Gut microbes in gastrointestinal cancers.

Gut microbes (GMs), dominated by bacteria, play important roles in many physiological processes. The structures and functions of GMs are closely related to human health, the occurrence and development of diseases and the rapid recovery of the body. Gastrointestinal cancers are the major diseases affecting human health worldwide. With the development of metagenomic technology and the wide application of new generation sequencing technology, a large number of studies suggest that complex GMs are related to the occurrence and development of gastrointestinal cancers. Fecal microbiota transplantation (FMT) and probiotics can treat and prevent the occurrence of gastrointestinal cancers. This article reviews the latest research progress of microbes in gastrointestinal cancers from the perspectives of the correlation, the influence mechanism and the application, so as to provide new directions for the prevention, early diagnosis and treatment of gastrointestinal cancers.

BMP9 functions as a negative regulator in the myogenic differentiation of primary mouse myoblasts.

BMP9, a member of the TGF-ß superfamily, reveals the great translational promise for it has been shown to have the strong effect of osteogenic activity in vitro and in vivo. However, the implantation of certain BMPs (bone morphogenetic proteins) into muscular tissues induces ectopic bone formation. BMPs induce osteoblastic differentiation in skeletal muscle, suggesting that myogenic stem cells, such as myoblasts, are the potential progenitors of osteoblasts during heterotopic bone differentiation. Here, we investigate the role of BMP9 during primary mouse myoblasts differentiation. We found BMP9 enhanced cell proliferation and reduced myogenic differentiation of primary mouse myoblasts. In addition, adenovirus-mediated overexpression of BMP9 delayed muscle regeneration after BaCl2-induced injury. ALK1 knockdown reversed the inhibition of myoblast differentiation induced by BMP9. Our data indicate that BMP9 inhibits myogenic differentiation in primary mouse myoblasts and delays skeletal muscle regeneration after injury.

Extracellular Vesicles and Fatty Liver.

Fatty liver is a complex pathological process caused by multiple etiologies. In recent years, the incidence of fatty liver has been increasing year by year, and it has developed into a common chronic disease that seriously affects people's health around the world. It is an important risk factor for liver cirrhosis, liver cancer, and a variety of extrahepatic chronic diseases. Therefore, the early diagnosis and early therapy of fatty liver are important. Except for invasive liver biopsy, there is still a lack of reliable diagnosis and staging methods. Extracellular vesicles are small double-layer lipid membrane vesicles derived from most types of cells. They play an important role in intercellular communication and participate in the occurrence and development of many diseases. Since extracellular vesicles can carry a variety of biologically active substances after they are released by cells, they have received widespread attention. The occurrence and development of fatty liver are also closely related to extracellular vesicles. In addition, extracellular vesicles are expected to provide a new direction for the diagnosis of fatty liver. This article reviews the relationship between extracellular vesicles and fatty liver, laying a theoretical foundation for the development of new strategies for the diagnosis and therapy of fatty liver.

HOXA13 promotes liver regeneration through regulation of BMP-7.

In-depth knowledge of liver regeneration could facilitate the development of therapies for liver injury and liver failure. As a member of the homeobox superfamily, HOXA13 plays an important role in regulating tumorigenesis and development. However, the exact role of HOXA13 in liver regeneration remains unclear. In this study, we confirmed that HOXA13 promotes hepatocyte proliferation both in vivo and in vitro. HOXA13 was upregulated during liver regeneration, and its overexpression further accelerated hepatocyte proliferation and liver function recovery during liver regeneration. Furthermore, we found that HOXA13 promoted hepatocyte proliferation and liver regeneration by upregulating bone morphogenetic protein-7 (BMP-7) mRNA. These findings provide a new potential target for the treatment of liver failure.

From a bulk to nanoconfined water chain: bridge water at the pore of the (6,6) carbon nanotube.

Hydrophobic porous materials with nano-pores are critical in many processes such as water desalination and biological membrane transportation. Herein, we performed molecular dynamics (MD) simulations on a prototypical hydrophobic nanochannel consisting of a (6,6) carbon nanotube (CNT) of 4.12 Å in radius and 13.72 Å in length immersed in water. The simulation shows that there are two major filling numbers of water N = 5 and N = 6, with the former being the most stable one. The confined waters form a single-file water chain with two hydrogen bonds per water. An extending water chain is formed for N = 5, with a bridge water near the pore of the CNT linking the water confined inside the CNT and hydration layer around the pore of the CNT. The bridge water can be considered as intermediate water characterized by three hydrogen bonds that distinguish from the confined water and bulk water. On the other hand, the hydration layer is depleted from the pore when N = 6. The analyses of the correlation of the bond order for the adjacent hydrogen bond pair of the hydration layer around the pore of the CNT does not show apparent difference from that of bulk water, though the former is slightly ordered. van Hove analysis of the bridge water shows that it tends to move inside the CNT when N < 5, in order to maintain the chemical equilibrium between the confined water and bulk water. This study highlights the unique structure of water around the hydrophobic pore of a sub-nanometer nanochannel.

Exercise and Type 1 Diabetes.

Diabetes mellitus (DM) is the most common endocrine and metabolic disease caused by absolute or insufficient insulin secretion. Under the context of an aging population worldwide, the number of diabetic patients is increasing year by year. Most patients with diabetes have multiple complications that severely threaten their survival and living quality. DM is mainly divided into type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). T1DM is caused by absolute lack of insulin secretion, so the current treatment for T1DM patients is exogenous insulin replacement therapy. At present, exercise therapy has been widely recognized in the prevention and treatment of diabetes, and regular aerobic exercise has become an important part of T1DM treatment. At the same time, exercise therapy is also used in conjunction with other treatments in the prevention and treatment of diabetic complications. However, for patients with T1DM, exercise still has the risk of hypoglycemia or hyperglycemia. T1DM Patients and specialist physician need to fully understand the effects of exercise on metabolism and implement individualized exercise programs. This chapter reviews the related content of exercise and T1DM.

Alleviation of hepatic fibrosis and autophagy via inhibition of transforming growth factor-ß1/Smads pathway through shikonin.

BACKGROUND AND AIM: Liver fibrosis is a worldwide clinical challenge during the progression of chronic liver disease to liver cirrhosis. Shikonin is extracted from the root of Lithospermum erythrorhizon with antioxidant, anti-inflammatory, anticancer, and wound-healing properties. The study aims to investigate the protective effect of shikonin on liver fibrosis and its underlying mechanism. METHODS: Two liver fibrosis models were established in male C57 mice by intraperitoneal injection of CCl4 or bile duct ligation. Shikonin was administered orally three times weekly at a dose of 2.5 or 5 mg/kg. Protein and mRNA expressions were assayed by quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemical staining. RESULTS: Shikonin significantly inhibited activation of hepatic stellate cells and extracellular matrix formation by downregulating the transforming growth factor-ß1 expression and maintaining the normal balance between metalloproteinase-2 and tissue inhibitor of metalloproteinase-1. Shikonin also decreased hepatic stellate cell energy production by inhibiting autophagy. CONCLUSIONS: The results confirmed that shikonin attenuated liver fibrosis by downregulating the transforming growth factor-ß1/Smads pathway and inhibiting autophagy.

Analysis of Density Functional Tight Binding with Natural Bonding Orbitals.

The description of chemical bonding by the density functional tight binding (DFTB) model is analyzed using natural bonding orbitals (NBOs) and compared to results from density functional theory (B3LYP/aug-cc-pVTZ) calculations. Several molecular systems have been chosen to represent fairly diverse bonding scenarios that include standard covalent bonds, hypervalent interactions, multicenter bonds, metal-ligand interactions (with and without the pseudo-Jahn-Teller effect), and through-space donor-acceptor interactions. Overall, the results suggest that DFTB3/3OB provides physically sound descriptions for the different bonding scenarios analyzed here, as reflected by the general agreement between DFTB3 and B3LYP NBO properties, such as the nature of the NBOs, the magnitudes of natural charges and bond orders, and the dominant donor-acceptor interactions. The degree of ligand-to-metal charge transfer and the ionic nature of pentavalent phosphate are overestimated, likely reflecting the minimal-basis nature of DFTB3/3OB. Moreover, certain orbital interactions, such as geminal interactions, are observed to be grossly overestimated by DFTB3 for hypervalent phosphate and several transition metal compounds that involve copper and nickel. The study indicates that results from NBO analysis can be instructive for identifying electronic structure descriptions at the approximate quantum-mechanical level that require improvement and thus for guiding the systematic improvement of these methods.

Vitiligo in a patient receiving infliximab for chronic plaque psoriasis.

Infliximab is a tumor necrosis factor-alpha (TNF-a) inhibitor widely used in the treatment of moderate to severe chronic plaque psoriasis. Here, we report a case of vitiligo following infliximab administration in a patient with chronic plaque psoriasis. The case serves as a reminder of vitiligo induced by TNF-a-antagonist therapy.

Isorhamnetin Inhibits Liver Fibrosis by Reducing Autophagy and Inhibiting Extracellular Matrix Formation via the TGF-ß1/Smad3 and TGF-ß1/p38 MAPK Pathways.

OBJECTIVE: Liver fibrosis is a consequence of wound-healing responses to chronic liver insult and may progress to liver cirrhosis if not controlled. This study investigated the protection against liver fibrosis by isorhamnetin. METHODS: Mouse models of hepatic fibrosis were established by intraperitoneal injection of carbon tetrachloride (CCl4) or bile duct ligation (BDL). Isorhamnetin 10 or 30 mg/kg was administered by gavage 5 days per week for 8 weeks in the CCl4 model and for 2 weeks in the BDL model. Protein and mRNA expressions were assayed by western blotting, immunohistochemistry, and quantitative real-time polymerase chain reaction. RESULTS: Isorhamnetin significantly inhibited liver fibrosis in both models, inhibiting hepatic stellate cell (HSC) activation, extracellular matrix (ECM) deposition, and autophagy. The effects were associated with downregulation of transforming growth factor ß1 (TGF-ß1) mediation of Smad3 and p38 mitogen-activated protein kinase (MAPK) signaling pathways. CONCLUSION: Isorhamnetin protected against liver fibrosis by reducing ECM formation and autophagy via inhibition of TGF-ß1-mediated Smad3 and p38 MAPK signaling pathways.

Regulation and Plasticity of Catalysis in Enzymes: Insights from Analysis of Mechanochemical Coupling in Myosin.

The mechanism of ATP hydrolysis in the myosin motor domain is analyzed using a combination of DFTB3/CHARMM simulations and enhanced sampling techniques. The motor domain is modeled in the pre-powerstroke state, in the post-rigor state, and as a hybrid based on the post-rigor state with a closed nucleotide-binding pocket. The ATP hydrolysis activity is found to depend on the positioning of nearby water molecules, and a network of polar residues facilitates proton transfer and charge redistribution during hydrolysis. Comparison of the observed hydrolysis pathways and the corresponding free energy profiles leads to detailed models for the mechanism of ATP hydrolysis in the pre-powerstroke state and proposes factors that regulate the hydrolysis activity in different conformational states. In the pre-powerstroke state, the scissile Pγ-O3ß bond breaks early in the reaction. Proton transfer from the lytic water to the γ-phosphate through active site residues is an important part of the kinetic bottleneck; several hydrolysis pathways that feature distinct proton transfer routes are found to have similar free energy barriers, suggesting a significant degree of plasticity in the hydrolysis mechanism. Comparison of hydrolysis in the pre-powerstroke state and the closed post-rigor model suggests that optimization of residues beyond the active site for electrostatic stabilization and preorganization is likely important to enzyme design.

By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In this study, two sorafenib-resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. High glycolysis and PFKFB3 overexpression occupied a dominant position in sorafenib resistance, and can be targeted and overcome by aspirin. Aspirin plus sorafenib induced apoptosis in tumors without inducing weight loss, hepatotoxicity or inflammation. Our results suggest that aspirin overcomes sorafenib resistance and their combination may be an effective treatment approach for HCC.

Genistein suppresses aerobic glycolysis and induces hepatocellular carcinoma cell death.

BACKGROUND: Genistein is a natural isoflavone with many health benefits, including antitumour effects. Increased hypoxia-inducible factor 1 α (HIF-1α) levels and glycolysis in tumour cells are associated with an increased risk of mortality, cancer progression, and resistance to therapy. However, the effect of genistein on HIF-1α and glycolysis in hepatocellular carcinoma (HCC) is still unclear. METHODS: Cell viability, apoptosis rate, lactate production, and glucose uptake were measured in HCC cell lines with genistein incubation. Lentivirus-expressed glucose transporter 1 (GLUT1) or/and hexokinase 2 (HK2) and siRNA of HIF-1α were used to test the direct target of genistein. Subcutaneous xenograft mouse models were used to measure in vivo efficacy of genistein and its combination with sorafenib. RESULTS: Genistein inhibited aerobic glycolysis and induced mitochondrial apoptosis in HCC cells. Neither inhibitors nor overexpression of HK2 or GLUTs enhance or alleviate this effect. Although stabiliser of HIF-1α reversed the effect of genistein, genistein no longer has effects on HIF-1α siRNA knockdown HCC cells. In addition, genistein enhanced the antitumour effect of sorafenib in sorafenib-resistant HCC cells and HCC-bearing mice. CONCLUSIONS: Genistein sensitised aerobic glycolytic HCC cells to apoptosis by directly downregulating HIF-1α, therefore inactivating GLUT1 and HK2 to suppress aerobic glycolysis. The inhibitory effect of genistein on tumour cell growth and glycolysis may help identify effective treatments for HCC patients at advanced stages.

Bullous Pemphigoid Associated with Erythrodermic Psoriasis: A Case Report.

Psoriasis is an immune-mediated systemic disease with multiple organs involvement, such as cardiovascular, live, gut, endocrine, and so on. Bullous pemphigoid (BP) is a rare comorbidity associated with psoriasis, while BP occurring in erythrodermic psoriasis (EP) is very rare. In this case, we reported a woman with severe EP who developed BP, in whom beta hemolytic streptococcus infection was a possible triggering factor. The complicated condition of such patients needs to draw attention of the physician and study further for better treatment.

Risk Factors of Atrial Arrhythmia in Patients With Liver Cirrhosis: A Retrospective Study.

Background and Objectives: Liver cirrhosis is known to be associated with atrial arrhythmia. However, the risk factors for atrial arrhythmia in patients with liver cirrhosis remain unclear. This retrospective study aimed to investigate the risk factors for atrial arrhythmia in patients with liver cirrhosis. Methods: In the present study, we collected data from 135 patients with liver cirrhosis who were admitted to the Department of Gastroenterology at Shanghai Tongji Hospital. We examined the clinical information recorded, with the aim of identifying the risk factors for atrial arrhythmia in patients with liver cirrhosis. Multiple logistic regression analysis was used to screen for significant factors differentiating liver cirrhosis patients with atrial arrhythmia from those without atrial arrhythmia. Results: The data showed that there were seven significantly different factors that distinguished the group with atrial arrhythmia from the group without atrial arrhythmia. The seven factors were age, white blood cell count (WBC), albumin (ALB), serum Na+, B-type natriuretic peptide (BNP), ascites, and Child-Pugh score. The results of multivariate logistic regression analysis suggested that age (ß = 0.094, OR = 1.098, 95% CI 1.039-1.161, P = 0.001) and ascites (ß =1.354, OR = 3.874, 95% CI 1.202-12.483, P = 0.023) were significantly associated with atrial arrhythmia. Conclusion: In the present study, age and ascites were confirmed to be risk factors associated with atrial arrhythmia in patients with liver cirrhosis.

Analysis of Phosphoryl-Transfer Enzymes with QM/MM Free Energy Simulations.

We discuss the application of quantum mechanics/molecular mechanics (QM/MM) free energy simulations to the analysis of phosphoryl transfers catalyzed by two enzymes: alkaline phosphatase and myosin. We focus on the nature of the transition state and the issue of mechanochemical coupling, respectively, in the two enzymes. The results illustrate unique insights that emerged from the QM/MM simulations, especially concerning the interpretation of experimental data regarding the nature of enzymatic transition states and coupling between global structural transition and catalysis in the active site. We also highlight a number of technical issues worthy of attention when applying QM/MM free energy simulations, and comment on a number of technical and mechanistic issues that require further studies.

Beraprost sodium preconditioning prevents inflammation, apoptosis, and autophagy during hepatic ischemia-reperfusion injury in mice via the P38 and JNK pathways.

OBJECTIVE: The goal of this study was to determine the effects of beraprost sodium (BPS) preconditioning on hepatic ischemia-reperfusion (IR) injury and its underlying mechanisms of action. MATERIALS AND METHODS: Mice were randomly divided into sham, IR, IR+BPS (50 µg/kg), and IR+BPS (100 µg/kg) groups. Saline or BPS was given to the mice by daily gavage for 1 week before the hepatic IR model was established. Liver tissues and orbital blood were collected at 2, 8, and 24 hours after reperfusion for the determination of liver enzymes, inflammatory mediators, apoptosis- and autophagy-related proteins, key proteins in P38 and c-Jun N-terminal kinase (JNK) cascades, and evaluation of liver histopathology. RESULTS: BPS preconditioning effectively reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, improved pathological damage, ameliorated production of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), and affected expressions of Bax, Bcl-2, Caspase-3, Caspase-8, and Caspase-9, microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, and P62. The protective effects of BPS preconditioning were associated with reduced P38 and JNK phosphorylation. CONCLUSION: BPS preconditioning ameliorated hepatic IR injury by suppressing inflammation, apoptosis, and autophagy, partially via inhibiting activation of the P38 and JNK cascades.

Fucosterol Protects against Concanavalin A-Induced Acute Liver Injury: Focus on P38 MAPK/NF-κB Pathway Activity.

OBJECTIVE: Fucosterol is derived from the brown alga Eisenia bicyclis and has various biological activities, including antioxidant, anticancer, and antidiabetic properties. The aim of this study was to investigate the protective effects of fucosterol pretreatment on Concanavalin A- (ConA-) induced acute liver injury in mice, and to understand its molecular mechanisms. MATERIALS AND METHODS: Acute liver injury was induced in BALB/c mice by ConA (25 mg/kg), and fucosterol (dissolved in 2% DMSO) was orally administered daily at doses of 25, 50, and 100 mg/kg. The levels of hepatic necrosis, apoptosis, and autophagy associated with inflammatory cytokines were measured at 2, 8, and 24 h. RESULTS: Fucosterol attenuated serum liver enzyme levels and hepatic necrosis and apoptosis induced by TNF-α, IL-6, and IL-1ß. Fucosterol also inhibited apoptosis and autophagy by upregulating Bcl-2, which decreased levels of functional Bax and Beclin-1. Furthermore, reduced P38 MAPK and NF-κB signaling were accompanied by PPARγ activation. CONCLUSION: This study showed that fucosterol could alleviate acute liver injury induced by ConA by inhibiting P38 MAPK/PPARγ/NF-κB signaling. These findings highlight that fucosterol is a promising potential therapeutic agent for acute liver injury.

Salidroside ameliorates autophagy and activation of hepatic stellate cells in mice via NF-κB and TGF-ß1/Smad3 pathways.

PURPOSE: Liver fibrosis is commonly seen and a necessary stage in chronic liver disease. The aim of this study was to explore the effect of salidroside on liver fibrosis in mice and its potential mechanisms. MATERIALS AND METHODS: Two mouse liver fibrosis models were established by intraperitoneal injection of carbon tetrachloride (CCl4) for 8 weeks and bile duct ligation for 14 days. Salidroside was injected intraperitoneally at doses of 10 and 20 mg/kg once a day. Gene and protein expression levels were determined by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, Western blot, immunohistochemistry, and immunofluorescence. RESULTS: Salidroside inhibited the production of extracellular matrix (ECM) and regulated the balance between MMP2 and TIMP1 and, therefore, alleviated liver fibrosis in the two fibrosis models. Salidroside reduced the production of transforming growth factor (TGF)-ß1 in Kupffer cells and hepatic stellate cells (HSCs) via the nuclear factor-κB signaling pathway and, therefore, inhibited the activation of HSCs and autophagy by downregulation of the TGF-ß1/Smad3 signaling pathway. CONCLUSION: Salidroside can effectively attenuate liver fibrosis by inhibiting the activation of HSCs in mice.

Portulaca Extract Attenuates Development of Dextran Sulfate Sodium Induced Colitis in Mice through Activation of PPARγ.

Portulaca oleracea L. is a traditional Chinese medicine, which has been used as adjuvant therapy for inflammatory bowel disease (IBD). However, the mechanism of its activity in IBD still remains unclear. Since previous studies have documented the anti-inflammatory effect of peroxisome proliferator activated receptors-γ (PPAR-γ), Portulaca regulation of PPAR-γ in inflammation was examined in current study. Ulcerative colitis (UC) was generated by 5% dextran sulfate sodium (DSS) in mice and four groups were established as normal control, DSS alone, DSS plus mesalamine, and DSS plus Portulaca. Severity of UC was evaluated by body weight, stool blood form, and length of colorectum. Inflammation was examined by determination of inflammatory cytokines (TNF-a, IL-6, and IL-1a). Portulaca extract was able to attenuate development of UC in DSS model similar to the treatment of mesalazine. Moreover, Portulaca extract inhibited proinflammatory cytokines release and reduced the level of DSS-induced NF-κB phosphorylation. Furthermore, Portulaca extract restored PPAR-γ level, which was reduced by DSS. In addition, Portulaca extract protected DSS induced apoptosis in mice. In conclusion, Portulaca extract can alleviate colitis in mice through regulation of inflammatory reaction, apoptosis, and PPAR-γ level; therefore, Portulaca extract can be a potential candidate for the treatment of IBD.