Pantoprazole suppresses carcinogenesis and growth of hepatocellular carcinoma by inhibiting glycolysis and Na+/H+ exchange.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. The prevention and therapy for this deadly disease remain a global medical challenge. In this study, we investigated the effect of pantoprazole (PPZ) on the carcinogenesis and growth of HCC. Both diethylnitrosamine (DEN) plus CCl4-induced and DEN plus high fat diet (HFD)-induced HCC models in mice were established. Cytokines and cell proliferation-associated gene in the liver tissues of mice and HCC cells were analyzed. Cellular glycolysis and Na+/H+ exchange activity were measured. The preventive administration of pantoprazole (PPZ) at a clinically relevant low dose markedly suppressed HCC carcinogenesis in both DEN plus CCl4-induced and HFD-induced murine HCC models, whereas the therapeutic administration of PPZ at the dose suppressed the growth of HCC. In the liver tissues of PPZ-treated mice, inflammatory cytokines, IL1, CXCL1, CXCL5, CXCL9, CXCL10, CCL2, CCL5, CCL6, CCL7, CCL20, and CCL22, were reduced. The administration of CXCL1, CXCL5, CCL2, or CCL20 all reversed PPZ-suppressed DEN plus CCL4-induced HCC carcinogenesis in mice. PPZ inhibited the expressions of CCNA2, CCNB2, CCNE2, CDC25C, CDCA5, CDK1, CDK2, TOP2A, TTK, AURKA, and BIRC5 in HCC cells. Further results showed that PPZ reduced the production of these inflammatory cytokines and the expression of these cell proliferation-associated genes through the inhibition of glycolysis and Na+/H+ exchange. In conclusion, PPZ suppresses the carcinogenesis and growth of HCC, which is related to inhibiting the production of inflammatory cytokines and the expression of cell proliferation-associated genes in the liver through the inhibition of glycolysis and Na+/H+ exchange.

Dynamic Optical Encryption Fueled via Tunable Mechanical Composite Micrograting Systems.

Optical grating devices based on micro/nanostructured functional surfaces are widely employed to precisely manipulate light propagation, which is significant for information technologies, optical data storage, and light sensors. However, the parameters of rigid periodic structures are difficult to tune after manufacturing, which seriously limits their capacity for in situ light manipulation. Here, a novel anti-eavesdropping, anti-damage, and anti-tamper dynamic optical encryption strategy are reported via tunable mechanical composite wrinkle micrograting encryption systems (MCWGES). By mechanically composing multiple in-situ tunable ordered wrinkle gratings, the dynamic keys with large space capacity are generated to obtain encrypted diffraction patterns, which can provide a higher level of security for the encrypted systems. Furthermore, a multiple grating cone diffraction model is proposed to reveal the dynamic optical encryption principle of MCWGES. Optical encryption communication using dynamic keys has the effect of preventing eavesdropping, damage, and tampering. This dynamic encryption method based on optical manipulation of wrinkle grating demonstrates the potential applications of micro/nanostructured functional surfaces in the field of information security.

Historical Review of Acute Pancreatitis Research Over the Last 80 Years.

OBJECTIVES: Research on acute pancreatitis (AP) has been ongoing for a long time. It is necessary to summarize and investigate the history of AP research. METHODS: Publications related to AP research were retrieved from PubMed. Medical Subject Headings (MeSH) terms, countries, journals, and publication dates were analyzed. Co-occurrence analysis was conducted to illustrate the holistic trend in AP research. A dynamic bar graph, heat maps, and line charts were created to illustrate change trends of MeSH terms. RESULTS: In total, 28,222 publications with 8558 MeSH terms were retrieved from 1941 to 2020. Among these, 16,575 publications with 7228 MeSH terms were from 2001 to 2020. The top 10 MeSH terms showed a considerable change from 1941 to 1970 but remained stable since the 1970s. Four clusters obtained from the co-occurrence analysis were "experiments on animals," "diagnosis and treatment," "prognosis and expectation," and "protein and enzyme." From 1941 to 2020, 33 MeSH terms with increasing trends (MH-I) and 15 MeSH terms with decreasing trends (MH-D) were selected to create a heat map (every decade). Meanwhile, 16 MH-I and 41 MH-D were selected to create the heat map from 2001 to 2020 (every 2 years). CONCLUSION: Over the past 80 years, the pathogenesis, treatment, risk management, and experimental model were the main research highlights. Optimal supportive management, minimally invasive treatment, and prediction of prognosis are subjects of interest for clinical practitioners; signal transduction to identify a target for precise treatment is the focus of experimental research in AP.

Nintedanib Alleviates Chronic Pancreatitis by Inhibiting the Activation of Pancreatic Stellate Cells via the JAK/STAT3 and ERK1/2 Pathways.

BACKGROUND: Nintedanib (Ninte) has been approved for the treatment of pulmonary fibrosis, and whether it can ameliorate chronic pancreatitis (CP) is unknown. AIMS: This study was conducted to investigate the effect and molecular mechanism of Ninte on pancreatic fibrosis and inflammation in vivo and in vitro. METHODS: The caerulein-induced CP model of murine was applied, and Ninte was orally administered. Pathological changes in pancreas were evaluated using hematoxylin & eosin, Sirius Red, Masson's trichrome, and anti-Ki-67 staining. For in vitro studies, the effects of Ninte on cell viability, apoptosis, and migration of pancreatic stellate cells (PSCs) were determined by CCK-8, flow cytometry, and wound healing assays, respectively. The potential molecular mechanisms of the effects of Ninte on PSCs were analyzed by RNA-Seq and verified at the gene expression and protein activity levels by qRT-PCR and Western Blot. RESULTS: Ninte significantly alleviated the weight loss in mice with caerulein-induced CP and simultaneously attenuated the pancreatic damage, as evidenced by reduced acinar atrophy, collagen deposition, infiltration of inflammatory cells, and inhibited cell proliferation/regeneration. Besides, Ninte markedly suppressed the transcription of fibrogenic and proinflammatory genes in pancreatic tissues. Further in vitro studies showed that Ninte significantly inhibited the transcription and protein expression of genes corresponding to fibrogenesis and proliferation in PSCs. The results of RNA-Seq analysis and subsequent verification assays indicated that Ninte inhibited the activation and proliferation of PSCs via the JAK/STAT3 and ERK1/2 pathways. CONCLUSIONS: These findings indicate that Ninte may be a potential anti-inflammatory and anti-fibrotic therapeutic agent for CP.

Deciphering the Biosynthesis of Novel Class I Lanthipeptides from Marine Pseudoalteromonas Reveals a Dehydratase PsfB with Dethiolation Activity.

Lanthipeptides are a representative class of RiPPs that possess characteristic lanthionine and/or methyllanthionine thioether cross-links. The biosynthetic potentials of marine-derived lanthipeptides remain largely unexplored. In this study, we characterized three novel lanthipeptides pseudorosin A-C by heterologous expression of a class I lanthipeptide biosynthetic gene cluster from marine Pseudoalteromonas flavipulchra S16. Interestingly, pseudorosin C contains a large loop spanning 18 amino acid residues, which is rare in lanthipeptides. Unexpectedly, the dehydratase PsfB could catalyze the dethiolation of specific Cys residues in all three core peptides, thereby generating dehydroalanines in the absence of LanC cyclase. To the best of our knowledge, we identified the first member of the LanB dehydratase family to perform glutamylation and subsequent elimination on Cys thiol groups, which likely represents a new bypass for class I lanthipeptide biosynthesis. Furthermore, we employed mutagenesis to determine the important motif of the core peptide for dethiolation activity. Moreover, sequence analysis revealed that PsfB exhibited a distinct phylogenetic distance from the characterized LanBs from Gram-positive bacteria. Our findings, therefore, pave the way for further genome mining of lanthipeptides, novel post-translational modification enzymes from marine Gram-negative bacteria, and bioengineering applications.

Clip-assisted endoloop ligation of the mucosal defect after resection of colorectal polyps decreased postprocedural delayed bleeding.

Background: Postprocedural delayed bleeding (PDB) remains the most common major complication of colorectal polypectomy. Incomplete clip closure of mucosal defect and unclosed injured blood vessels in gaps between clips may be the risk factors for PDB. Objectives: To observe whether completely no-gap closure of mucosal defect after polypectomy can reduce PDB occurrence. Design: Single-center, retrospective case-control study. Methods: In this study based on historical comparisons of patients in 2 time periods, only the patients with polyps sized between 6 and 15 mm were included. A new clip-assisted endoloop ligation (CAEL, treatment group) method was used between January 2019 and December 2020, and a traditional simple clip closure (SCC, control) was used Between January 2017 and December 2018 to prevent PDB after polypectomy. The rate of PDB of two groups and risk factors for PDB were evaluated. Results: Totally 4560 patients were included in the study; 2418 patients belong to CAEL group, and 2142 patients belong to SCC group. The overall rate of PDB was significantly lower in CAEL group compared to SCC group (0.6% versus 1.5%, p < 0.00). On multivariate logistic analysis, CAEL was a significant independent preventive factor for PDB (odds ratio (OR), 0.092; 95% confidence interval (CI), 0.029-0.3335; p = 0.000). Polyps located at rectum (colon versus rectum) represented a significant independent risk factor for PDB (OR, 11.888; 95% CI, 3.343-42.269; p = 0.001). Conclusion: Completely no-gap closure of mucosal defect after polypectomy further reduced the rate of PDB for polyps sized between 6 and 15 mm. CAEL may be a significant independent preventive factor for PDB. Polyps located at the rectum may be a significant independent risk factor for PDB.

Global status of acute pancreatitis research in the last 20 years: A bibliometric study.

Acute pancreatitis (AP) is a common digestive disease encountered in Emergency Departments that carries a heavy socioeconomic burden. This study was conducted to determine the global status of AP research. Articles related to AP published in 1999 to 2018 were retrieved from the Web of Science (WOS) database and the 20 highest-output countries or regions were determined based on the total number of publications. Correlation analysis of AP research output and the gross domestic product (GDP) of each country or region was conducted. The quantity and quality of research of these 20 highest-output countries were compared to the total output, outputs per capita, and average impact factor (IF). All annual data were analyzed using time-trend analysis. A keyword co-occurrence analysis was conducted to determine the highlights in AP research. In total, 17,698 publications were retrieved, and 16,461 papers (93.0%) of them were from the 20 highest-output countries. A significantly positive correlation was identified between AP research output and the GDP (R = 0.973, P < .001). The 5 highest-output countries were the USA (24.9%), China (12.3%), Germany (7.5%), Japan (6.7%), and the UK (6.1%). Finland ranked 1st in the number of publication per capita, the USA had the highest accumulated IF (25,432.758) and total citations (104,592), Switzerland had the highest average IF (6.723), and Netherland had the highest average citations (51.90). Genetic research and AP-related hyperglycemia were research highlights. Analysis of the global output of research of AP research showed signs of growth. Research output was positively correlated with GDP. For the most productive countries, research quality was stable. Although developing countries lagged behind in output per capita and quality, great progress has been made in the past 2 decades.

Clinical characteristics of smoking-related chronic pancreatitis.

Objective: The pathogenesis of chronic pancreatitis (CP) is not completely clear. With further studies, smoking is toxic to the pancreas. This study classified smoking-related CP as a new etiology of CP and defined the cutoff of smoking. Design: Patients with CP admitted from January 2000 to December 2013 were included in the study. The characteristics were compared between smoking patients, drinking patients, and a group of patients who never smoke or drink (control group). The cumulative rates of steatorrhea, diabetes mellitus (DM), pancreatic pseudocyst (PPC), pancreatic stone, and biliary stricture after the onset of CP were calculated, respectively. Results: A total of 1,324 patients were included. Among them, 55 were smoking patients, 80 were drinking patients, and 1,189 were controls. The characteristics of smokers are different from the other two groups, especially in age at the onset and diagnosis of CP, initial manifestation, and type of pain. The development of DM (P = 0.011) and PPC (P = 0.033) was significantly more common and earlier in the smokers than in the other two groups. Steatorrhea also developed significantly more in the smokers than in the controls (P = 0.029). Smokers tend to delay the formation of pancreatic stones and steatorrhea. Conclusion: The clinical characteristics of smoking-related CP is different from CP of other etiologies. A new type of CP, smoking-related CP, was put forward. Smoking-related CP should be separated from idiopathic CP and defined as a new independent subtype of CP different from alcoholic CP or idiopathic CP.

Success and Safety of Needle Knife Papillotomy and Fistulotomy Based on Papillary Anatomy: A Prospective Controlled Trial.

BACKGROUND: Needle knife papillotomy (NKP) and fistulotomy (NKF) are the two most commonly used rescue techniques for patients with difficult biliary cannulation (DBC). Anatomy of the major duodenal papillae (MDP) influences the optimal precut technique for biliary access. However, comparative studies of the success and safety of NKP and NKF based on the anatomy of MDP have been scarce. METHODS: Patients with intact MDPs for therapeutic endoscopic retrograde cholangio-pancreatography (ERCP) in our center were enrolled. Early needle knife precuts were uniformly applied to patients with DBC. Difficult MDPs were classified into one of five types based on their endoscopic anatomy. Each type of MDP was allocated to NKP or NKF treatment. Patients with types 1 and 2 papillae always received NKF, 3 and 4 received NKP, and 5 could receive either. The safety and efficacy were analyzed between NKP and NKF, and among different types of MDPs. RESULTS: A total of 188 out of 1674 patients undergoing ERCP satisfied the criteria for early precutting: 75 patients were assigned to the NKP group and 113 to the NKF group. The total initial success rate of biliary cannulation (ISRBC) of the precut techniques (both NKP and NKF) for patients with DBC was 91.5%. The ISRBC of patients of the NKP group was similar to that of the NKF group (90.7% vs 92.0%, P > 0.05). The ISRBC of the patients in the swollen MDP subgroup (96.1%) was higher than that of patients in the distorted MDP subgroup (81.8%, P = 0.030). The total and specific complications of the patients of the NKP group were similar to those of the NKF group (P > 0.05). CONCLUSIONS: NKP and NKF, as selected on the basis of MDP anatomy, are equally safe and highly efficient for patients with DBC to allow biliary cannulation. Patients with swollen MDPs had a higher ISRBC than patients with distorted MDPs. Selecting a precut method based on MDP anatomy is an effective and safe strategy for patients with DBC.

New framework for recombination and adaptive evolution analysis with application to the novel coronavirus SARS-CoV-2.

The 2019 novel coronavirus (SARS-CoV-2) has spread rapidly worldwide and was declared a pandemic by the WHO in March 2020. The evolution of SARS-CoV-2, either in its natural reservoir or in the human population, is still unclear, but this knowledge is essential for effective prevention and control. We propose a new framework to systematically identify recombination events, excluding those due to noise and convergent evolution. We found that several recombination events occurred for SARS-CoV-2 before its transfer to humans, including a more recent recombination event in the receptor-binding domain. We also constructed a probabilistic mutation network to explore the diversity and evolution of SARS-CoV-2 after human infection. Clustering results show that the novel coronavirus has diverged into several clusters that cocirculate over time in various regions and that several mutations across the genome are fixed during transmission throughout the human population, including D614G in the S gene and two accompanied mutations in ORF1ab. Together, these findings suggest that SARS-CoV-2 experienced a complicated evolution process in the natural environment and point to its continuous adaptation to humans. The new framework proposed in this study can help our understanding of and response to other emerging pathogens.