hydrogel significantly facilitated endometrium regeneration and restored fertility in a rat endometrial damage model. Mechanistically, in vivo results indicated that the UCMSCs-laden injectable hydrogel effectively promoted macrophage recruitment and facilitated M2 phenotype polarization. Collectively, this hydrogel demonstrated efficacy in regenerating damaged endometrium, leading to the restoration of fertility. Consequently, it holds promise as a potential therapeutic strategy for endometrial damage and fertility decline arising from intrauterine adhesions. STATEMENT OF SIGNIFICANCE: Severe endometrial traumas frequently lead to intrauterine adhesions and subsequent infertility. Stem cell therapy shows promising potential for the clinical treatment of IUA; however, challenges remain, including low delivery efficiency and compromised stem cell activity during the delivery process. In this study, we fabricated an injectable hydrogel loaded with UCMSCs via the Diels-Alder click reaction, which exhibited unique bioorthogonality. The in situ-gelling hydrogels could be introduced through a minimally invasive procedure and adapt to the intricate anatomy of the uterus. The UCMSCs-laden injectable hydrogel promoted endometrial regeneration and fertility restoration in a rat endometrial damage model, efficaciously augmenting macrophage recruitment and promoting their polarization to the M2 phenotype. The administration of UCMSCs-laden injectable hydrogel presents a promising therapeutic strategy for patients with severe intrauterine adhesion.

Single-dose Administration of Recombinant Human Thrombopoietin Enhances Survival and Hematopoietic Reconstruction in Canines Irradiated with 3 Gy Gamma Radiation.

We conducted this study to investigate the radioprotective effects of recombinant human thrombopoietin (rhTPO) on beagle dogs irradiated with 3.0 Gy 60Co gamma rays. Fifteen healthy adult beagles were randomly assigned to a control group with alleviating care, and 5 and 10 µg/kg rhTPO treatment group. All animals received total-body irradiation using 60Co γ-ray source at a dose of 3.0 Gy (dose rate was 69.1 cGy/min). The treatment group received intramuscular injection of rhTPO 5 and 10 µg/kg at 2 h postirradiation, and the control group was administrated the same volume of normal saline. The survival rate, clinical signs, peripheral hemogram, serum biochemistry, and histopathological examination of animals in each group were assessed. Single administration of 10 µg/kg rhTPO at 2 h postirradiation promoted the recovery of multilineage hematopoiesis and improved the survival rate of beagles irradiated with 3 Gy 60Co γ rays. The administration of 10 µg/kg rhTPO alleviated fever and bleeding, reduced the requirement for supportive care, and may have mitigated multiple organ damage.

TET3-overexpressing macrophages promote endometriosis.

Endometriosis is a debilitating, chronic inflammatory disease affecting ~10% of reproductive age women worldwide with no cure. While macrophages have been intrinsically linked to the pathophysiology of endometriosis, targeting them therapeutically has been extremely challenging due to their high heterogeneity and because these disease-associated macrophages (DAMs) can be either pathogenic or protective. Here, we reported identification of pathogenic macrophages characterized by TET3 overexpression in human endometriosis lesions. We showed that factors from the disease microenvironment upregulated TET3 expression transforming macrophages into pathogenic DAMs. TET3 overexpression stimulated pro-inflammatory cytokine production via a feedback mechanism involving inhibition of let-7 miRNA expression. Remarkably, these cells relied on TET3 overexpression for survival, hence vulnerable to TET3 knockdown. We demonstrated that Bobcat339, a synthetic cytosine derivative, triggered TET3 degradation both in human and mouse macrophages. This degradation was dependent on a VHL E3 ubiquitin ligase whose expression was also upregulated in TET3-overexpressing macrophages. Furthermore, depleting TET3-overexpressing macrophages either through myeloid-specific Tet3 ablation or using Bobcat339 strongly inhibited endometriosis progression in mice. Our results defined TET3-overexpressing macrophages as key pathogenic contributors to and attractive therapeutic targets for endometriosis. Our findings may also be applicable to other chronic inflammatory diseases where DAMs have important roles.