It is butyrate, instead of other substances produced by F. prausnitzii, that maintains Th17/Treg balance and exerts significant anti-inflammatory effects in colorectal colitis rodents, by inhibiting HDAC1 to promote Foxp3 and block the IL-6/STAT3/IL-17 downstream pathway. F. prausnitzii could be an option for further investigation for IBD treatment. Targeting the butyrate-HDAC1-T-cell axis offers an effective novel approach in the treatment of inflammatory disease.

Metastasis is the most important feature of gastric cancer (GC) and the most widely recognized reason for GC-related deaths. Unfortunately, the underlying mechanism behind this metastasis remains unknown. Mounting evidence suggests the dynamic regulatory role of sirtuin2 (SIRT2), a histone deacetylase (HDAC), in cell migration and invasion. The present study aims to evaluate the biological function of SIRT2 in GC and identify the target of SIRT2 as well as evaluate its therapeutic efficacy. We found that SIRT2 was upregulated in GC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival. Although CCK8 and colony-formation assays showed that SIRT2 overexpression marginally promoted proliferation in GC cell lines, SIRT2 knockdown or treatment with SirReal2 decreased the migration and invasion of GC cells. We demonstrated both in vitro and in vivo that SirReal2 could inhibit the deacetylation activity of SIRT2 and its downstream target PEPCK1, which is related to mitochondrial metabolism and RAS/ERK/JNK/MMP-9 pathway. Taken together, these results demonstrate for the first time that SirReal2 selectively targets SIRT2 and decreases migration as well as invasion in human GC cells. SirReal2 therefore shows promise as a new drug candidate for GC therapy.

Calponin has been implicated in the regulation of smooth muscle contraction through its interaction with F-actin and inhibition of the actin-activated MgATPase activity of phosphorylated myosin. Both properties are lost following phosphorylation (primarily at serine 175) by protein kinase C or calmodulin-dependent protein kinase II. To evaluate further the functional importance of serine 175, wild-type calponin and three site-specific mutants (S175A, S175D, and S175T) were expressed in Escherichia coli and compared with calponin purified from chicken gizzard smooth muscle in terms of actin binding, actomyosin MgATPase inhibition, and phosphorylation by protein kinase C and calmodulin-dependent protein kinase II. The affinities of skeletal muscle F-actin for wild-type and S175T calponins were similar to that for the tissue-purified protein (K d ‫؍‬ 0.8, 1.3, and 1.0 M, respectively), whereas the affinities for S175A and S175D calponins were much lower (K d ‫؍‬ 26.8 and 44.2 M, respectively). Tissue-purified, wild-type, and S175T calponins displayed comparable inhibition of the smooth muscle actin-activated myosin MgATPase, whereas S175A and S175D calponins were much less effective. Phosphorylation confirmed serine 175 as the principal site of phosphorylation by both kinases. These results indicate that the hydroxyl side chain at position 175 of calponin plays a critical role in the binding of calponin to actin and inhibition of the cross-bridge cycling rate.Calponin is a 32-kDa, thin filament-associated protein that has been implicated in the regulation of smooth muscle contraction (1-4). Through its interaction with actin, calponin inhibits the actin-activated MgATPase activity of phosphorylated smooth muscle myosin (1) and inhibits the relative movement of actin and myosin in in vitro motility assays (5, 6). Exogenous calponin attenuated Ca 2ϩ -induced contractions of permeabilized rabbit mesenteric arterial smooth muscle strips in a concentration-dependent manner (7). Inhibition of the actomyosin ATPase occurs predominantly by a reduction of V max rather than an effect on the affinity of phosphorylated myosin heads for actin (8 -10). The inhibitory effect of calponin can be alleviated by phosphorylation catalyzed by protein kinase C (PKC) 1 or Ca 2ϩ /calmodulin-dependent protein kinase II (CaM kinase II) (1, 11) and restored following dephosphorylation by type 2A (12) or 2B protein phosphatases (13). Phosphorylation-induced loss of inhibition results from a marked reduction in the affinity of phosphorylated calponin for actin (1). Several examples of phosphorylation of calponin in intact muscle in response to various contractile stimuli have been reported (11, 14 -16), and in response to phenylephrine (an ␣ 1 -adrenergic agonist known to trigger activation of PKC) calponin translocates from cytosolic filamentous structures to a region underlying the sarcolemma (17). Other investigators, however, have reported that calponin is not phosphorylated in intact muscle (18 -20). The principal site of phosphorylation b...

Hepatocellular carcinoma (HCC) is one of the most common neoplasms, and metastasis is the most important feature for HCC-related deaths. Mounting evidence implies the dynamic regulatory role of SIRT2, a histone deacetylase, in cancer cells. Unfortunately, the role of SIRT2 and the antitumor activity of its inhibition are not known in HCC. The present study aims to evaluate the biological function of SIRT2 in HCC and identify the target of SIRT2 as well as evaluate its therapeutic efficacy. We found that SIRT2 was upregulated in HCC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival. Although CCK8 and colony-formation assays showed that SIRT2 inhibiton marginally promotes proliferation in HCC cell lines, SIRT2 knockdown decreased the invasion of HCC cells. We demonstrated that downregulation of SIRT2 could inhibit its downstream target phosphoenolpyruvate carboxykinase 1 and glutaminase, which is related to mitochondrial metabolism and the E-Cadherin pathway. These results demonstrate, for the first time that downregulation of SIRT2 decreases migration as well as invasion in human HCC cells, indicating that inhibiting SIRT2 may be an effective therapeutic strategy for treating HCC.

Background We aimed to develop and validate a real-time deep convolutional neural networks (DCNNs) system for detecting early gastric cancer (EGC). Methods All 45,240 endoscopic images from 1364 patients were divided into a training dataset (35823 images from 1085 patients) and a validation dataset (9417 images from 279 patients). Another 1514 images from three other hospitals were used as external validation. We compared the diagnostic performance of the DCNN system with endoscopists, and then evaluated the performance of endoscopists with or without referring to the system. Thereafter, we evaluated the diagnostic ability of the DCNN system in video streams. The accuracy, sensitivity, specificity, positive predictive value, negative predictive value and Cohen's kappa coefficient were measured to assess the detection performance. Finding The DCNN system showed good performance in EGC detection in validation datasets, with accuracy (85.1%–91.2%), sensitivity (85.9%–95.5%), specificity (81.7%–90.3%), and AUC (0.887–0.940). The DCNN system showed better diagnostic performance than endoscopists and improved the performance of endoscopists. The DCNN system was able to process oesophagogastroduodenoscopy (OGD) video streams to detect EGC lesions in real time. Interpretation We developed a real-time DCNN system for EGC detection with high accuracy and stability. Multicentre prospective validation is needed to acquire high-level evidence for its clinical application. Funding This work was supported by the National Natural Science Foundation of China (grant nos. 81672935 and 81871947), Jiangsu Clinical Medical Center of Digestive System Diseases and Gastrointestinal Cancer (grant no. YXZXB2016002), and Nanjing Science and Technology Development Foundation (grant no. 2017sb332019).