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.

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.

Cysteine dioxygenase type 1 (CDO1): Its functional role in physiological and pathophysiological processes.

Cysteine dioxygenase type 1 (CDO1), belonging to the mammalian non-heme Fe(II) dioxygenases family, is a key enzyme for cysteine catabolism. Its activity and expression is regulated through multiple mechanisms. CDO1 is involved in a spectrum of physiological processes including lipid metabolism, adipogenesis, osteoblastic differentiation, redox homeostasis, fertility, bile acid metabolism, sulfide metabolism, and organismal growth and development. Many of these processes are regulated directly or indirectly by CDO1-mediated metabolism of cysteine. In pathophysiological processes, the degree of CDO1 promoter methylation is closely related to the progression and malignancy of tumors, and overexpression of CDO1 will promote ferroptosis of cancer cells. Moreover, CDO1 may ameliorate metabolic disorders through the taurine-mediated improvement of lipid metabolism and insulin sensitivity and improve neurodegenerative diseases by regulating cysteine level. Therefore, elucidation of the mechanisms underlying the role of CDO1 would provide a clearer view of the therapeutic potential and possible risks of targeting this important enzyme.

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.

Chronic social comparison elicits depression- and anxiety-like behaviors and alterations in brain-derived neurotrophic factor expression in male rats.

Social comparison is a fundamental human characteristic; however, long-term social comparison may induce psychological stress and can lead to depression and anxiety. Recent studies have shown that nonhuman primates compare themselves with others; however, no studies have investigated whether social comparisons exist among rodents. In the present study, we established a rat model of social comparison. This model was subsequently used to examine the effects of the differential environment of a partner on depression- and anxiety-like behaviors in male rats, as well as to assess the changes in serum, medial prefrontal cortex (mPFC), and dorsal hippocampus brain-derived neurotrophic factor (BDNF) levels induced by long-term social comparison. Compared to rats whose partners were exposed to the same environment, rats whose partners were exposed to two combined enriched environmental stimuli for 14 days showed significantly decreased social novelty preference and sucrose consumption. No anxiety-like behaviors were observed. Rats whose partners were exposed to one enriched environment for 31 days showed significantly increased immobility time in the forced swimming test, and significantly decreased time spent in the center area in the open-field test. Further, rats whose partners were exposed to one enriched environment for 31 days showed lower BDNF levels in the mPFC and dorsal hippocampus, but not following partner exposure for 14 days. These results suggest that social comparisons exist in rats and can induce psychosocial stress and other negative affect. This model will not only provide the possibility to reveal the neurobiological basis of the emotional impact of social comparison, but could also be used to confirm the conservative evolutionary characteristics of social comparison as a behavioral attribute.

Beyond Boolean: Ternary networks and dynamics.

Boolean networks introduced by Kauffman, originally intended as a prototypical model for gaining insights into gene regulatory dynamics, have become a paradigm for understanding a variety of complex systems described by binary state variables. However, there are situations, e.g., in biology, where a binary state description of the underlying dynamical system is inadequate. We propose random ternary networks and investigate the general dynamical properties associated with the ternary discretization of the variables. We find that the ternary dynamics can be either ordered or disordered with a positive Lyapunov exponent, and the boundary between them in the parameter space can be determined analytically. A dynamical event that is key to determining the boundary is the emergence of an additional fixed point for which we provide numerical verification. We also find that the nodes playing a pivotal role in shaping the system dynamics have characteristically distinct behaviors in different regions of the parameter space, and, remarkably, the boundary between these regions coincides with that separating the ordered and disordered dynamics. Overall, our framework of ternary networks significantly broadens the classical Boolean paradigm by enabling a quantitative description of richer and more complex dynamical behaviors.

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.

Exercise-Mediated Browning of White Adipose Tissue: Its Significance, Mechanism and Effectiveness.

As a metabolic organ, adipose tissue plays an important role in regulating metabolism. In adults, most adipose tissue is white adipose tissue (WAT), and excessive expansion of WAT will lead to obesity. It is worth noting that exercise can reduce the fat mass. There is also a lot of evidence that exercise can promote the browning of WAT, which is beneficial for metabolic homeostasis. Multiple factors, including reactive oxygen species (ROS), metabolites, nervous system, exerkines and lipolysis can facilitate exercise-mediated browning of WAT. In this review, the roles and the underlying mechanisms of exercise-mediated browning of WAT are summarized. The effects of different styles of exercise on the browning of WAT are also discussed, with the aim to propose better exercise strategies to enhance exercise-mediated browning of WAT, so as to promote metabolic health. Finally, the different reactivity of WAT at different anatomical sites to exercise-mediated browning is reviewed, which may provide potential suggestion for people with different fat loss needs.

[Bisphosphonate-related osteonecrosis of the jaw complicated with wrist scaphoid osteomyelitis: a case report].

Bisphosphonates can directly inhibit osteoclasts, which may lead to increased bone density, reduced blood flow, and osteonecrosis of the jaw. Bisphosphonate-related osteonecrosis is usually observed in the jaw bone. In this article, we report a patient with bisphosphonate-related osteonecrosis of the jaw (BRONJ) complicated with wrist scaphoid osteomyelitis. Furthermore, we introduce the pathogenesis, treatment, and prevention of BRONJ.

Role of TGF­ß1 expressed in bone marrow­derived mesenchymal stem cells in promoting bone formation in a rabbit femoral defect model.

Bone defects represent a major clinical and socioeconomic problem without suitable treatment options. Previous studies have shown that transforming growth factor ß1 (TGF­ß1) is important in the development of various diseases. The present study aimed to investigate the therapeutic potential of rabbit bone marrow­derived mesenchymal stem cells (BMSCs) expressing TGF­ß1 in the treatment of rabbit femoral defects. First, rabbit BMSCs were identified and cultured. TGF­ß1 was then stably overexpressed in the rabbit BMSCs by lentivirus transfection, which was expressed at a high level in the femoral defects treated with TGF­ß1­overexpressing BMSCs, compared with PBS­treated controls. In addition, the TGF­ß1­overexpressing BMSCs promoted new bone formation in the rabbit femoral defect model, and increased the expression of bone­related markers at week 2 and week 6. Therefore, the study demonstrated that BMSCs overexpressing TGF­ß1 may provide a novel therapeutic option for femoral defects.