Methionine-choline deficient diet deteriorates DSS-induced murine colitis through disturbance of gut microbes and infiltration of macrophages.

Ulcerative colitis (UC) is associated with changed dietary habits and mainly linked with the gut microbiota dysbiosis, necroptosis of epithelial cells, and mucosal ulcerations. Liver dysfunction and abnormal level of liver metabolism indices were identified in UC patients, suggesting a close interaction between gut and liver disorders. Methionine-choline deficient diet (MCD) has been shown to induce persistent alterations of gut microbiota and metabolome during hepatitis. In this study we further explored the disease phenotypes in UC patients and investigated whether MCD functioned as a trigger for UC susceptibility. After assessing 88 serum specimens from UC patients, we found significant liver dysfunction and dyslipidemia including abnormal ALT, AST, TG, TC, LDL-c and HDL-c. Liver dysfunction and dyslipidemia were confirmed in DSS-induced colitis mice. We fed mice with MCD for 14 days to cause mild liver damage, and then treated with DSS for 7 days. We found that MCD intake significantly exacerbated the pathogenesis of mucosal inflammation in DSS-induced acute, progressive, and chronic colitis, referring to promotion of mucosal ulcers, colon shortening, diarrhea, inflammatory immune cell infiltration, cytokines release, and abnormal activation of inflammatory macrophages in colon and liver specimens. Intraperitoneal injection of clodronate liposomes to globally delete macrophages dramatically compromised the pathogenesis of MCD-triggering colitis. In addition, MCD intake markedly changed the production pattern of short-chain fatty acids (SCFAs) in murine stools, colons, and livers. We demonstrated that MCD-induced colitis pathogenesis largely depended on the gut microbes and the disease phenotypes could be transmissible through fecal microbiota transplantation (FMT). In conclusion, this study supports the concept that intake of MCD predisposes to experimental colitis and enhances its pathogenesis via modulating gut microbes and macrophages in mice.

Assessing the causal relationship between immune traits and systemic lupus erythematosus by bi-directional Mendelian randomization analysis.

Previous studies have observed relationships between immune cells and systemic lupus erythematosus (SLE), but their causal links remain undetermined. Based on the public available genome-wide association studies (GWAS) summary statistics, we conducted two-sample Mendelian randomization (MR) to evaluate the associations between 731 immune phenotypes and SLE pairs. Pairwise pleiotropy analysis was performed to identify pleiotropic genes for significant immunophenotype-SLE pairs. A comprehensive gene function analysis was undertaken to explore the mechanisms of immune cells in SLE. By using the instrumental variables extracted from GWAS data, we observed that increased levels of five immune phenotypes were causally associated with SLE risk (FDR < 0.05), that were CD20 on IgD+ CD38- naïve, BAFF-R on IgD+ CD38dim, CD39+ secreting Treg AC, CD14- CD16+ monocyte AC, and HLA DR on CD14+ monocyte. Pairwise gene-based analyses identified a total of 38 pleiotropic genes for 5 significant pairs identified and gene set enrichment analysis revealed the involvement of the identified pleiotropic genes in complex pathways (i.e., systemic lupus erythematosus, an integral component of luminal side of endoplasmic reticulum membrane, C-type lectin receptor signaling pathway and regulation of hormone secretion). This study demonstrates that the immune response influences the progression of SLE in a complex pattern. These findings greatly improve our understanding of the interaction between immune response and SLE risk and also aid in the design of therapeutic strategies from an immunological perspective.

Inhibitory effects of temozolomide on glioma cells is sensitized by RSL3-induced ferroptosis but negatively correlated with expression of ferritin heavy chain 1 and ferritin light chain.

Invasive growth of glioblastoma makes residual tumor unremovable by surgery and leads to disease relapse. Temozolomide is widely used first-line chemotherapy drug to treat glioma patients, but development of temozolomide resistance is almost inevitable. Ferroptosis, an iron-dependent form of non-apoptotic cell death, is found to be related to temozolomide response of gliomas. However, whether inducing ferroptosis could affect invasive growth of glioblastoma cells and which ferroptosis-related regulators were involved in temozolomide resistance are still unclear. In this study, we treated glioblastoma cells with RSL3, a ferroptosis inducer, in vitro (cell lines) and in vivo (subcutaneous and orthotopic animal models). The treated glioblastoma cells with wild-type or mutant IDH1 were subjected to RNA sequencing for transcriptomic profiling. We then analyze data from our RNA sequencing and public TCGA glioma database to identify ferroptosis-related biomarkers for prediction of prognosis and temozolomide resistance in gliomas. Analysis of transcriptome data from RSL3-treated glioblastoma cells suggested that RSL3 could inhibit glioblastoma cell growth and suppress expression of genes involved in cell cycle. RSL3 effectively reduced mobility of glioblastoma cells through downregulation of critical genes involved in epithelial-mesenchymal transition. Moreover, RSL3 in combination with temozolomide showed suppressive efficacy on glioblastoma cell growth, providing a promising therapeutic strategy for glioblastoma treatment. Although temozolomide attenuated invasion of glioblastoma cells with mutant IDH1 more than those with wild-type IDH1, the combination of RSL3 and temozolomide similarly impaired invasive ability of glioblastoma cells in spite of IDH1 status. Finally, we noticed that both ferritin heavy chain 1 and ferritin light chain predicted unfavorable prognosis of glioma patients and were significantly correlated with mRNA levels of methylguanine methyltransferase as well as temozolomide resistance. Altogether, our study provided rationale for combination of RSL3 with temozolomide to suppress glioblastoma cells and revealed ferritin heavy chain 1 and ferritin light chain as biomarkers to predict prognosis and temozolomide resistance of glioma patients.

Inhibition of PDE4 by apremilast attenuates skin fibrosis through directly suppressing activation of M1 and T cells.

Systemic sclerosis (SSc) is a life-threatening chronic connective tissue disease with the characteristics of skin fibrosis, vascular injury, and inflammatory infiltrations. Though inhibition of phosphodiesterase 4 (PDE4) has been turned out to be an effective strategy in suppressing inflammation through promoting the accumulation of intracellular cyclic adenosine monophosphate (cAMP), little is known about the functional modes of inhibiting PDE4 by apremilast on the process of SSc. The present research aimed to investigate the therapeutic effects and underlying mechanism of apremilast on SSc. Herein, we found that apremilast could markedly ameliorate the pathological manifestations of SSc, including skin dermal thickness, deposition of collagens, and increased expression of α-SMA. Further study demonstrated that apremilast suppressed the recruitment and activation of macrophages and T cells, along with the secretion of inflammatory cytokines, which accounted for the effects of apremilast on modulating the pro-fibrotic processes. Interestingly, apremilast could dose-dependently inhibit the activation of M1 and T cells in vitro through promoting the phosphorylation of CREB. In summary, our research suggested that inhibiting PDE4 by apremilast might provide a novel therapeutic option for clinical treatment of SSc patients.

STING inhibitor ameliorates LPS-induced ALI by preventing vascular endothelial cells-mediated immune cells chemotaxis and adhesion.

Acute lung injury (ALI) is a common and devastating clinical disorder featured by excessive inflammatory responses. Stimulator of interferon genes (STING) is an indispensable molecule for regulating inflammation and immune response in multiple diseases, but the role of STING in the ALI pathogenesis is not well elucidated. In this study, we explored the molecular mechanisms of STING in regulating lipopolysaccharide (LPS)-induced lung injury. Mice were pretreated with a STING inhibitor C-176 (15, 30 mg/kg, i.p.) before LPS inhalation to induce ALI. We showed that LPS inhalation significantly increased STING expression in the lung tissues, whereas C-176 pretreatment dose-dependently suppressed the expression of STING, decreased the production of inflammatory cytokines including TNF-α, IL-6, IL-12, and IL-1ß, and restrained the expression of chemokines and adhesion molecule vascular cell adhesion protein-1 (VCAM-1) in the lung tissues. Consistently, in vitro experiments conducted in TNF-α-stimulated HMEC-1cells (common and classic vascular endothelial cells) revealed that human STING inhibitor H-151 or STING siRNA downregulated the expression levels of adhesion molecule and chemokines in HMEC-1cells, accompanied by decreased adhesive ability and chemotaxis of immunocytes upon TNF-α stimulation. We further revealed that STING inhibitor H-151 or STING knockdown significantly decreased the phosphorylation of transcription factor STAT1, which subsequently influenced its binding to chemokine CCL2 and adhesive molecule VCAM-1 gene promoter. Collectively, STING inhibitor can alleviate LPS-induced ALI in mice by preventing vascular endothelial cells-mediated immune cell chemotaxis and adhesion, suggesting that STING may be a promising therapeutic target for the treatment of ALI.

CCL8 secreted by tumor-associated macrophages promotes invasion and stemness of glioblastoma cells via ERK1/2 signaling.

Tumor-associated macrophages (TAMs) constitute a large population of glioblastoma and facilitate tumor growth and invasion of tumor cells, but the underlying mechanism remains undefined. In this study, we demonstrate that chemokine (C-C motif) ligand 8 (CCL8) is highly expressed by TAMs and contributes to pseudopodia formation by GBM cells. The presence of CCL8 in the glioma microenvironment promotes progression of tumor cells. Moreover, CCL8 induces invasion and stem-like traits of GBM cells, and CCR1 and CCR5 are the main receptors that mediate CCL8-induced biological behavior. Finally, CCL8 dramatically activates ERK1/2 phosphorylation in GBM cells, and blocking TAM-secreted CCL8 by neutralized antibody significantly decreases invasion of glioma cells. Taken together, our data reveal that CCL8 is a TAM-associated factor to mediate invasion and stemness of GBM, and targeting CCL8 may provide an insight strategy for GBM treatment.

Antimicrobial activity and safety evaluation of Enterococcus faecium KQ 2.6 isolated from peacock feces.

BACKGROUND: The objective of this paper was to study antimicrobial activity and safety of Enterococcus faecium KQ 2.6 (E. faecium KQ 2.6) isolated from peacock feces. METHODS: Agar well diffusion method was adopted in antimicrobial activity assay. Disk diffusion test was used to determine the antibiotic resistance. The identification and virulence potential of E. faecium KQ 2.6 were investigated using PCR amplification. RESULTS: The results indicated that cell free supernatant (CFS) of the strain had the good antimicrobial activity against selected gram-positive and gram-negative bacteria. The biochemical characteristics of antimicrobial substances were investigated. The results indicated that the antimicrobial substances were still active after treatment with catalase and proteinase, respectively. Moreover, the stability of antimicrobial substances did not change after heat treatment at 40, 50, 60, 70 and 80°C for 30 min, respectively. The activity of antimicrobial substances remained stable at 4 and -20°C after long time storage. The antimicrobial activity of CFS was compared with that of the buffer with similar strength and pH. The inhibitory zone of the buffer was apparently smaller than that of CFS, which meant that the acid in CFS was not the only factor that was contributed to antibacterial activity of CFS. The antibiotic resistance and virulence potential were evaluated using disk diffusion test and PCR amplification. The results showed that E. faecium KQ 2.6 did not harbor any tested virulence genes such as gelE, esp, asa1, cylA, efaA and hyl. It was susceptible to most of tested antibiotics except for vancomycin and polymyxin B. CONCLUSION: E. faecium KQ 2.6 may be used as bio-preservative cultures for the production of fermented foods.

[The Effects of Thymosin alpha1 on Immune Function of Mice after Skin Transplantation].

OBJECTIVE: By establishing C57-BABL/c mice allogeneic skin transplantation model, to analyze the immune system function with the administration of thymosin al (Tal) in mouse after skin transplantation; and to explore the mechanism of specific immune tolerance induced by Tal in vivo. METHODS: 80 C57 mice and 80 BABL/c mice were used as donor and acceptor respectively to establish C57-BABL/c mice allogeneic skin transplantation model and divided into four groups: Group A, control group (without any treatment, n=20); Group B, CsA treatment group (CsA 10 mg/kg, n=20); Group C, Tal treatment group (Tal 400 microg/kg, n=20) and Group D, combination therapy group (CsA 10 mg/kg & Talphal 400 microg/kg, n=20). In the three experimental group, the drug of each group were respectively administrated by intraperitoneal injection daily, for 21 d. The survival of skin graft were observed and recorded, the Luminexx MAP for cytokine detection were performed in 1, 7, 14, 21 d after treatment, skin grafts were taking for HE staining, and flow cytometry were performed for lymphocyte phenotype. RESULTS: After transplantation, in 1, 7, 14, 21 d, the cytokine of Group B, C and ID compared to Group A, as well as Group D to B&C respectively, shows a decreaing of IL-1, IL-2, IL-6, IL-17 value and increasing of IL-10 significantly (P<0.05) at the same time point; While no statistical significance shows between Group B and C. Compared with other groups, Group D have a high ratio of CD4/CD8, and a high percentage of CD4+ CD25+ T cells (P<0.05). CONCLUSION: Administrated Tal after transplantation, can decrease the graft damage from T cells, but could not prevent rejection.

[Expression of CD163 in children with Epstein-Barr virus infection].

OBJECTIVE: To study the clinical significance of CD163 in the diagnosis and the evaluation of severity and prognosis of childhood hemophagocytic lymphohistiocytosis (HLH). METHODS: Ninety-four children were classified into Epstein-Barr virus (EBV)-positive (n=55) and EBV-negative groups (n=39; control group). The EBV-positive group was subgrouped into infectious mononucleosis (IM; n=47) and HLH (n=8). Serum levels of soluble CD163 were measured using ELISA. Expression of CD163 on mononuclear cells was detected by flow cytometry. RESULTS: The serum levels of soluble CD163 were>10 000 ng/mL in all eight HLH patients (>30 000 ng/mL in 3 cases). The mean serum levels of soluble CD163 in the HLH group were significantly higher than in the control and IM groups (P<0.05). The serum levels of soluble CD163 in EBV-positive children were positively correlated with EBV-DNA copies and serum levels of ferritin and LDH, but were negatively correlated with white blood cell count, neutrophil count, hemoglobin and platelet count. The follow-up after treatment for three HLH patients showed that serum levels of soluble CD163 were significantly reduced, but the soluble CD163 levels rebounded in one patient who was complicated by fungal pneumonia infection. CONCLUSIONS: The levels of serum soluble CD163 may be related to the severity in children with HLH. The EBV-positive children with soluble CD163 levels >10 000 ng/mL should be considered the possibility of HLH.

Triple-layer duct-to-mucosa pancreaticojejunostomy with resection of jejunal serosa decreased pancreatic fistula after pancreaticoduodenectomy.

BACKGROUND: Pancreatic fistula (PF) is one of the most common complications after pancreaticoduodenectomy (PD). We described a new method of pancreaticojejunostomy (PJ) developed by combining triple-layer duct-to-mucosa PJ with resection of jejunal serosa, which was named as modified layer-to-layer PJ (MLLPJ). The aim of the present study was to observe whether the new technique would effectively reduce the PF rate in comparison with two-layer duct-to-mucosa PJ (TLPJ). METHODS: Data on 184 consecutive patients who underwent the two methods of PJ after standard PD between January 1, 2010 and January 31, 2013 were collected retrospectively from a prospective database. The primary endpoint was the PF rate. The risk factors of PF were investigated by using univariate and multivariate analyses. RESULTS: A total of 88 patients received TLPJ and 96 underwent MLLPJ. Rate of PF for the entire cohort was 8.2%. There were 11 fistulas (12.5%) in the TLPJ group and four fistulas (4.2%) in the MLLPJ group (P = 0.039). Body mass index, pancreatic texture, pancreatic duct diameter, and methods of PJ anastomosis had significant effects on the formation of PF on univariate analysis. Multivariate analysis showed that pancreatic duct diameter ≤3 mm and TLPJ were the significant risk factors of PF. CONCLUSIONS: MLLPJ effectively reduces the PF rate after PD in comparison with TLPJ. Results confirm increased PF rates in patients with pancreatic duct diameter ≤3 mm compared with pancreatic duct diameter >3 mm.

[The electroluminescence spectra of InGan/GaN blue LEDs during aging time].

The luminescence spectra of InGaN/GaN multiple quantum wells light-emitting diodes under low level injection current (<4 mA) during aging process was investigated for the first time. Comparing the electroluminescence (EL) spectra of LEDs before and after aging time it was found that the peak wavelength and the full width at half maximum (FWHM) decreased with stress time and the changes of EL spectrum had two different stages-drastic decrease at the early stress stage and slow decrease later showing the same trend with the output optical power of LEDs, which indicates that the effective polarization electric field of LEDs becomes weak during the aging process and the change has a clear correlation with the increase of the defects in the multiple quantum wells of LEDs. Electrical measurement revealed that junction capacitance (C(j)) under the same junction voltage (V(j) = 1.8 V) and the junction voltage (V(j)) with the same injection current 1 mA calculated by ac small-signal IV method increased along with aging time, which explicates that the carrier density under the same low injection increases as the aging time increases. Analyses indicate that the polarization field in the quantum well is more seriously screened by the increased carriers captured by defects activated during stress time, the weaker effective polarization electric field makes the tilt of the energy band smaller, the energy radiated through the band edge and the density of energy states of the band edge increase which leads to the behaviors of peak wavelength and the FWHM of InGaN/GaN multiple quantum wells LEDs under low level injection current.

[Effects of thymosin alpha1 on immune effector molecules of mouse].

OBJECTIVE: To analysis the effects of Talpha1 on the immune effector molecules in mouse immune system. METHODS: Sixty five BABL/c mice were divided into four groups: CsA group (n=20), Talpha1 group (n= 20), CsA+Talpha1 group (n=20) and control group (n=5). In the 3 experimental groups, 10 mg/kg CsA, 400 microg/ kg Talpha1, 10 mg/kg CsA+400 microg/kg Talpha1 were respectively administrated by intraperitoneal injection daily. Luminex was performed for cytokine detection at 1 d, 7 d, 14 d, 21 d day after the above treatments. Lymphocyte culture was prepared with the mouse spleen suspension, and then treated with 0. 25 mg/mL CsA, 10 microg/mL Talpha1 or 0.25 mg/mL CsA+10 microg/mL Talpha1 in vitro, respectively. Three days later, OD values of each treated lymphocyte culture and several cytokines in the culture were measured. RESULTS: Compared with other groups, CsA+Talpha1 group had significant lower IL-1alpha, IL-2, IL-6, IL-17, and significant higher IL-10 at 1 d, 7 d, 14 d, 21 d after the treatments (P < 0.05). Three days after the culture, OD value in the control group was significantly higher than that in Talppha1 group, CsA group, and CsA+ Talpha1 group (P < 0.05). IL-1alpa and IL-6 in the control group were significantly higher than those in the experiment groups (P < 0.05), while IL-10 in the control group was significantly lower than that in the experiment groups (P < 0.05). IL-2 and IL-17 were similar. CONCLUSION: Talpha1 show regulatory effect on the immune effector molecules which could promote Th1 cells transforming to Th2 cells.

Different timing for abdominal paracentesis catheter placement and drainage in severe acute pancreatitis complicated by intra-abdominal fluid accumulation.

BACKGROUND: Non-surgical methods such as percutaneous drainage are crucial for the treatment of patients with severe acute pancreatitis (SAP). However, there is still an ongoing debate regarding the optimal timing for abdominal paracentesis catheter placement and drainage. AIM: To explore the influence of different timing for abdominal paracentesis catheter placement and drainage in SAP complicated by intra-abdominal fluid accumulation. METHODS: Using a retrospective approach, 184 cases of SAP complicated by intra-abdominal fluid accumulation were enrolled and categorized into three groups based on the timing of catheter placement: group A (catheter placement within 2 d of symptom onset, n = 89), group B (catheter placement between days 3 and 5 after symptom onset, n = 55), and group C (catheter placement between days 6 and 7 after symptom onset, n = 40). The differences in progression rate, mortality rate, and the number of cases with organ dysfunction were compared among the three groups. RESULTS: The progression rate of group A was significantly lower than those in groups B and groups C (2.25% vs 21.82% and 32.50%, P < 0.05). Further, the proportion of patients with at least one organ dysfunction in group A was significantly lower than those in groups B and groups C (41.57% vs 70.91% and 75.00%, P < 0.05). The mortality rates in group A, group B, and group C were similar (P > 0.05). At postoperative day 3, the levels of C-reactive protein (55.41 ± 19.32 mg/L vs 82.25 ± 20.41 mg/L and 88.65 ± 19.14 mg/L, P < 0.05), procalcitonin (1.36 ± 0.51 ng/mL vs 3.20 ± 0.97 ng/mL and 3.41 ± 0.98 ng/mL, P < 0.05), tumor necrosis factor-alpha (15.12 ± 6.63 pg/L vs 22.26 ± 9.96 pg/L and 23.39 ± 9.12 pg/L, P < 0.05), interleukin-6 (332.14 ± 90.16 ng/L vs 412.20 ± 88.50 ng/L and 420.08 ± 87.65ng/L, P < 0.05), interleukin-8 (415.54 ± 68.43 ng/L vs 505.80 ± 66.90 ng/L and 510.43 ± 68.23ng/L, P < 0.05) and serum amyloid A (270.06 ± 78.49 mg/L vs 344.41 ± 81.96 mg/L and 350.60 ± 80.42 mg/L, P < 0.05) were significantly lower in group A compared to those in groups B and group C. The length of hospital stay in group A was significantly lower than those in groups B and group C (24.50 ± 4.16 d vs 35.54 ± 6.62 d and 38.89 ± 7.10 d, P < 0.05). The hospitalization expenses in group A were also significantly lower than those in groups B and groups C [2.70 (1.20, 3.55) ten-thousand-yuan vs 5.50 (2.98, 7.12) ten-thousand-yuan and 6.00 (3.10, 8.05) ten-thousand-yuan, P < 0.05). The incidence of complications in group A was markedly lower than that in group C (5.62% vs 25.00%, P < 0.05), and similar to group B (P > 0.05). CONCLUSION: Percutaneous catheter drainage for the treatment of SAP complicated by intra-abdominal fluid accumulation is most effective when performed within 2 d of onset.

FAM53B promotes pancreatic ductal adenocarcinoma metastasis by regulating macrophage M2 polarization.

BACKGROUND: Our study investigated the role of FAM53B in regulating macrophage M2 polarization and its potential mechanisms in promoting pancreatic ductal adenocarcinoma (PDAC) metastasis. AIM: To further investigate the role of FAM53B in regulating macrophage M2 polarization and its potential mechanism in promoting PDAC metastasis. Our goal is to determine how FAM53B affects macrophage M2 polarization and to define its underlying mechanism in PDAC metastasis. METHODS: Cell culture and various experiments, including protein analysis, immunohistochemistry, and animal model experiments, were conducted. We compared FAM53B expression between PDAC tissues and healthy tissues and assessed the correlation of FAM53B expression with clinical features. Our study analyzed the role of FAM53B in macrophage M2 polarization in vitro by examining the expression of relevant markers. Finally, we used a murine model to study the role of FAM53B in PDAC metastasis and analyzed the potential underlying mechanisms. RESULTS: Our research showed that there was a significant increase in FAM53B levels in PDAC tissues, which was linked to adverse tumor features. Experimental findings indicated that FAM53B can enhance macrophage M2 polarization, leading to increased anti-inflammatory factor release. The results from the mouse model further supported the role of FAM53B in PDAC metastasis, as blocking FAM53B prevented tumor cell invasion and metastasis. CONCLUSION: FAM53B promotes PDAC metastasis by regulating macrophage M2 polarization. This discovery could lead to the development of new strategies for treating PDAC. For example, interfering with the FAM53B signaling pathway may prevent cancer spread. Our research findings also provide important information for expanding our understanding of PDAC pathogenesis.

RIPK1 inhibitor ameliorates pulmonary injury by modulating the function of neutrophils and vascular endothelial cells.

Acute lung injury (ALI) is an acute and progressive hypoxic respiratory failure that could progress to acute respiratory distress syndrome (ARDS) with a high mortality rate, thus immediate medical attention and supportive care are necessary. The pathophysiology of ALI is characterized by the disruption of the alveolar-capillary barrier and activation of neutrophils, leading to lung tissue damage. The receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising target for the treatment of multiple inflammatory diseases, but the role of RIPK1 in the ALI remains poorly understood. In this study, we aimed to figure out the pathological role of RIPK1 in ALI, especially in the pulmonary immune microenvironment involving neutrophils and endothelial cells. In vivo experiments showed that RIPK1 inhibitor protected against lipopolysaccharide (LPS)-induced lung injury in mouse models, with reduced neutrophils and monocytes infiltration in the lungs. Further studies demonstrated that, besides the inhibitory action on necroptosis, RIPK1 inhibitor directly suppressed reactive oxygen species (ROS) generation and inflammatory cytokines secretion from neutrophils. Furthermore, RIPK1 inhibition maintains the barrier function in TNF-α-primed vascular endothelial cells and prevents their activation induced by the supernatant from LPS-stimulated neutrophils. Mechanistically, the aforementioned effects of RIPK1 inhibitor are associated with the NF-κB signaling pathway, which is partially independent of necroptosis inhibition. These results provide new evidence that RIPK1 inhibitor directly regulates the function of neutrophils and endothelial cells, as well as interferes with the interactions between these two cell types, therefore contributing to a better understanding of RIPK1 in ALI and providing a potential avenue for future therapeutic interventions.

Early or delayed cholecystectomy (LC) for acute gallstone pancreatitis? An experience and review.

BACKGROUND/AIMS: The timing for the management of gallstones pancreatitis remains a contentious issue. Various scholars have their own achievement in in regards to this issue. METHODOLOGY: We reviewed our hospital charts from Jan 2007 to December 2010 and made a comparative study about early and delayed LC for mild to moderate gallstone pancreatitis in 80 patients. RESULTS: Successful management was obtained in all patients. Out of 80 patients, 54 had underwent for early LC within 48 hours and 26 delayed LC (6-8 weeks). CONCLUSIONS: Our study reveals that early cholecystectomy has nice outcomes in terms of shorter hospital stay and expenses. Proper consultation should be taken from radiological colleague if CBD dilations are >6 mm and contraction of gallbladder appears on imaging modalities. Comorbid conditions, past history of cholecystitis cannot be avoided for proper surgical outcomes. Postoperative complications can be deterred by early LC for mild gallstone pancreatitis. However, large volume studies are essential from different places to answer the debated topic of which management protocol is justifiable for the management of mild to moderate gall stone pancreatitis.

[The expressions and correlation of bcl-2 and Beclin-1 in pancreatic cancer].

OBJECTIVE: To investigate the expressions of Bcl-2 and Beclin-1 in pancreatic cancer and analyze the correlation between them. METHODS: The pancreatic tissue samples were collected from each 6 cases of pancreatic cancer, pancreatic exocrine benign tumor, chronic pancreatitis and normal pancreas and marked as group A, group B, group C and group D, respectively. The mRNA expression levels of Bcl-2 and Beclin-1 were detected by real-time fluorescence quantitative PCR and the protein expression levels of Bcl-2 and Beclin-1 were detected through immunohistochemistry. RESULTS: The expression levels of Bcl-2 mRNA and protein, were the lowest in group D and the highest in group A (P < 0.05). The expression levels of Beclin-1 mRNA and protein in group A were significantly lower than those in group B and group D (P < 0.05). However, the expression levels of Beclin-1 between group A and group C were not significantly different (P > 0.05). The correlation coefficient between Bcl-2 and Beclin-1 protein expression in pancreatic cancer is--0.827 (P = 0. 042). CONCLUSION: Compared with normal pancreatic tissue, pancreatic cancer had Bcl-2 expression upregulated and Beclin-1 expression downregulated. The increased anti-apoptotic effect of Bcl-2 and the decreased autophagic effect of Beclin-1 may collaboratively contribute to the occurrence of pancreatic cancer.

Development and validation of a prediction model for moderately severe and severe acute pancreatitis in pregnancy.

BACKGROUND: The severity of acute pancreatitis in pregnancy (APIP) is correlated with higher risks of maternal and fetal death. AIM: To develop a nomogram that could predict moderately severe and severe acute pancreatitis in pregnancy (MSIP). METHODS: Patients with APIP admitted to West China Hospital between January 2012 and December 2018 were included in this study. They were divided into mild acute pancreatitis in pregnancy (MAIP) and MSIP. Characteristic parameters and laboratory results were collected. The training set and test set were randomly divided at a ratio of 7:3. Least absolute shrinkage and selection operator regression was used to select potential prognostic factors. A nomogram was developed by logistic regression. A random forest model was used to validate the stability of the prediction factors. Receiver operating characteristic curves and calibration curves were used to evaluate the model's predictive performance. RESULTS: A total of 190 patients were included in this study. A total of 134 patients (70.5%) and 56 patients (29.5%) were classified as having MAIP and MSIP, respectively. Four independent predictors (lactate dehydrogenase, triglyceride, cholesterol, and albumin levels) were identified for MSIP. A nomogram prediction model based on these factors was established. The model had areas under the curve of 0.865 and 0.853 in the training and validation sets, respectively. The calibration curves showed that the nomogram has a good consistency. CONCLUSION: A nomogram including lactate dehydrogenase, triglyceride, cholesterol, and albumin levels as independent predictors was built with good performance for MSIP prediction.

MyD88 deficiency aggravates the severity of acute pancreatitis by promoting MyD88-independent TRIF pathway-mediated necrosis.

Background: With uncontrolled inflammatory progression, acute pancreatitis (AP) can progress to severe acute pancreatitis (SAP). Inflammation and parenchymal cell death are key pathologic responses of AP. Toll-like receptor 4 (TLR4) plays a pro-inflammatory role in AP. Myeloid differentiation primary response protein 88 (MyD88) is the most essential utilized adaptor of TLR4, but its role in AP remains unclear. We investigated the potential role of MyD88 in the pathogenesis of AP. Methods: An AP model was induced by administering either cerulein or L-arginine to wild-type or MyD88-deficient mice. Additionally, receptor-interacting protein kinase 1 (RIP1) inhibitor necrostatin-1 (Nec-1) was administered to the MyD88-/- mice. The severity of AP was determined by measuring serum amylase and lipase activities, quantifying pancreatic myeloperoxidase (MPO) activity, and histological examination. The effects of MyD88 deletion on cell death and the inflammatory response were determined by measuring apoptosis, necrosis, and inflammatory cytokines. Western blot was used to assess the necrotic mediators, RIP1 and RIP3. Results: The deletion of MyD88 resulted in more severe acute experimental pancreatitis as assessed by increased amylase and lipase activities, increased pancreatic MPO activity, a reduced anti-inflammatory response, reduced apoptosis, and increased necrosis. Additionally, Nec-1 treatment significantly reduced necrosis in the MyD88-/- mice. Conclusions: The deletion of MyD88 inhibited the TLR4/MyD88-dependent pathway mediated protective immune defense response and enhanced TLR4/MyD88-independent TRIF pathway-mediated pancreatic necrosis, which in turn aggravated the severity of AP. The critical role of MyD88 in immune defense response and cell death indicates that MyD88 represents a potential therapeutic target in the management of AP.