Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD), characterized with hepatocellular steatosis, ballooning, lobular inflammation, fibrotic ...progression, and insulin resistance. NASH may progress to cirrhosis and hepatocellular carcinoma (HCC), which are the major indications for liver transplantation and the causes for mortality. Thus far, there are no approved pharmacotherapeutics for the treatment of NASH. Given the complexity of NASH pathogenesis at multifaceted aspects, such as lipotoxicity, inflammation, insulin resistance, mitochondrial dysfunction and fibrotic progression, pharmacotherapeutics under investigation target different key pathogenic pathways to gain either the resolution of steatohepatitis or regression of fibrosis, ideally both. Varieties of pharmacologic candidates have been tested in clinical trials and have generated some positive results. On the other hand, recent failure or termination of a few phase II and III trials is disappointing in this field. In face to growing challenges in pharmaceutical development, this review intends to summarize the latest data of new medications which have completed phase II or III trials, and discuss the rationale and preliminary results of several combinatory options. It is anticipated that with improved understanding of NASH pathogenesis and critical endpoints, efficient pharmacotherapeutics will be available for the treatment of NASH with an acceptable safety profile.
Abstract
Background
Since interferon regulatory factor (IRF) family functions in immune response to viral infection, its role in colorectal cancer (CRC) has not been inspected before. This study ...tries to investigate members of IRF family using bioinformatics approaches in aspect of differential expressions, biological function, tumor immune infiltration and clinical prognostic value for patients with CRC.
Methods
Transcriptome profiles data, somatic mutations and clinical information of CRC were obtained from COAD/READ dataset of The Cancer Genome Atlas (TCGA) as a training set. Gene expression data (GSE17536 and GSE39582) were downloaded from the Gene Expression Omnibus as a validating set. A random forest algorithm was used to score the risk for every case. Analyzing gene and function enrichment, constructing protein–protein interaction and noncoding RNA network, identifying hub-gene, characterizing tumor immune infiltration, evaluating differences in tumor mutational burden (TMB) and sensitivity to chemotherapeutics or immunotherapy were performed by a series of online tools and R packages. Immunohistochemical (IHC) examinations were carried out validation in tissue samples.
Results
Principal-component analysis (PCA) suggested that the transcript expression levels of nine members of IRF family differed between normal colorectum and CRC. The risk score constructed by IRF family not only acted as an independent factor for predicting survival in CRC patients with different biological processes, signaling pathways and TMB, but also indicated different immunotherapy response with diverse immune and stromal cells infiltration. IRF3 and IRF7 were upregulated in CRC and suggested a shorter survival time in patients with CRC. Differentially expressed members of IRF family exhibited varying degrees of immune cell infiltration. IHC analysis showed a positive association between IRF3 and IRF7 expression and tumor-infiltrating immune cells, including CD4
+
T cell and CD68
+
macrophages.
Conclusions
On account of differential expression, IRF family members can help to predict both response to immunotherapy and clinical prognosis of patients with CRC. Our bioinformatic investigation not only gives a preliminary picture of the genetic features as well as tumor microenvironment, but it may provide a clue for further experimental exploration and verification on IRF family members in CRC.
Abstract
Background
Tumor-associated macrophages (TAM) are immunosuppressive cells that contribute to impaired anti-cancer immunity. Iron plays a critical role in regulating macrophage function. ...However, it is still elusive whether it can drive the functional polarization of macrophages in the context of cancer and how tumor cells affect the iron-handing properties of TAM. In this study, using hepatocellular carcinoma (HCC) as a study model, we aimed to explore the effect and mechanism of reduced ferrous iron in TAM.
Methods
TAM from HCC patients and mouse HCC tissues were collected to analyze the level of ferrous iron. Quantitative real-time PCR was used to assess M1 or M2 signature genes of macrophages treated with iron chelators. A co-culture system was established to explore the iron competition between macrophages and HCC cells. Flow cytometry analysis was performed to determine the holo-transferrin uptake of macrophages. HCC samples from The Cancer Genome Atlas (TCGA) were enrolled to evaluate the prognostic value of transferrin receptor (TFRC) and its relevance to tumor-infiltrating M2 macrophages.
Results
We revealed that ferrous iron in M2-like TAM is lower than that in M1-like TAM. In vitro analysis showed that loss of iron-induced immunosuppressive M2 polarization of mouse macrophages. Further experiments showed that TFRC, the primary receptor for transferrin-mediated iron uptake, was overexpressed on HCC cells but not TAM. Mechanistically, HCC cells competed with macrophages for iron to upregulate the expression of M2-related genes via induction of HIF-1α, thus contributing to M2-like TAM polarization. We further clarified the oncogenic role of TFRC in HCC patients by TCGA. TFRC is significantly increased in varieties of malignancies, including HCC, and HCC patients with high TFRC levels have considerably shortened overall survival. Also, TFRC is shown to be positively related to tumor-infiltrating M2 macrophages.
Conclusions
Collectively, we identified iron starvation through TFRC-mediated iron competition drives functional immunosuppressive polarization of TAM, providing new insight into the interconnection between iron metabolism and tumor immunity.
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•The presence of bile acids in the hepatopancreas of E. sinensis was first reported.•Bile acids and bitter-free amino acids may be the main contributors to bitterness.•The color of ...hepatopancreas was determined by bile and carotenoids.•There were inextricable links between the coloration and bitter components.•Bile was the key metabolite that led to the hepatopancreas brown and bitter.
Chinese mitten crab (Eriocheir sinensis) is an important economic seafood in China, and the hepatopancreatic dim color and bitter taste of crabs significantly affects the consumer’s acceptance. The crabs with brown hepatopancreas (BH) generally taste bitter, while the orange hepatopancreas (OH) does not taste bitter. While the metabolites perform their physiological functions, their metabolic relationship may directly affect the color and taste quality of the crab hepatopancreas. This study investigated the metabolic relationship of key metabolites related to the color and bitterness in the OH and BH of E. sinensis. The contents of total bile acids (BAs) (10.62 vs. 3.72 μg/g), bitter free amino acids (FAAs) (5.15 vs. 2.46 mg/g) and lutein (6.88 vs. 2.55 μg/g) in the BH group were significantly higher (P < 0.01) than those in the OH group, while β-carotene (314.47 vs. 478.52 μg/g) in the BH group was significantly lower (P < 0.05) than that in the OH group. In addition, BAs were positively correlated with lutein, saturated and monounsaturated fatty acids (SFA and MUFA) and bitter FAAs, and negatively correlated with color value, β-carotene and polyunsaturated fatty acids (PUFA). In conclusion, BAs and bitter FAAs may be the major contributors to the bitterness of BH, and the high content of BAs in the BH group may promote lipid catabolism, inhibit β-carotene absorption and enhance amino acid metabolism, leading to the hepatopancreas brown and bitter.
•Naringenin fortification in bread inhibited the formation of toxicants.•Antioxidant and antibacterial activity of bread were also enhanced.•Naringenin reduced AGEs-induced cellular oxidative stress ...and inflammation.
Dietary flavonoids as popular food additives have attracted a wide range of research interests. Naringenin, a common flavanone, was evaluated of its impact on the formation of advanced glycation endproducts (AGEs) in bread crust. It was found that with the increase of naringenin content in bread (0.25–1% w/w), the formation of CML and total fluorescent AGEs were significantly inhibited (9.67–54.27% and 11.79–35.19%, respectively). In addition, the fortification with naringenin could also significantly inhibit the formation of acrylamide in bread crust, while enhancing the antioxidant and antibacterial activity of bread crumb without bringing undesirable changes to the bread quality attributes. Moreover, in RAW264.7 cells, naringenin significantly reduced of AGEs-induced ROS production as well as the contents of some inflammatory mediators. Altogether, our finding indicated naringenin can have dual inhibitory effects on both AGEs’ formation in foods and AGEs-induced cellular oxidative stress and inflammation.
Interferon regulatory factor 2 (IRF-2) acts as an anti-oncogene in gastric cancer (GC); however, the underlying mechanism remains unknown.
This study determined the expression of IRF-2 in GC tissues ...and adjacent non-tumor tissues using immunohistochemistry (IHC) and explored the predictive value of IRF-2 for the prognoses of GC patients. Cell function and xenograft tumor growth experiments in nude mice were performed to test tumor proliferation ability, both in vitro and in vivo. Chromatin immunoprecipitation sequencing (ChIP-Seq) assay was used to verify the direct target of IRF-2.
We found that IRF-2 expression was downregulated in GC tissues and was negatively correlated with the prognoses of GC patients. IRF-2 negatively affected GC cell proliferation both in vitro and in vivo. ChIP-Seq assay showed that IRF-2 could directly activate AMER-1 transcription and regulate the Wnt/β-catenin signaling pathway, which was validated using IHC, in both tissue microarray and xenografted tumor tissues, western blot analysis, and cell function experiments.
Increased expression of IRF-2 can inhibit tumor growth and affect the prognoses of patients by directly regulating AMER-1 transcription in GC and inhibiting the Wnt/β-catenin signaling pathway.
•Eriocheir sinensis, an euryhaline crustacean, is a specialty freshwater product.•Tri-step IR spectroscopy was an effective method to identify the taste components.•The contents of main ...salinity-responsive contributors were determined.•The optimal period of temporary rearing in the brackish water was about 4 weeks.
We investigated the effect of temporary rearing in brackish water on the taste quality in meat of crab cooked. The main salinity-responsive factors included 5ʹ-nucleotides and free amino acids (FAAs) in crab meat that were identified using tri-step infrared spectroscopy. Compared to the fresh water group, the contents of 5ʹ-adenosine monophosphate and 5ʹ-inosine monophosphate in the brackish water group significantly increased in the 2nd week and decreased in the 6th week, respectively. The contribution ratio of umami FAAs increased from 8.1 to 13.5% in the 4th week in the brackish water group, showing maximum value of equivalent umami concentration. Moreover, Ca2+ and Cl− contents significantly increased in the 4th and 6th weeks, respectively (P < 0.05). Infrared spectroscopy was an effective method to identify the taste components. With respect to the taste quality, four weeks were determined as the best period for temporary rearing of the crab in brackish water.
Recently, there is a growing interest in fortifying food products with flavonoids to enhance health benefits. Naringenin, naringin, hesperetin, and dihydromyricetin are four typical flavonoids ...constituting a natural part of our diet. In the present work, they were fortified into a chia oil cookie model to evaluate their thermal stability during baking as well as their impact on antioxidant capacity and toxicant formation. Among them dihydromyricetin was the most unstable one (only 36.1% of which was left after baking at 180 °C for 20 min) and led to a loss of brightness in cookie. However, the antioxidant capacity of cookie fortified with dihydromyricetin was significantly enhanced compared with untreated cookie; on the other hand, dihydromyricetin showed the strongest effect to attenuate lipid and protein oxidation as well as decrease the level of fluorescent advanced glycation endproducts and carboxymethyl lysine in cookie model. Overall, among the four selected flavonoids, dihydromyricetin might be the most promising functional bakery additive enhancing the antioxidant capacity while decreasing the formation of toxicants.
Objectives
Essential tremor (ET) patients presenting tremor in the midline structures may be a distinct subtype of the syndrome. Therefore, we sought to explore the clinical manifestations, ...especially non‐motor symptoms (NMS) of Chinese ET patients with midline tremor (MT).
Methods
In the cross‐sectional study, we grouped 290 definite or probable ET patients based on their MT conditions. The NMS in ET patients were evaluated using the NMS scale (NMSS). NMS and other clinical correlates were then compared among subgroups with, and without MT.
Results
We revealed that 39.0%, 27.6%, and 6.9% of the patients respectively had neck, voice, and facial tremors. With the accumulation of tremor in midline structures, NMS became more severe and prevalent. Logistic regression analyses revealed that factors such as: female gender (OR = 2.164, 95% CI: 1.307‐3.583), having least or highest action arm tremor (OR = 2.512, 95% CI: 1.520‐4.151), having higher score of sleep/fatigue domain (OR = 1.692, 95% CI: 1.004‐2.850) and mood/apathy (OR = 1.926, 95% CI: 1.143‐3.246) domain, to be independently associated with MT manifestation.
Conclusions
Our study demonstrates the heterogeneity of symptoms in ET patients with MT, especially in prominent NMS. In addition, the discrepancy of NMS between patients with, and without MT provides novel insight into the underlying pathophysiology and therapeutic of ET.
This study investigated the effects of temporary rearing (6 weeks) in brackish water on the taste-related metabolites of crab muscle for adult male E. sinensis. Salinity-responsive factors, including ...5ʹ-nucleotides and free amino acids (FAAs) of crab muscle, were identified using tri-step infrared spectroscopy. Compared to the fresh water group, the content of umami and sweet FAAs were higher in the 2nd and 4th week in the brackish water group (P < 0.05). Similarly, the content of 5ʹ-adenosine triphosphate (ATP) significantly increased in the 2 nd week in the brackish water group (P < 0.05). Cl− contents were significantly increased in the 4th and 6th weeks in the brackish water group (P < 0.05). The salinity-responsive contributors, including aspartic acid, glutamic acid, threonine, alanine, lysine, cystine, Ca2+ and Cl− were involved in osmoregulation. Crab muscle was able to accumulate ATP, which could increase the adaptive capacity of an organism and form flavor nucleotides. The infrared spectroscopy could effectively identify the main difference of taste-related metabolites. According to our results, the optimal period for temporary rearing of crabs in brackish water was 2–4 weeks.
•Tri-step IR spectroscopy could monitor the main differences in taste-related metabolites.•The content of sweet and umami FAAs of brackish water group would increase in the 2nd and 4th week.•After 2 weeks of salinity adaptation, crabs have the highest accumulation of ATP.•The optimal period of temporary rearing in the brackish water was 2–4 weeks.
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