Inhibition of Pck1 in intestinal epithelial cells alleviates acute pancreatitis via modulating intestinal homeostasis.

Intestinal barrier dysfunction usually occurred in acute pancreatitis (AP) but the mechanism remains unclear. In this study, RNA sequencing of ileum in L-arginine-induced AP mice demonstrated that phosphoenolpyruvate kinase 1 (Pck1) was significantly up-regulated. Increased Pck1 expression in intestinal epithelial cells (IECs) was further validated in ileum of AP mice and duodenum of AP patients. In AP mice, level of Pck1 was positively correlated with pancreatic and ileal histopathological scores, serum amylase activity, and intestinal permeability (serum diamine oxidase (DAO), D-lactate, and endotoxin). In AP patients, level of Pck1 had a positive correlation with Ranson scores, white blood cell count and C-reactive protein. Inhibition of Pck1 by 3-Mercaptopicolinic acid hydrochloride (3-MPA) alleviated pancreatic and ileal injuries in AP mice. AP + 3-MPA mice showed improved intestinal permeability, including less epithelial apoptosis, increased tight junction proteins (TJPs) expression, decreased serum DAO, D-lactate, endotoxin, and FITC-Dextran levels, and reduced bacteria translocation. Lysozyme secreted by Paneth cells and mucin2 (MUC2) secretion in goblet cells were also partly restored in AP + 3-MPA mice. Meanwhile, inhibition of Pck1 improved intestinal immune response during AP, including elevation of M2/M1 macrophages ratio and secretory immunoglobulin A (sIgA) and reduction in neutrophils infiltration. In vitro, administration of 3-MPA dramatically ameliorated inflammation and injuries of epithelial cells in enteroids treated by LPS. In conclusion, inhibition of Pck1 in IECs might alleviate AP via modulating intestinal homeostasis.

Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii served as key components of fecal microbiota transplantation to alleviate colitis.

Fecal microbiota transplantation (FMT) is a promising therapy for inflammatory bowel disease (IBD) via rectifying gut microbiota. The aim of this study was to identify a mechanism of how specific bacteria-associated immune response contributes to alleviated colitis. Forty donors were divided into high (donor H) and low (donor L) groups according to the diversity and the abundance of Bacteroides and Faecalibacterium by 16S rRNA sequencing. FMT was performed on dextran sulfate sodium (DSS)-induced colitis in mice. Mice with colitis showed significant improvement in intestinal injury and immune imbalance after FMT with group donor H (P < 0.05). Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii were identified as targeted strains in donor feces by real-time PCR and droplet digital PCR. Mice with colitis were treated with mono- or dual-bacterial gavage therapy. Dual-bacterial therapy significantly ameliorated intestinal injury compared with mono-bacterial therapy (P < 0.05). Dual-bacterial therapy increased the M2/M1 macrophage polarization and improved the Th17/Treg imbalance and elevated IL-10 production by Tregs compared with the DSS group (P < 0.05). Metabolomics showed increased abundance of lecithin in the glycerophospholipid metabolism pathway. In conclusion, B. thetaiotaomicron and F. prausnitzii, as the key bacteria in donor feces, alleviate colitis in mice. The mechanism may involve increasing lecithin and regulating IL-10 production of intestinal Tregs.NEW & NOTEWORTHY We demonstrate that donors with high abundance of Bacteroides and Faecalibacterium ameliorate dextran sulfate sodium (DSS)-induced colitis in mice by fecal microbiota transplantation (FMT). The combination therapy of Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii is superior to mono-bacterial therapy in ameliorating colitis in mice, of which mechanism may involve promoting lecithin and inducing IL-10 production of intestinal Tregs.

Colonic mucin-2 attenuates acute necrotizing pancreatitis in rats by modulating intestinal homeostasis.

Mucin-2 (MUC2) secreted by goblet cells participates in the intestinal barrier, but its mechanism in acute necrotizing pancreatitis (ANP) remains unclear. In acute pancreatitis (AP) patients, the functions of goblet cells (MUC2, FCGBP, CLCA1, and TFF3) decreased, and MUC2 was negatively correlated with AP severity. ANP rats treated with pilocarpine (PILO) (PILO+ANP rats) to deplete MUC2 showed more serious pancreatic and colonic injuries, goblet cell dysfunction, gut dysbiosis, and bacterial translocation than those of ANP rats. GC-MS analysis of feces showed that PILO+ANP rats had lower levels of butyric acid, isobutyric acid, isovaleric acid, and hexanoic acid than those of ANP rats. The expression of MUC2 was associated with colonic injury and gut dysbiosis. All these phenomena could be relieved, and goblet cell functions were also partially reversed by MUC2 supplementation in ANP rats. TNF-α-treated colonoids had exacerbated goblet cell dysfunction. MUC2 expression was negatively correlated with the levels of pro-inflammatory cytokines (IL-1ß and IL-6) (p < .05) and positively related to the expression of tight junction proteins (Claudin 1, Occludin, and ZO1) (p < .05). Downregulating MUC2 by siRNA increased the levels of the pro-inflammatory cytokines in colonoids. MUC2 might maintain intestinal homeostasis to alleviate ANP.

Fecal microbiota transplantation versus glucocorticoids for the induction of remission in mild to moderate ulcerative colitis.

OBJECTIVE: To compare efficacy and safety of fecal microbiota transplantation (FMT) with glucocorticoid as induction therapy in ulcerative colitis (UC). METHODS: The patients with active mild to moderate UC were recruited into the single-center, prospective cohort study. The patients were treated with either FMT (FMT group) or glucocorticoids (GCs group). Patients received FMT administration for 3 days. The primary outcome was clinical and endoscopic remission at week 12. Inflammatory parameters were assessed by routine blood tests. Safety was assessed by adverse events recorded. The serum levels of TNF-α, IFN-γ, IL-1ß, IL-4, IL-5, IL-6, IL-10 IL-8, IL-12p70, IL-13, IL-17A and IL-23 following FMT were measured by Luminex multiplex assay. RESULTS: Of the 122 patients, 62 patients were treated with FMT and 60 with glucocorticoids. 34 patients in FMT group (54.8%) and 29 in GCs group (48.3%) reached the primary outcome (p = 0.30). The incidence of adverse events in GCs group (35/60, 58.3%) was significantly higher than that in FMT group (14/62, 22.6%) and two serious adverse events were observed following GCs. Patients in FMT group were stratified into responders (RE) and non-responders (NR) groups. The level of TNF-α and IL-6 decreased significantly in RE group, while IL-10 decreased significantly in NR group. CONCLUSION: FMT therapy was as effective as glucocorticoids to induce remission in active mild to moderate UC, accompanied by fewer adverse events. The modification of serum TNF-α, IL-6 and IL-10 might be related to the efficacy of FMT in UC. Trial registration This study was registered with ClinicalTrials.gov (NCT02435160). Registered on 6 April, 2015. https://clinicaltrials.gov/ct2/results?cond=&term=NCT02435160&cntry=&state=&city=&dist=.

Pretreatment with chitosan oligosaccharides attenuate experimental severe acute pancreatitis via inhibiting oxidative stress and modulating intestinal homeostasis.

Severe acute pancreatitis (SAP) is a severe acute abdominal disease. Recent evidence shows that intestinal homeostasis is essential for the management of acute pancreatitis. Chitosan oligosaccharides (COS) possess antioxidant activity that are effective in treating various inflammatory diseases. In this study we explored the potential therapeutic effects of COS on SAP and underlying mechanisms. Mice were treated with COS (200 mg·kg-1·d-1, po) for 4 weeks, then SAP was induced in the mice by intraperitoneal injection of caerulein. We found that COS administration significantly alleviated the severity of SAP: the serum amylase and lipase levels as well as pancreatic myeloperoxidase activity were significantly reduced. COS administration suppressed the production of proinflammatory cytokines (TNF-α, IL-1ß, CXCL2 and MCP1) in the pancreas and ileums. Moreover, COS administration decreased pancreatic inflammatory infiltration and oxidative stress in SAP mice, accompanied by activated Nrf2/HO-1 and inhibited TLR4/NF-κB and MAPK pathways. We further demonstrated that COS administration restored SAP-associated ileal damage and barrier dysfunction. In addition, gut microbiome analyses revealed that the beneficial effect of COS administration was associated with its ability to improve the pancreatitis-associated gut microbiota dysbiosis; in particular, probiotics Akkermansia were markedly increased, while pathogenic bacteria Escherichia-Shigella and Enterococcus were almost eliminated. The study demonstrates that COS administration remarkably attenuates SAP by reducing oxidative stress and restoring intestinal homeostasis, suggesting that COS might be a promising prebiotic agent for the treatment of SAP.

Commensal Escherichia coli Aggravates Acute Necrotizing Pancreatitis through Targeting of Intestinal Epithelial Cells.

An increase of Escherichia-Shigella was previously reported in acute necrotizing pancreatitis (ANP). We investigated whether Escherichia coli MG1655, an Escherichia commensal organism, increased intestinal injury and aggravated ANP in rats. ANP was induced by retrograde injection of 3.5% sodium taurocholate into the biliopancreatic duct. Using gut microbiota-depleted rats, we demonstrated that gut microbiota was involved in the pancreatic injury and intestinal barrier dysfunction in ANP. Using 16S rRNA gene sequencing and quantitative PCR, we found intestinal dysbiosis and a significant increase of E. coli MG1655 in ANP. Afterward, administration of E. coli MG1655 by gavage to gut microbiota-depleted rats with ANP was performed. We observed that after ANP induction, E. coli MG1655-monocolonized rats presented more severe injury in the pancreas and intestinal barrier function than gut microbiota-depleted rats. Furthermore, Toll-like receptor 4 (TLR4)/MyD88/p38 mitogen-activated protein (MAPK) and endoplasmic reticulum stress (ERS) activation in intestinal epithelial cells were also increased more significantly in the MG1655-monocolonized ANP rats. In vitro, the rat ileal epithelial cell line IEC-18 displayed aggravated tumor necrosis factor alpha-induced inflammation and loss of tight-junction proteins in coculture with E. coli MG1655, as well as TLR4, MyD88, and Bip upregulation. In conclusion, our study shows that commensal E. coli MG1655 increases TLR4/MyD88/p38 MAPK and ERS signaling-induced intestinal epithelial injury and aggravates ANP in rats. Our study also describes the harmful potential of commensal E. coli in ANP.IMPORTANCE This study describes the harmful potential of commensal E. coli in ANP, which has not been demonstrated in previous studies. Our work provides new insights into gut bacterium-ANP cross talk, suggesting that nonpathogenic commensals could also exhibit adverse effects in the context of diseases.

Paneth Cell Ablation Aggravates Pancreatic and Intestinal Injuries in a Rat Model of Acute Necrotizing Pancreatitis after Normal and High-Fat Diet.

We previously reported that acute necrotizing pancreatitis (ANP) after normal or high-fat diet is associated with a decreased number of Paneth cells in ileal crypts. Here, we ablated Paneth cells in a rat model of ANP after normal and high-fat diet to investigate the effects on disease symptoms. Adult male Sprague-Dawley rats received standard rat chow or a high-fat diet for 2 weeks, after which they were treated with dithizone to deplete Paneth cells. Six hours later, ANP was established by retrograde injection of sodium taurocholate into the biliopancreatic duct. Rats were sacrificed at 6, 12, and 24 h for assessment. We found dithizone aggravated ANP-associated pathological injuries to the pancreas and ileum in rats on high-fat or standard diets. Lysozyme expression in ileal crypts was decreased, while serum inflammatory cytokines (TNFα, IL-1ß, and IL-17A) and intestinal permeability (serum DAO activity and D-lactate) were increased. Expression of tight junction proteins (claudin-1, zo-1, and occludin) was decreased. Using high-throughput 16S rRNA sequencing, we found dithizone reduced microbiota diversity and altered microbiota composition in rats on high-fat or standard diets. Dithizone decreased fecal short-chain fatty acids (SCFAs) in rats on high-fat or standard diets. Changes in intestinal microbiota correlated significantly with SCFAs, lysozyme, DAO activity, D-lactate, inflammatory cytokines, and pathological injury to the pancreas and ileum in rats on high-fat or standard diets. In conclusion, ablation of Paneth cells exacerbates pancreatic and intestinal injuries in ANP after normal and high-fat diet. These symptoms may be related to changes in the intestinal microbiota.

Characterization of the duodenal bacterial microbiota in patients with pancreatic head cancer vs. healthy controls.

An increasing number of reports have demonstrated that there is an association between the presence of pathogenic microorganisms and pancreatic cancer. However, the role of the duodenal microbiota in pancreatic carcinogenesis remains unknown. In this study, duodenal mucosal microbiota was analyzed in 14 patients with pancreatic head cancer and 14 healthy controls using 16S rRNA gene pyrosequencing methods. Plasma endotoxin activity and the concentrations of the proinflammatory cytokine IL-6 and C-reactive protein (CRP) were measured in blood samples. The urea breath test was used to detect Helicobacter pylori infections. Endoscopic duodenal mucosal biopsies were evaluated by histological examinations. Statistical comparisons of inflammatory factors revealed significantly higher levels of CRP and IL-6 in the pancreatic cancer group as compared to healthy controls. Patients with pancreatic cancer also had a higher incidence of H. pylori infections and showed mucosal changes, including villous abnormalities and diffuse inflammatory cell infiltration in the lamina propria. The sequences analysis showed that based on linear discriminant analysis effect size (LEfSe) analysis at the genus level, Acinetobacter, Aquabacterium, Oceanobacillus, Rahnella, Massilia, Delftia, Deinococcus, and Sphingobium were more abundant in the duodenal mucosa of pancreatic cancer patients, whereas the duodenal microbiotas of healthy controls were enriched with Porphyromonas, Paenibacillus, Enhydrobacter, Escherichia, Shigella, and Pseudomonas. These results reveal a picture of duodenal microbiota in pancreatic head cancer patients that could be useful in future trials investigating the role of gut microbiota in pancreatic cancer.

Impact of multiple quaternary ammonium salts on dynamic properties of BSA adsorption layer at different pH values.

The interaction mechanism of multiple quaternary ammonium salts (MQAS) with bovine serum albumin (BSA) was examined by the fluorescence quenching method and circular dichroism (CD) spectra. Moreover, the effects of MQAS on the dynamic properties of BSA adsorption layers at different pH values were investigated using dilational interfacial rheology. Results show that the quenching constants increase with an increase in pH values and decrease with an increase in the experiment temperature at pH 5.3. The quenching mechanism is static quenching, and the electrostatic force dominates the interaction between MQAS and BSA at pH 5.3. Due to three positive head groups, MQAS can significantly affect the dynamic interfacial activity of BSA molecules at a relatively low concentration. At pH 4.3, the electrostatic repulsion is unfavorable for the formation of MQAS/BSA complexes. Consequently, MQAS molecules will replace BSA molecules from the interface by competitive adsorption. At the pH value above the isoelectric point of BSA, the electrostatic attraction is better for the formation of MQAS/BSA complexes, which exhibit a rapid adsorption rate and an enhanced interfacial activity. Moreover, the kinetic dependencies of interfacial dilational elasticity for the MQAS/BSA mixtures become nonmonotonous. The appearance of the maximum interfacial elasticity values can be attributed to the formation of tails and loops, which suggests that the addition of MQAS destroys the secondary and tertiary structure of protein in the bulk phase. In addition, the effects of MQAS on the secondary structure of protein were demonstrated by CD spectra.

The effects of caffeine on pancreatic diseases: the known and possible mechanisms.

Caffeine, a controversial substance, was once known to be addictive and harmful. In recent years, new effects of caffeine on the human body have been confirmed. Recent research over the past few decades has shown the potential of caffeine in treating pancreas-related diseases. This review aims to analyze the known and possible mechanisms of caffeine on pancreatic diseases and provides an overview of the current research status regarding the correlation between caffeine and pancreatic disease, while enhancing our understanding of their relationship.

Tumor microenvironment responsive self-cascade catalysis for synergistic chemo/chemodynamic therapy by multifunctional biomimetic nanozymes.

Chemodynamic therapy (CDT) is an emerging approach to treat cancer based on the tumor microenvironment (TME), but its limited content of endogenous hydrogen peroxide (H2O2) weakens the anticancer effects. Herein, a multifunctional biomimetic nanozyme (Se@SiO2-Mn@Au/DOX, named as SSMA/DOX) is fabricated, which undergoes TME responsive self-cascade catalysis to facilitate MRI guided enhanced chemo/chemodynamic therapy. The SSMA/DOX nanocomposites (NCs) responsively degrade in acidic conditions of tumor to release Se, DOX, Au and Mn2+. Mn2+ not only enables MRI to guided therapy, but also catalyzes the endogenous H2O2 into hydroxyl radical (˙OH) for CDT. In addition, the Au NPs continuously catalyze glucose to generate H2O2, enhancing CDT by supplementing a sufficiently reactive material and cutting off the energy supply of the tumor by consuming glucose. Simultaneously, Se enhances the chemotherapy of doxorubicin hydrochloride (DOX) and CDT by upregulating ROS in the tumor cells, achieving remarkable inhibition effect towards tumor. Moreover, SSMA/DOX NCs have good biocompatibility and degradability, which avoid long-term toxicity and side effects. Overall, the degradable SSMA/DOX NCs provide an innovative strategy for tumor microenvironment responsive self-cascade catalysis to enhance tumor therapy.

Ulcerative Colitis in Response to Fecal Microbiota Transplantation via Modulation of Gut Microbiota and Th17/Treg Cell Balance.

Background: Fecal microbiota transplantation (FMT) may contribute to disease remission in ulcerative colitis (UC). We studied the microbiota change and its regulation on T cells after FMT. Methods: Patients with mild to moderately active UC were included to receive FMT. The intestinal histopathological changes and barrier function were evaluated. The fecal samples of donors and patients were analyzed by 16S rRNA gene-based microbiota analysis, and the colon Th17 and Treg cells were assessed. Results: Fifteen patients completed the 8-week-follow-up. A total of 10 patients (66.7%) were in the responders (RE) group and five in the non-responders (NR) group. The Nancy histological index and fecal calprotectin decreased (p < 0.001, p = 0.06, respectively) and Occludin and Claudin1 increased in the RE group. The abundance of Faecalibaterium increased significantly by 2.3-fold in the RE group at week 8 (p = 0.043), but it was suppressed in the NR group. Fecal calprotectin (r = −0.382, p = 0.003) and Nancy index (r = −0.497, p = 0.006) were correlated inversely with the abundance of Faecalibacterium, respectively. In the RE group the relative mRNA expression of RORγt decreased and Foxp3 increased. Significantly decreased CD4+ RORγt+ Th17 and increased CD4+ Foxp3+ Treg were also observed in the RE group. The relative abundance of Faecalibacterium correlated with CD4+ RORγt+ Th17 (r = −0.430, p = 0.018) and CD4+ Foxp3+ Treg (r = 0.571, p = 0.001). Conclusions: The long-term Faecalibaterium colonization following FMT plays a crucial role in UC remission by alleviating intestinal inflammation. This anti-inflammatory effect of Faecalibacterium may be achieved by regulating the imbalance of Th17/Treg levels in UC.

Paneth Cells Protect against Acute Pancreatitis via Modulating Gut Microbiota Dysbiosis.

Acute pancreatitis (AP) is usually accompanied by intestinal failure, but its mechanism is still unclear. In AP patients, the functions of Paneth cells (lysozyme, HD5, Reg3γ, and Wnt3a) decreased. Compared with AP mice, injuries and inflammation of the pancreas and ileum were aggravated in AP mice treated with dithizone (Dith) (Dith+AP mice). Intestinal permeability and bacterial translocation were also increased. 16S rRNA sequencing showed that the gut microbiota of Dith mice and Dith+AP mice exhibited a marked increase in the pathogenic bacterium Helicobacter and a significant decrease in the probiotic bacterium Blautia. Lysozyme gavage in Dith+AP mice effectively alleviated injuries of the pancreas and small intestine. The beneficial effect of lysozyme was associated with a significant increase in the probiotic bacterium Blautia and a virtual absence of the pathogenic bacterium Helicobacter. The severity of AP in antibiotic-treated mice (ABX mice) was significantly aggravated when receiving feces from Dith mice and was markedly alleviated when receiving feces from lysozyme-gavaged mice. In vitro, lysozyme increased the proliferation of enteroids by promoting the activation of the Wnt pathway and Lgr5 expression in intestinal stem cells. IMPORTANCE We demonstrate that AP patients and experimental AP mice exhibited a dysfunction of Paneth cells. Our in vivo research showed that the severity of AP was exacerbated by the long-term dysfunction of Paneth cells, which was associated with gut microbiota disorder. Restoring part of Paneth cell functions through lysozyme supplementation alleviated the severity of AP and gut microbiota dysbiosis. This study provides novel insight into the link of pancreas-gut interactions in the pathogenesis of AP, providing a new direction for the clinical treatment of intestinal complications during AP.

A biodegradable "Nano-donut" for magnetic resonance imaging and enhanced chemo/photothermal/chemodynamic therapy through responsive catalysis in tumor microenvironment.

Prussian blue (PB) is a safe photothermal agent for tumor therapy, yet poor photothermal effect and single therapeutic function severely restrict its further clinical applications. Herein, a biodegradable "Nano-donut" (CMPB-MoS2-PEG) is fabricated for magnetic resonance (MR) imaging and enhanced photothermal therapy (PTT)/ chemodynamic therapy (CDT)/chemotherapy through responsive catalysis in tumor microenvironment (TME). The "Nano-donut" is organically composed of Cu/Mn ions doped-PB and MoS2. The porous donut structure of CMPB-MoS2-PEG endows them as a carrier for delivery of doxorubicin hydrochloride (DOX) to tumor site. The framework of Nano-donut specifically decomposes in TME due to the reaction between Fe2+/Fe3+ and H2O2. The multivalent elements (Cu/Fe/Mn ions) decrease the bandgap and then enhance CDT by synergistically catalyzing H2O2 into toxic ·OH. Meanwhile, the Mn4+ also reacts with H2O2 to generate O2, improving the hypoxia of TME and enhancing the chemotherapy effect of released DOX. The MoS2 mingles in the PB, which significantly enhances photothermal conversion efficiency (η) effect of PB from 16.02% to 38.0%. In addition, Fe3+ as T2-weighted MR imaging agent can achieve MR imaging-guided therapy. The data clearly shows Nano-donut/DOX nanocomposites (NCs) have a remarkable inhibition for cancer cells and excellent biological safety in tumor treatment.

Alteration of gut microbiota in acute pancreatitis and associated therapeutic strategies.

Gut microbiome is considered as a crucial regulator of human health. Alteration of gut microbiome has been reported in acute pancreatitis (AP) and probably contributes to the severity of disease. Explore the precise role of gut microbiome in the pathogenesis of AP could offer new strategies to improve the clinical outcomes of AP. This review summarizes the role of gut microbiome in AP, lists possible mechanisms associated with it and offers an overview of current treatments based on gut microbiome.

Porous COS@SiO2 Nanocomposites Ameliorate Severe Acute Pancreatitis and Associated Lung Injury by Regulating the Nrf2 Signaling Pathway in Mice.

Severe acute pancreatitis (SAP) is associated with high rates of mortality and morbidity. Chitosan oligosaccharides (COSs) are agents with antioxidant properties. We developed porous COS@SiO2 nanocomposites to study the protective effects and mechanisms of COS nanomedicine for the treatment of acute pancreatitis. Porous COS@SiO2 nanocomposites released COSs slowly under pH control, enabling sustained release and maintaining the drug at a higher concentration. This study aimed to determine whether porous COS@SiO2 nanocomposites ameliorate SAP and associated lung injury. The SAP model was established in male C57BL/6 mice by intraperitoneal injection of caerulein. The expression levels of myeloperoxidase, malondialdehyde, superoxide dismutase, nuclear factor-kappa B (NF-κB), the NOD-like receptor protein 3 (NLRP3) inflammasome, nuclear factor E2-related factor 2 (Nrf2), and inflammatory cytokines were detected, and a histological analysis of mouse pancreatic and lung tissues was performed. In the SAP groups, systemic inflammation and oxidative stress occurred, and pathological damage to the pancreas and lung was obvious. Combined with porous COS@SiO2 nanocomposites before treatment, the systemic inflammatory response was obviously reduced, as were oxidative stress indicators in targeted tissues. It was found that Nrf2 was significantly activated in the COS@SiO2 treatment group, and the expressions of NF-κB and the NLRP3 inflammasome were notably decreased. In addition, this protective effect was significantly weakened when Nrf2 signaling was inhibited by ML385. This demonstrated that porous COS@SiO2 nanocomposites activate the Nrf2 signaling pathway to inhibit oxidative stress and reduce the expression of NF-κB and the NLRP3 inflammasome and the release of inflammatory factors, thus blocking the systemic inflammatory response and ultimately ameliorating SAP and associated lung injury.

Rapamycin Alleviates Hypertriglyceridemia-Related Acute Pancreatitis via Restoring Autophagy Flux and Inhibiting Endoplasmic Reticulum Stress.

Hypertriglyceridemia (HTG) can aggravate acute pancreatitis (AP), but its pathogenesis remains unclear. As autophagic activity is closely related to lipid metabolism and AP, we investigated the autophagic response in models of AP aggravated by HTG and explored whether rapamycin has a protective effect against HTG-related pancreatitis. HTG-associated AP models were established in vivo in rats and in vitro. The degree of inflammation, pancreatic injury, the expression of endoplasmic reticulum (ER) stress, and autophagy markers (P62, LC3) were compared. Autophagic flux were assessed using immunostaining, electron microscopy, and immunoblotting. Compared with the normal diet group, the high-fat diet (HFD) AP group exhibited more severe pancreatic injury, apoptosis, and blocked autophagic flux. In addition, the three branches (PERK-eIF2α, ATF-6-GRP78, and IRE1-sXBP1) of the unfolded protein response and mTORC1/S6K1 pathway were activated in HFD AP models. Moreover, the same phenomena were confirmed in vitro in palmitic acid-stimulated pancreatic acinar cells. Preincubation with the mTOR inhibitor rapamycin restored the autophagic flux and markedly reduced the adverse effects of HTG. In conclusion, the autophagic flux is impaired in HFD-induced AP models and is strongly associated with ER stress. Rapamycin could prevent the aggravation of HTG-associated AP via inhibiting mTORC1/S6K1 pathway.

The relationship between the psychological stress of adolescents in school and the prevalence of chronic low back pain: a cross-sectional study in China.

BACKGROUND: Accumulating evidence supports an association between an unhealthy mental state and low back pain (LBP). However, the degree of the association between mental health and chronic low back pain (CLBP) in the general population is poorly understood. The objective of this study was to analyze the incidence of CLBP in Chinese college students and to examine the association between students' unhealthy mental states and the prevalence of CLBP. METHODS: This is a cross-sectional study. A total of 10,000 questionnaires were distributed in the second semester of the 2017-2018 academic year by the School of Medicine, Shanghai JiaoTong University. Eligible participants were students aged ≥ 18 years from randomly selected Chinese colleges. Participants completed a questionnaire survey that included items from the Symptom Checklist-90 (SCL-90) and items on demographic factors, LBP prevalence, quality of life at their university, study-related stress and interpersonal relationships. The evaluation of students' mental states in the survey was divided into two major parts: direct and indirect indicators. A multivariate logistic regression model was mainly used to explore the relationship between CLBP and the students' mental health. RESULTS: There was a high incidence of CLBP in the college students. Multiple logistic regression analysis indicated that the risk of CLBP increased with increasing scores on the SCL-90, and a clinically unhealthy mental state (scores greater than 3) was significantly associated with CLBP (adjusted odds ratios for depression, anxiety, coercion, paranoia, and interpersonal sensitivity were 7.209, 6.593, 3.959, 4.465, and 4.283, respectively; p < 0.001). Participants who had poor living habits or uncomfortable campus lives and those who experienced heavy academic pressure also showed a higher positive association with CLBP compared with the full sample. CONCLUSIONS: Unhealthy psychological conditions, which may be attributed to unsatisfying school lives, excessive learning pressure, and uncomfortable interpersonal relationships, represent a risk factor for CLBP in college students.