Metabolomics study of Berberidis Radix in intervening ulcerative colitis based on UPLC-Q-TOF-MS / 中国中药杂志

The effect of Tujia medicine Berberidis Radix on endogenous metabolites in the serum and feces of mice with ulcerative colitis(UC) induced by dextran sulfate sodium(DSS) was analyzed by metabolomics technology to explore the metabolic pathway and underlying mechanism of Berberidis Radix in the intervention of UC. The UC model was induced in mice by DSS. Body weight, disease activity index(DAI), and colon length were recorded. The levels of tumor necrosis factor-α(TNF-α) and interleukin-10(IL-10) in colon tissues were determined by ELISA. The levels of endogenous metabolites in the serum and feces were detected by ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS). Principal component analysis(PCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA) were employed to characterize and screen differential metabolites. The potential metabolic pathways were analyzed by MetaboAnalyst 5.0. The results showed that Berberidis Radix could significantly improve the symptoms of UC mice and increase the level of the anti-inflammatory factor IL-10. A total of 56 and 43 differential metabolites were identified in the serum and feces, respectively, belonging to lipids, amino acids, fatty acids, etc. After the intervention by Berberidis Radix, the metabolic disorder gradually recovered. The involved metabolic pathways included biosynthesis of phenylalanine, tyrosine, and tryptophan, linoleic acid metabolism, phenylalanine metabolism, and glycerophospholipid metabolism. Berberidis Radix can alleviate the symptoms of mice with DSS-induced UC, and the mechanism may be closely related to the re-gulation of lipid metabolism, amino acid metabolism, and energy metabolism.

Platycodon grandiflorus polysaccharide regulates colonic immunity through mesenteric lymphatic circulation to attenuate ulcerative colitis / 中国天然药物

Platycodon grandiflorus polysaccharide (PGP) is one of the main components of P. grandiflorus, but the mechanism of its anti-inflammatory effect has not been fully elucidated. The aim of this study was to evaluate the therapeutic effect of PGP on mice with dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) and explore the underlying mechanisms. The results showed that PGP treatment inhibited the weight loss of DSS-induced UC mice, increased colon length, and reduced DAI, spleen index, and pathological damage within the colon. PGP also reduced the levels of pro-inflammatory cytokines and inhibited the enhancement of oxidative stress and MPO activity. Meanwhile, PGP restored the levels of Th1, Th2, Th17, and Treg cell-related cytokines and transcription factors in the colon to regulate colonic immunity. Further studies revealed that PGP regulated the balance of colonic immune cells through mesenteric lymphatic circulation. Taken together, PGP exerts anti-inflammatory and anti-oxidant effect and regulates colonic immunity to attenuate DSS-induced UC through mesenteric lymphatic circulation.

Therapeutic effect of ursodeoxycholic acid-berberine supramolecular nanoparticles on ulcerative colitis based on supramolecular system induced by weak bond / 中国中药杂志

Ulcerative colitis(UC) is a recurrent, intractable inflammatory bowel disease. Coptidis Rhizoma and Bovis Calculus, serving as heat-clearing and toxin-removing drugs, have long been used in the treatment of UC. Berberine(BBR) and ursodeoxycholic acid(UDCA), the main active components of Coptidis Rhizoma and Bovis Calculus, respectively, were employed to obtain UDCA-BBR supramolecular nanoparticles by stimulated co-decocting process for enhancing the therapeutic effect on UC. As revealed by the characterization of supramolecular nanoparticles by field emission scanning electron microscopy(FE-SEM) and dynamic light scattering(DLS), the supramolecular nanoparticles were tetrahedral nanoparticles with an average particle size of 180 nm. The molecular structure was described by ultraviolet spectroscopy, fluorescence spectroscopy, infrared spectroscopy, high-resolution mass spectrometry, and hydrogen-nuclear magnetic resonance(H-NMR) spectroscopy. The results showed that the formation of the supramolecular nano-particle was attributed to the mutual electrostatic attraction and hydrophobic interaction between BBR and UDCA. Additionally, supramolecular nanoparticles were also characterized by sustained release and pH sensitivity. The acute UC model was induced by dextran sulfate sodium(DSS) in mice. It was found that supramolecular nanoparticles could effectively improve body mass reduction and colon shortening in mice with UC(P<0.001) and decrease disease activity index(DAI)(P<0.01). There were statistically significant differences between the supramolecular nanoparticles group and the mechanical mixture group(P<0.001, P<0.05). Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), and the results showed that supramolecular nanoparticles could reduce serum TNF-α and IL-6 levels(P<0.001) and exhibited an obvious difference with the mechanical mixture group(P<0.01, P<0.05). Flow cytometry indicated that supramolecular nanoparticles could reduce the recruitment of neutrophils in the lamina propria of the colon(P<0.05), which was significantly different from the mechanical mixture group(P<0.05). These findings suggested that as compared with the mechanical mixture, the supramolecular nanoparticles could effectively improve the symptoms of acute UC in mice. The study provides a new research idea for the poor absorption of small molecules and the unsatisfactory therapeutic effect of traditional Chinese medicine and lays a foundation for the research on the nano-drug delivery system of traditional Chinese medicine.

Mechanism of tryptanthrin in treatment of ulcerative colitis in mice based on serum metabolomics / 中国中药杂志

This study aims to explore the effect of tryptanthrin on potential metabolic biomarkers in the serum of mice with ulcerative colitis(UC) induced by dextran sulfate sodium(DSS) based on liquid chromatography-mass spectrometry(LC-MS) and predict the related metabolic pathways. C57BL/6 mice were randomly assigned into a tryptanthrin group, a sulfasalazine group, a control group, and a model group. The mouse model of UC was established by free drinking of 3% DSS solution for 11 days, and corresponding drugs were adminsitrated at the same time. The signs of mice were observed and the disease activity index(DAI) score was recorded from the first day. Colon tissue samples were collected after the experiment and observed by hematoxylin-eosin(HE) staining. The levels of interleukin-4(IL-4), interleukin-10(IL-10), tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-8(IL-8) in the serum were measured by enzyme linked immunosorbent assay(ELISA). The serum samples were collected from 6 mice in each group for widely targeted metabolomics. The metabolic pathways were enriched by MetaboAnalyst 5.0. The results showed that compared with the model group, tryptanthrin treatment decreased the DAI score(P<0.05), alleviated the injury of the colon tissue and the infiltration of inflammatory cells, lowered the levels of proinflammatory cytokines, and elevated the levels of anti-inflammatory cytokines in the serum. The metabolomic analysis revealed 28 differential metabolites which were involved in 3 metabolic pathways including purine metabolism, arachidonic acid metabolism, and tryptophan metabolism. Tryptanthrin may restore the metabolism of the mice with UC induced by DSS to the normal level by regulating the purine metabolism, arachidonic acid metabolism, and tryptophan metabolism. This study employed metabolomics to analyze the mechanism of tryptanthrin in the treatment of UC, providing an experimental basis for the utilization and development of tryptanthrin.

Huangqin Decoction Attenuates DSS-Induced Mucosal Damage and Promotes Epithelial Repair via Inhibiting TNF-α-Induced NF-κB Activation / 中国结合医学杂志

OBJECTIVE@#To investigate the protective effect of Chinese herbal formula Huangqin Decoction (HQD) on ulcerative colitis mouse model induced by dextran sulphate sodium (DSS) and human intestinal epithelial cell injury induced by tumour necrosis factor-α (TNF-α).@*METHODS@#In vivo, 30 male C57BL/6 mice were divided into 5 groups using a random number table (n=6 per group), including control, DSS, 5-aminosalicylic acid (5-ASA), HQD low- (HQD-L) and high-dose (HQD-H) groups. The colitis mouse model was established by 3% (w/v) DSS water for 5 days. Meanwhile, mice in the HQD-L, HQD-H and 5-ASA groups were administrated with 100, 200 mg/kg HQD or 100 mg/kg 5-ASA, respectively, once daily by gavage. After 9 days of administration, the body weight, disease activity index (DAI) score and colon length of mice were measured, the pathological changes of colons were analyzed by hematoxylin-eosin staining (HE) staining, and the levels of serum interleukin (IL)-6, IL-1β and TNF-α were measured by enzyme linked immunosorbent assay. In vitro, the human colon epithelial normal cells (FHC cells) were exposed to HQD (0.6 mg/mL) for 12 h and then treated with TNF-α (10 ng/mL) for 24 h. The tight junction (TJ) protein expression levels of Claudin-4 and Occludin, and the protein phosphorylation levels of p65 and inhibitor of nuclear factor kappaB (NF-κB)-α (IκBα) were measured by Western blot.@*RESULTS@#In vivo, compared with the DSS group, HQD-H treatment attenuated the weight loss and reduced DAI score of mice on the 8th day (P<0.05). Moreover, HQD-H treatment ameliorated the colon shortening in the DSS-induced colitis mice (P<0.05). HE staining showed HQD attenuated the pathological changes of colitis mice, and the histological scores of HQD-H and 5-ASA groups were significantly decreased compared with the DSS group (P<0.05). Meanwhile, HQD-H and 5-ASA significantly decreased the serum IL-1β, IL-6 and TNF-α levels of mice (P<0.05). In vitro experiments showed that HQD up-regulated Occludin and Claudin-4 protein expressions and inhibited p-p65 and p-IκBα levels in FHC cells compared with the TNF-α group (P<0.05).@*CONCLUSION@#HQD significantly relieved the symptoms in DSS-induced colitis mice by inhibiting pro-inflammatory cytokines expression and maintained the homeostasis of TJ protein in FHC cells by suppressing TNF-α-induced NF-κB activation.

Study on serum pharmacodynamic material basis of Gegen Qinlian Decoction in treatment of ulcerative colitis based on UHPLC-Q-Orbitrap-MS / 中国中药杂志

This study established a mouse model of ulcerative colitis and explored the serum transitional components of Gegen Qinlian Decoction by UHPLC-Q-Orbitrap-MS. Based on the exact relative molecular weight and MS/MS spectrum, 55 prototype components and 59 metabolites were identified from the model group, while 18 prototype components and 35 metabolites from the control group. The prototype components in serum were mainly flavonoids and the characteristic components of the model group were alkaloids. Glucuronidation, sulfonation, and glycosylation have been confirmed to be the main metabolic types in vivo. The results of comparative analysis of differences indicated that puerarin, baicalin, wogonoside, wogonin, chrysin, oroxylin A, berberine, berberrubine, and palmatine were the characteristic components in model state, which at the same time, were confirmed by pharmacological studies to be the serum pharmacodynamic material basis of Gegen Qinlian Decoction in the treatment of ulcerative colitis. This study has provided reference for explaining the metabolic transformation pattern and mechanism of action of Gegen Qinlian Decoction in vivo.

E.faecium QH06 alleviates TNBS-induced colonic mucosal injury in rats / 南方医科大学学报

OBJECTIVE@#To investigate the effect of Enterococcus faecium QH06 on TNBS-induced ulcerative colitis (UC) in rats and explore the mechanisms in light of intestinal flora and intestinal immunity.@*METHODS@#Thirty-six male Wistar rats were randomized equally into control group, UC model group, and E.faecium QH06 intervention group. The rats in the latter two groups were subjected to colonic enema with 5% TNBS/ethanol to induce UC, followed by treatment with intragastric administration of distilled water or E.faecium QH06 at the dose of 0.21 g/kg. After 14 days of treatment, the rats were examined for colon pathologies with HE staining. The mRNA and protein expression levels of IL-4, IL-10, IL-12, and IFN-γ in the colon tissues were detected using RT-qPCR and ELISA, and the expression of TLR2 protein was detected with immunohistochemistry and ELISA. Illumina Miseq platform was used for sequencing analysis of the intestinal flora of the rats with bioinformatics analysis. The correlations of the parameters of the intestinal flora with the expression levels of TLR2 and cytokines were analyzed.@*RESULTS@#The rats with TNBS- induced UC showed obvious weight loss (P < 0.01) and severe colon tissue injury with high pathological scores (P < 0.01). The protein expression levels of IFN-γ, IL-12, and TLR2 (P < 0.01) and the mRNA expression levels of IFN-γ, IL-12 and IL-10 (P < 0.05) were significantly increased in the colon tissues of the rats with UC. Illumina Miseq sequence analysis showed that in UC rats, the Shannon index (P < 0.05) ACE (P < 0.01)and Chao (P < 0.05) index for the diversity of intestinal flora both decreased with a significantly increased abundance of Enterobacteriaceae (P < 0.01) and a lowered abundance of Burkholderiaceae (P < 0.05). Compared with the UC rats, the rats treated with E. faecium QH06 showed obvious body weight gain (P < 0.05), lessened colon injuries, lowered pathological score of the colon tissue (P < 0.05), decreased protein expressions of IFN- γ, IL- 12, and TLR2 and mRNA expressions of IFN- γ and IL-12 (P < 0.01 or 0.05), and increased protein expressions of IL- 4 (P < 0.05). The Shannon index ACE (P < 0.05) and Chao (P < 0.05) index of intestinal microflora were significantly increased, the abundance of Enterobacteriaceae was lowered and that of Burkholderiaceae and Rikenellaceae was increased in E.faecium QH06- treated rats (P < 0.01 or 0.05). Correlation analysis showed that IFN-γ was positively correlated with the abundance of Enterobacteriaceae, and IFN-γ was negatively correlated with the abundance of Prevotellaceae, Desulfovibrionaceae, norank_o_Mollicutes_RF39 and Clostridiales_vadinBB60_group; TLR2 was negatively correlated with Clostridiales_vadinBB60_group, norank_o_Mollicutes_RF39 and Prevotellaceae.@*CONCLUSION@#E.faecium QH06 can alleviate TNBS-induced colonic mucosal injury in rats, and its effect is mediated possibly by increasing the abundance of SCFA-producing bacteria such as Prevotellaceae and inhibiting abnormal immune responses mediated by TLR2.

Psoriasis paradójica palmoplantar secundaria al tratamiento de la colitis ulcerosa con adalimumab / Paradoxical psoriasis of the palms and soles due to treatment of ulcerative colitis with adalimumab

Los anticuerpos anti-TNF-a (tumor necrosis factor alpha) se utilizan para tratar tanto la psoriasis como la enfermedad inflamatoria intestinal (EII). Sin embargo, estos fármacos han sido implicados en la ocurrencia de la psoriasis paradójica en los pacientes sin antecedentes de psoriasis que reciben tratamiento por una colitis ulcerosa (CU) y otras enfermedades autoinmunes. Se presenta el caso de un paciente de 29 años, sin antecedentes de dermatosis, que desarrolló una psoriasis palmoplantar paradójica por el uso del adalimumab que recibía por un diagnóstico de CU. El cuadro remitió al suspender el medicamento y recurrió al reiniciarlo, motivo por el cual se rotó al ustekinumab. La CU respondió satisfactoriamente, sin nuevas lesiones dermatológicas.

Anti TNF-a (tumor necrosis factor alpha) antibodies are used to treat both psoriasis and inflammatory bowel disease (IBD). However, these drugs have been implicated in the occurrence of the so-called paradoxical psoriasis in patients with no previous history of psoriasis, who receive treatment for ulcerative colitis and other autoimmune diseases. We present a 29-year-old male patient, with no previous history of dermatosis, who developed paradoxical palmar-plantar psoriasis due to the use of adalimumab that he was receiving for a diagnosis of ulcerative colitis. The condition remitted when the drug was suspended and recurred when it was restarted, and for that reason, treatment was rotated to ustekinumab. Ulcerative colitis responded satisfactorily, with no new dermatological lesions.

Researching Interventions to Improve Medication Adherence in Ulcerative Colitis Patients / Pesquisando intervenções para a melhoria da adesão à medicação em pacientes com colite ulcerativa

Abstract The purpose of this review was to identify interventions that improve adherence to medications in patients with ulcerative colitis (UC). The literature search was carried out between April and June 2020 in the PubMed/MEDLINE database, with the combination of MeSH terms medication adherence; intervention; ulcerative colitis; and inflammatory bowel disease.We restricted our search to articles published in English and Portuguese between March 2010 and March 2020. After the selection, recovery of fulltext articles and analysis of the defined criteria, the interventions described in the studies were classified into four domains: educational; behavioral, cognitive behavioral, and multicomponent. In total, six clinical trials met the inclusion criteria and were analyzed. Half of the studies (3; 50%) used multicomponent interventions, 2 (33.3%) focused on behavioral interventions, and 1 (16.7%) applied isolated educational interventions. All studies used indirect methods to measure adherence, with an emphasis on scales and questionnaires. Half of the studies (3; 50%) showed a positive impact on adherence in patients with UC, with evidence that multicomponent interventions, when properly implemented in a clinical trial combining direct and indirect methods to measure medication adherence, appear to increase the chances of better results. We believe that future studies focusing on improving adherence in patients with UC are necessary.

Resumo O objetivo desta revisão foi identificar intervenções para a melhoria da adesão a medicamentos em pacientes com colite ulcerativa (CU). A busca na literatura foi realizada entre abril e junho de 2020 na base de dados do PubMed/MEDLINE, com a combinação dos descritores medication adherence; intervention; ulcerative colitis; e inflammatory bowel disease. Restringimos a busca aos artigos publicados em inglês e português entre março de 2010 e março de 2020. Após a seleção, recuperação dos textos dos artigos, e análise dos critérios definidos, as intervenções descritas nos estudos foram classificadas em quatro domínios: educacional; comportamental, cognitivo comportamental, e multicomponente. No total, seis ensaios clínicos atenderam aos critérios de inclusão e foram analisados. Metade dos estudos (3; 50%) usaram intervenções do tipo multicomponente, 2 (33.3%) centraram-se em intervenções comportamentais, e 1 (16.7%) aplicou intervenções educacionais isoladamente. Todos os estudos utilizaram métodos indiretos para mensurar a adesão, comênfase em escalas e questionários. Metade dos estudos (3; 50%) demonstraram impacto positivo na adesão em pacientes com CU, com indícios de que intervenções do tipo multicomponente, quando apropriadamente implementadas em ensaio clínicos que associam métodos diretos e indiretos para a mensuração da adesão a medicamentos, parecem aumentar as chances de melhores resultados. Consideramos que estudos futuros centrados na melhoria da adesão em pacientes com CU se fazem necessários.

Study on the effect of the treatment of Periplaneta americana L. extract Ento-B by Dinitrochlorobenzene combined with acetic acid induced UC in rats

ABSTRACT Purpose To study the Periplaneta americana L. extract Ento-B on the treatment of chronic ulcerative colitis induced by 2,4-dinitrochlorobenzene and acetic acid in rats and to explore its primary mechanism of action. Methods Using 2,4-dinitrochlorobenzene combined with acetic acid to induce chronic ulcerative colitis (chronic UC) in rats. The sulfasalazine (400 mg/kg) and Ento-B (200 mg/kg, 100 mg/kg,50 mg/kg) were given by intragastric administration and the effect was evaluated according to the disease activity index (DAI) score, colon mucosal injury index (CMDI) score, histopathological score (HS) and the serum levels of Interleukin-4(IL-4), Interleukin-10(IL-10), Tumor necrosis factor-α(TNF-α), Malondialdehyde(MDA), Superoxide dismutase(SOD) and Inducible nitric oxide synthase(iNOS.) Results Compared with the model group, all doses of Ento-B could reduce the score of CMDI (p < 0.05), HS(p < 0.05 or p < 0.01), significantly increased the expression of IL-4, IL-10, SOD (p < 0.01) and decreased the levels of TNF-α, MDA, iNOS in serum of UC rats, significantly improving the degree of colon lesionsin UC rats. Conclusions Ento-B may play an important role in the treatment of ulcerative colitis induced byUC rats. The mechanism may be related to the increased expression of IL-4, IL-10, SOD and reduced expression of TNF-α, MDA, iNOS.

Evaluation of mesalazine polymeric conjugate in the treatment of actinic proctitis in rats

ABSTRACT Purpose: The present study aimed at testing a new formulation of mesalazine linked to chondroitin sulfate and its components alone in the treatment of actinic proctitis in rats. Methods: Forty-seven female Wistar rats were submitted to pelvic radiation and divided into eight groups: control A, mesalazine A, chondroitin A, and conjugate A, gavage of the according substance two weeks after irradiation and sacrifice three weeks after oral treatment; control C, mesalazine C, chondroitin C, and conjugate C, sacrifice six weeks after oral treatment. The rectum was submitted to histological characterization for each of the findings: inflammatory infiltrate, epithelial degeneration, mucosal necrosis, and fibrosis. Results: The inflammatory infiltrate was more intense in chondroitin A, mesalazine A, and conjugate C. The collagen deposition was less intense in chondroitin A, and mesalazine A, and more intense in control C. Conclusions: Mesalazine and chondroitin alone were efficacious in inducing a delayed inflammatory response, hence reducing the late fibrosis. The conjugate was able to induce an ever more delayed inflammatory response.

Data mining of drug use rules based on traditional Chinese medicine treatment of ulcerative colitis / 中国中药杂志

To explore the drug use rules of traditional Chinese medicine(TCM) in the treatment of ulcerative colitis, and to provide some references for clinical treatment. The full-text search of "ulcerative colitis+TCM" was conducted based on CNKI. The literatures published from 2000 to 2020 were selected, and the clinical prescriptions for ulcerative colitis were selected according to the inclusion and exclusion criteria. The statistical processing and association rule analysis were carried out with use of Excel 2013, Clementine 12.0 and IBM SPSS Statistics 25.0 statistical software. A total of 177 prescriptions were obtained after retrieval of 3 432 relevant literatures, including 93 oral prescriptions and 84 enema prescriptions. Among them, Glycyrrhizae Radix et Rhizoma, Atractylodis Macrocephalae Rhizoma, Coptidis Rhizoma, Aucklandiae Radix and Paeoniae Radix Alba were the most frequently used drugs in oral administration, with the functions of tonifying, heat clearing and Qi regulating. The drugs with high frequency in enema included Bletillae Rhizoma, Coptidis Rhizoma, Sanguisorbae Radix, Phellodendri Chinensis Cortex and Sophorae Flavescentis Radix, with the functions of heat clearing, blood stopping and tonifying. Both oral and enema means of drugs were mainly of warm, cold and slightly cold properties, and bitter and sweet flavors, involving spleen, stomach, lung and large intestine. In cluster analysis, oral and enema drugs were divi-ded into 5 groups. Accordingly, in the treatment of ulcerative colitis, tonifying medicine, heat clearing medicine and Qi regulating medicine are often used for oral administration and heat clearing medicine, hemostatic medicine and tonifying medicine are often used for enema administration. On this basis, they are combined with diuretic drugs and astringent drugs respectively.

Effect of Huangqin Decoction on pyroptosis pathway of NLRP3/caspase-1 in mice with ulcerative colitis / 中国中药杂志

To explore the effect of Huangqin Decoction on ulcerative colitis(UC) pyroptosis, and to explain the mechanism of pyroptosis based on NOD-like receptor thermoprotein domain 3(NLRP3)/cysteine proteinase 1(caspase-1) pathway. The animal model of UC induced with 3% dextran sodium sulfate(DSS) was established. The experimental animals were divided into control group, model group, low-dose(4.55 g·kg~(-1)), medium-dose(9.1 g·kg~(-1)) and high-dose(18.2 g·kg~(-1)) Huangqin Decoction groups and salazosulfapyridine group(0.45 g·kg~(-1)). While modeling, intragastric administration was given for 7 consecutive days. On the 8 th day, the mice were euthanized, the colon length was collected, and the histopathological changes were observed by HE staining. The content of interleukin-18(IL-18) was observed by ELISA. The content of lactatedehydrogenase(LDH)was determined by microplate method. TUNEL assay kit was used to detect the cell death. The immunohistochemical staining was used to detect the expressions of NLRP3 and apoptosis-associated speck-like protein containing a CARD(ASC). Western blot was used to detect the expressions of interleukin-1β(IL-1β), caspase-1 and gasdermin D(GSDMD).The experimental study showed that compared with normal group, the LDH content, TUNEL positive staining, inflammatory factors(IL-18, IL-1β), and proteins associated with pyroptosis were significantly increased(P<0.05). Compared with model control group, the LDH content, TUNEL positive staining, inflammatory factors(IL-18, IL-1β), and proteins associated with pyroptosis were decreased, and these results were more significant in high-dose groups(P<0.05). The results of HE staining showed that Huangqin Decoction could improve the pathological changes of colon. Huangqin Decoction could inhibit UC cell pyroptosis, and the mechanism may be closely related to NLRP3/caspase-1 signaling pathway.

Anti-inflammatory effect, plasma effective components and therapeutic targets of Huanglian Jiedu Decoction on ulcerative colitis mice / 中国中药杂志

This paper was to investigate the effect of Huanglian Jiedu Decoction(HLJD) on ulcerative colitis(UC) in mice, and determine the effective components in plasma, and virtually screen its therapeutic target, and predict its mechanism. Sixty Balb/c mice were randomly divided into blank group, model group, mesalazine treatment group(0.3 g·kg~(-1)), and HLJD treatment groups(24.66, 12.33, 6.17 g·kg~(-1)). Excepted for the blank group, all the mice in HLJD and mesalazine treatment groups were gavage administration. All mice freely drank 2.5% DSS solution for seven days to induce UC. The disease activity index(DAI) was detected each day. At the end of the experiment, HE staining was used to observe the pathological changes in colon. The content of IL-1β, IL-6 and TNF-α in colon were determined by ELISA. The effective components in plasma were determined by UPLC-Q-TOF-MS. The reverse docking in PharmMapper was used to screen the component targets. The disease targets of UC were collected by searching TTD, OMIM and GeneCards databases. The intersection of the component targets and disease targets was selected as the therapeutic targets. Then the therapeutic targets were imported into the STRING for GO and KEGG enrichment analysis. Discovery Studio was used to simulate the docking between the components and the targets. RESULTS:: showed that the DAI in the model group increased significantly(P<0.05), and the number of inflammatory cells and infiltration degree increased significantly compared with the blank group. The DAI in HLJD treatment group was significantly reduced(P<0.05), and the number and infiltration degree of inflammatory cells were reduced compared with the model group. The ELISA results showed that the levels of IL-1β, IL-6 and TNF-α were increased significantly in the model group(P<0.01) compared with the blank group, and significantly down regulated in the HLJD treatment group(P<0.05) compared with the model group. After UPLC-Q-TOF-MS analyse, ten components were identified. The network pharmacology analysis showed that the action targets were significantly enriched in 129 of biological processes, such as response to organic substance, chemical and oxygen-containing compound, etc., as well as 16 of signal pathways, such as IL-17, TNF and hepatitis B signal pathways, were enriched too. The results of molecular docking showed that limonin, palmatine and berberine could bind to CASP3 and MMP9 by hydrogen bond. In conclusion, HLJD could alleviate the colonic mucosal inflammatory infiltration and mucosal damage in UC mice. The mechanism may be related to the anti-inflammatory effect on UC mice by reducing the levels of IL-1β, IL-6 and TNF-α in colon through limonin, palmatine and berberine regulating IL-17 signal pathway and TNF signal pathway via CASP3 and MMP9 meditated.

Effect of Banxia Xiexin Decoction on intestinal flora of mice with ulcerative colitis induced by dextran sodium sulfate / 中国中药杂志

The aim of this paper was to investigate the effect of Banxia Xiexin Decoction(BXD) on inflammatory factors and intestinal flora in a dextran sulfate sodium induced ulcerative colitis(DSS-UC) mouse model, and to explore the mechanism of BXD in treating ulcerative colitis from the perspective of flora disorder. Forty C57 BL/6 J mice were randomly divided into control group, model group and BXD group. A 2.5% DSS-induced ulcerative colitis model was established. On the 8 th day, normal saline, normal saline, and BXD were given daily for 14 days. After 14 days, HE staining was used to observe histopathological changes of the colon. Serum inflammatory factor content was detected by ELISA, and the change of intestinal flora in mice feces was detected by 16 S rRNA sequencing technology. Compared with control group, the colonic tissue of mice in model group was damaged seriously, and the contents of IL-6 and TNF-α in serum were significantly increased(P<0.05). Compared with model group, mice in BXD group had less colonic damage, and the contents of IL-6, TNF-α in serum were decreased significantly(P<0.05). After creation, the richness of Patescibacteria was increased significantly at the phylum level(P<0.05). At the same time, the richness of Faecalibaculum(P<0.01), norank_f_Muribaculaceae(P<0.01) were decreased significantly at the genus level, while the richness of Turicibacter(P<0.01), Romboutsia(P<0.01), Clostridium_sensu_stricto_1(P<0.01) were increased significantly. After the intervention with BXD, the content of Patescibacteria was significantly reduced at the phylum level(P<0.05), and the contents of Lactobacillus(P<0.01), Clostri-dium_sensu_stricto_1(P<0.01), Enterorhabdus(P<0.01), Candidatus_Saccharimonas(P<0.05), Eubacterium_fissicatena_group(P<0.05) were decreased significantly at the genus level, while the contents of Dubosiella, Bacteroides and Allobaculum were increased significantly. Therefore, BXD could significantly improve the symptoms of DSS-UC mice. It not only could reduce the contents of IL-6 and TNF-α, but also could reduce the richness of Patescibacteria at the phylum level, and those of Clostridium_sensu_stricto_1, Candidatus_Saccharimonas, Eubacterium_fissicatena_group at the genus level. Inaddition, BXD could increase the richness of Bacteroides and Bifidobacterium. It suggested that BXD could play a role in the treatment of ulcerative colitis partially through reducing inflammatory factors and regulating the structure of the gut microbiota.

Pharmacological effects of Huangqin Decoction prepared from roots of multi-originated peony on ulcerative colitis in mice:a comparative study / 中国中药杂志

Huangqin Decoction(HQD) is a classic prescription for treating dysentery in the Treatise on Cold Damage and now is mainly used for the treatment of ulcerative colitis(UC). Since there are no requirements on specific Paeonia species, both Paeoniae Radix Alba(white peony root, WPR) and Paeoniae Radix Rubra(red peony root, RPR) are clinically used in HQD now. Although the two types of peony roots are close in origin and similar in primary components, the medicinal properties and efficacies are different. Furthermore, the systematic comparative analysis on the efficacy differences in treating UC of HQD with the roots of multi-originated peony has been seldom reported. This study compared and evaluated the pharmacological effects of HQD prepared from the roots of multi-originated peony, including WPR, RPR-l(derived from P. lactiflora), and RPR-v(derived from P. veitchii) based on the mouse model of UC induced by dextran sodium sulfate(DSS) by animal behaviors, pathological section(colon), and cytokine expression(IL-1β and IL-6), aiming to provide evidence for the identification of the original resource of peony root in HQD. The results indicated that all HQD samples prepared from WPR, RPR-l, and RPR-v could improve the symptoms of UC. Compared with the HQD-WPR, HQD-RPR-l and HQD-RPR-v were significantly different in weight loss, colon length, and disease activity index(DAI) score, but there was no significant difference between HQD-RPR-l and HQD-RPR-v. Moreover, HQD-RPR-v exhibited the most significant improvement in the pathological morphology of colonic tissue and mucosal defects. According to the previous comparative analysis of chemical profiling and content distribution of HQD prepared from the roots of multi-originated peony, RPR-v in HQD was potent in protecting against UC, which was presumedly attributed to a large number of monoterpene glycosides and galloyl glucoses. This study provided a scientific basis for the determination of peony root in HQD and its clinical medication.

Atendimento da doença inflamatória intestinal no Brasil: como é feito, os entraves e as demandas sob a ótica dos médicos / Inflammatory bowel disease care in brazil: how it is performed, obstacles and demands from the physicians' perspective

ABSTRACT BACKGROUND: Inflammatory bowel diseases (IBD) are chronic inflammatory affections of recurrent nature whose incidence and prevalence rates have increased, including in Brazil. In long term, they are responsible for structural damage that impacts quality of life, morbidity and mortality of patients. OBJECTIVE: To describe the profile of physicians who treat IBD patients as well as the characteristics of IBD care, unmet demands and difficulties. METHODS: A questionnaire containing 17 items was prepared and sent to 286 physicians from 101 Brazilian cities across 21 states and the Federal District, selected from the register of the State Commission of the "Study Group of Inflammatory Bowel Disease of Brazil" (GEDIIB). RESULTS: The majority of the physicians who answered the questionnaire were gastroenterologists and colorectal surgeons. More than 60% had up to 20 years of experience in the specialty and 53.14% worked at three or more locations. Difficulties in accessing or releasing medicines were evident in this questionnaire, as was referrals to allied healthy professionals working in IBD-related fields. More than 75% of physicians reported difficulties in performing double-balloon enteroscopy and capsule endoscopy, and 67.8% reported difficulties in measuring calprotectin. With regard to the number of patients seen by each physician, it was shown that patients do not concentrate under the responsibility of few doctors. Infliximab and adalimumab were the most commonly used biological medicines and there was a higher prescription of 5-ASA derivatives for ulcerative colitis than for Crohn's disease. Steroids were prescribed to a smaller proportion of patients in both diseases. The topics "biological therapy failure" and "new drugs" were reported as those with higher priority for discussion in medical congresses. In relation to possible differences among the country's regions, physicians from the North region reported greater difficulty in accessing complementary exams while those from the Northeast region indicated greater difficulty in accessing or releasing medicines. CONCLUSION: The data obtained through this study demonstrate the profile of specialized medical care in IBD and are a useful tool for the implementation of government policies and for the Brazilian society as a whole.

RESUMO CONTEXTO: As doenças inflamatórias intestinais (DII) são afecções inflamatórias crônicas de caráter recorrente, cujas taxas de incidência e prevalência têm aumentado, inclusive no Brasil. A longo prazo, são responsáveis por danos estruturais que impactam na qualidade de vida, morbidade e mortalidade dos pacientes. OBJETIVO: Avaliar o perfil dos médicos que atendem pacientes com DII, assim como as características deste atendimento, demandas não atendidas e dificuldades. MÉTODOS: Um questionário contendo 17 variáveis foi elaborado e enviado para médicos, selecionados a partir do cadastro da Comissão das Estaduais do Grupo de Estudos da Doença Inflamatória Intestinal do Brasil (GEDIIB), totalizando 286 médicos de 101 cidades brasileiras distribuídas por 21 estados e Distrito Federal. RESULTADOS: A maioria dos médicos que respondeu o questionário foram Gastroenterologistas e Coloproctologistas. Mais de 60% tinham até 20 anos de atuação na especialidade e 53,14% trabalhavam em três locais ou mais. A dificuldade no acesso ou liberação de medicamentos ficou evidenciada neste questionário, assim como a dificuldade no encaminhamento para profissionais não médicos que atuam em DII. Mais de 75% dos médicos relataram dificuldades para realização de enteroscopia por duplo balão e cápsula endoscópica, e 67,8% para realização da calprotectina. Em relação ao número de pacientes atendidos por cada médico, foi evidenciado que não há uma concentração de pacientes sob a responsabilidade de poucos médicos. O infliximabe e o adalimumabe foram os biológicos mais utilizados e ficou evidenciada prescrição maior de derivados de 5-ASA para retocolite ulcerativa quando comparada à doença de Crohn. Os corticoides foram prescritos para uma parcela menor de pacientes em ambas doenças. Os temas "falha a terapia biológica" e "novas drogas" foram referidos como aqueles com maior prioridade para discussão em eventos científicos. Em relação às possíveis diferenças entre cada região e o restante do país, os médicos da região Norte relataram maior dificuldade no acesso a exames complementares e os médicos da região Nordeste, maior dificuldade no acesso ou liberação de medicamentos. CONCLUSÃO: Os dados obtidos por meio deste estudo mostram o perfil do atendimento médico especializado em DII e podem se constituir em ferramenta útil para para elaboração de políticas governamentais e para sociedade brasileira como um todo.

Fatores associados com a escolha da terapia nos pacientes com doença inflamatória intestinal no Brasil / Factors associated with patient´s preference in choosing their therapy for inflammatory bowel disease in brazil

BACKGROUND: Biological therapy and new drugs have revolutionized the treatment of inflammatory bowel disease. Ideally, the choice of medication should be a shared decision with the patient, aiming at greater satisfaction, compliance, and consequently, favorable clinical outcome. OBJECTIVE: This study aims to evaluate patient's preferences in the choice of their therapy and the factors that influence this choice. METHODS: This cross-sectional study enrolled 101 outpatients with Crohn's disease or ulcerative colitis. The inclusion criteria were age ≥18 years and no previous exposure to biological therapy. Patients' preferences were assessed through questions that addressed the preferred mode of administration (oral, subcutaneous, or intravenous) and the factors that determined the choice of medication (efficacy, medical indication, fear of medication, convenience, mode of application, and personal doctors' indication). RESULTS: The mean age was 43.6±13.5 years, 75.3% were female, and 81.2% were cases of ulcerative colitis. Regarding the mode of administration, the majority of patients preferred oral (87.1%), followed by intravenous (6.93%) and subcutaneous (5.94%) medications. The reasons were "I prefer to take it at home" (42.57%), "I have more freedom" (36.63%), "I don't like self-application" (29.70%), and "I believe it works better" (19.80%). Younger patients and patients in clinical disease activity preferred intravenous mode compared to the oral route (P<0.05). Doctor's opinion (98%) was an important factor associated with the medication choice. CONCLUSION: Oral route was the preferred mode of administration and most patients took their physician's opinion into account in their choice of medication.

RESUMO CONTEXTO: A terapia biológica e os novos medicamentos revolucionaram o tratamento da doença inflamatória intestinal. A escolha do medicamento deve ser compartilhada com o paciente, visando maior satisfação, adesão e, consequentemente, desfecho clínico favorável. OBJETIVO: Este estudo teve como objetivo avaliar as preferências do paciente na escolha de sua terapia e os fatores que influenciaram essa escolha. MÉTODOS: Este estudo transversal incluiu 101 pacientes ambulatoriais com doença de Crohn ou retocolite ulcerativa. Os critérios de inclusão foram idade ≥18 anos e nenhuma exposição prévia à terapia biológica. A preferência dos pacientes foi avaliada por meio de perguntas que abordaram o modo de administração preferido (oral, subcutâneo ou intravenoso) e os fatores que determinaram a escolha do medicamento (eficácia, indicação médica, medo da injeção, conveniência, modo de aplicação e opinião pessoal do médico). RESULTADOS: A idade média foi de 43,6±13,5 anos, 75,3% eram mulheres e 81,2% eram portadores de retocolite ulcerativa. Em relação ao modo de administração, a maioria dos pacientes preferiu os medicamentos orais (87,1%), seguidos dos endovenosos (6,93%) e subcutâneos (5,94%). Os motivos foram "prefiro aplicar em casa" (42,57%), "tenho mais liberdade com essa medicação" (36,63%), "não gosto de autoaplicação" (29,70%) e "acredito que funcione melhor" (19,80%). Pacientes jovens e pacientes em atividade clínica preferiram a via intravenosa em comparação com a via oral (P<0,05). A opinião do médico (98%) foi um fator importante associado à escolha do medicamento. CONCLUSÃO: A via oral foi preferida e a maioria dos pacientes levou em consideração a opinião do seu médico na escolha do medicamento.

Hemophagocytic lymphohistiocytosis as a presentation of inflammatory bowel disease / Linfohistiocitosis hemofagocítica como presentación de la enfermedad inflamatoria intestinal

Abstract Background: Hemophagocytic lymphohistiocytosis (HLH) is considered a medical emergency that should be recognized in patients with fever, splenomegaly, and progressive deterioration of the general condition. Laboratory findings include cytopenia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. For HLH diagnosis, it is essential, although not mandatory, to perform a bone marrow biopsy. Given its nature, secondary causes of HLH should be sought, mainly infections, hemato-oncological disorders, autoimmune diseases, and auto-inflammatory conditions. Case report: We present the case of a female adolescent who presented with fever and lower gastrointestinal bleeding. Upon admission, acute liver failure and pancytopenia were documented. A bone marrow aspirate was performed, which revealed hemophagocytosis; other tests confirmed HLH diagnosis. During the diagnostic approach, inflammatory bowel disease was diagnosed. The patient received first-line treatment with an adequate response. Conclusions: Inflammatory bowel disease can be considered a cause of secondary HLH, particularly in patients with suggestive symptoms, such as digestive bleeding in the absence of other secondary causes of HLH.

Resumen Introducción: La linfohistiocitosis hemofagocítica (LHH) es considerada una urgencia médica que debe reconocerse en pacientes con deterioro progresivo del estado general, fiebre, pancitopenia y esplenomegalia. Los hallazgos de laboratorio incluyen citopenia, hipertrigliceridemia, hipofibrinogenemia e hiperferritinemia. Para su diagnóstico es importante, aunque no obligatoria, la realización de aspirado de médula ósea. Dada su naturaleza, se deben buscar causas secundarias de LHH, principalmente enfermedades infecciosas, hematooncológicas, autoinmunitarias y autoinflamatorias. Caso clínico: Se presenta el caso de una adolescente que inició con fiebre y sangrado digestivo bajo. A su ingreso, se documentó falla hepática aguda y pancitopenia. Se realizó aspirado de médula ósea y se encontró hemofagocitocis; el resto de los exámenes concluyeron LHH. Durante su abordaje se diagnosticó enfermedad inflamatoria intestinal. La paciente recibió tratamiento de primera línea con adecuada respuesta. Conclusiones: La enfermedad inflamatoria intestinal puede considerarse como una causa secundaria de LHH, en particular en pacientes con clínica sugestiva, como es el sangrado digestivo, en ausencia de otras causas secundarias de LHH.

Tofacitinib en el tratamiento de la colitis ulcerosa: casos clínicos / Tofacitinib for the treatment of ulcerative colitis: report of two cases

Biological therapy dramatically changed the management of Ulcerative Colitis (UC). However, a significant number of these patients fail to respond or have secondary loss of response to this strategy. In this clinical situation, the options include intensification of anti-TNF therapy, the use of a second anti-TNF or being switched to another drug class. Among the later, tofacitinib, an oral small molecule directed against the JAK/STAT pathway, is safe and effective in inducing and maintaining remission in patients with moderate-severe UC. We report two patients with UC refractory to conventional treatment and biological therapy, who responded successfully to the use of tofacitinib.