Inhibitory Regulation of FOXO1 in PPARδ Expression Drives Mitochondrial Dysfunction and Insulin Resistance.

Forkhead box O1 (FOXO1) regulates muscle growth, but the metabolic role of FOXO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FOXO1 in skeletal muscle, we generated skeletal muscle-specific Foxo1 inducible knockout (mFOXO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFOXO1 iKO mice and assessed the correlation between FOXO1 and mitochondria-related protein in the skeletal muscle of patients with diabetes. Obese mFOXO1 iKO mice exhibited improved mitochondrial respiratory capacity, which was followed by attenuated insulin resistance, enhanced fatty acid oxidation, and improved skeletal muscle exercise capacity. Transcriptional inhibition of FOXO1 in peroxisome proliferator-activated receptor δ (PPARδ) expression was confirmed in skeletal muscle, and deletion of PPARδ abolished the beneficial effects of FOXO1 deficiency. FOXO1 protein levels were higher in the skeletal muscle of patients with diabetes and negatively correlated with PPARδ and electron transport chain protein levels. These findings highlight FOXO1 as a new repressor in PPARδ gene expression in skeletal muscle and suggest that FOXO1 links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ.

In Situ Tetraalkylammonium Ligand Engineering of Organic-Inorganic Hybrid Perovskite Nanoparticles for Enhancing Long-Term Stability and Optical Tunability.

Organic-inorganic hybrid perovskite nanoparticles (OIHP NPs) have attracted scientific attention owing to their efficient photoluminescence with optical tunability, which is highly advantageous for optoelectronic applications. However, the limited long-term stability of OIHP NPs has significantly hindered their practical application. Despite several synthetic strategies and encapsulation methods to stabilize OIHP NPs, complicated multi-step procedures are often required. In this study, we introduce an in situ ligand engineering method for stabilizing and controlling the optical properties of OIHP NPs using tetraalkylammonium (TAA) halides with various molecular structures at different concentrations. Our one-pot ligand engineering substantially enhanced the stability of the OIHP NPs without post-synthetic processes. Moreover, in certain cases, approximately 90% of the initial photoluminescence (PL) intensity was preserved even after a month under ambient conditions (room temperature, 20-50% relative humidity). To determine the role of ligand engineering in stabilizing the OIHP NPs, the surface binding properties of the TAA ligands were thoroughly analyzed using Raman spectroscopy. Specifically, the permanent positive charge of the TAA cations and consequent effective electrostatic interactions with the surfaces of the OIHP NPs are pivotal for preserving the initial PL intensity. Our investigation is beneficial for developing OIHP nanomaterials with improved stability and controlled photoluminescence for various optoelectronic applications, such as light-emitting devices, photosensitizers, photodetectors, photocatalysis, and solar cells.

Banhasasim-Tang Ameliorates Spatial Memory by Suppressing Oxidative Stress through Regulation of ERK/p38 Signaling in Hippocampus of Mice.

Since ancient times, Banhasasim-tang (BHS) has been used to treat functional dyspepsia in East Asia. Here, we aimed to determine the protective action of BHS on hippocampal neurons against oxidative stress. We investigated the functional effect of BHS on a scopolamine-induced mouse model, and molecular analysis was performed in glutamate-induced HT22 cells. We observed that BHS administration ameliorated memory dysfunction in scopolamine-treated mice. BHS administration also increased neuronal survival and acetylcholine activity and phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus of mice. In hippocampal cells, BHS treatment rescued glutamate-induced cytotoxicity, apoptosis, and oxidative stress. We observed an increase of HO-1 and a decrease of Nrf2 protein expression in glutamate-induced oxidative stress; however, the expression level of these proteins was significantly rescued by BHS treatment. BHS treatment also regulated phosphorylation of p38, p53, ERK, and CREB. Therefore, our data indicated that BHS may reduce oxidative stress through regulation of ERK-CREB and p38-p53 signaling in the hippocampus, resulting in decreased neuronal damage and improved memory in rodent models of neurodegenerative disease.

Construction of 2D Interdigitated Polyrotaxane Layers and their Transformation to a 3D Polyrotaxane by a Photocycloaddition Reaction between Wheels.

Following the pioneering work of Sauvage and Stoddart on rotaxanes, construction of higher dimensional polyrotaxanes in metal-organic frameworks (MOFs) via a modified protocol is challenging. We present the formation of a two-dimensional (2D) polyrotaxane and its conversion to a three-dimensional (3D) polyrotaxane MOF via a photoreaction between interdigitated "olefin wheels". For this purpose, a 2-fold entangled 2D MOF [Pb2(bpp)(sdc)2] (1), showing a 2D + 2D → 2D polyrotaxane motif, has been synthesized from the solvothermal reaction of lead(II) nitrate, 3,3'-stilbenedicarboxylic acid (H2sdc) containing an olefin group, and 1,4-bis(4-pyridyl)piperazine (bpp). The single-crystal X-ray diffraction analysis of 1 revealed that the adjacent entangled 2D layers are interdigitated, with the separation of 3.72 Šbetween C═C bond pairs in adjacent layers satisfying Schmidt's criteria for the occurrence of a [2 + 2] photocycloaddition reaction. Irradiation of the single crystals of 1 under UV light resulted in formation of a 3D polyrotaxane, [Pb2(bpp)(rctt-tccb)]n (2), due to a [2 + 2] photocycloaddition reaction between two wheels via a single-crystal to single-crystal transformation. The photocycloaddition and partial thermal cleavage reaction between 1 and 2 were confirmed by 1H NMR and powder X-ray diffraction (PXRD) in solution and the solid state, respectively. The present approach could contribute to the understanding of the construction of higher dimensional polyrotaxanes which are not accessible by the traditional routes.

Pillar[5]-bis-trithiacrown: Influence of Host-Guest Interactions on the Formation of Coordination Networks.

A pillar[5]-bis-trithiacrown (L) capable of metal binding and organic guest threading simultaneously has been employed, and the influence of dinitrile guests [CN(CH2)nCN (n = 2-6: abbreviated C2-C6)] on the coordination behaviors has been investigated. When the ditopic ligand L was reacted with HgCl2 in the presence of the C2-C6 guests, the shorter guests C2 and C3 afforded a two-dimensional coordination polymer [Hg7Cl14(C2@L)2]n (1) and a one-dimensional coordination polymer [(Hg3Cl6)2(C3@L)2]n (2), respectively. In 1 and 2, each dinitrile guest threads into the pillararene cavity to form a C2@L or C3@L unit via the host-guest interaction. Further linking of these units by exocyclic Hg-S bonds and anion coordination lead to the formation of coordination products with different dimensionalities. While the use of the longer guests C4-C6 under the same reactions yielded a discrete dimercury(II) complex 3, [Hg2Cl4(CH3CN@L)] which contains one acetonitrile solvent molecule because the longer dinitriles do not serve as effective guests. In the NMR and UV-vis studies, the association constants (log K1:1) for the host-guest interactions of L with the dinitrile guests are C2 (4.75) > C3 (4.17) ≫ C4 (2.85) > C5 (2.45) > C6 (too small), indicating that the shorter guests C2 or C3 interact more strongly than longer ones due to the confined interior space of L. Taken collectively, the C2 and C3 guests with proper size-matching promote the formation of coordination polymers and vice versa, suggesting that the guest size could be a controlling factor.

Correction: Metallosupramolecules of pillar[5]-bis-trithiacrown including a mercury(II) iodide ion-triplet complex.

Correction for 'Metallosupramolecules of pillar[5]-bis-trithiacrown including a mercury(ii) iodide ion-triplet complex' by Mingyeong Shin et al., Chem. Commun., 2020, DOI: 10.1039/d0cc03902k.

Metallosupramolecules of pillar[5]-bis-trithiacrown including a mercury(ii) iodide ion-triplet complex.

A combination of pillar[5]-bis-trithiacrown (L) and mercury(ii) halides afforded a monomer complex (Cl--form), a 1-D coordination polymer (Br--form) and a supramolecular ion-triplet complex [(I·Hg·I)@L] (I--form). In the ion-triplet complex, the host encapsulates the (I--Hg2+-I-) entity via Hg2+π and C-HI- interactions, reflecting geometrical complementarity.

High-throughput and all-solution phase African Swine Fever Virus (ASFV) detection using CRISPR-Cas12a and fluorescence based point-of-care system.

Here we report the development of a high throughput, all-solution phase, and isothermal detection system for African Swine Fever Virus (ASFV). CRISPR-Cas12a programmed with a CRISPR RNA (crRNA) is used to detect ASFV target DNA. Upon ASFV DNA binding, the Cas12a/crRNA/ASFV DNA complex becomes activated and degrades a fluorescent single stranded DNA (ssDNA) reporter present in the assay. We combine this powerful CRISPR-Cas assay with a fluorescence-based point-of-care (POC) system for rapid and accurate virus detection. Without nucleic acid amplification, a detection limit of 1 pM is achieved within 2 h. In addition, the ternary Cas12a/crRNA/ASFV DNA complex is highly stable at physiological temperature and continues to cleave the ssDNA reporter even after 24 h of incubation, resulting in an improved detection limit of 100 fM. We show that this system is very specific and can differentiate nucleic acid targets with closely matched sequences. The high sensitivity and selectivity of our system enables the detection of ASFV in femtomolar range. Importantly, this system features a disposable cartridge and a sensitive custom designed fluorometer, enabling compact and simple ASFV detection, intended for low resource settings.

Ischemia-induced Netrin-4 promotes neovascularization through endothelial progenitor cell activation via Unc-5 Netrin receptor B.

Endothelial progenitor cells (EPCs) promote neovascularization and tissue repair by migrating to vascular injury sites; therefore, factors that enhance EPC homing to damaged tissues are of interest. Here, we provide evidence of the prominent role of the Netrin-4 (NTN4)-Unc-5 Netrin receptor B (UNC5B) axis in EPC-specific promotion of ischemic neovascularization. Our results showed that NTN4 promoted the proliferation, chemotactic migration, and paracrine effects of small EPCs (SEPCs) and significantly increased the incorporation of large EPCs (LEPCs) into tubule networks. Additionally, NTN4 prominently augmented neovascularization in mice with hindlimb ischemia by increasing the homing of exogenously transplanted EPCs to the ischemic limb and incorporating EPCs into vessels. Moreover, silencing of UNC5B, an NTN4 receptor, abrogated the NTN4-induced cellular activities of SEPCs in vitro and blood-flow recovery and neovascularization in vivo in ischemic muscle by reducing EPC homing and incorporation. These findings suggest NTN4 as an EPC-based therapy for treating angiogenesis-dependent diseases.

Selenoprotein W deficiency does not affect oxidative stress and insulin sensitivity in the skeletal muscle of high-fat diet-fed obese mice.

Selenoprotein W (SelW) is a selenium-containing protein with a redox motif found abundantly in the skeletal muscle of rodents. Previous in vitro studies suggest that SelW plays an antioxidant role; however, relatively few in vivo studies have addressed the antioxidant role of SelW. Since oxidative stress is a causative factor for the development of insulin resistance in obese subjects, we hypothesized that if SelW plays a role as an antioxidant, SelW deficiency could aggravate the oxidative stress and insulin resistance caused by a high-fat diet. SelW deficiency did not affect insulin sensitivity and H2O2 levels in the skeletal muscle of control diet-fed mice. SelW levels in the skeletal muscle were decreased by high-fat diet feeding for 12 wk. High-fat diet induced obesity and insulin resistance and increased the levels of H2O2 and oxidative stress makers, which were not affected by SelW deficiency. High-fat diet feeding increased the expression of antioxidant enzymes; however, SelW deficiency did not affect the expression levels of antioxidants. These results suggest that SelW does not play a protective role against oxidative stress and insulin resistance in the skeletal muscle of high-fat diet-fed obese mice.

Beta-lapachone attenuates immobilization-induced skeletal muscle atrophy in mice.

Skeletal muscle atrophy reduces quality of life and increases morbidity and mortality in patients with chronic conditions. Oxidative stress is a key factor contributing to skeletal muscle atrophy by altering both protein synthesis and protein degradation pathways. Beta-lapachone (Beta-L) is known to act as a pro-oxidant in cancer cells but suppresses oxidative stress in normal cells and tissues. In the present study, we examined whether Beta-L (100 mg/kg body weight) prevents immobilization-induced skeletal muscle atrophy in male C57BL/6N mice. Skeletal muscle atrophy was induced by immobilization of left hindlimbs for two weeks, and right hindlimbs were used as controls. The muscle weights of gastrocnemius (0.132 ±â€¯0.003 g vs. 0.115 ±â€¯0.003 g in Beta-L and SLS, respectively, p < 0.01) and tibialis anterior (0.043 ±â€¯0.001 vs. 0.027 ±â€¯0.002 in Beta-L and SLS, respectively, p < 0.001) were significantly heavier in Beta-L-treated mice than that in SLS-treated mice in immobilization group, which was accompanied by improved skeletal muscle function as tested by treadmill exhaustion and grip strength test. Immobilization increased H2O2 levels, while Beta-L treatment normalized such levels (1.6 ±â€¯0.16 µM vs. 2.7 ±â€¯0.44 µM in Beta-L and vehicle, respectively, p < 0.05). Oxidative stress makers were also normalized by Beta-L treatment. Protein synthesis signaling pathways were unaltered in the case of both immobilization and Beta-L treatment. However, protein catabolic, ubiquitin-proteasomal, and autophagy-lysosomal pathways were stimulated by immobilization and were normalized by Beta-L treatment. Upregulation of transforming growth factor ß and Smad 2/3 after immobilization was significantly diminished by Beta-L treatment. These results suggest that Beta-L attenuates the loss of muscle weight and function induced by immobilization through suppression of oxidative stress.

Placental growth factor regulates the generation of TH17 cells to link angiogenesis with autoimmunity.

Helper T cells actively communicate with adjacent cells by secreting soluble mediators, yet crosstalk between helper T cells and endothelial cells remains poorly understood. Here we found that placental growth factor (PlGF), a homolog of the vascular endothelial growth factor that enhances an angiogenic switch in disease, was selectively secreted by the TH17 subset of helper T cells and promoted angiogenesis. Interestingly, the 'angio-lymphokine' PlGF, in turn, specifically induced the differentiation of pathogenic TH17 cells by activating the transcription factor STAT3 via binding to its receptors and replaced the activity of interleukin-6 in the production of interleukin-17, whereas it suppressed the generation of regulatory T cells. Moreover, T cell-derived PlGF was required for the progression of autoimmune diseases associated with TH17 differentiation, including experimental autoimmune encephalomyelitis and collagen-induced arthritis, in mice. Collectively, our findings provide insights into the PlGF-dictated links among angiogenesis, TH17 cell development and autoimmunity.