Hepatic Klf10-Fh1 axis promotes exercise-mediated amelioration of NASH in mice.

Exercise is an effective non-pharmacological strategy for the treatment of nonalcoholic steatohepatitis (NASH), but the underlying mechanism needs further investigation. Kruppel-like factor 10 (Klf10) is a transcriptional factor that is expressed in multiple tissues including liver, whose role in NASH is not well defined. In our study, exercise induces hepatic Klf10 expression through the cAMP/PKA/CREB pathway. Hepatocyte-specific knockout of Klf10 (Klf10LKO) increases lipid accumulation, cell death, inflammation and fibrosis in NASH diet-fed mice and reduces the protective effects of treadmill exercise against NASH, while hepatocyte-specific overexpression of Klf10 (Klf10LTG) works in concert with exercise to reduce NASH in mice. Mechanistically, Klf10 promotes the expression of fumarate hydratase 1 (Fh1), thereby reducing fumarate accumulation in hepatocytes. This decreases the trimethyl (me3) levels of histone 3 lysine 4 (H3K4me3) on lipogenic genes promoters to attenuate lipogenesis, thus ameliorating free fatty acids (FFAs)-induced hepatocytes steatosis, apoptosis, insulin resistance and blunting dysfunctional hepatocytes-mediated activation of macrophages and hepatic stellate cells. Therefore, by regulating the Fh1/fumarate/H3K4me3 pathway, Klf10 acts as a downstream effector of exercise to combat NASH.

The comparison of corneal higher-order aberration and surgically induced astigmatism between the clear corneal incision and the limbus tunnel incision of posterior chamber implantable collamer lens implantation.

BACKGROUND: This study aimed to compare the corneal high-order aberrations and surgically induced astigmatism between the clear corneal incision and limbus tunnel incision for posterior chamber implantable collamer lens (ICL/TICL) implantation. METHODS: A total of 127 eyes from 73 myopic patients underwent ICL V4c implantation, with 70 eyes receiving clear corneal incisions and 57 eyes receiving limbus tunnel incisions. The anterior and back corneal surfaces were measured and the Root Mean Square of all activated aberrations (TRMS) was calculated, including higher-order aberration (HOA RMS), spherical aberration Z40, coma coefficients (Coma RMS) Z3-1 Z31, and surgically induced astigmatism (SIA). The measurements were taken preoperatively and postoperatively at 1 day, 1 week, and 1, 3, and 6 months. In this study, the corneal higher-order aberration was estimated as the Zernike coefficient calculated up to 5th order. The measurements were taken at a maximum diameter of 6.5 mm using Pentacam. RESULTS: One week after the operation, the corneal back Z31 of the clear corneal incision group was 0.06 ± 0.06, while the limbus tunnel incision group showed a measurement of 0.05 ± 0.06 (p = 0.031). The corneal back Z40 of the clear corneal incision group was -0.02 ± 0.25, compared to -0.04 ± 0.21 in the limbus tunnel incision group (p = 0.01). One month after the operation, the corneal back SIA of the clear corneal incision group was 0.11 ± 0.11, compared to 0.08 ± 0.11of the limbus tunnel incision group (p = 0.013), the corneal total SIA of the clear corneal incision group was 0.33 ± 0.30, compared to 0.15 ± 0.16 in the limbus tunnel incision group (p = 0.004); the clear corneal incision group exhibited higher levels of back astigmatism and total SIA than the limbus tunnel incision in the post-operation one month period. During the 6- month post-operative follow-up period, no significant difference in Z31, Z40, and other HOA RMS data was observed between the two groups. The total SIA of the corneal incision group and the limbus tunnel incision group were 0.24 ± 0.14 and 0.33 ± 0.32, respectively (p = 0.393), showing no significant difference between the two groups 6 months after the operation. CONCLUSION: Our data showed no significant difference in the high-order aberration and SIA between clear corneal incision and limbus tunnel incision up to 6 months after ICL-V4c implantation.

Cdo1-Camkk2-AMPK axis confers the protective effects of exercise against NAFLD in mice.

Exercise is an effective non-pharmacological strategy for ameliorating nonalcoholic fatty liver disease (NAFLD), but the underlying mechanism needs further investigation. Cysteine dioxygenase type 1 (Cdo1) is a key enzyme for cysteine catabolism that is enriched in liver, whose role in NAFLD remains poorly understood. Here, we show that exercise induces the expression of hepatic Cdo1 via the cAMP/PKA/CREB signaling pathway. Hepatocyte-specific knockout of Cdo1 (Cdo1LKO) decreases basal metabolic rate of the mice and impairs the effect of exercise against NAFLD, whereas hepatocyte-specific overexpression of Cdo1 (Cdo1LTG) increases basal metabolic rate of the mice and synergizes with exercise to ameliorate NAFLD. Mechanistically, Cdo1 tethers Camkk2 to AMPK by interacting with both of them, thereby activating AMPK signaling. This promotes fatty acid oxidation and mitochondrial biogenesis in hepatocytes to attenuate hepatosteatosis. Therefore, by promoting hepatic Camkk2-AMPK signaling pathway, Cdo1 acts as an important downstream effector of exercise to combat against NAFLD.

Krüppel-like factor 10 (KLF10) as a critical signaling mediator: Versatile functions in physiological and pathophysiological processes.

Krüppel-like factor 10 (KLF10), also known as TGFß-inducible early gene-1 (TIEG1), was first found in human osteoblasts. Early studies show that KLF10 plays an important role in osteogenic differentiation. Through decades of research, KLF10 has been found to have complex functions in many different cell types, and its expression and function is regulated in multiple ways. As a downstream factor of transforming growth factor ß (TGFß)/SMAD signaling, KLF10 is involved in various biological functions, including glucose and lipid metabolism in liver and adipose tissue, the maintenance of mitochondrial structure and function of the skeletal muscle, cell proliferation and apoptosis, and plays roles in multiple disease processes, such as nonalcoholic steatohepatitis (NASH) and tumor. Besides, KLF10 shows gender-dependent difference of regulation and function in many aspects. In this review, the biological functions of KLF10 and its roles in disease states is updated and discussed, which would provide new insights into the functional roles of KLF10 and a clearer view of potential therapeutic strategies by targeting KLF10.

The functional role of Higd1a in mitochondrial homeostasis and in multiple disease processes.

Higd1a is a conserved gene in evolution which is widely expressed in many tissues in mammals. Accumulating evidence has revealed multiple functions of Higd1a, as a mitochondrial inner membrane protein, in the regulation of metabolic homeostasis. It plays an important role in anti-apoptosis and promotes cellular survival in several cell types under hypoxic condition. And the survival of porcine Sertoli cells facilitated by Higd1a helps to support reproduction. In some cases, Higd1a can serve as a sign of metabolic stress. Over the past several years, a considerable amount of studies about how tumor fate is determined and how cancerous proliferation is regulated by Higd1a have been performed. In this review, we summarize the physiological functions of Higd1a in metabolic homeostasis and its pathophysiological roles in distinct diseases including cancer, nonalcoholic fatty liver disease (NAFLD), type II diabetes and mitochondrial diseases. The prospect of Higd1a with potential to preserve mammal health is also discussed. This review might pave the way for Higd1a-based research and application in clinical practice.

Central toxic keratopathy after small incision lenticule extraction surgery:A case report.

PURPOSE: To report a rare case of central toxic keratopathy after small incision lenticule extraction surgery (SMILE). CASE REPORT: A 38-year-old female presented with visual loss 10 days after undergoing SMILE. Subsequently, transparent band keratopathy was protruded in the left cornea and corneal cap opacity was increased, which was accompanied by hyperopic shift and corneal thinning. The patient's condition rapidly improved with the administration of prednisolone acetate and autologous serum, with significant resolution of the transparent band keratopathy within 5 weeks of treatment initiation and subsequent complete visual recovery. CONCLUSIONS: Central toxic keratopathy is a severe complication after undergoing SMILE, which might be effectively treated using with steroids and autologous serum.

Higd1a facilitates exercise-mediated alleviation of fatty liver in diet-induced obese mice.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common liver disease. Exercise is an effective strategy against NAFLD, but its underlying molecular mechanism is not completely understood. METHODS: Higd1a, a mitochondrial inner membrane protein, was knocked down or overexpressed in mice livers by tail vein injection of adeno-associated virus (AAV) vectors. High fat diet-induced obese mice were subjected to treadmill training. Alpha mouse liver 12 (AML12) cells were used for in vitro studies. RESULTS: Higd1a was upregulated in mice livers after treadmill exercise training. Knockdown of Higd1a in diet-induced obese mice livers impaired exercise-mediated alleviation of hepatic steatosis, liver injury and inflammation. On the contrary, hepatic overexpression of Higd1a ameliorated fatty liver, liver injury and inflammation in synergy with exercise. Mechanistically, deficiency of Higd1a in hepatocytes promoted free fatty acids (FFAs)-induced apoptosis and oxidative stress, and elevated the cytosolic level of oxidized mitochondrial DNA (ox-mtDNA) to activate NLRP3 inflammasome and JNK signaling, leading to decreased expression of critical genes involved in fatty acid oxidation (FAO), such as Ppara, Cpt1a and Acadm. Overexpression of Higd1a in hepatocytes blunted the above effects, which ultimately increased FAO genes expression and alleviated fat accumulation in hepatocytes. CONCLUSION: These results identify a Higd1a-mediated inhibition of cytosolic ox-mtDNA/NLRP3 inflammasomes/JNK pathway that facilitates exercise-mediated alleviation of hepatosteatosis.

hUC-MSCs: evaluation of acute and long-term routine toxicity testing in mice and rats.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are present in human umbilical connective tissue and can differentiate into various cell types. Our previous studies have proved that hUC-MSCs do not lead to allergies and tumorigenesis. In the present study, the acute and long-term toxicity of hUC-MSCs in mice and rats was evaluated. The acute toxicity of hUC-MSCs was assessed in 8-week-old mice receiving two caudal intravenous (i.v.) injections of hUC-MSCs at the maximum tolerated dose of 1.5 × 107 cells/kg with an interval of 8 h and the observation period sustained for 14 days. For the long-term toxicity evaluation, rats were randomly divided into control, low-dose (3.0 × 105 cells/kg), mid-dose (1.5 × 106 cells/kg), and high-dose (7.5 × 106 cells/kg) groups, which were treated with hUC-MSCs via a caudal i.v. injection every 3 days for 90 days. Weight and food intake evaluation was performed for all rats for 2 weeks after the hUC-MSC administration. The animals were then sacrificed for hematological, blood biochemical, and pathological analyses, as well as organ index determination. We observed no obvious acute toxicity of hUC-MSCs in mice at the maximum tolerated dose. Long-term toxicity tests in rats showed no significant differences between HUC-MSC-treated and control groups in the following parameters: body weight, hematological and blood biochemical parameters, and histopathologic changes in the heart, liver, kidneys, and lungs. This study provides evidence of the safety of i.v. hUC-MSCs infusion for future clinical therapies.

AuAg nanocages/graphdiyne for rapid elimination and detection of trace pathogenic bacteria.

We prepared a biocompatible AuAg nanocages/graphdiyne @ polyethylene glycol (AuAg/GDY@PEG) composite. The combination of AuAg and GDY to obtain a synergistically enhanced photothermal effect, and the antibacterial effect of GDY and AuAg are used in combined anti-infective therapy. The in vitro antibacterial activity of AuAg/GDY@PEG was investigated, showing an impressive broad-spectrum antibacterial activity with the killing rate > 99.999%. Based on the photothermal conversion ability of AuAg/GDY@PEG, a simple photothermal immunoassay for pathogenic bacteria was successfully established. Sandwich immune response was performed on a microporous plate, the microplate containing the antibody binds specifically to the bacterium being tested, which then binds to the material with the antibody on its surface, and the signal was a change in temperature under 808 nm near-infrared light. The limit of detection (LOD) for S. typhimurium detection is 103 CFU mL-1, with a range of 103-107 CFU mL-1. This method is accurate, rapid and low-cost, which can be used for on-site detection of pathogenic bacteria in food.

Expression of Collagen (Types I, III, and V), HSP47, MMP-2, and TIMP-1 in Retrobulbar Adipose Tissue of Patients with Thyroid-Associated Orbitopathy.

OBJECTIVE: This study aimed to investigate the expression of collagen (types I, III, and V), heat shock protein 47 (HSP47), matrix metalloproteinase-2 (MMP-2), and tissue inhibitors of metalloproteinase-1 (TIMP-1) in the retrobulbar adipose tissues of patients with thyroid-associated orbitopathy (TAO). MATERIALS AND METHODS: The retrobulbar adipose tissues were collected from 4 TAO patients undergoing orbital decompression and 4 ocular enucleation patients with atrophic eyeball caused by ocular trauma between May 2019 and September 2019. Masson staining was performed to analyze the differences in collagen expression and degree of histologic fibrosis in each sample. The protein expressions of collagen (types I, III, and V), HSP47, MMP-2, and TIMP-1 were determined by western blotting. The data of western blotting were analyzed using SPSS version 17.0, with independent t-tests. RESULTS: The results of Masson staining showed that the expression of collagen fibers in the TAO group was significantly higher than that in the control group, and the fibers were diffuse and irregular in distribution. The expression level of collagen (types I, III, and V), HSP47, MMP-2, and TIMP-1 in the TAO group were significantly higher than that in the control group (P < 0.05). CONCLUSION: The proliferation and fibrosis of retrobulbar adipose tissue in TAO patients might be related to the increased expression of collagen (types I, III, and V) and HSP47 and decreased degradation of extracellular matrix.