Mendelian randomization analysis reveals causal effects of food intakes on inflammatory bowel disease risk.

Traditional observational studies have indicated a link between specific food intakes and inflammatory bowel disease (IBD), but the nature of such links remains unknown. We sought to assess the potential causal relationship between food intakes and IBD risk using Mendelian randomization methods. This study used summary statistics data from large-scale genome-wide association studies (GWAS) on food intakes, Crohn's disease (CD), and ulcerative colitis (UC). In the primary analysis, we used the inverse variance-weighted method to determine whether specific food was causal for CD and UC. In addition, we also ran four other Mendelian randomization methods, including MR Egger, weighted median, maximum likelihood, and weighted mode as a complement. The primary analysis showed that high consumption of poultry (OR, 3.696; 95% CI, 1.056-12.937; p = 0.041) and cereal (OR, 2.449; 95% CI, 1.094-5.482; p = 0.029) had a significant causal association with CD, while high oily fish intake level was found to be statistically significantly associated with the risk of UC (OR, 1.482; 95% CI, 1.002-2.194; p = 0.049). This MR study provides evidence of a potential causal link between certain food intake and CD and UC.

Radiosensitivity of colorectal cancer and radiation-induced gut damages are regulated by gasdermin E.

Although radiotherapy is an important clinical option available for colorectal cancer (CRC), its use is restricted due to low radiosensitivity of CRC and high toxicity to surrounding normal tissues. The purpose of this study is to investigate the molecular mechanism by which CRC is not sensitive to radiation and radiation causes toxicity to surrounding normal tissues. Here we found that GSDME was silenced in CRC but markedly expressed in their surrounding normal tissues. GSDME determines radiation-induced pyroptosis in CRC cells and normal epithelial cells through the caspase-3-dependent pathway. GSDME expression sensitizes radioresistant CRC cells to radiation. In the homograft model, after radiation treatment, the tumor volume and weight were significantly decreased in GSDME-expressed homograft tumors compared to GSDME-knockout homograft tumors. On the mechanism, radiation induced GSDME-mediated pyroptosis in CRC cells, which recruited and activated NK cells to enhance antitumor immunity. In addition, GSDME-knockout mice were protected from radiation-induced weight loss and tissue damages in the intestine, stomach, liver and pancreas compared to wild-type control littermates. In summary, we show that GSDME determines CRC radiosensitivity and radiation-related toxicity to surrounding normal tissues through caspase-3-dependent pyroptosis. Our finding reveals a previously unrecognized link between radiation and pyroptosis.

An IRF1-dependent Pathway of TNFα-induced Shedding in Intestinal Epithelial Cells.

BACKGROUND: Shedding of intestinal epithelial cells [IECs] is a potent cause of barrier loss which plays an important role in the pathogenesis of inflammatory bowel disease [IBD]. TNFα can induce IEC shedding, but little is known about this process. METHODS: To investigate the molecular mechanism regulating IEC shedding, mice lacking interferon regulatory factor1 [IRF1], caspase-3, or gasdermin E [GSDME] and their control wild-type [WT] littermates were intravenously injected with tumour necrosis factor alpha [TNFα] to establish an IEC shedding model. A dual-luciferase reporter assay and a chromatin immunoprecipitation assay were used to determine the role of IRF1 in regulating caspase-3 expression. RESULTS: TNFα administration induced obvious IEC shedding in WT mice, but IRF1-/- and caspase-3-/-mice were completely protected from TNFα-induced IEC shedding. As a critical transcription factor, IRF1 was found to be required for caspase-3 expression in IECs by binding to IRF1-binding sites in the caspase-3 promoter. In WT mice, plasma membrane integrity was disrupted in shed IECs; these cells were swollen and contained GSDME-N terminal [NT] fragments which are responsible for the induction of pyroptosis. However, in GSDME-/- mice, plasma membrane integrity was not disrupted in shed IECs, which were not swollen and did not contain GSDME-NT, indicating that GSDME converted TNFα-induced IEC shedding into a pyroptotic cell death process. In addition, IRF1 deficiency resulted in decreases in mucosal inflammation and mucosal bacteria levels in TNFα-challenged colons. CONCLUSIONS: IRF1 deficiency maintains intestinal barrier integrity by restricting TNFα-induced IEC shedding.

Predictors of infliximab-induced deep remission in treatment-naïve patients with isolated small bowel Crohn's disease.

OBJECTIVES: Deep remission should be induced early in the disease course of Crohn's disease (CD), because it significantly prevents disease progression. Identifying predictors of deep remission before treatment is important to guide therapeutic strategy. Little is known about the predictors of infliximab-induced deep remission in treatment-naïve patients with isolated small bowel CD. We aimed to investigate the predictors of infliximab-induced deep remission in these patients. MATERIALS AND METHODS: From January 2015 to December 2019, all consecutive treatment-naïve patients with isolated small bowel CD who started infliximab induction therapy (5 mg/kg at week 0, 2, and 6) and underwent capsule endoscopy (CE) at week 14 were retrospectively included. Deep remission was defined as clinical remission in combination with CE-identified mucosal healing. Logistic regression was used to investigate the predictors of 14-week deep remission. RESULTS: Ninety-one patients were included. At week 14 after infliximab induction therapy, deep remission was found in 42 patients. Multivariate logistic regression analysis showed that a moderate-to-severe endoscopic disease [odds ratio (OR), 0.28; p = .01] and the presence of fibrofatty proliferation (OR, 0.26; p = .04) at baseline were independently associated with a decreased possibility of deep remission. CONCLUSIONS: In treatment-naïve patients with isolated small bowel CD, a moderate-to-severe endoscopic disease and the presence of fibrofatty proliferation at baseline reduce the possibility of infliximab-induced deep remission. Patients with such risk factors may need more aggressive treatment at the beginning of induction therapy to promote deep remission at an early stage.

Gasdermin-E-mediated pyroptosis participates in the pathogenesis of Crohn's disease by promoting intestinal inflammation.

Crohn's disease (CD) is a kind of refractory intestinal inflammatory diseases. Pyroptosis was recently identified as a gasdermin-mediated proinflammatory cell death. However, it is unclear whether gasdermin-mediated pyroptosis participates in the pathogenesis of CD. Here, we show that the pyroptosis-inducing fragment GSDME N-terminal is obviously detected in the inflamed colonic mucosa but not in the uninflamed mucosa of patients with CD, suggesting that GSDME-mediated pyroptosis may be correlated with intestinal mucosal inflammation in CD. To investigate the role of GSDME in colitis development, Gsdme-/- mice and wild-type (WT) littermate controls were treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce colitis. We found that Gsdme-/- mice exhibit less-severe intestinal inflammation than WT controls do. Furthermore, our results indicate that GSDME-mediated epithelial-cell pyroptosis induces intestinal inflammation through the release of proinflammatory intracellular contents. In summary, we show that GSDME participates in the pathogenesis of CD through GSDME-mediated pyroptosis to release proinflammatory cytokines.

In Vivo and In Vitro Genome-Wide Profiling of RNA Secondary Structures Reveals Key Regulatory Features in Plasmodium falciparum.

It is widely accepted that the structure of RNA plays important roles in a number of biological processes, such as polyadenylation, splicing, and catalytic functions. Dynamic changes in RNA structure are able to regulate the gene expression programme and can be used as a highly specific and subtle mechanism for governing cellular processes. However, the nature of most RNA secondary structures in Plasmodium falciparum has not been determined. To investigate the genome-wide RNA secondary structural features at single-nucleotide resolution in P. falciparum, we applied a novel high-throughput method utilizing the chemical modification of RNA structures to characterize these structures. Structural data from parasites are in close agreement with the known 18S ribosomal RNA secondary structures of P. falciparum and can help to predict the in vivo RNA secondary structure of a total of 3,396 transcripts in the ring-stage and trophozoite-stage developmental cycles. By parallel analysis of RNA structures in vivo and in vitro during the Plasmodium parasite ring-stage and trophozoite-stage intraerythrocytic developmental cycles, we identified some key regulatory features. Recent studies have established that the RNA structure is a ubiquitous and fundamental regulator of gene expression. Our study indicate that there is a critical connection between RNA secondary structure and mRNA abundance during the complex biological programme of P. falciparum. This work presents a useful framework and important results, which may facilitate further research investigating the interactions between RNA secondary structure and the complex biological programme in P. falciparum. The RNA secondary structure characterized in this study has potential applications and important implications regarding the identification of RNA structural elements, which are important for parasite infection and elucidating host-parasite interactions and parasites in the environment.

Efficacy of infliximab in treatment-naïve patients with stricturing small bowel Crohn's disease.

OBJECTIVES: The efficacy of infliximab in treatment-naïve patients with stricturing small bowel Crohn's disease (CD) has not been well studied. We aimed to evaluate the efficacy of infliximab in these patients. MATERIALS AND METHODS: This was a retrospective study of all consecutive treatment-naïve patients with newly diagnosed CD with small bowel stricture who started regular infliximab therapy in Nanfang Hospital between January 2015 and December 2019. An effective infliximab therapy was defined as infliximab continuation without the use of steroids, new biologics, endoscopic interventions or intestinal surgery. RESULTS: Seventy-nine patients were included. After a median 38 months follow-up, an effective infliximab therapy was achieved in 37 patients. Long diagnostic delay (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.19-0.78; p= .008), pre-stenotic dilatation (HR 0.17, 95%CI 0.09-0.35; p < .001), long segmental stricture (HR 0.20, 95%CI 0.10-0.41; p < .001), and penetrating disease (HR 0.22, 95%CI 0.10-0.49; p < .001) were negatively correlated with an effective infliximab therapy. CONCLUSIONS: Infliximab is effective in nearly 50% of treatment-naïve patients with CD with small bowel stricture, and an effective therapy is more likely to be achieved in patients without long diagnostic delay, pre-stenotic dilatation, long segmental stricture or penetrating disease.

RNA Secondary Structurome Revealed Distinct Thermoregulation in Plasmodium falciparum.

The development of Plasmodium parasites, a causative agent of malaria, requests two hosts and the completion of 11 different parasite stages during development. Therefore, an efficient and fast response of parasites to various complex environmental changes, such as ambient temperature, pH, ions, and nutrients, is essential for parasite development and survival. Among many of these environmental changes, temperature is a decisive factor for parasite development and pathogenesis, including the thermoregulation of rRNA expression, gametogenesis, and parasite sequestration in cerebral malaria. However, the exact mechanism of how Plasmodium parasites rapidly respond and adapt to temperature change remains elusive. As a fundamental and pervasive regulator of gene expression, RNA structure can be a specific mechanism for fine tuning various biological processes. For example, dynamic and temperature-dependent changes in RNA secondary structures can control the expression of different gene programs, as shown by RNA thermometers. In this study, we applied the in vitro and in vivo transcriptomic-wide secondary structurome approach icSHAPE to measure parasite RNA structure changes with temperature alteration at single-nucleotide resolution for ring and trophozoite stage parasites. Among 3,000 probed structures at different temperatures, our data showed structural changes in the global transcriptome, such as S-type rRNA, HRPII gene, and the erythrocyte membrane protein family. When the temperature drops from 37°C to 26°C, most of the genes in the trophozoite stage cause significantly more changes to the RNA structure than the genes in the ring stage. A multi-omics analysis of transcriptome data from RNA-seq and RNA structure data from icSHAPE reveals that the specific RNA secondary structure plays a significant role in the regulation of transcript expression for parasites in response to temperature changes. In addition, we identified several RNA thermometers (RNATs) that responded quickly to temperature changes. The possible thermo-responsive RNAs in Plasmodium falciparum were further mapped. To this end, we identified dynamic and temperature-dependent RNA structural changes in the P. falciparum transcriptome and performed a comprehensive characterization of RNA secondary structures over the course of temperature stress in blood stage development. These findings not only contribute to a better understanding of the function of the RNA secondary structure but may also provide novel targets for efficient vaccines or drugs.

6-Benzylaminopurine alleviates chilling injury of postharvest cucumber fruit through modulating antioxidant system and energy status.

BACKGROUND: 6-Benzylaminopurine (6-BA) has a close relationship with the stress resistance of plants. Little research has been carried out on the effects of 6-BA on the cold resistance of postharvest fruits and vegetables. Therefore the aim of the present study was to evaluate the effects of 6-BA on chilling injury (CI), antioxidant system and energy status in cucumber during storage. RESULTS: The results showed that 6-BA at 50 mmol L(-1) was most effective to restrain CI in cucumber fruit. Fruits treated with 50 mmol L(-1) 6-BA maintained higher levels of chlorophyll, ascorbic acid, total phenolics and total antioxidant capacity. Furthermore, this treatment reduced the increases in membrane permeability and lipid peroxidation, delayed the increases in both rate of O2•- production and H2O2 content and increased the activities of superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and glutathione reductase (GR) under chilling stress. The treatment also increased the content of adenosine triphosphate (ATP) and resulted in a higher level of energy charge. CONCLUSION: These results indicated that 6-BA alleviated CI in cucumber fruit through improving antioxidant enzyme activities and total antioxidant capacity and maintaining higher levels of ATP content and energy charge.

Bis(benzimidazol-1-yl)methane dihydrate.

The bis-(benzimidazol-1-yl)methane mol-ecule of the title compound, C(15)H(12)N(4)·2H(2)O, displays a trans conformation with a twofold axis running through the methylene C atom. Two adjacent water mol-ecules are bonded to this mol-ecule through O-H⋯N hydrogen bonds, forming a trimer. Adjacent trimers are connected together via C-H⋯O inter-actions, forming a chain running along the b-axis direction. Two such chains are joined together via π-π inter-actions [centroid-centroid distance = 3.556 (2) Å], forming double chains, which are connected via the water mol-ecules through C-H⋯O associations, forming a sheet structure. The sheets are stacked on top of each other along the a-axis direction and connected through O-H⋯O and C-H⋯O inter-actions, forming a three-dimensional ABAB layer network structure.

Oxonium picrate.

The title compound, H(3)O(+)·C(6)H(2)N(3)O(7) (-), consists of one picrate anion and one oxonium cation. The oxonium cation is located on a crystallographic twofold axis and both its H atoms are disordered, each over two symmetry-equivalent positions with occupancy ratios of 0.75. The picrate anions are also located on twofold axes bis-ecting the phenolate and p-nitro groups. π-π inter-actions between the rings of the picrates [centroid-to-centroid distances of 3.324 (2) Å] connect the anions to form stacks along the a-axis direction. The stacks are further joined together by the protonated water mol-ecules through hydrogen bonds to form two-dimensional sheets extending parallel to the ab plane. The sheets are stacked on top of each other along the c-axis direction and connected through C-H⋯O inter-actions between the CH groups of the benzene rings and the picrate nitro groups, with C⋯O distances of 3.450 (2) Å.

A novel starch-based adsorbent for removing toxic Hg(II) and Pb(II) ions from aqueous solution.

A novel effective starch-based adsorbent was prepared through two common reactions, which included the esterification of starch with excess maleic anhydride in the presence of pyridine and the cross-linking reaction of the obtained macromonomer with acrylic acid by using potassium persulphate as initiator. The percentage of carboxylic groups of the macromonomer ranged from 14% to 33.4%. The cross-linking degree of the adsorbent was tailored with the amount of acrylic acid which varied from 10wt% to 80wt%. Both Fourier transform infrared spectra and thermogravimetric analysis results verified the structure of the adsorbent. The maximum gel fraction and swelling ratio of the adsorbent were about 72% and 6.25, respectively, and they were able to be adjusted with the amount of monomers. The weight loss percentage of the adsorbent could reach 96.9% after immersing in the buffer solution that contained α-amylase for 14h. It was found that the adsorption capacities of the adsorbent for lead and mercury ions could be 123.2 and 131.2mg/g, respectively. In addition, the adsorbent was able to remove ca. 51-90% Pb(II) and Hg(II) ions that existed in the decoctions of four medicinal herbals.