ß-hydroxybutyrate: A crucial therapeutic target for diverse liver diseases.

ß-hydroxybutyrate (ß-HB), the most abundant ketone body, is produced primarily in the liver and acts as a substitute energy fuel to provide energy to extrahepatic tissues in the event of hypoglycemia or glycogen depletion. We now have an improved understanding of ß-HB as a signal molecule and epigenetic regulatory factor as a result of intensive research over the last ten years. Because ß-HB regulates various physiological and pathological processes, it may have a potential role in the treatment of metabolic diseases. The liver is the most significant metabolic organ, and the part that ß-HB plays in liver disorders is receiving increasing attention. In this review, we summarize the therapeutic effects of ß-HB on liver diseases and its underlying mechanisms of action. Moreover, we explore the prospects of exogenous supplements and endogenous ketosis including fasting, caloric restriction (CR), ketogenic diet (KD), and exercise as adjuvant nutritional therapies to protect the liver from damage and provide insights and strategies for exploring the treatment of various liver diseases.

[Regulatory effects and mechanisms of branched chain amino acids and metabolic intermediates on insulin resistance].

Branched chain amino acids, as essential amino acids, can be used to synthesize nitrogen-containing compounds and also act as signal molecules to regulate substance metabolism. Studies have shown that the elevated level of branched chain amino acids is closely related to insulin resistance and type 2 diabetes. It can affect insulin signal transduction by activating mammalian target of rapamycin (mTOR) signal pathway, and regulate insulin resistance by damaging lipid metabolism and affecting mitochondrial function. In addition, abnormal catabolism of branched amino acids can lead to the accumulation of metabolic intermediates, such as branched chain α-keto acids, 3-hydroxyisobutyrate and ß-aminoisobutyric acid. Branched chain α-keto acids and 3-hydroxyisobutyrate can induce insulin resistance by affecting insulin signaling pathway and damaging lipid metabolism. ß-aminoisobutyric acid can improve insulin resistance by reducing lipid accumulation and inflammatory reaction and enhancing fatty acid oxidation. This paper systematically reviewed the regulatory effects and mechanisms of branched chain amino acids and their metabolic intermediates on insulin resistance, which will provide a new direction for the prevention and treatment of insulin resistance and type 2 diabetes.

Beneficial Effects and Potential Mechanisms of Tai Chi on Lower Limb Osteoarthritis: A Biopsychosocial Perspective.

Lower limb osteoarthritis (OA) is a chronic, multifactorial disease characterized by impaired physical function, chronic pain, compromised psychological health and decreased social functioning. Chronic inflammation plays a critical role in the pathophysiology of OA. Tai Chi is a type of classical mind-body exercise derived from ancient Chinese martial arts. Evidence supports that Tai Chi has significant benefits for relieving lower limb OA symptoms. Using a biopsychosocial framework, this review aims to elucidate the beneficial effects of Tai Chi in lower limb OA and disentangle its potential mechanisms from the perspective of biology, psychology, and social factors. Complex biomechanical, biochemical, neurological, psychological, and social mechanisms, including strengthening of muscles, proprioception improvement, joint mechanical stress reduction, change of brain activation and sensitization, attenuation of inflammation, emotion modulation and social support, are discussed.

[Lipid metabolic intermediates regulate skeletal muscle insulin sensitivity].

Skeletal muscle is the largest organ of human body, which completes 80%-90% of glucose intake stimulated by insulin, and is closely related to the occurrence and development of insulin resistance (IR). Skeletal muscle is one of the main places of lipid metabolism, and lipid metabolites participate in skeletal muscle metabolism as signal molecules. Fatty acids regulate skeletal muscle insulin sensitivity through insulin signaling pathway, inflammatory response and mitochondrial function. Saturated fatty acids (SFAs) induce insulin resistance by impairing insulin signal transduction, inducing mitochondrial dysfunction and inflammatory response, while unsaturated fatty acids reverse the adverse effects of SFAs and ameliorate IR by enhancing insulin signal transduction and anti-inflammatory effect. In addition, disorders of lipid metabolism in skeletal muscle cause accumulation of harmful metabolic intermediates, such as diacylglycerol, ceramide and long-chain acyl-coenzyme A, and induce IR by directly or indirectly damaging insulin signaling pathway. This article reviews the research progress of lipid metabolic intermediates regulating insulin sensitivity in skeletal muscle, which will help to better understand the pathogenesis of diabetes.

The Tumor-Associated Macrophage-M2-Cancer Cell Complex and the Observation of Heterogeneous Modification of the Morphological Structure of Lung Adenocarcinoma.

OBJECTIVE: The aim of this study was to investigate the effect of the tumor-associated macrophage-m2-cancer cell complex (TAM-M2-CC) on the heterostructural modification of lung adenocarcinoma. METHODS: The expression of CD163+/CD68+ in macrophages in the microenvironment of 161 cases of lung adenocarcinoma was identified by dual immunohistochemistry, and the association between a TAM-M2-CC and its growth, as well as the histological changes in lung adenocarcinoma cells, was assessed. RESULTS: The morphological change of lung adenocarcinoma was related to the number of m2 phenotypes of the macrophages in the microenvironment of lung adenocarcinoma. TAM-M2-CCs were involved in the process of cancer cell recognition, association, and reconstruction. CONCLUSION: The microenvironment of lung adenocarcinoma can affect the phenotypic distinction of macrophages, and the polarization recruitment, zombification, and formation of a TAM-M2-CC, which can also affect the local differentiation of lung adenocarcinoma to a certain extent. The applicable pathogenesis needs to be verified and studied further.

Mechanism of increased risk of insulin resistance in aging skeletal muscle.

As age increases, the risk of developing type 2 diabetes increases, which is associated with senile skeletal muscle dysfunction. During skeletal muscle aging, mitochondrial dysfunction, intramyocellular lipid accumulation, increased inflammation, oxidative stress, modified activity of insulin sensitivity regulatory enzymes, endoplasmic reticulum stress, decreased autophagy, sarcopenia and over-activated renin-angiotensin system may occur. These changes can impair skeletal muscle insulin sensitivity and increase the risk of insulin resistance and type 2 diabetes during skeletal muscle aging. This review of the mechanism of the increased risk of insulin resistance during skeletal muscle aging will provide a more comprehensive explanation for the increased incidence of type 2 diabetes in elderly individuals, and will also provide a more comprehensive perspective for the prevention and treatment of type 2 diabetes in elderly populations.

Urban closed lakes: Nutrient sources, assimilative capacity and pollutant reduction under different precipitation frequencies.

Many natural and man-made urban lakes have been developed under urbanization. A unique feature of these lakes is the lack of an outlet; thus, they are defined as urban closed lakes (UCLs). UCLs are facing unexpected eutrophication under climate change and human activities. Our study assessed the trophic state, assimilative capacity (AC) and pollutant reduction of UCLs under different precipitation frequencies in Wuhan, China based on Carlson's Trophic State Index, assimilative capacity modelling, field investigations and observed data. The UCLs in Wuhan are nearly eutrophic in summer. Three primary nutrient sources are atmospheric deposition, pollutants carried in rainfall and nutrients released by sediments. TN and TP in the UCL water column are primarily contributed by surface runoff. The ACs of TN and TP in 2015 for Lingjiao Lake, Yue Lake, and Houxianghe Lake were 3472.07 kg, 13,800.99 kg, and 2805.58 kg, respectively, and 641.66 kg, 8386.79 kg, and 800.14 kg, respectively. The ACs of TN and TP were much higher at a 25% precipitation frequency (wet year) compared with a 50% frequency, and the lowest AC was observed at a 75% precipitation frequency (dry year). A comparison of the pollution load and AC showed that TN and TP reduction was highest in the dry and wet years, respectively. We found that specific meteorological conditions in the early stage led to the algal bloom. These results can facilitate governmental decision making in the future.

The Effects of BCAAs on Insulin Resistance in Athletes.

The toxic catabolic intermediates of branched chain amino acids can cause insulin resistance, and are involved in different mechanisms in different metabolic tissues. In skeletal muscle, 3-hydroxy-isobutyrate produced by valine promotes skeletal muscle fatty acid uptake, resulting in the accumulation of incompletely oxidized lipids in skeletal muscle, causing skeletal muscle insulin resistance. In the liver, branched-chain α-keto acids decompose in large amounts, promote hepatic gluconeogenesis, and lead to the accumulation of multiple acylcarnitines, which damages the mitochondrial tricarboxylic acid cycle, resulting in the accumulation of incomplete oxidation products, oxidative stress in mitochondria, and hepatic insulin resistance. In adipose tissue, the expression of branched-chain amino acid catabolic enzymes (branched-chain amino acid transaminase, branched-chain α-keto acid dehydrogenase) is reduced, resulting in an increased level of plasma branched-chain amino acids, thereby causing massive decomposition of branched-chain amino acids in tissues such as skeletal muscle and liver, and inducing insulin resistance. However, branched-chain amino acids, as a common nutritional supplement for athletes, do not induce insulin resistance. A possible explanation for this phenomenon is that exercise can enhance the mitochondrial oxidative potential of branched-chain amino acids, alleviate or even eliminate the accumulation of branched-chain amino acid catabolic intermediates, and promotes branched-chain amino acids catabolism into beta-aminoisobutyric acid, increasing plasma beta-aminoisobutyric acid concentration, improving insulin resistance. This article reveals the mechanism of BCAA-induced insulin resistance and the relationship between exercise and BCAAs metabolism, adds a guarantee for the use of BCAAs, and provides a new explanation for the occurrence of diabetes and how exercise improves diabetes.

[Signaling pathways controlling skeletal muscle mass].

The skeletal muscle mass accounts for more than 40% of the body weight of healthy adults. The skeletal muscle not only plays an important role in physical activities but also affects the function of other organs as a secretory organ secreting multiple muscle factors. Therefore, it is important to maintain the normal quantity and function of skeletal muscle. Skeletal muscle mass is the basis of skeletal muscle function and is often affected by many factors such as exercise and disease. Resistance exercise training induces increased protein synthesis in skeletal muscle cells, while limb disuse, chronic obstructive pulmonary disease, heart failure, chronic kidney disease, cachexia, Duchenne muscular dystrophy and many other pathological conditions lead to decreased protein synthesis or enhanced protein degradation of skeletal muscle cells. The process of skeletal muscle hypertrophy involves changes in multiple signaling pathways, such as IGF-1/PI3K/Akt, myostatin and G protein. On the other hand, activations of the ubiquitin-proteasome system, IGF-1/Akt/FoxO, autophagy-lysosomal pathway, NF-κB, and the glucocorticoid-mediated signaling pathways play important roles in regulating muscle atrophy. These signaling pathways regulate skeletal muscle mass and are modulated by some different conditions. This review briefly summarizes the signaling pathways of skeletal muscle mass control.

[Roles and mechanism of microRNAs in the regulation of skeletal muscle insulin resistance].

Insulin resistance is a common pathophysiological mechanism of obesity and type 2 diabetes mellitus. Skeletal muscle is one of the major target organs of insulin-mediated glucose uptake, metabolism and utilization, and it is the earliest and most important site of insulin resistance. Studies have shown that the impairments of glucose uptake, insulin signaling pathway and mitochondrial biosynthesis are closely related to skeletal muscle insulin resistance. When insulin resistance develops in skeletal muscle, multiple microRNAs (miRNAs) are up-regulated (miR-106b, miR-23a, miR-761, miR-135a, Let-7 and miR-29a) or down-regulated (miR-133a, miR-149 and miR-1). They participate in the regulation of skeletal muscle glucose uptake, insulin signaling pathway and mitochondrial biogenesis, and thus play important roles in the occurrence and development of skeletal muscle insulin resistance. Therefore, these miRNAs may serve as potential targets for the treatment of skeletal muscle insulin resistance or diabetes.

[Mechanism of the occurrence of sarcopenia in the elderly].

The decline in skeletal muscle mass and function with age is referred as sarcopenia. It is characterized by the muscle fiber's quality, strength, muscle endurance and metabolic ability decreasing as well as the fat and connective tissue growing. Previous studies have shown that sarcopenia in itself features decreased number and cross-sectional area of muscle fibers and the net degradation of protein, which results from the joint effects of multiple factors such as the exacerbation of inflammation, oxidative stress injury, mitochondrial dysfunction, abnormal autophagy and dysregulation of muscle quality regulatory factors. In this review, we systematically displayed the molecular mechanism of sarcopenia, which will be helpful to deepen our understanding of sarcopenia and provide potential targets for the prevention and treatment of sarcopenia.

[Macrophages depletion impairs skeletal muscle regeneration by regulating inflammation and oxidative stress levels].

The objective of this study was to explore the roles of macrophages in the regeneration of injured skeletal muscle and the mechanisms involved. Mice were randomly divided into the following groups: muscle contusion (S), muscle contusion control (SCon), macrophages depleted (T) and macrophages depleted control (TCon) groups. Muscle contusion model was created by high-energy blunt injury. Macrophages depletion model was constructed by injection of clodronate-liposomes. Their gastrocnemius muscles were harvested at the time points of 1, 3, 7 and 14 d post-injury. The changes in skeletal muscle morphology were assessed by hematoxylin-eosin (HE) staining and Masson's trichrome staining. The mRNA and protein levels of inflammatory cytokines, chemokines and oxidative stress factors were analyzed by real-time polymerase chain reaction (RCR) and Western blotting, respectively. HE staining results showed that a small amount of regenerating myofibers were observed in the S group (14 d post-injury), whereas a large number of regenerating muscle fibers were observed in the T group. Quantitative analyses showed that the sizes of regenerating myofibers were significantly smaller in the T group as compared with the S group at 14 d post-injury (P < 0.05). At the same time, Masson staining results showed that macrophage depletion significantly increased the area of fibrosis as compared with the S group at 14 d post-injury (P < 0.01). The expression levels of inflammatory cytokines, chemokines, and oxidative stress factors were increased significantly after muscle injury. Moreover, macrophage depletion increased the expressions of inflammatory cytokines, chemokines and oxidative stress factors as compared with the S group during the later stage of injury (7-14 d post-injury). These results suggest that macrophages depletion can aggravate fibrosis and impair muscle regeneration, and inflammatory cytokines, chemokines and oxidative stress factors may be involved in this process.

[Fat deposition in skeletal muscle and its regulation].

Under normal condition, there are a few lipid droplets in skeletal muscle. But in skeletal muscle acute injury, muscular dystrophy, muscle atrophy, obesity, diabetes and other pathological conditions, the fat deposition in skeletal muscle increases, which implicate that the fat deposition may play an important role in the pathogenesis of these diseases. However, the mechanisms of development and regulation of fat deposition in skeletal muscle are not clear. Clarifying the key signaling pathways and regulatory factors that affect fat deposition in skeletal muscle, and exploring new ways to improve the fat deposition in skeletal muscle will not only help to deepen our understanding of the pathogenesis of these diseases, but also provide new ideas for the treatment of these diseases. This paper reviews the research progresses and main mechanisms of fat deposition in skeletal muscle.

A distal ileum malignant peripheral nerve sheath tumor causing intussusception in a patient in China: a case report.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) arise from a peripheral nerve or display nerve sheath differentiation. Most MPNSTs typically originate on the trunk, extremities, head, neck, and paravertebral regions. Gastrointestinal MPNSTs are rare entities with only 10 cases reported worldwide in the literatures. CASE PRESENTATION: Here, we report the first Chinese case of a malignant peripheral nerve sheath tumor of the distal ileum presenting as intussusception. A 53-year-old female patient without pathological antecedent for neurofibromatosis was admitted with pain in the right lower abdomen and multiple episodes of vomiting for 1 week. Preoperative diagnosis was intussusception with a contrast-enhanced computed tomography scan (CECT) of the abdomen showing characteristic target sign. Due to difficulty reducing the ileum-colon intussusception, right hemicolectomy with ileocolostomy was performed. Histopathology was suggestive of low-grade MPNST. The patient received postoperative care and was followed up for 9 months. There is no sign of tumor recurrence and metastatic disease. CONCLUSIONS: This case is unique in terms of a rare tumor presenting with unusual complication.

Cellular Uptake and Intra-Organ Biodistribution of Functionalized Silica-Coated Gold Nanorods.

PURPOSE: To develop a new nanobiosystem based on folate-functionalized silica-coated gold nanorods and to investigate its cellular uptake and intra-organ biodistribution in vitro and in vivo. PROCEDURES: Ellipsoidal silica-coated gold nanorods (GNRs@SIO2) were prepared by seeded growth method using silicon dioxide (SIO2) as the shell material. Rhodamine-labeled GNRs@SiO2-folic acid (FA) were obtained by reacting the amino group located on GNRs@SiO2-FA with rhodamine isothiocyanate. The characteristics of the prepared GNRs@SiO2-FA were studied using transmission electron microscopy (TEM) and UV spectra. The 3-[4, 5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide (MTT) colorimetric method was used to assess the biocompatibility of GNRs@SiO2-FA, and their uptake into cells was observed using TEM. In vivo experiments of cellular uptake and study of the intra-organ biodistribution of GNRs@SiO2-FA were detected using intrinsic two-photon luminescence. RESULTS: Analysis of UV spectra confirmed the successfu1 preparation of GNRs@SiO2-FA. Results of the MTT assay demonstrated that surface modification of GNRs@SiO2-FA resulted in excellent biocompatibility. TEM examination revealed that GNRs@SiO2-FA entered the cells via endocytosis, which could connect to cancer cells with high folic acid expression. We found that GNRs exhibit bright luminescence and could be visualized in vivo by direct imaging of these particles within the tissue. Additionally, GNRs@SiO2-FA could specifically bind to tumor cells. GNRs@SiO2-FA entered tumor cells within 24 h and had a heterogeneous distribution with higher accumulation at the tumor cytoplasm. CONCLUSION: GNRs@SiO2-FA can bind to cells and were found to be internalized by targeted folate receptor-expressing cells via a ligand-receptor-mediated endocytosis pathway, which is very useful in diagnosing diseases as well as in treating neoplasm with I-125 particles.

[The Role of Hepatocyte Growth Factor in Keletal Muscle Regeneration]

Skeletal muscle repair after injury includes three stages which are inflammation, repair and tissue remodeling. The ability of Skeletal muscle to regenerate in response to injury is solely dependen on the activation, proliferation and differentiation of satellite cells. After skeletal muscle injury, hepatocyte growth factor (HGF) can regular muscle satellite cell function in the manner of autocrine, paracrine or endocrine, thus affecting the regeneration of damaged skeletal muscle. Studies about the mechanism have shown that HGF may bind to its receptor, e-met, to start the relevant signaling pathways involved in skeletal muscle satellite cell activation, proliferation, differentiation and migration, which affects skeletal muscle regeneration process.

GNRs@SiO2-FA in combination with radiotherapy induces the apoptosis of HepG2 cells by modulating the expression of apoptosis-related proteins.

The aim of the present study was to examine the apoptosis of the hepatocellular carcinoma cell line, HepG2, induced by treatment with folic acid-conjugated silica-coated gold nanorods (GNRs@SiO2-FA) in combination with radiotherapy, and to determine the involvement of apoptosis-related proteins. An MTT colorimetric assay was used to assess the biocompatibility of GNRs@SiO2-FA. The distribution of GNRs@SiO2-FA into the cells was observed using transmission electron microscopy (TEM). HepG2 cells cultured in vitro were divided into the following 4 groups: i)the control group (untreated), ii) the GNRs@SiO2-FA group, iii) the radiotherapy group (iodine 125 seeds) and iv) the combination group (treated with GNRs@SiO2-FA and iodine 125 seeds) groups. The apoptosis of the HepG2 cells was detected by flow cytometry. The concentration range of <40 µg/ml GNRs@SiO2-FA was found to be safe for the biological activity of the HepG2 cells. GNRs@SiO2-FA entered the cytoplasm through endocytosis. The apoptotic rates of the HepG2 cells were higher in the GNRs@SiO2-FA and radiotherapy groups than in the control group (P<0.05). The apoptotic rate was also significantly higher in the combination group than the GNRs@SiO2-FA and radiotherapy groups (P<0.05). Taken together, these findings demonstrate that the combination of GNRs@SiO2-FA and radiotherapy more effectively induces the apoptosis of HepG2 cells. These apoptotic effects are achieved by increasing the protein expression of Bax and caspase-3, and inhibiting the protein expression of Bcl-2 and Ki-67. The combination of GNRs@SiO2-FA and radiotherapy may thus prove to be a new approach in the treatment of primary liver cancer.

Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy.

The mechanisms linking hepatitis B virus (HBV) and hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) remain largely unknown. Natural killer (NK) cells account for 25%-50% of the total number of liver lymphocytes, suggesting that NK cells play an important role in liver immunity. The number of NK cells in the blood and tumor tissues of HCC patients is positively correlated with their survival and prognosis. Furthermore, a group of NK cell-associated genes in HCC tissues is positively associated with the prolonged survival. These facts suggest that NK cells and HCC progression are strongly associated. In this review, we describe the abnormal NK cells and their functional impairment in patients with chronic HBV and HCV infection, which contribute to the progression of HCC. Then, we summarize the association of NK cells with HCC based on the abnormalities in the numbers and phenotypes of blood and liver NK cells in HCC patients. In particular, the exhaustion of NK cells that represents lower cytotoxicity and impaired cytokine production may serve as a predictor for the occurrence of HCC. Finally, we present the current achievements in NK cell immunotherapy conducted in mouse models of liver cancer and in clinical trials, highlighting how chemoimmunotherapy, NK cell transfer, gene therapy, cytokine therapy and mAb therapy improve NK cell function in HCC treatment. It is conceivable that NK cell-based anti-HCC therapeutic strategies alone or in combination with other therapies will be great promise for HCC treatment.

Reversed expression of GRIM-1 and GRP78 in human non-small cell lung cancer.

Gene associated with retinoid and interferon-induced mortality 1 (GRIM-1) acts as a tumor growth suppressor via apoptosis induction. However, GRIM-1 expression in human non-small cell lung cancer (NSCLC) and its potential interaction with another apoptosis-associated protein-glucose-regulated protein 78 (GRP78)-are as yet unknown. Using 40 surgical specimens, we showed significantly lower expression of GRIM-1 in NSCLC at both protein and messenger RNA (mRNA) levels compared with that in normal tissues (P < .01 and P < .001, respectively). Interestingly, these tumors tended to express higher basal amounts of GRP78 protein and mRNA (P < .05 and P < .001, respectively). Similarly, in the NSCLC tissues, weaker staining for GRIM-1 (main intensity + to ++) but stronger staining for GRP78 (main intensity +++ to ++++) was observed. Correlation analysis showed that protein and mRNA expression or the percentage of cells immunoreactive for GRIM-1 was negatively correlated with that of GRP78 (r = -0.279, r = -0.326, or r = -0.571, respectively). Coimmunoprecipitation and transient transfection revealed that GRIM-1 interacted with GRP78 and suppressed GRP78 protein expression. In addition, there was no correlation between GRIM-1 expression and clinical characteristics, whereas GRP78 expression was significantly correlated with tumor-nodes-metastasis (TNM) stage (stage 3 + 4 versus stage 1 + 2). In conclusion, the expression of GRIM-1 and GRP78 was negatively correlated in human NSCLC tissues, and the down-regulation of GRP78 by GRIM-1 provides a possible mechanism for their interaction. This study suggests a novel potential molecular pathway inactivated during the development of NSCLC.