Zinc and Inflammatory Bowel Disease: From Clinical Study to Animal Experiment.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract (GI) with a high incidence rate globally, and IBD patients are often accompanied by zinc deficiency. This review aims to summarize the potential therapeutic value of zinc supplementation in IBD clinical patients and animal models. Zinc supplementation can relieve the severity of IBD especially in patients with zinc deficiency. The clinical severity of IBD were mainly evaluated through some scoring methods involving clinical performance, endoscopic observation, blood biochemistry, and pathologic biopsy. Through conducting animal experiments, it has been found that zinc plays an important role in alleviating clinical symptoms and improving pathological lesions. In both clinical observation and animal experiment of IBD, the therapeutic mechanisms of zinc interventions have been found to be related to immunomodulation, intestinal epithelial repair, and gut microbiota's balance. Furthermore, the antioxidant activity of zinc was clarified in animal experiment. Appropriate zinc supplementation is beneficial for IBD therapy, and the present evidence highlights that alleviating zinc-deficient status can effectively improve the severity of clinical symptoms in IBD patients and animal models.

Bacterial community succession in aerobic-anaerobic-coupled and aerobic composting with mown hay affected C and N losses.

The primary objective of this work was to investigate how the dominant microbial species change and affect C and N losses under aerobic and aerobic-anaerobic-coupled composting of mown hay (MH, ryegrass) and corn stover (CS) mix. Results showed that C and N losses in aerobic compost of MH-CS were significantly decreased by 19.57-31.47% and 29.04-41.18%, respectively. 16S rRNA gene sequencing indicated that the bacterial microbiota showed significant differences in aerobic and aerobic-anaerobic-coupled composting. LEfSe analyses showed that aerobic composting promoted the growth of bacteria related to lignocellulosic degradation and nitrogen fixation, while aerobic-anaerobic-coupled composting promoted the growth of bacteria related to denitrification. Correlation analysis between bacterial community and environmental factors indicated that moisture content (MC) was the most important environmental factor influencing the differentiation of bacterial growth. KEGG analysis showed that aerobic composting enhanced the amino acid, carbohydrate, and other advantageous metabolic functions compared to that of aerobic-anaerobic-coupled composting. As a conclusion, the addition of 10-20% corn stover (w/w) to new-mown hay (ryegrass) appeared to inhibit anaerobic composting and prompt aerobic composting in MH-CS mix, which led to the effective utilization of mown hay as a resource for composting.

Transmission and retention of antibiotic resistance genes (ARGs) in chicken and sheep manure composting.

Transmission of ARGs during composting with different feedstocks (i.e., sheep manure (SM), chicken manure (CM) and mixed manure (MM, SM:CM = 3:1 ratio) was studied by metagenomic sequencing. 53 subtypes of ARGs for 22 types of antibiotics were identified as commonly present in these compost mixes; among them, CM had higher abundance of ARGs, 1.69 times than that in SM, while the whole elimination rate of CM, MM and SM were 55.2%, 54.7% and 42.9%, respectively. More than 50 subtypes of ARGs (with 8.6%, 11.4% and 20.9% abundance in the initial stage in CM, MM and SM composting) were "diehard" ARGs, and their abundance grew significantly to 56.5%, 63.2% and 69.9% at the mature stage. These "diehard" ARGs were transferred from initial hosts of pathogenic and/or probiotic bacteria to final hosts of thermophilic bacteria, by horizontal gene transfer (HGT) via mobile gene elements (MGEs), and became rooted in composting products.

The Application of Pyrrolo[2, 3-d]pyrimidine Scaffold in Medicinal Chemistry from 2017 to 2021.

The application of privileged structures in drug design is an effective strategy, which usually leads to innovative hits/leads and successful structural optimization. Pyrrolo[2, 3- d]pyrimidine are such a scaffold which are frequently used in many clinical drugs. The biocompounds bearing pyrrolo[2, 3-d]pyrimidine skeleton show different pharmacological effects such as anti-neurodegenerative, anti-inflammatory, antibacterial, and antitumor activities. In this article, we reviewed the representative structures and biological characteristics of reported synthetic pyrrolo[2, 3-d]pyrimidine compounds from 2017 to 2021. The linked diseases and targets were also mentioned briefly. This work might provide a reference for the subsequent drug discovery based on pyrrolo[2, 3-d]pyrimidine scaffold.

Feedstock-dependent abundance of functional genes related to nitrogen transformation controlled nitrogen loss in composting.

The objective of this work was to explore how selection of feedstock affects nitrogen cycle genes during composting, which eventually determines the nitrogen loss. Four composting mixes (CM: chicken manure; SM: sheep manure; MM1/3: mixed manure with CM: SM = 1:3 w/w, MM3/1: CM: SM = 3:1 w/w) were investigated. Results showed that adding 25 % and 75 % SM to CM reduced 26.5 % and 57.9 % nitrogen loss, respectively. CM contained more ammonification genes and nrfA gene, while SM had more denitrification genes. Nitrogen fixation genes in CM were slightly higher than that in SM at the initial stage, but they sharply dropped off as the composting entered the high temperature stage. MM1/3 showed significantly reduced ammonification genes than CM, and increased nitrogen fixation and NH4+ assimilation genes. Therefore, adding SM to CM could change the abundance of genes and enzymes related to nitrogen cycle to reduce nitrogen loss.

Derivatives of sarcodonin A isolated from Sarcodon scabrosus reversed LPS-induced M1 polarization in microglia through MAPK/NF-κB pathway.

Emerging evidence suggests the regulation of microglial phenotype balance between M1 and M2 will be a potential therapeutic strategy for microglia-mediated neuroinflammation in Alzheimer's disease (AD). Herein, we evaluated the anti-neuroinflammatory effects and the underlying mechanism of a natural cyathane diterpenoid sarcodonin A (1) derived from the mushroom Sarcodon scabrosus and its six new derivatives (2-7). Lipopolysaccharide (LPS)-activated primary microglia and microglia cell lines were used as models. The nitrite test and immunostaining showed that the derivative named 6 was more effective in inhibiting neuroinflammation. qRT-PCR, ELISA, and western blotting revealed that 6 showed more significant suppression on mRNA and protein expression of proinflammatory M1 markers of TNF-α, IL-6, IL-1ß, iNOS, and COX-2, while more obvious potentiation on mRNA and protein levels of anti-inflammatory M2 markers of IL-10 and ARG-1. In mechanism, western blotting demonstrated that 6 inhibited LPS-induced activation of MAPK, and prevented LPS-stimulated nuclear translocation of NF-κB p65. Molecular docking revealed that 1 and 6 constructed interactions with iNOS. Collectively, the present study indicated that 1 and 6 might support neuroprotection by reversing LPS-induced microglia M1 polarization, implying that sarcodonin A can be a promising candidate for developing new therapeutics against AD by targeting microglia-mediated neuroinflammation.

Highly oxygenated chemical constitutes and rearranged derivatives with neurotrophic activity from Ganoderma cochlear.

ETHNOPHARMACOLOGICAL RELEVANCE: The morphological characteristics of Ganoderma cochlear (Blume & T. Nees) Bres were identical to G. sinsense J.D. Zhao, L.W. Hsu & X.Q. Zhang, however, with the fungus stipe lying in the back of the pileus. Fruiting bodies and spores of G. cochear have been traditionally used for smoothing, sleeping improvement, memory impairment, anti-aging, and prolonging life. Alzheimer's disease (AD) is a chromic progressive neurodegenerative disorder associated with loss of memory and cognition. Hallmarks of AD include aging, amyloid-ß plaques, neurofibrillary tangles, neuron loss, neuronal degeneration, network disruption, cognitive dysfunction, inflammation and oxidation stress. In this study, norlanostanoids from G. cochear are identified as potential neurotrophic chemists related to the memory impairment usage to slow down pathogenetic process and restore neural circuits for AD. AIM OF STUDY: Chemical and biological investigations in this study uncovered the potential constituents related to the traditional usage of G. cochlear. MATERIALS AND METHODS: The extract of the mushrooms was purified using various column chromatography techniques and high-performance liquid chromatography (HPLC). The structures of the isolates were elucidated by combination of spectral, and single crystal X-ray diffraction analysis. The neurotrophic activity was evaluated by the differentiation state of PC12 cells, and the dose-dependent and time-dependant expression of growth-associated protein (GAP-43) was analyzed by western blotting. RESULTS: Ganorbifates J-T (1-11), eleven previously undescribed triterpenoids together with five known trinorlanostanoids (12-16) were isolated from the fruiting bodies of G. Cochlear. Among them, ganorbifates N-O (5-6) had a demethylation at C-28 compared to the classic skeleton of 3,4-seco-25,26,27-trinorlanostanoids to form a new group of 3,4-seco-25,26,27,28-tetranorlanostanoids. Based on this, a novel skeleton of ganorbifate M (4) was further established by the arrangement of C-29 from C-4 to C-7. A plausible biosynthetic pathway of compounds 4-6 was proposed. Eight of the sixteen isolates showed neurotrophic activity with the concentration of 10 µM. Furthermore, compound 15 exhibited a dose-dependent neurogenic activity, and also strengthened the expression of the growth-associated protein (GAP-43) in NGF-induced PC-12 cells, whereas 11 showed an inhibitory effect at higher concentration. CONCLUSION: These results demonstrated that 3,4-seco-norlanostanoids had reliable potential in promoting the outgrowth of PC-12 cells and could be used in the prevention and treatment of Alzheimer's disease, which is consist with the beneficial effects of G. Cochlear.

A review of synthetic bioactive tetrahydro-ß-carbolines: A medicinal chemistry perspective.

1, 2, 3, 4-Tetrahydro-ß-carboline (THßC) scaffold is widespread in many natural products (NPs) and synthetic compounds which show a variety of pharmacological activities. In this article, we reviewed the design, structures and biological characteristics of reported synthetic THßC compounds, and structure and activity relationship (SAR) of them were also discussed. This work might provide a reference for subsequent drug development based on THßC.

Impact of B-mode-ultrasound-guided transhepatic and transperitoneal cholecystostomy tube placement on laparoscopic cholecystectomy.

BACKGROUND: B-mode-ultrasound-guided percutaneous cholecystostomy (PC) may be performed by a transhepatic or transperitoneal approach, called percutaneous transhepatic gallbladder drainage (PHGD) and percutaneous transperitoneal gallbladder drainage (PPGD), respectively. We compared the impact of PC related to the route of catheter placement on subsequent laparoscopic cholecystectomy (LC). AIM: To compare the impact of PC related to the route of catheter placement on subsequent LC. METHODS: We retrospectively studied 103 patients with acute calculous cholecystitis who underwent scheduled LC after PC between January 2010 and January 2019. Group I included 58 patients who underwent scheduled LC after PHGD. Group II included 45 patients who underwent scheduled LC after PPGD. Clinical outcomes were analyzed according to each group. RESULTS: Baseline demographic characteristics did not differ significantly between both groups (P > 0.05). Both PHGD and PPGD were able to quickly resolve cholecystitis sepsis. Group I showed significantly higher efficacy than group II in terms of lower pain score during puncture (3.1 vs 4.5; P = 0.001) and at 12 h follow-up (1.5 vs 2.2; P = 0.001), lower rate of fever within 24 h after PC (13.8% vs 42.2%; P = 0.001), shorted operation duration (118.3 vs 139.6 min; P = 0.001), lower amount of intraoperative bleeding (72.1 vs 109.4 mL; P = 0.001) and shorter length of hospital stay (14.3 d vs 18.0 d; P = 0.001). However, group II had significantly lower rate of local bleeding at the PC site (2.2% vs 20.7%; P = 0.005) and lower rate of severe adhesion (33.5% vs 55.2%; P = 0.048). No significant differences were noted between both groups regarding the conversion rate to laparotomy, rate of subtotal cholecystectomy, complications and pathology. CONCLUSION: B-mode-ultrasound-guided PHGD is superior to PPGD followed by LC for treatment of acute calculous cholecystitis, with shorter operating time, minimal amount of intraoperative bleeding and short length of hospital stay.

Methylation-Mediated Silencing of GATA5 Gene Suppresses Cholangiocarcinoma Cell Proliferation and Metastasis.

Cholangiocarcinoma (CCA) is one of the most common hepatic and biliary malignancies, accounting for about 3% of all gastrointestinal tumors. GATA5 is a transcription factor capable of suppressing the development of various human cancer types. Transcriptional inactivation and CpG island (CGI) methylation of GATA3 and GATA5, two members of the GATA family of transcription factors, have been observed in some human cancers. But whether high-density CGI methylation of GATA5 is associated with the clinical course of CCA patients has not been clarified. Herein, we observed reduced expression of GATA5 in CCA tissues compared with noncancerous tissues. Treatment with the demethylating agent 5-aza-2'-deoxycytidine restored GATA5 expression in CCA cell lines. Furthermore, GATA5 expression was downregulated after treatment with IL-6 in human intrahepatic biliary epithelial cells. Upregulated GATA5 inhibited CCA cell growth and metastasis. Mechanistically, GATA5 suppressed CCA cell growth and metastasis via Wnt/ß-catenin pathway. Specific ß-catenin inhibitor or siRNA abolished the discrepancy of the proliferation and metastasis capacity between GATA5-overexpression CCA cells and their control cells, which further confirmed that Wnt/ß-catenin was required in GATA5-inhibited CCA cell growth and metastasis.

The TimeGeo modeling framework for urban motility without travel surveys.

Well-established fine-scale urban mobility models today depend on detailed but cumbersome and expensive travel surveys for their calibration. Not much is known, however, about the set of mechanisms needed to generate complete mobility profiles if only using passive datasets with mostly sparse traces of individuals. In this study, we present a mechanistic modeling framework (TimeGeo) that effectively generates urban mobility patterns with resolution of 10 min and hundreds of meters. It ties together the inference of home and work activity locations from data, with the modeling of flexible activities (e.g., other) in space and time. The temporal choices are captured by only three features: the weekly home-based tour number, the dwell rate, and the burst rate. These combined generate for each individual: (i) stay duration of activities, (ii) number of visited locations per day, and (iii) daily mobility networks. These parameters capture how an individual deviates from the circadian rhythm of the population, and generate the wide spectrum of empirically observed mobility behaviors. The spatial choices of visited locations are modeled by a rank-based exploration and preferential return (r-EPR) mechanism that incorporates space in the EPR model. Finally, we show that a hierarchical multiplicative cascade method can measure the interaction between land use and generation of trips. In this way, urban structure is directly related to the observed distance of travels. This framework allows us to fully embrace the massive amount of individual data generated by information and communication technologies (ICTs) worldwide to comprehensively model urban mobility without travel surveys.

Limits of predictability in commuting flows in the absence of data for calibration.

The estimation of commuting flows at different spatial scales is a fundamental problem for different areas of study. Many current methods rely on parameters requiring calibration from empirical trip volumes. Their values are often not generalizable to cases without calibration data. To solve this problem we develop a statistical expression to calculate commuting trips with a quantitative functional form to estimate the model parameter when empirical trip data is not available. We calculate commuting trip volumes at scales from within a city to an entire country, introducing a scaling parameter α to the recently proposed parameter free radiation model. The model requires only widely available population and facility density distributions. The parameter can be interpreted as the influence of the region scale and the degree of heterogeneity in the facility distribution. We explore in detail the scaling limitations of this problem, namely under which conditions the proposed model can be applied without trip data for calibration. On the other hand, when empirical trip data is available, we show that the proposed model's estimation accuracy is as good as other existing models. We validated the model in different regions in the U.S., then successfully applied it in three different countries.

Prognostic significance of the combined expression of neutral endopeptidase and dipeptidyl peptidase IV in intrahepatic cholangiocarcinoma patients after surgery resection.

AIM: The aim of this study was to investigate the relationship between the expression of neutral endopeptidase (NEP) and dipeptidyl peptidase IV (DPP IV) proteins, and the clinical significance of the two proteins in patients with intrahepatic cholangiocarcinomas (IHCC). METHODS: Expression patterns and subcellular localizations of NEP and DPP IV proteins in 186 primary IHCC and 60 noncancerous liver tissue specimens were detected by immunohistochemistry. RESULTS: Both the expression of NEP and DPP IV proteins in IHCC tissues were significantly higher than those in noncancerous liver tissues (both P<0.001). Of 186 patients with IHCC, 128 (68.82%) highly expressed both NEP and DPP IV proteins. In addition, the coexpression of NEP and DPP IV proteins was significantly associated with advanced tumor stage (P=0.009), positive lymph node metastasis (P=0.016) and distant metastasis (P=0.013), and the presence of recurrence (P=0.027). Moreover, Kaplan-Meier analysis showed that IHCC patients with high NEP expression, high DPP IV expression, and combined overexpression of NEP and DPP IV proteins all had poorer overall survival and early recurrence after surgery. Furthermore, Cox analysis suggested that NEP expression, DPP IV expression, and combined expression of NEP and DPP IV proteins were all independent prognostic markers for overall survival and recurrence-free survival in patients with IHCC. CONCLUSION: Our data suggest, for the first time, that both the expression of NEP and DPP IV proteins may be upregulated in human IHCC tissues and the combined expression of NEP and DPP IV proteins may play important roles in progression and prognosis of patients with IHCC.

Choice of approach for hepatectomy for hepatocellular carcinoma located in the caudate lobe: isolated or combined lobectomy?

AIM: To investigate the significance of the surgical approaches in the prognosis of hepatocellular carcinoma (HCC) located in the caudate lobe with a multivariate regression analysis using a Cox proportional hazard model. METHODS: Thirty-six patients with HCC underwent caudate lobectomy at a single tertiary referral center between January 1995 and June 2010. In this series, left-sided, right-sided and bilateral approaches were used. The outcomes of patients who underwent isolated caudate lobectomy or caudate lobectomy combined with an additional partial hepatectomy were compared. The survival curves of the isolated and combined resection groups were generated by the Kaplan-Meier method and compared by a log-rank test. RESULTS: Sixteen (44.4%) of 36 patients underwent isolated total or partial caudate lobectomy whereas 20 (55.6%) received a total or partial caudate lobectomy combined with an additional partial hepatectomy. The median diameter of the tumor was 6.7 cm (range, 2.1-15.8 cm). Patients who underwent an isolated caudate lobectomy had significantly longer operative time (240 min vs 170 min), longer length of hospital stay (18 d vs 13 d) and more blood loss (780 mL vs 270 mL) than patients who underwent a combined caudate lobectomy (P < 0.05). There were no perioperative deaths in both groups of patients. The complication rate was higher in the patients who underwent an isolated caudate lobectomy than in those who underwent combined caudate lobectomy (31.3% vs 10.0%, P < 0.05). The 1-, 3- and 5-year disease-free survival rates for the isolated caudate lobectomy and the combined caudate lobectomy groups were 54.5%, 6.5% and 0% and 85.8%, 37.6% and 0%, respectively (P < 0.05). The corresponding overall survival rates were 73.8%, 18.5% and 0% and 93.1%, 43.6% and 6.7% (P < 0.05). CONCLUSION: The caudate lobectomy combined with an additional partial hepatectomy is preferred because this approach is technically less demanding and offers an adequate surgical margin.

The effects of TLR activation on T-cell development and differentiation.

Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.

Immunomodulatory effects of dsRNA and its potential as vaccine adjuvant.

dsRNA can be detected by pattern recognition receptors, for example, TLR3, MDA-5, NLRP3 to induce proinflammatory cytokines responsible for innate/adaptive immunity. Recognized by endosomal TLR3 in myeloid DCs (mDCs), dsRNA can activate mDCs into mature antigen presenting cells (mAPCs) which in turn present antigen epitopes with MHC-I molecules to naïve T cells. Coadministration of protein and synthetic dsRNA analogues can elicit an antigen-specific Th1-polarized immune response which stimulates the CD8+ CTL response and possibly dampen Th17 response. Synthetic dsRNA analogues have been tested as vaccine adjuvant against viral infections in animal models. However, a dsRNA receptor, TLR3 can be expressed in tumor cells while other members of TLR family, for example, TLR4 and TLR2 have been shown to promote tumor progression, metastasis, and chemoresistance. Thus, the promising potential of dsRNA analogues as a tumor therapeutic vaccine adjuvant should be evaluated cautiously.

[Early fracture fixation alleviates gut barrier function damage after multiple firearm injuries in pigs].

OBJECTIVE: To explore if early fracture fixation can alleviate gut barrier function damage caused by multiple firearm injuries in pigs. METHODS: Twelve healthy pigs were subjected to tangential fracture of parietal bone and comminuted fractures of bilateral femora (ISS >or= 16) due to 5.8 mm bullets shooting and these pigs were divided randomly into 2 groups. Control group (n = 6) were not treated at all. Fracture fixation Group (n = 6) were managed by immediate fracture fixation of bilateral femora with intramedullary nails. Plasma concentration of D-lactate, DAO and endotoxin (in portal vein) were detected at different intervals before and after trauma. The portal vein blood was cultured and the percentage of positive isolation was calculated. The concentration of DAO in small bowel was also detected 72 hours later after trauma. RESULTS: In control group, the plasma concentrations of D-lactate, DAO and endotoxin increased at early stage and kept high till 72 hours after trauma; the percentage of positive blood culture was 63.3%. In Group F, the levels of plasma D-lactate, DAO and endotoxin were also elevated at early stage (6 - 12 h), but declined significantly from 24 h or 48 h after trauma compared with control group (P < 0.05), and the percentage of positive blood culture was lower (30.0%, P < 0.05). The concentrations of DAO in small bowel decreased in both groups, but to a less extent in Group F. CONCLUSION: Bacterial and endotoxin translocation emerged with increasing gut permeability after multiple firearm injuries. The damage of gut barrier function could be alleviated and the chance of enterogenous infection could be by early fracture fixation after trauma.