Traditional Chinese Medicine Shi-Bi-Man ameliorates psoriasis via inhibiting IL-23/Th17 axis and CXCL16-mediated endothelial activation.

BACKGROUND: Psoriasis is a chronic inflammatory genetic disease, mainly manifesting in the skin. Conventional therapies, such as glucocorticosteroids and corticosteroids, have adverse effects that limit drug use. Hence, it is imperative to identify a new therapeutic strategy that exhibits a favorable safety profile. Shi-Bi-Man (SBM) is a safe herbal supplement sourced from various natural plants, including ginseng, angelica sinensis, polygonum multiflorum, and aloe vera. PURPOSE: We aimed to find a potential treatment for psoriasis and investigate the underlying mechanism through which SBM alleviates psoriatic-like skin inflammation in mice. METHODS: We investigated the effects of supplementing with SBM through intragastric administration or smear administration in a murine model of imiquimod-induced psoriasis. The changes in body weight and Psoriasis Area and Severity Index (PASI) score were recorded throughout the entire process. Additionally, we used hematoxylin-eosin staining to observe the skin structure and performed single-cell RNA sequencing to explore the underlying mechanism of SBM in influencing the psoriasis-like phenotype. Immunofluorescence was conducted to verify our findings. Furthermore, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was employed to investigate the impact of Tetrahydroxy stilbene glycoside (TSG) on the expression levels of IL23 in HaCaT cells. RESULTS: SBM remarkably alleviated the psoriasis-like phenotype by inhibiting IL-23/Th17 cell axis. Single-cell RNA sequencing analysis revealed a decrease in the expression of Il17 and Il23 in keratinocytes and T cells, concomitant with a reduction in the proportion of Th17 cells. Meanwhile, the activation of endothelial cells was inhibited, accompanied by a decrease in the expression of Cxcl16. In vitro, the addition of TSG to HaCaT cells resulted in significant suppression of IL23 expression stimulated by tumor necrosis factor-alpha (TNF-α).

Traditional Chinese Medicine Shi-Bi-Man regulates lactic acid metabolism and drives hair follicle stem cell activation to promote hair regeneration.

BACKGROUND: As a supplement for promoting hair health, Shi-Bi-Man (SBM) is a prescription comprising various traditional Chinese medicines. Though SBM has been reported to promote hair regeneration, its molecular mechanism remains unclear. Cynomolgus monkeys (Macaca fascicularis) are non-human primates with a gene expression profile similar to that of humans. The purpose of this research is to evaluate the effect of SBM on promoting hair regeneration in cynomolgus monkeys and to reveal the underlying mechanism. METHODS: The effect of SBM on hair regeneration was observed by skin administration on 6 cynomolgus monkeys with artificial back shaving. The molecular mechanism of SBM was studied using single-cell RNA sequencing (scRNA-seq) in combination with quantitative polymerase chain reaction (qPCR) detection for gene transcription level, and immunofluorescence staining verification for protein level. RESULTS: SBM significantly induced hair regeneration in cynomolgus monkeys, increased hair follicle number and facilitated hair follicle development. ScRNA-seq revealed an increase in the number of hair follicle stem cells (HFSCs) with a higher activation state, as evidenced by the higher expression of activation marker LDHA related to metabolism and the proliferation marker MKI67. Immunofluorescence analysis at the protein level and qPCR at the mRNA level confirmed the sequencing data. Cellchat analysis revealed an enrichment of ligand-receptor pairs involved in intercellular communication in Laminin-related pathways. CONCLUSION: SBM significantly promotes hair regeneration in cynomolgus monkeys. Mechanically, SBM can up-regulate LDHA-mediated lactic acid metabolism and drive HFSC activation, which in turn promotes the proliferation and differentiation of HFSCs.

New opportunities and challenges of natural products research: When target identification meets single-cell multiomics.

Natural products, and especially the active ingredients found in traditional Chinese medicine (TCM), have a thousand-year-long history of clinical use and a strong theoretical basis in TCM. As such, traditional remedies provide shortcuts for the development of original new drugs in China, and increasing numbers of natural products are showing great therapeutic potential in various diseases. This paper reviews the molecular mechanisms of action of natural products from different sources used in the treatment of inflammatory diseases and cancer, introduces the methods and newly emerging technologies used to identify and validate the targets of natural active ingredients, enumerates the expansive list of TCM used to treat inflammatory diseases and cancer, and summarizes the patterns of action of emerging technologies such as single-cell multiomics, network pharmacology, and artificial intelligence in the pharmacological studies of natural products to provide insights for the development of innovative natural product-based drugs. Our hope is that we can make use of advances in target identification and single-cell multiomics to obtain a deeper understanding of actions of mechanisms of natural products that will allow innovation and revitalization of TCM and its swift industrialization and internationalization.

Endoscopic treatment can be a viable therapeutic option for esophageal gastrointestinal stromal tumors.

BACKGROUND: Esophageal gastrointestinal stromal tumors(GISTs) are extremely rare. We sought to determine whether endoscopic treatment can be a viable therapeutic option for esophageal GISTs. METHODS: A total of 20 cases with histological diagnosis of esophageal GISTs were obtained from our center between 2008 and 2020. Data on the clinicopathological features and treatment were recorded. RESULTS: There were 9 males (45%) and 11 females (55%) in this study, with a median age of 56 years. The tumors preferentially occurred in the middle and lower parts of the thoracic esophagus (45 and 40%, respectively). The mean size of the tumors was 2.27 cm and mitotic index was no more than 5/50 high power field (HPF) in all patients. In this study, 11 patients received endoscopic treatment and nine patients underwent surgical resection. Tumors ranged from 0.6 to 4 cm in the endoscopic treatment patients and 0.5 to 7 cm in the surgical patients. There were no significant differences in gender, age, symptoms, tumor location, tumor size, mitotic index, and adjuvant imatinib therapy between the endoscopic treatment group and the surgery group (all p > .05). The Kaplan-Meier curve suggested that there was also no significant difference in disease-free survival between the two groups (p = .264). CONCLUSIONS: Endoscopic treatment may be an option for the treatment of esophageal GISTs smaller than 5 cm with a mitotic index no more than 5/50 HPF.

Revisiting an Expression Dataset of Discordant Inflammatory Bowel Disease Twin Pairs Using a Mutation Burden Test Reveals CYP2C18 as a Novel Marker.

The aim of this study was to investigate the expression features of discordant inflammatory bowel disease (IBD) twin pairs to identify novel molecular features and markers. We collected an expression dataset of discordant twin pairs with ulcerative colitis and performed integrative analysis to identify the genetic-independent expression features. Through deconvolution of the immune cell populations and tissue expression specificity, we refined the candidate genes for susceptibility to ulcerative colitis. We found that dysregulated immune systems and NOD-related pathways were enriched in the expression network of the discordant IBD twin pairs. Among the identified factors were significantly increased proportions of immune cells, including megakaryocytes, neutrophils, natural killer T cells, and lymphatic endothelial cells. The differentially expressed genes were significantly enriched in a gene set associated with cortical and medullary thymocytes. Finally, by combining these expression features with genetic resources, we identified some candidate genes with potential to serve as novel markers of ulcerative colitis, such as CYP2C18. Ulcerative colitis is a subtype of inflammatory bowel disease and a polygenic disorder. Through integrative analysis, we identified some genes, such as CYP2C18, that are involved in the pathogenesis of IBD as well as some candidate therapeutic targets, such as LOXL2.

Diagnosis and Treatment of Duodenal Gastrointestinal Stromal Tumors.

OBJECTIVES: The diagnostic value of different noninvasive diagnostic modalities and the endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) reliability of duodenal gastrointestinal stromal tumors (GISTs) are ambiguous in the present studies. METHODS: Patients with a histopathological diagnosis of the primary duodenal GISTs between the years 2008 and 2018 were analyzed. Data on the treatment and clinicopathological features were recorded. Furthermore, the computed tomography (CT)/magnetic resonance imaging (MRI), EUS, and EUS-FNA results were collected and compared. RESULTS: A total of 142 patients were enrolled into the study. In all patients, the most common symptom was gastrointestinal bleeding (44.4%), followed by abdominal pain and bloating (27.5%). Duodenal GISTs were mostly located in the second duodenal portion (52.1%), followed by the first portion (19.0%). EUS had significantly higher sensitivity and positive predictive values than CT or MRI (P = 0.047 and P = 0.005, respectively). The EUS-FNA sensitivity of duodenal GISTs was also significantly higher than the conventional endoscopic biopsy (73.3% vs 33.3%, P = 0.006). A total of 131 patients underwent surgery, including limited resection or pancreaticoduodenectomy. The tumor size and postoperative complication rates were higher in patients who underwent pancreaticoduodenectomy (P = 0.001 and P < 0.001, respectively). DISCUSSION: The diagnostic value of EUS is significantly higher than that of CT and MRI for duodenal GISTs. The EUS-FNA can provide a histological diagnosis of duodenal GISTs in most cases.

Characteristics and prognosis of isolated small-bowel Crohn's disease.

BACKGROUND: Previous studies suggest that Crohn's disease (CD) with both small bowel and colon involvement is more serious than colonic CD. However, clinical features of isolated small-bowel CD have not been fully investigated. METHODS: In this retrospective case-control study, 89 patients were divided into two groups according to capsule endoscopy, ileocolonoscopy, and enhanced computed tomography results. The case group was isolated small-bowel CD (n = 50) and the control group was CD with both small bowel and colon involvement (n = 39). We collected data of the patients and analyze it. RESULTS: In univariate analysis, isolated small-bowel CD group had higher percentage of stricture, Lewis score, platelet, plateletcrit and lower Harvey-Bradshaw index, high-sensitivity C-reactive protein, and erythrocyte sedimentation rate. In multivariable analysis, it had lower Harvey-Bradshaw index (p = 0.000), which meaned relatively mild symptoms. However, it had higher Lewis score (p = 0.007), which meaned more serious small-bowel inflammation. The Kaplan-Meier survival curve also suggested that isolated small-bowel CD patients were more likely to accept partial small intestinal resection surgery (p = 0.029). CONCLUSIONS: Isolated small-bowel CD is easily overlooked for milder clinical symptoms and relatively limited lessions, but severe small-bowel histological injury results in owing worse clinical outcomes. Clinicians should pay more attention to the isolated small-bowel CD and take aggressive intervention during therapy.

Increased risk of herpes zoster infection in patients with inflammatory bowel disease: a meta-analysis of cohort studies.

Previous studies have shown increased risk of herpes zoster (HZ) infection in patients with inflammatory bowel disease (IBD). The aim of this study is to better characterize this possible association by conducting a meta-analysis. A comprehensive search of relevant literature until April 30, 2019, was performed. Data on HZ infection and medications in patients with IBD and controls were extracted. The relative risk (RR) and 95% confidence interval (CI) were calculated. Subgroup analyses were performed to assess the source of heterogeneity. Seven cohort studies were included that involved more than 1,000,000 participants. The RR of HZ infection in patients with Crohn's disease (CD) compared with non-CD patients was 1.74 (95% CI 1.57-1.92, p < 0.001). The pooled RR of HZ infection in patients with ulcerative colitis (UC) compared with non-UC was 1.40 (95% CI 1.31-1.50, p < 0.001). Subgroup analyses revealed that age, race, and publication year contribute to heterogeneity. We also found that steroid users were at increased risk of HZ in CD (OR = 1.78, 95% CI 1.10-2.88). Steroid users and anti-TNFα users were at increased risk of HZ in UC, with RRs of 1.99 (95% CI 1.64-2.42) and 2.29 (95% CI 1.52-3.45), respectively. Begg's test and Egger's test suggested no publication bias. There was a 74% increased risk of HZ infection in patients with CD and 40% increased risk of HZ infection in patients with UC compared with that in non-IBD. IBD patients with high risk of HZ infection may benefit from an HZ vaccine.

Serum proteome profiles to differentiate Crohn disease from intestinal tuberculosis and primary intestinal lymphoma: A pilot study.

The differential diagnosis of Crohn disease (CD) from intestinal tuberculosis (ITB) and primary intestinal lymphoma (PIL) is challenging in patients who exhibit atypical clinical characteristics. The aim of the present study was to explore the serum proteome profiles of CD, PIL and ITB and to identify their differentiations.Treatment-naïve patients with CD (n = 10), PIL (n = 10) and ITB (n = 10) were enrolled in the present study. Differentially expressed proteins (DEPs) in patient serum samples were compared between groups using tandem mass tag labeled proteomic technology. A principal component analysis (PCA) plot and volcano maps were also visualized. Functional pathway analysis was performed using Reactome. The Area under the Curve (AUC) was calculated for each DEP.A total of 818 proteins were identified through proteomic quantification. Among them, 108 DEPs were identified to be differentiated between CD and ITB, 105 proteins between CD and PIL and 55 proteins between ITB and PIL. The proteome from the three groups was distinguishable in the PCA plot. The results revealed that 19, 12, and 10 proteins (AUC ≥ 0.95) were differentially expressed between CD and PIL, CD and ITB, and PIL and ITB, respectively. Among these DEPs, tumor necrosis factor ligand superfamily member 13 was higher in CD than in ITB and PIL. Peroxiredoxin-5, T-complex protein 1 subunit Gamma, CutA, and Fibulin-5 were increased in CD and PIL when compared with ITB. The levels of fibrinogen chains were also significantly higher in patients with PIL compared with CD.The current study demonstrated that serum proteome was distinguishable among patients with CD, PIL, and ITB. The identified proteins may assist in the clinical differentiation among them.

EZH2 Regulates Intestinal Inflammation and Necroptosis Through the JNK Signaling Pathway in Intestinal Epithelial Cells.

BACKGROUND: Inflammatory bowel disease (IBD) is a common disorder of chronic intestinal inflammation that can be caused by the disruption of intestinal immune homeostasis. AIM: We aimed to evaluate the role of enhancer of zeste homolog 2 (EZH2) in the inflammatory response and explore the association between EZH2 and necroptosis in human epithelial colorectal adenocarcinoma cell lines. METHODS: In both in vitro and in vivo models, expression of EZH2 in intestinal tissues was verified by histology. The expression of inflammatory cytokines in cell lines treated with EZH2 siRNA with or without stimulus was analyzed by quantitative real-time polymerase chain reaction. An intestinal necroptosis cell model was established to elucidate whether EZH2 is involved in necroptosis. RESULTS: Our present data indicated that EZH2 expression was decreased in in vitro and in vivo models and in patients with inflammatory bowel disease. EZH2 downregulation increased the expression of inflammatory factors, including TNF-α, IL-8, IL-17, CCL5, and CCL20 in a Caco-2 cell model. The JNK pathway was activated with the reduction of EZH2. In the necroptosis model, downregulation of EZH2 was detected with the upregulation of necroptotic markers RIP1 and RIP3. In addition, EZH2 knockdown with siRNA increased p-JNK and p-c-Jun. CONCLUSION: Our data suggest that EZH2 plays an important role in the development of intestinal inflammation and necroptosis. Hence, EZH2 could be a potential therapeutic target for IBD.

Quantitative Proteomic Analysis Reveals the Deregulation of Nicotinamide Adenine Dinucleotide Metabolism and CD38 in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) has become a major health challenge worldwide. However, the precise etiological and pathophysiological factors involved in IBD remain unclear. Proteomics can be used for large-scale protein identification analysis. In the current study, using tandem mass tag- (TMT-) based shotgun proteomics, proteomic differences between intestinal tissue from health controls, patients with Crohn's disease (CD), and patients with ulcerative colitis (UC) were compared. Proteins with fold change >2 or <0.5 and P value < 0.05 between groups were considered differentially expressed. ProteinAtlas was used to analyze the tissue specificity of differentially expressed proteins (DEPs). Reactome pathway analysis was applied to cluster functional pathways. A total of 4786 proteins were identified, with 59 proteins showing higher levels and 43 showing lower levels in patients with IBD than in controls. Seventeen proteins, including angiotensin converting enzyme 2 (ACE2) and angiotensin converting enzyme 1 (ACE), showed higher levels in CD than in UC. Several novel proteins such as CD38, chitinase 3-like 1 (CHI3L1), olfactomedin 4 (OLFM4), and intelectin 1 were screened out between patients with IBD and controls. When proteins with fold change >1.2 or <0.84 and P value < 0.05 between groups were considered differentially expressed, the expression of 10 proteins, including CD38, involved in the nicotinamide adenine dinucleotide (NAD) metabolism and signaling pathway showed significant changes in IBD. Using the NCBI GEO database, we confirmed increased CD38 mRNA expression in patients with UC and in mouse colitis models. Protein CD38 expression was higher in CD and UC than in normal controls. CD38 expression was higher in inflamed tissues than in noninflamed tissues, and CD38 was located in F4/80-positive cells. Our study may provide novel insights into the molecular pathogenesis of IBD. Further studies are required on the role of NAD metabolism and CD38 in intestinal inflammation.

Association between Helicobacter pylori infection and nonalcoholic fatty liver disease: a systemic review and meta-analysis.

Although clinical studies have shown possible links of Helicobacter pylori infection with the development of nonalcoholic fatty liver disease (NAFLD), the results remain controversial. The aim of this meta-analysis is to investigate the association between H. pylori infection and NAFLD. A comprehensive search of relevant studies was performed up to November 2018. Data on H. pylori infection in NAFLD patients and controls were extracted. Odds ratio (OR) and 95% confidence interval (CI) were calculated using a random-effects model. Twelve studies involving 27 400 NAFLD patients and 60 347 controls were included. The pooled overall OR of H. pylori infection in NAFLD patients compared with controls was 1.36 (95% CI: 1.22-1.53, I=89.6%, P=0.000). Meta-regression and subgroup analysis showed that the sample size and the case-control ratio may have accounted for some of the heterogeneity. When stratified by publication year, the diagnostic method used for H. pylori, and Newcastle-Ottawa Scale scores, the OR remained significant. However, possible publication bias was observed. Of the 12 studies, six had carried out multivariable analysis after adjusting for potential confounders. The pooled results from these studies still indicated a higher risk of NAFLD in patients infected with H. pylori (OR=1.17, 95% CI: 1.01-1.36, I=72.4%, P=0.003). There is a 36% increased risk of NAFLD in patients with H. pylori infection. Further studies are warranted to investigate whether eradication of H. pylori is useful in the prevention and treatment of NAFLD.

EBV-positive lymphoproliferative disease: a case report.

Bloody stool with fever may always be considered as inflammatory bowel disease or intestinal tuberculosis. Epstein-Barr virus (EBV) infection is common. But EBV-positive lymphoproliferative disease (EBV+-LPD) involvement of gut is pretty rare and is hardly taken into consideration. A 34-year-old woman was admitted to our hospital for bloody stools over one month and fever over one week with multiple black brown nodular erythema on face. With the electronic colonoscope, intestinal tuberculosis was considered firstly, but Crohn's disease and lymphoma cannot be ruled out. So the patient received diagnostic anti-tuberculosis therapy on Aug. 2nd, 2012. After 8 months of antituberculosis therapy and drug withdrawal for 4 months, the patient developed symptoms of umbilicus pain accompanied with vomit, diarrhea and hyperpyrexia up to 40.3°C. The discomfort didn't get complete remission after symptomatic treatment. And on Apr. 20th, 2015, colonoscopy showed multiple ulcers in colon, so inflammatory bowel disease was considered firstly. As a result, the patient was treated with Mesalazine. However, there was little symptomatic improvement and more black brown nodular erythema occurred on her face. Then on Jun. 11th, 2015, she underwent colonoscopy again and the immunohistochemical of intestinal tissue suggested EB virus infection. What's more, we found serum EB virus IgM: - S/CO, serum EB virus IgG: + 12.5 S/CO, blood EBV-DNA: 5.71*10E5/mL (0-500). Furthermore, on Jun. 25th, 2015, skin biopsy showed (forehead) T lymphocytes hyperplasia and focal necrosis, according with characteristics of EBV related T lymphocyte proliferative disease (EBV+T-LPD). Ultimately, we got definitive diagnosis of the patient: 1. EBV+-LPD, hydroa vacciniforme-like lymphoma. 2. Multiple ulcers in small intestine and colon: according with EBV+-LPD. And she was treated with definitive therapy. This case shows we must consider rare disease for patients accompanied by gastrointestinal symptoms with conventional treatment ineffectively.