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The present study aimed to investigate the potential effects of white hyacinth bean polysaccharide (WHBP) against type 2 diabetic mellitus (T2DM) which was established by high-glucose/high-fat for 8 weeks, combined with a low-dose streptozotocin (STZ) injection. Our results showed that WHBP behaved the hypoglycemic effect by attenuating fasting blood glucose in vivo. WHBP-mediated anti-diabetic effects associated with the attenuation of insulin resistance and pancreatic impairment, as evidenced by the mitigation of pathological changes, inflammatory response and oxidative stress in the pancreas of T2DM rats. Meanwhile, gut protection was also shown during WHBP-mediated anti-diabetic effects, and glucagon-like peptide-1 (GLP-1), a mediator of the entero-insular axis, was observed to be elevated in both gut and pancreas of WHBP groups when compared to DM group, suggesting that hypoglycemic effects of WHBP were implicated in gut-pancreas interaction. Subsequently, untargeted metabolomics analysis performed by UPLC-QTOF/MS and showed that WHBP administration significantly adjusted the levels of 40 metabolites when compared to DM group. Further data concerning pathway analysis showed that WHBP administration significantly regulated the phenylalanine metabolism, tryptophan metabolism, arginine and proline, isoleucine metabolism, and glycerophospholipid metabolism in T2DM rats. Together, our results suggested that WHBP performed hypoglycemic effects and pancreatic protection linked to entero-insular axis involvement with GLP-1 and reversed metabolic disturbances in T2DM rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The unsustainable use of manmade chemicals poses significant threats to biodiversity and human health. Emerging evidence highlights the potential of certain chemicals to cause transgenerational impacts on metabolic health. Here, we investigate male transmitted epigenetic transgenerational effects of the anti-androgenic herbicide linuron in the pancreas of Xenopus tropicalis frogs, and their association with metabolic phenotypes. Reduced representation bisulfite sequencing (RRBS) was used to assess genome-wide DNA methylation patterns in the pancreas of adult male F2 generation ancestrally exposed to environmentally relevant linuron levels (44 ± 4.7 μg/L). We identified 1117 differentially methylated regions (DMRs) distributed across the X. tropicalis genome, revealing potential regulatory mechanisms underlying metabolic disturbances. DMRs were identified in genes crucial for pancreatic function, including calcium signalling (clstn2, cacna1d and cadps2), genes associated with type 2 diabetes (tcf7l2 and adcy5) and a biomarker for pancreatic ductal adenocarcinoma (plec). Correlation analysis revealed associations between DNA methylation levels in these genes and metabolic phenotypes, indicating epigenetic regulation of glucose metabolism. Moreover, differential methylation in genes related to histone modifications suggests alterations in the epigenetic machinery. These findings underscore the long-term consequences of environmental contamination on pancreatic function and raise concerns about the health risks associated with transgenerational effects of pesticides., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Cecilia Berg is now employed at The Swedish Medical Products Agency, and Sofie Svanholm is now employed at The Swedish Chemicals Agency, but The Swedish Medical Products Agency or The Swedish Chemicals Agency were not involved in any part of this study. All work was carried out when employed at Uppsala University. The views expressed in this study are that of the authors alone and do not reflect those of The Swedish Medical Products Agency or The Swedish Chemicals Agency., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Chronic pancreatic dysfunction is frequently observed as a consequence of prolonged high-fat diet consumption and is a serious public health concern. This pro-diabetic insult aggravates inflammation-influenced fibrotic lesions and is associated with deregulated autophagy. Metformin, a conventional anti-hyperglycemic drug, might be beneficial for pancreatic health, but the complex molecular regulations are not clarified. Considering the worldwide prevalence of chronic pancreatic dysfunction in obese individuals, we aimed to unwind the molecular intricacies explaining the involvement of oxidative stress, inflammation and fibrosis and to approbate metformin as a plausible intervention in this crossroad., Main Methods: Age-matched Swiss Albino mice were exposed to high-fat diet (60 kcal%) against control diet (10 kcal%) to establish diet-induced stress model. Metformin treatment was introduced after 4 weeks to metformin-control and HFD-exposed metformin groups. After 8 weeks, metabolic and molecular outcomes were assessed to establish the impact of metformin on chronic consequences of HFD-mediated injury., Key Findings: High-fat diet administration to healthy mice primes oxidative stress-mediated chronic inflammation through Nrf2/Keap1/NF-κB interplay. Besides, pro-inflammatory cytokine bias leading to fibrotic (increased TGF-β, α-SMA, and MMP9) and pro-EMT (Twist1, Slug, Vimentin, E-cadherin) repercussions in pancreatic lobules were evident. Metformin distinctly rescues high-fat diet-induced remodeling of pancreatic pro-diabetic alterations and cellular survival/death switch. Further, metformin abrogates the p62-Twist1 crosstalk in an autophagy-dependent manner (elevated beclin1, LC3-II/I, Lamp2) to restore pancreatic homeostasis., Conclusion: Our research validates the therapeutic potential of metformin in the inflammation-fibrosis nexus to ameliorate high-fat diet-induced pancreatic dysfunction and related metabolic alterations., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Inhibition of pancreatic lipase (PL) is a strategy to prevent obesity. The inhibitory effects of Flos Sophorae Immaturus (FSI) extract and its main flavonoid components, rutin and quercetin, on PL were investigated. The contents of rutin and quercetin in FSI extract were 44.10 ± 1.33 % and 6.07 ± 1.62 %, respectively. The IC 50 values of FSI extract, rutin and quercetin on PL were 322, 258 and 71 μg/mL, respectively. Rutin and quercetin inhibited PL in a reversible and noncompetitive manner. The combination of rutin and quercetin exhibited synergistic inhibitory effects at low concentration. The binding of rutin/quercetin with PL caused the fluorescence quenching of protein. Fluorescence titration showed the binding affinity of quercetin with PL protein was stronger than that of rutin. Circular dichroism analysis showed the binding changed the secondary structure of PL with an increase in random coil and a decrease in α-Helix and β-Sheet. Molecular docking revealed that rutin and quercetin could interact with the amino acid residues around the catalytic site through multiple secondary interactions. In vivo studies showed that FSI extract can reduce fat absorption and promote fecal fat excretion through inhibition of PL activity, and the effects were mainly due to rutin and quercetin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Human pancreatic lipase (hPL) is a vital digestive enzyme responsible for breaking down dietary fats in humans, inhibiting hPL is a feasible strategy for preventing and treating obesity. This study aims to investigate the structure-activity relationships (SARs) of flavonoids as hPL inhibitors, and to find potent hPL inhibitors from natural and synthetic flavonoids. In this work, the anti-hPL effects of forty-nine structurally diverse naturally occurring flavonoids were assessed and the SARs were summarized. The results demonstrated that the pyrogallol group on the A ring was a key moiety for hPL inhibition. Subsequently, a series of baicalein derivatives were synthesized, while 4'-amino baicalein (ABA) and 4'-pyrrolidine baicalein (PBA) were identified as novel potent hPL inhibitors (IC 50  < 1 μM). Further investigations showed that scutellarein, ABA and PBA potently inhibited hPL in a non-competitive manner (K i  < 1 μM). Among all tested flavonoids, PBA showed the most potent anti-hPL effect in vitro, while this agent also exhibited favorable safety profiles, unique tissue distribution (high exposure level to intestinal system but low exposure levels to deep organs) and impressive in vivo effects for lowering blood triglyceride levels in mice. Collectively, this work uncovers the SARs of flavonoids against hPL, while a newly synthetic flavonoid (PBA) emerges as a potent hPL inhibitor with favorable safety profiles and impressive anti-hPL effects in vivo., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Hexafluoropropylene oxide trimer acid (HFPO-TA), a perfluorooctanoic acid (PFOA) substitute, exhibited strong affinity and capability to activate peroxisome proliferator activated receptor gamma (PPARγ), a lipid metabolism regulator, suggesting potential to induce metabolic toxicities., Methods: Fertile chicken eggs were exposed to 0, 0.5, 1 or 2 mg/kg (egg weight) HFPO-TA and incubated until hatch. Serum from 0- and 3- month-old chickens were subjected to liquid chromatography ultra-high resolution mass spectrometry for HFPO-TA concentration, while liver, pancreas and adipose tissue samples were collected for histopathological assessments. In ovo PPARγ reporter and silencing system were established with lentivirus microinjection. qRT-PCR and immunohistochemistry were utilized to evaluate the expression levels of PPARγ downstream genes., Results: In 3-month-old animals developmentally exposed to HFPO-TA, adipose tissue hyperplasia, hepatic steatosis, pancreas islet hypertrophy and elevated serum free fatty acid / insulin levels were observed. Results of reporter assay and qRT-PCR indicated HFPO-TA-mediated PPARγ transactivation in chicken embryo. Silencing of PPARγ alleviated HFPO-TA-induced changes, while PPARγ agonist rosiglitazone mimicked HFPO-TA-induced effects. qRT-PCR and immunohistochemistry revealed that FASN and GPD1 were upregulated following developmental exposure to HFPO-TA in 3-month-old animals., Conclusions: Developmental exposure to HFPO-TA induced persistent metabolic toxicities in chickens, in which PPARγ played a central role., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Qixiao Jiang reports financial support was provided by National Natural Science Foundation of China. Qixiao Jiang reports financial support was provided by Natural Science Foundation of Shandong Province, China. Yuxu Zhong reports financial support was provided by Logistics Scientific Research Plan., (Copyright © 2024 Elsevier B.V. All rights reserved.)

PVC microplastics (PVC-MPs) are environmental pollutants that interact with cadmium (Cd) to exert various biological effects. Ducks belong to the waterfowl family of birds and therefore are at a higher risk of exposure to PVC-MPs and Cd than other animals. However, the effects of co-exposure of ducks to Cd and PVC-MPs are poorly understood. Here, we used Muscovy ducks to establish an in vivo model to explore the effects of co-exposure to 1 mg/L PVC-MPs and 50 mg/kg Cd on duck pancreas. After 2 months of treatment with 50 mg/kg Cd, pancreas weight decreased by 21 %, and the content of amylase and lipase increased by 25 % and 233 %. However, exposure to PVC-MPs did not significantly affect the pancreas. Moreover, co-exposure to PVC-MPs and Cd worsened the reduction of pancreas weight and disruption of pancreas function compared to exposure to either substance alone. Furthermore, our research has revealed that exposure to PVC-MPs or Cd disrupted mitochondrial structure, reduced ATP levels by 10 % and 18 %, inhibited antioxidant enzyme activity, and increased malondialdehyde levels by 153.8 % and 232.5 %. It was found that exposure to either PVC-MPs or Cd can induce inflammation and fibrosis in the duck pancreas. Notably, co-exposure to PVC-MPs and Cd exacerbated inflammation and fibrosis, with the content of IL-1, IL-6, and TNF-α increasing by 169 %, 199 %, and 98 %, compared to Cd exposure alone. The study emphasizes the significance of comprehending the potential hazards linked to exposure to these substances. In conclusion, it presents promising preliminary evidence that PVC-MPs accumulate in duck pancreas, and increase the accumulation of Cd. Co-exposure to PVC-MPs and Cd disrupts the structure and function of mitochondria and promotes the development of pancreas inflammation and fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study was conducted to investigate the potential toxicity of repeated oral dose of SUNACTIVE Zn-P240, a new type of zinc supplement, in Sprague-Dawley rats. SUNACTIVE Zn-P240 was administered once daily by gavage at doses of 0, 500, 1000, and 2000 mg/kg/day for each group over a 28-day period. At 2000 mg/kg/day, there were increases in serum alkaline phosphatase (ALP) and alanine aminotransferase, liver weight, histopathological changes in stomach, liver, and pancreas and decreases in body weight, food consumption, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration, total protein (TP), and albumin. At 1000 mg/kg/day, there was an increase in the serum ALP level and there were decreases in the MCV, MCH, and TP. There were no treatment-related adverse effects in the 500 mg/kg/day group. Under the present experimental conditions, the target organs in rats were determined to be the stomach, pancreas, liver, and erythrocyte and the no-observed-adverse-effect level (NOAEL) in rats was considered to be 500 mg/kg/day., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A newly designed series of imidazolyl-methyl- l-2,4-thiazolidinediones 9 (a-m) were synthesized and In Silico studies were carried out to rationalize their anti-diabetic activity. Generally, all newly synthesized thiazolidinediones had anti-hyperglycemic activity compared with a diabetic-control group, without toxicity in 3T3 cells (viability ≥ 90%). These studies revealed that the compounds 9e and 9b (11∗10 -6 mol/kg) lowered blood glucose more effectively when compared to pioglitazone at the same dose. Following the administration of compound 9e, no weight gains or any serious side effects on liver and pancreas were observed. Moreover, the glucose consumption assay results showed a significant glucose-lowering effect (p < 0.001) in HepG2 cells, which were exposed to 11 mM of glucose at concentrations of 1.25-10 mM of compound 9e. Also, the PPAR-γ gene expression study revealed that pioglitazone and 9e showed similar behavior relative to the control group., (Copyright © 2021. Published by Elsevier Inc.)

Aims: The present study aimed to evaluate the protective action of thymol towards l-arginine-induced acute pancreatitis (AP) by studying the function of rat peritoneal immune cells., Main Methods: Rat peritoneal exudate cells (PECs), obtained 24 h after the injection of l-arginine (350 mg/100 g of b.w.), were evaluated for mitochondrial activity (MTT assay), adherence capacity (methylene-blue assay), and phagocyte enzyme activity (myeloperoxidase, MPO, assay). The activity of α-amylase and free MPO, as well as the concentration of reactive oxygen species (ROS, i.e. O 2 - ), were determined in the peritoneal exudate fluid. Also, serum α-amylase activity determination and pancreatic tissue pathohistological analysis were performed., Key Finding: The administered thymol (50 and 100 mg/kg, per os) caused a significant decrease in the PEC mitochondrial activity and adherence capacity when compared with these functions of PECs isolated from rats with AP. A decrease in cellular MPO activity, as well as in the levels of ROS, α-amylase, and free MPO in peritoneal exudates was found in animals treated with thymol compared to the control animals with AP. Additionally, thymol administration prevented an increase in serum α-amylase activity, accompanied by the decrease in pancreatic tissue damage that follows l-arginine application., Significance: The present results showed that thymol exerts significant immunomodulatory properties and a potential to silence PEC functions in inflammatory conditions such as the AP induced by l-arginine., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cytolytic pore-forming protein, perforin, has been associated with autoimmune destruction of pancreatic β-cells in type 1 diabetes mellitus (T1DM) once released from CD8 + T cells. Curiously, perforinopathy has also been implicated in numerous brain diseases. Therefore, inhibitors of perforin have been in demand with targeted delivery in mind. l-Type amino acid transporter 1 (LAT1) is known to be expressed in both the above-mentioned target tissues, in the pancreas as well as in the brain. Thus, in the present study, the distribution of two LAT1-utilizing prodrugs of investigational perforin inhibitors into the pancreas was explored after intraperitoneal (i.p., 30 μmol/kg) bolus injection to mice. The effects of prodrug 1 were also studied in lipopolysaccharide (LPS)-induced in vitro (50 μg/mL) and in vivo (250 μg/kg x 3 days) apoptosis and pancreatitis models by determining the cellular apoptotic levels with human umbilical vein endothelial cells (HUVEC) and pancreatic caspase-3/-7 activity in mice. Furthermore, the biocompatibility of prodrug 1 was explored in human plasma and towards red blood cells. According to the results, both prodrugs were accumulated more effectively into the pancreas than their parent drugs (in addition to the brain that has been previously reported). Prodrug 1 (30 μmol/kg) also decreased the pancreatic caspase-3/-7 activity (52%) and with 2.5 μM concentration, the number of early and late apoptotic cells (32-53%). Since prodrug 1 was also found to be hemocompatible and not affecting human plasma hemostasis or inducing hemolysis of erythrocytes at the concentration <50 μM, it can be considered biocompatible in systemic circulation and ready to be studied in the future as a dual-acting drug candidate (in the pancreas and brain) in diseases like T1DM with neurodegenerative comorbidities., (Copyright © 2021 Elsevier B.V. All rights reserved.)

(AP) is a kind of inflammatory misorder existing in pancreas. Non-coding RNAs (ncRNAs) have been reported to play important roles in development of AP. The current study was designed to explore the role of circular RNA zinc finger protein 644 (circRNA circ&#95;ZFP644) in caerulein-induced AR42J cells. AP model in vitro was established by exposure of rat pancreatic acinar AR42J cells to caerulein. Amylase activity was measured using a kit. Enzyme-linked immunosorbent assay (ELISA) was performed to examine the levels of several inflammatory factors. The expression of circ&#95;ZFP644, microRNA (miR)-106b and protein inhibitor of activated STAT 3 (Pias3) was detected by quantitative real-time PCR (qRT-PCR) or western blot assay. And flow cytometry was employed to monitor cell apoptosis. Western blot assay was also conducted to analyze the expression of apoptosis-related proteins. The association among circ&#95;ZFP644, miR-106b and Pias3 was validated by dual-luciferase reporter assay. Caerulein treatment activated amylase activity and promoted the secretion of inflammatory cytokines in AR42J cells. Circ&#95;ZFP644 and Pias3 were downregulated, but miR-106b was upregulated in caerulein-induced AR42J cells. Enforced expression of circ&#95;ZFP644 or miR-106b inhibition could reduce amylase activity and inflammatory cytokine secretion, while promote apoptosis in caerulein-induced AR42J cells, which was almost reversed by Pias3 knockdown. Circ&#95;ZFP644 targeted miR-106b to upregulate Pias3 expression. Circ&#95;ZFP644 might exert its anti-inflammation and pro-apoptosis roles in caerulein-induced AR42J cells by regulating miR-106b/Pias3 axis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Natural cannabidiol ((-)-CBD) and its derivatives have increased interest for medicinal applications due to their broad biological activity spectrum, including targeting of the cannabinoid receptors type 1 (CB 1 R) and type 2 (CB 2 R). Herein, we synthesized the (+)-enantiomer of CBD and its derivative (+)-CBD hydroxypentylester ((+)-CBD-HPE) that showed enhanced CB 1 R and CB 2 R binding and functional activities compared to their respective (-) enantiomers. (+)-CBD-HPE Ki values for CB 1 R and CB 2 R were 3.1 ± 1.1 and 0.8 ± 0.1 nM respectively acting as CB 1 R antagonist and CB 2 R agonist. We further tested the capacity of (+)-CBD-HPE to prevent hyperglycemia and its complications in a mouse model. (+)-CBD-HPE significantly reduced streptozotocin (STZ)-induced hyperglycemia and glucose intolerance by preserving pancreatic beta cell mass. (+)-CBD-HPE significantly reduced activation of NF-κB by phosphorylation by 15% compared to STZ-vehicle mice, and CD3 + T cell infiltration into the islets was avoided. Consequently, (+)-CBD-HPE prevented STZ-induced apoptosis in islets. STZ induced inflammation and kidney damage, visualized by a significant increase in plasma proinflammatory cytokines, creatinine, and BUN. Treatment with (+)-CBD-HPE significantly reduced 2.5-fold plasma IFN-γ and increased 3-fold IL-5 levels compared to STZ-treated mice, without altering IL-18. (+)-CBD-HPE also significantly reduced creatinine and BUN levels to those comparable to healthy controls. At the macroscopy level, (+)-CBD-HPE prevented STZ-induced lesions in the kidney and voided renal fibrosis and CD3 + T cell infiltration. Thus, (+)-enantiomers of CBD, particularly (+)-CBD-HPE, have a promising potential due to their pharmacological profile and synthesis, potentially to be used for metabolic and immune-related disorders., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Recent findings suggest that the accumulation of misfolded aggregates of islet amyloid peptide (IAPP) plays an essential role in pancreatic damage and type 2 diabetes (T2D). Pancreastatin (PST), a chromogranin derived peptide, instigates insulin resistance (IR) and promotes T2D. Here, we aimed to investigate whether PST induces IAPP aggregation in the pancreas, liver, and skeletal muscles. Foremost, we unraveled kinetics of fibril formation by ThT kinetic assay, ANS binding, turbidity, and far UV-CD. Subsequently, we checked the microarchitecture of fibril by TEM. Moreover, the PST action on IAPP expression was examined by immunocytochemistry, immunohistochemistry, western blotting, and real-time PCR. The outcome of spectral analysis and TEM demonstrated the fibril formation in the alone IAPP group but not in the alone PST; however, PST with IAPP produced stronger fibril. Moreover, PST was found to stimulate IAPP aggregation and expression more prominently in PANC1 and HepG2 cells, and pancreas and liver tissues than in L6 and skeletal muscle. Subsequently, pancreastatin inhibitor manifested a decline in the extent of the IAPP fibril formation and its expression. To conclude, PST upon combination induces the aggregation of IAPP in the pancreas, liver, and skeletal muscle, which may have the potential to generate IR and cause T2D., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Although Cynomorium songaricum Rupr. polysaccharide (CSP) has been examined for its effects on glucose regulation, its underlying mechanism is still unclear. To address this issue, a MS-based lipidomics strategy was developed to gain a system-level understanding of the mechanism of CSP on improving type 2 diabetes mellitus (T2DM). UPLC-QTOF/MS and multivariate statistical tools were used to identify the alteration of serum metabolites associated with T2DM and responses to CSP treatment. As a result, 35 potential biomarkers were found and identified in serum, amongst which 26 metabolites were regulated to normal like levels after the administration of CSP. By analyzing the metabolic pathways, glycerophospholipid metabolism was suggested to be closely involved. These results indicated that the intake of CSP exhibited promising anti-diabetic activity, largely due to the regulation of phospholipid metabolism, including phosphatidylcholines, lysophosphatydylcholines, phosphtatidylethanolamines and sphingomyelins., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Globally, type 2 diabetes (T2D) is the most common chronic disease. It affects approximately 500 million people worldwide. Dysregulation of the solute carrier family 2 member 4 (SLC2A4) gene and miR-335-5p has been associated with T2D progression. However, the mechanisms underlying this dysregulation are unclear. The levels of miR-335-5p and SLC2A4 in blood samples collected from patients with T2D (T2D blood samples) and pancreatic cell lines were measured by Real Time quantitative PCR (RT-qPCR). The relationship between miR-335-5p and SLC2A4 was investigated using a luciferase assay. The role of the miR-335-5p-SLC2A4 axis was detected by CCK8, BrdU, and caspase-3 assays in pancreatic cells treated with 25 mM glucose. Increased miR-335-5p and decreased SLC2A4 expression was observed in both T2D blood samples and pancreatic cell lines. The miR-335-5p mimic markedly suppressed proliferation and elevated apoptosis in glucose-treated pancreatic cells. SLC2A4 overexpression significantly enhanced proliferation but inhibited apoptosis in glucose-treated pancreatic cells. Moreover, miR-335-5p inhibited the expression of SLC2A4 in the pancreatic cells and suppressed the growth of these cells. The data indicated that miR-335-5p targeting of SLC2A4 could hamper the growth of T2D cell model by inhibiting their proliferation and elevating apoptosis. Collectively, our findings implicate miR-335-5p and SLC2A4 as potentially effective therapeutic targets for patients with T2D., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cadmium (Cd), an environmental pollutant, causes several adverse reactions in animals. High dose of Cd has serious cytotoxicities, including the induction of programmed cell necrosis, autophagy and apoptosis, which has aroused wide public concern. The balance of cytokine network is affected by Th1/Th2 balance which is closely related to immune response and the occurrence, development, treatment and outcome of various diseases. Cd can induce severe apoptosis, but the relationship between Cd induced apoptosis and Th1/Th2 balance has not been clarified. In this study, we established a pig Cd poisoning model, exposing to CdCl 2 for 40 days (20 mg Cd/kg diet). Firstly, deviation of Th1/Th2 balance was observed by fluorescence staining, and apoptosis was observed by TUNEL staining. Then, real-time fluorescence quantitative analysis and Western blot were used to detect the expression of related proteins. The results show that Cd can interfere with the balance of Th1/Th2 and shift the balance towards Th1. In addition, through the experiments, we found that Cd exposure can increase the expression of glucose-regulated protein 94 (GRP94) and glucose-regulated protein 78 (GRP78), marker proteins of unfolded protein response (UPR). Cd exposure can increase the expression of pancreatic endoplasmic reticulum kinase (PERK), CCAAT-enhancer-binding protein homologous protein (CHOP), inositol-requiring enzyme 1 (IRE-1), activating transcription factor 6 (ATF-6), cysteinyl aspartate specific proteinase (Caspase12), indicating the three branches (ATF6, PERK and IRE-1) of endoplasmic reticulum stress (ER-stress) were activated. Moreover, we found that the expression of pro-apoptosis genes in the downstream pathway of ER-stress increased. In summary, our results indicated that Cd exposure upregulated the expression of pro-apoptosis related genes and caused apoptosis via the activation of the ER-stress signaling pathways in pancreas cells. And these negative effects were correlated with the equilibrium drift of Th1/Th2, increase in the expression and secretion of Th1 cytokines., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Human pancreatic lipase (triacylglycerol acyl hydrolase EC3.1.1.3) is the most widely studied member of the human lipase superfamily related to carboxyl esterase. It is secreted from the acinar cell of pancreas and has strong preference for triacylglycerides over cholesterol esters, phospholipids, and galactolipids. Apart from the hydrolysis of triacylglycerides, pancreatic lipase may cause the hydrolysis of retinyl esters in vivo. So, it is very much evidenced that pancreatic lipase with its cofactor colipase has prominent role in efficient digestion of dietary fat. Hence, the modulation of human pancreatic lipase may represent a new insight in the discovery of a number of therapeutics that can inhibit the absorption of fat in body and can be used in obesity and other related metabolic disorders. Even, the only Food and drug administration (FDA) approved antiobesity drug, orlistat, is also an inhibitor of pancreatic lipase. This review summarizes studies about structure, mechanistic approach of pancreatic lipase enzyme while emphasizing on the various synthetic pancreatic lipase inhibitors with their structure activity relationship (SAR)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Pancreatic cancer is a rapidly progressing disease with a poor prognosis. We still have many questions about the pathogenesis, early diagnosis and precise treatment of this disease. Organoids, a rapidly emerging technology, can simulate the characteristics of pancreatic tumors. Using the organoid model of pancreatic cancer, we can study and explore the characteristics of pancreatic cancer, thereby effectively guiding clinical practice and improving patient prognosis. This review introduces the development of organoids, comparisons of organoids with other preclinical models and the status of organoids in basic research and clinical applications for pancreatic cancer., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Peripheral serotonin regulates energy metabolism in several mammalian species, however, the potential contribution of serotonergic mechanisms as metabolic and endocrine regulators in growing dairy calves remain unexplored. Objectives were to characterize the role of serotonin in glucose and insulin metabolism in dairy calves with increased serotonin bioavailability. Milk replacer was supplemented with saline, 5-hydroxytryptophan (90 mg/d), or fluoxetine (40 mg/d) for 10-d (n = 8/treatment). Blood was collected daily during supplementation and on days 2, 7, and 14 during withdrawal. Calves were euthanized after 10-d supplementation or 14-d withdrawal periods to harvest liver and pancreas tissue. 5-hydroxytryptophan increased circulating insulin concentrations during the supplementation period, whereas both treatments increased circulating glucose concentration during the withdrawal period. The liver and pancreas of preweaned calves express serotonin factors (ie, TPH1, SERT, and cell surface receptors), indicating their ability to synthesize, uptake, and respond to serotonin. Supplementation of 5-hydroxytryptophan increased hepatic and pancreatic serotonin concentrations. After the withdrawal period, fluoxetine cleared from the pancreas but not liver tissue. Supplementation of 5-hydroxytryptophan upregulated hepatic mRNA expression of serotonin receptors (ie, 5-HTR1B, -1D, -2A, and -2B), and downregulated pancreatic 5-HTR1F mRNA and insulin-related proteins (ie, Akt and pAkt). Fluoxetine-supplemented calves had fewer pancreatic islets per microscopic field with reduced insulin intensity, whereas 5-hydroxytryptophan supplemented calves had increased islet number and area with greater insulin and serotonin and less glucagon intensities. After the 14-d withdrawal of 5-hydroxytryptophan, hepatic mRNA expression of glycolytic and gluconeogenic enzymes were simultaneously downregulated. Improving serotonin bioavailability could serve as a potent regulator of endocrine and metabolic processes in dairy calves., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This study aimed to reveal the interaction and inhibitory mechanisms of tangeretin (TAN), nobiletin (NBT), and their acidic hydroxylated forms, 5-demethyltangeretin (5-DT) and 5-demethylnobiletin (5-DN) on porcine pancreatic lipase (PPL) using spectroscopic techniques and molecular dynamics (MD) simulation. PPL inhibition assay showed that the inhibitory activity of NBT (IC 50 value of 3.60 ± 0.19 μM) was superior to those of three polymethoxylated flavones (PMFs), indicating it may be related to the methoxy groups at the 3'-position in its molecular structure. Inhibition kinetic analyses demonstrated that the inhibition types of the 4 PMFs were consistent with the mixed inhibition model, which agreed well with the results from the ultraviolet-visible (UV-Vis) spectroscopy, Circular dichroism (CD), fluorescence spectroscopy, molecular docking, and MD simulation that PMFs could bind to the PPL catalytic site and non-catalytic site, affecting the normal spatial conformation of PPL and weakening its ability to decompose the substrate. All these findings suggest that PMFs are a kind of natural lipase inhibitors, and NBT has the potential as a lipase inhibition precursor because of its unique flavone skeleton structure., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Environmental toxicants such as dioxins and polycyclic aromatic carbons are risk factors for pancreatitis and pancreatic cancer. These toxicants activate aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, of which activation regulates many downstream biological events, including xenobiotic metabolism, inflammation, and cancer cell growth and transformation. Here, we identified that environmental toxicant-activated AHR increased expression of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in pancreatic cancer cells and pancreatic tissues. The MALAT1 is a long noncoding (lnc) RNA which interacts with Enhancer of Zeste 2 (EZH2), a histone methyltransferase with epigenetic silencer activity, and the MALAT1-EZH2 interaction increased its epigenetic silencing activity. In contrast, AHR antagonist, CH223191 or resveratrol, counteracted the AHR-mediated MALAT1 induction and MALAT1-enahnced EZH2 activity. Collectively, these results revealed a novel pathway of how environmental exposure leads to epigenetic alteration via activation of AHR-MALAT1-EZH2 signaling axis under pancreatic tissue- and cancer cell-context., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The aim of the present study was to evaluate lipid profile (triglyceride, total cholesterol, HDL, LDL, and VLDL), pancreas (lipase and amylase), liver (AST, ALT, and ALP), blood urea nitrogen, creatinine, uric acid, sodium and potassium function indicators in cats undergoing two different durations of anesthesia with propofol. Ten adult female cats were randomly divided into two groups (n= 5) and anaesthetized with propofol 1% (induction: 8 mg/kg; infusion: 0.3 mg/kg/min) for either 45 or 90 minutes. Blood samples were collected at predetermined intervals up to 72 hours later. Comparison of the measured variables between treatments did not show significant differences. Triglyceride and cholesterol levels showed significant increase after induction of anesthesia (P < .05). The highest triglyceride and cholesterol values were recorded at 6 and 24 hours. HDL was lower while LDL and VLDL were higher at several time points after anesthesia (P < .05). Higher values of lipase, ALT and AST were detected after induction (P < .05). All the observed alterations were within normal ranges. In conclusion, propofol anesthesia was associated with some changes in lipid profile, as well as pancreatic and liver function indices, which should be considered in clinical situations. It seems that in the absence of pre- or co-existing disturbances, induction and maintenance of anesthesia with propofol did not carry additional risk to cats., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Inhibition of pancreatic lipase (PL) is considered one of the important therapeutic interventions against obesity. In the present study, the inhibition of porcine (mammalian) PL (PPL) by two tripeptides glutathione (GSH) and s-allyl glutathione (SAG) was studied. In vitro kinetic analysis was done to determine the inhibition of GSH and SAG against PPL. The binding of GSH and SAG with PPL was elucidated by fluorescence spectroscopy analysis. Docking and molecular dynamics (MD) simulation analysis was carried out to understand the intermolecular interaction between both GSH and SAG with PPL as well as human PL (HPL). Both GSH and SAG inhibited PPL in mixed non-competitive manner. The IC 50 value for GSH and SAG against PPL was found to be 2.97 and 6.4 mM, respectively. Both GSH and SAG quenched the intrinsic fluorescence of PPL through static quenching that is through forming complex with the PPL. SAG and GSH interacted with amino acids involved in catalysis of both PPL and HPL. MD simulation showed interactions of SAG and GSH with both PPL and HPL were stable. These results would lead to the further studies and application of GSH and SAG against obesity through inhibition of PL., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Diabetes is a worldwide healthy concern, which affects approximately 9% of the population. Tetrahydrocurcumin (THC) is the main metabolite of curcumin, which exerts the anti-diabetic activity. However, the underlying mechanism has not been clarified. In the research, we investigated whether THC could improve diabetes by regulating the gut microbiota and the expression of pancreatic glucagon-like peptide-1 (GLP-1) in the db/db mice. After 8-week THC administration (ig., once a day, THCH group: 200 mg/kg, THCL group: 100 mg/kg), the fasting blood glucose (FBG) was measured every two weeks. Serum insulin levels, the expression of GLP-1 in the pancreas, the histopathology of pancreas and the composition of gut microbiota were evaluated at the end of the experiment. Compared to the diabetic group, THC treatment decreased significantly blood glucose, increased the secretion of insulin and the expression of GLP-1 in the pancreas. Histomorphological analysis revealed that THC could protect pancreatic islet cells against hyperglycemic insult. Furthermore, the data from the sequencing of the 16S rDNA genes in gut microbiome displayed that THC could restore the intestinal dysbiosis, including the lowered relative abundance of Proteobacteria, Actinobacteria and the ratio of Firmicutes to Bacteroidetes. The linear regression analysis showed a close correlation between the GLP-1 expression and the proportion of the intestinal microflora. Altogether, these results demonstrated that THC might have a direct regulatory effect on gut microflora, which indirectly decrease the FBG levels by modulating GLP-1 expression in the pancreas., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction and Aims: Polycystic ovary syndrome (PCOS) is a widespread endocrine disorder affecting females. Mechanisms underlying PCOS complicated pathology remain largely unknown, making current treatment only symptomatic. Increasing reports suggest impaired PI3K/AKT/mTOR pathway and tumor necrosis factor-α (TNF-α) levels are involved in cellular proliferation and metabolism-related disorders. However, rare data explored their role in PCOS. Hence, this study investigated TNF-α and pancreatic PI3K/AKT/mTOR levels in PCOS animal model and evaluated their effects on developed pancreatic deficits. Secondly; we explored the impact of nanocurcumin as powerful anti-inflammatory supplement against these developed pancreatic pathologies., Methods: PCOS was induced in rats using letrozole. Nanocurcumin was formulated to increase solubility and bioavailability of curcumin. Transmission electron microscopy (TEM), zeta potential and Infra-red spectroscopy (FT-IR) were used for characterization. Nanocurcumin was orally ingested for 15 days., Findings: PCOS group exhibited significant disturbance in sex hormones, oxidative stress markers, and TNF-α levels as determined by immunoassay. Western blotting revealed significant reduction of PI3K/AKT/mTOR levels leading to impaired insulin sensitivity, decreased β cells function and mass as confirmed by HOMA assessments and immunohistochemistry. Nanocurcumin significantly improved oxidative markers, glucose indices and TNF-α levels. It reinstated PI3K/AKT/mTOR levels, alleviated insulin resistance, and retained islets integrity consequently restoring normal sex hormonal levels., Significance: To the best of our knowledge, the study is the first to report pancreatic role of PI3K/AKT/mTOR and TNF-α in PCOS and the first to demonstrate nanocurcumin promising potential against PCOS-related pancreatic molecular and histological pathologies that can indeed offer better control of the disease., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The ability of human embryonic stem cells (hESCs) to proliferate unlimitedly and give rise to all tissues makes these cells a promising source for cell replacement therapies. To realize the full potential of hESCs in cell therapy, it is necessary to interrogate regulatory pathways that influence hESC maintenance and commitment. Here, we reveal that pharmacological attenuation of p38 mitogen-activated protein kinase (p38-MAPK) in hESCs concomitantly augments some characteristics associated with pluripotency and the expressions of early lineage markers. Moreover, this blockage capacitates hESCs to differentiate towards an endoderm lineage at the expense of other lineages upon spontaneous hESC differentiation. Notably, hESCs pre-treated with p38-MAPK inhibitor exhibit significantly improved pancreatic progenitor directed differentiation. Together, our findings suggest a new approach to the robust endoderm differentiation of hESCs and potentially enables the facile derivation of various endoderm-derived lineages such as pancreatic cells., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This study aimed to investigate the toxic effects of microcystin-LR (MC-LR), which is released from several bloom-forming cyanobacteria, on the glucose metabolism of pancreatic β cells in vivo and in vitro. Male mice and the pancreatic MIN6 cells were respectively treated with varying concentrations of MC-LR. After 3- or 6- months of MC-LR exposure, increase in the body weight of mice was found to be inhibited, and the structure of their pancreatic tissues was damaged with impaired glucose tolerance and impaired insulin secretion. Further, these toxic effects became more pronounced with time and with increased dosages. Direct cytotoxic effects of MC-LR were observed in the MIN6 pancreatic β-cells possibly due to their expression of the MC-LR specific transporter. MC-LR entered the MIN6 cells that significantly reduced the cell viability. Both in vivo and in vitro experiments demonstrated that MC-LR was able to induce apoptosis, possibly associated with mitochondrial damage. Above all, these findings implied that MC-LR may be transported into the pancreatic β cells and cause subsequent cytotoxicity., Competing Interests: Declaration of Competing Interest All authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: We reported that the pancreas of the interferon-regulatory factor (IRF) 2 knock-out (KO) mouse represents an early phase of acute pancreatitis, including defective regulatory exocytosis, intracellular activation of trypsin, and disturbance of autophagy. The significantly upregulated and downregulated genes in the IRF2 KO pancreas have been reported. The catalogue of gene transcripts included two types of calcium-binding proteins (S100 calcium binding protein G [S100g] and Annexin A10 [Anxa10]), which were highly upregulated in the IRF2 KO pancreas. As the intracellular calcium signal plays a pivotal role in regulatory exocytosis and its disturbance is related to pancreatitis, we then evaluated the role of S100g and Anxa10 in acute pancreatitis., Method: We induced cerulein-pancreatitis in wild-type mice and examined the changes in the expression of these genes by qPCR and immunohistochemistry. We constructed S100g-overexpressing or Anxa10-overexpressing AR42J cells (AR42J-S100g, AR42J-Anxa10). We examined the changes in amylase secretion, intracellular calcium ([Ca 2+ ]i), and cell viability in these cells, when incubated with cholecystokinin (CCK)., Results: The expression of S100g and Anxa10 was increased in cerulean-induced pancreatitis. The acini were patchily stained for S100g and the cytosol of acini was evenly but weakly stained for Anxa10. Stimulation with 100pM CCK-8, decreased amylase secretion and inhibited the [Ca 2+ ]i increase in AR42J-S100g cells. These effects were weak in AR42J-Anxa10 cells. Cell viability was not changed by incubation with cerulein., Conclusion: In cerulean pancreatitis, the expression of S100g and Anxa10 was induced in the acini. S100g may work as a Ca 2+ buffer in acute pancreatitis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic pancreatitis (CP) is one of the leading causes of mortality worldwide with no clinically approved therapeutic interventions. The present study was designed to investigate the protective effect of nimbolide (NB), an active constituent of neem tree (Azadirachta indica), by targeting β-catenin/Smad/SIRT1 in cerulein-induced CP model. The effects of NB was investigated on cerulein (50 μg/kg/hr*6 exposures /day, 3 days a week for 3 weeks) induced CP in mice. Amylase and lipase activity were measured and histopathological evaluation was performed. Collagen deposition in the pancreatic tissue was estimated by hydroxyproline assay, and collagen specific staining picrosirius red and Masson's trichrome. Cerulein-induced CP was significantly controlled by NB treatment, as shown by the downregulation of β-catenin/Smad signaling in a SIRT1 dependent manner. NB treatment significantly decreased α-SMA, MMP-2, collagen1a, fibronectin, TGF-β1, p-Smad-2/3 expression and extracellular matrix (ECM) deposition in pancreatic tissue. However, the protective effects of NB on cerulein-induced CP were undermined by nicotinamide (NMD) or splitomicin, sirtuin 1 (SIRT1) inhibitors treatment. NB treatment modulated protein expression by activating SIRT1 and decreasing the expression of β-catenin/Smad proteins in CP mice. However, the expression of SIRT1 in pancreatic tissue was elevated by NB treatment and it was decreased by NMD or splitomicin treatment. In summary, our results strongly suggest that NB exerted promising protective effects in cerulein-induced CP model by inhibiting β-catenin/Smad in a sirtuin-dependent manner, which could be attributed to its anti-inflammatory and antifibrotic effects. Our study suggests that NB could be an effective therapeutic intervention for the treatment of CP., Competing Interests: Declaration of Competing Interest The author declares that there is no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims: The use of natural agents with anti-diabetic effect in combination therapy adds further positive clinical implications in the management of diabetes mellitus. Interestingly, quercetin is one of the most potent naturally occurring antioxidant which possesses various pharmacological actions including anti-diabetic effect. Thus, this research was conducted to assess the efficiency of a new combination from gliclazide and quercetin on glycemic control as well as pancreatic islets and beta cells in STZ-experimental model of diabetes., Main Methods: Diabetes has been induced by a single intraperitoneal injection of streptozotocin (STZ; 45 mg/kg) in adult male Wistar rats. For 3 consecutive weeks, diabetic rats were given orally either gliclazide (10 mg/kg), quercetin (50 mg/kg), or their combination. At the end of the experiment, histological, immunohistochemical and morphometrical examination of pancreatic tissues was performed. Furthermore, the changes in glucose metabolism, lipid profile, oxidative and inflammatory status were evaluated., Key Findings: Treatment with gliclazide alone decreased serum glucose, total cholesterol, triglycerides, malondialdehyde, tumor necrosis factor-alpha and nuclear factor kappa-Beta while increased serum C-peptide, superoxide dismutase, reduced glutathione and adiponectin levels. Combined administration of quercetin with gliclazide markedly augmented serum superoxide dismutase and reduced glutathione more than gliclazide alone and normalized all the above-mentioned parameters. Besides, this combination therapy restored immunostaining intensity, number of pancreatic islets and beta cells along with its area and perimeter., Significance: Based on the aforementioned results, this combination could be considered a promising one in diabetes mellitus management., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Small intestinal starch digestion in ruminants is potentially limited by inadequate production of carbohydrases. Previous research has demonstrated that small intestinal starch digestion can be improved by postruminal supply of casein or glutamic acid. However, the mechanisms by which casein and glutamic acid increase starch digestion are not well understood., Objectives: The objective of this experiment was to evaluate the effects of duodenal infusions of starch with casein or glutamic acid on postruminal carbohydrase activities in cattle., Methods: Twenty-two steers [mean body weight (BW) = 179 ± 4.23 kg] were surgically fitted with duodenal and ileal cannulas and limit-fed a soybean hull-based diet containing small amounts of starch. Raw cornstarch (1.61 ± 0.0869 kg/d) was infused into the duodenum alone (control), or with 118 ± 7.21 g glutamic acid/d, or 428 ± 19.4 g casein/d. Treatments were infused continuously for 58 d and then steers were killed for tissue collection. Activities of pancreatic (α-amylase) and intestinal (maltase, isomaltase, glucoamylase, sucrase) carbohydrases were determined. Data were analyzed as a randomized complete block (replicate group) design using the GLM procedure of SAS to determine effects of infusion treatment., Results: Duodenal casein infusion increased (P < 0.05) pancreatic α-amylase activity by 290%. Duodenal glutamic acid infusion increased (P < 0.03) duodenal maltase activity by 233%. Duodenal casein infusion increased jejunal maltase (P = 0.02) and glucoamylase (P = 0.03) activity per gram protein by 62.9% and 97.4%, respectively. Duodenal casein infusion tended to increase (P = 0.10) isomaltase activity per gram jejunum by 38.5% in the jejunum. Sucrase activity was not detected in any segment of the small intestine., Conclusions: These results suggest that small intestinal starch digestion can be improved in cattle with increased small intestinal flow of casein through increases in postruminal carbohydrase activities., (Copyright © The Author(s) 2019.)

Advanced cancer patients exhibit cachexia, a condition characterized by a significant reduction in the body weight predominantly from loss of skeletal muscle and adipose tissue. Cachexia is one of the major causes of morbidity and mortality in cancer patients. Decreased food intake and multi-organ energy imbalance in cancer patients worsen the cachexia syndrome. Cachectic cancer patients have a low tolerance for chemo- and radiation therapies and also have a reduced quality of life. The presence of tumors and the current treatment options for cancer further exacerbate the cachexia condition, which remains an unmet medical need. The onset of cachexia involves crosstalk between different organs leading to muscle wasting. Recent advancements in understanding the molecular mechanisms of skeletal muscle atrophy/hypertrophy and adipose tissue wasting/browning provide a platform for the development of new targeted therapies. Therefore, a better understanding of this multifactorial disorder will help to improve the quality of life of cachectic patients. In this review, we summarize the metabolic mediators of cachexia, their molecular functions, affected organs especially with respect to muscle atrophy and adipose browning and then discuss advanced therapeutic approaches to cancer cachexia., Competing Interests: Declaration of competing interest SKB is one of the co-founders of Sanguine Diagnostics and Therapeutics, Inc. The other authors declare no competing interests. The authors have declared that the submitted manuscript is original, is not under consideration by another journal, and has not been published previously in any form. Every author is aware of and has agreed to the content of this paper., (Copyright © 2020. Published by Elsevier B.V.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with poor prognosis and high mortality. Molecular aberrations associated with PDAC pathogenesis and progression have been extensively investigated. Nevertheless, these findings have not been translated into clinical practice. Lack of therapeutics for PDAC treatment is another challenge. Recent application of molecularly targeted and immunoregulatory therapies appears to be disappointing. Thus, discovery of new targets and therapeutics is urgently needed to combat this malignant disease. The RON receptor tyrosine kinase is a tumorigenic determinant in PDAC malignancy, which provides the rationale to target RON for PDAC treatment. In this review, we summarize the latest evidence of RON in PDAC pathogenesis and the development of anti-RON antibody-drug conjugates for potential PDAC therapy. The finding that anti-RON antibody-drug conjugates show efficacy in preclinical animal models highlights the potential of this novel class of anti-cancer biotherapeutics in future clinical trials., Competing Interests: Declaration of Competing Interest All authors declare that they have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

1,4-Dichlorobutane (1,4-DCB) is used as raw materials for drugs, pesticides, fragrances, and chemical fibers, and being used as a solvent. Its toxicity data was insufficient for screening assessment under the Japanese Chemical Substances Control Law. We conducted toxicity tests and hazard classification for screening assessment 1,4-DCB showed negative in the Ames test, positive in the in vitro chromosomal aberrations test with metabolic activation, and negative in the in vivo mouse bone-marrow micronucleus test. The 28-day repeated-dose toxicity study, where male and female rats were administered 1,4-DCB by gavage at 0, 12, 60, and 300 mg/kg/day, showed significant effects on the liver and pancreas from 12 mg/kg/day and kidney at 300 mg/kg/day. Based on periportal hepatocellular hypertrophy and decreased zymogen granules in pancreas, the lowest observed adverse effect level (LOAEL) of 12 mg/kg/day was obtained. The reproductive/developmental toxicity screening study, in which male and female rats were administered 1,4-DCB by gavage at dose of 0, 2.4, 12, and 60 mg/kg/day for 42-46 days, showed that the delivery index was decreased at 60 mg/kg/day without maternal toxicity. Based on the general toxicity, we classified this chemical as hazard class 2, with a D-value (Derived No Effect Level) of 0.002 mg/kg/day., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chronic arsenic exposure is a significantly risk factor for pancreatic dysfunction and type 2 diabetes (T2D). Ferroptosis is a newly identified iron-dependent form of oxidative cell death that relies on lipid peroxidation. Previous data have indicated that ferroptosis is involved in various diseases, including cancers, neurodegenerative diseases, and T2D. However, the concrete effect and mechanism of ferroptosis on pancreatic dysfunction triggered by arsenic remains unknown. In this study, we verified that ferroptosis occurred in animal models of arsenic-induced pancreatic dysfunction through assessing proferroptotic markers and morphological changes in mitochondria. In vitro, arsenic caused execution of ferroptosis in a dose-dependent manner, which could be significantly reduced by ferrostatin-1. Additionally, arsenic damaged mitochondria manifested as diminishing of mitochondrial membrane potential, reduced cytochrome c level and production of mitochondrial reactive oxygen species (MtROS) in MIN6 cells. Using the Mito-TEMPO, we found the autophagy level and subsequent ferroptotic cell death induced by arsenic were both alleviated. With autophagy inhibitor chloroquine, we further revealed that ferritin regulated ferroptosis through the MtROS-autophagy pathway. Collectively, NaAsO 2 -induced ferroptotic cell death is relied on the MtROS-dependent autophagy by regulating the iron homeostasis. Ferroptosis is involved in pancreatic dysfunction triggered by arsenic, and arsenic-induced ferroptosis involves MtROS, autophagy, ferritin., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Acute pancreatitis (AP) is one of the leading causes of hospital admission for gastrointestinal disorders. Although lipid peroxides are produced in AP, it is unknown if targeting lipid peroxides prevents AP. This study aimed to investigate the role of mitochondrial aldehyde dehydrogenase 2 (ALDH2), a critical enzyme for lipid peroxide degradation, in AP and the possible underlying mechanisms. Cerulein was used to induce AP in C57BL/6 J male mice and pancreatic acinar cells were used to elucidate underlying mechanisms in vitro. Pancreatic enzymes in the serum, lipid peroxidation products malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and Bcl-2, Bax and cleaved caspase-3 were measured. ALDH2 activation with a small-molecule activator, Alda-1, reduced the levels of the pancreatic enzymes in the serum and the lipid peroxidation products MDA and 4-HNE. In addition, Alda-1 decreased Bax and cleaved caspase-3 expression and increased Bcl-2 expression in vivo and in vitro. In conclusion, ALDH2 activation by Alda-1 has a protective effect in cerulein-induced AP by mitigating apoptosis in pancreatic acinar cells by alleviating lipid peroxidation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Nine new xanthones, cudracuspixanthones I - Q (12-14, 25, 32-36), and 30 known xanthones (1-11, 15-24, 26-31, 37-39) were isolated from the stems of Cudrania tricuspidata (Moraceae). The structures of isolated compounds were established by using 1D and 2D NMR in combination with HR-TOF-MS. Xanthones from the stems of C. tricuspidata exerted pancreatic lipase inhibitory activity. In addition, cudracuspixanthone P (35), a new xanthone, reduced the fat accumulation in liver cells stimulated with fatty acids. Therefore, these compounds might be beneficial in the treatment of metabolic diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Starch digestion in the small intestines of the dairy cow is low, to a large extent, due to a shortage of syntheses of α-amylase. One strategy to improve the situation is to enhance the synthesis of α-amylase. The mammalian target of rapamycin (mTOR) signalling pathway, which acts as a central regulator of protein synthesis, can be activated by leucine. Our objectives were to investigate the effects of leucine on the mTOR signalling pathway and to define the associations between these signalling activities and the synthesis of pancreatic enzymes using an in vitro model of cultured Holstein dairy calf pancreatic tissue. The pancreatic tissue was incubated in culture medium containing l-leucine for 3 h, and samples were collected hourly, with the control being included but not containing l-leucine. The leucine supplementation increased α-amylase and trypsin activities and the messenger RNA expression of their coding genes (P <0.05), and it enhanced the mTOR synthesis and the phosphorylation of mTOR, ribosomal protein S6 kinase 1 and eukaryotic initiation factor 4E-binding protein 1 (P <0.05). In addition, rapamycin inhibited the mTOR signal pathway factors during leucine treatment. In sum, the leucine regulates α-amylase and trypsin synthesis in dairy calves through the regulation of the mTOR signal pathways.

Chronic pancreatitis (CP) is characterized by persistent inflammation and fibrosis of the pancreas. To date, no clinical therapy is available to reverse the inflammatory damage or pancreatic fibrosis associated with CP. This study systematically investigated the effect of Dasatinib, a multiple tyrosine kinases (TKs) inhibitor, on pancreatic fibrosis and inflammation in vivo and in vitro. We found that Dasatinib notably ameliorated pancreatic fibrosis and infiltration of macrophages in a model of caerulein-induced murine CP. Further RNA-seq and phosphoproteomic analysis and in vitro validation assays indicated that Dasatinib exerted a marked inhibition on the proliferation and activation of PSCs, which may be resulted from increased GSK3β-mediated β-catenin cytosol retention by inhibiting upstream multiple TKs (such as PDGFR and Src) and MAPK cascades (including ERK1/2 and p38 MAPK). In addition, Dasatinib significantly restrained both the M1 and M2 polarization of macrophages, and impeded its recruitment and crosstalk with PSCs. Our findings indicated that Dasatinib is a potential anti-inflammatory and anti-fibrotic therapeutic strategy for CP., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This study focused on the effect of varying trypsin inhibitor activity (TIA), heat-degraded lysine concentration and protein solubility in potassium hydroxide on broiler performance and pancreas weight. Two soybean breeds were subject to varying thermal, hydrothermal, pressure, and kilning processing. This resulted in a total of 34 soy cake variants, widely varying in TIA (0.25 to 23.6 mg/g), heat-degraded lysine (1.40 to 8.60 g/kg), and potassium hydroxide (65.5 to 97.6%), respectively. These soy cake variants as well as a commercial soybean meal extract were included into a common grower and finisher diet for broiler chicks at fixed amounts (grower: 35%; finisher: 25%) and tested in a 35 d fattening experiment with 1680 broiler chicks (grower phase: day 11 to 24; finisher phase day 25 to 35). TIA was the dominant factor affecting zootechnical performance and pancreas weight at slaughter (day 35), depressing liveweight at day 24 (P < 0.006), and day 35 (0.026), weight gain (grower: P < 0.006) and feed: gain ratio during grower phase (P < 0.005) and increasing pancreas weight (P < 0.010) at the time of slaughter. Negative effects of TIA were also visible in soy cake variants below recommended thresholds. This highlights the necessity of complete elimination of TIA in broiler diets as far as technically possible., (© 2019 Poultry Science Association Inc.)

Oxandrolone is a synthetic oral non-aromatizable testosterone derivative. This drug has been used successfully for several decades to safely treat growth delays in various diseases including Turner's syndrome. Currently the use of oxandrolone is under clinical testing in children with burn injury; the available data indicate that the anabolic steroid increases net muscle protein balance, maintains lean body mass, and reduces intensive care unit stay. Although oxandrolone is already in clinical trials in burn patients, preclinical burn-related studies with oxandrolone - especially those that go beyond muscle-related parameters and focus on burn-associated organ dysfunction, inflammatory response and wound healing - remain to be conducted. In the current project, using a well-characterized murine model of third-degree burn, we have tested the effect of oxandrolone on indices of organ injury, clinical chemistry parameters and plasma levels of inflammatory mediators. In oxandrolone-treated mice (1mg/kg/day for up to 21 days) there was a significant amelioration of burn-induced accumulation of myeloperoxidase levels in heart and lung (but not the liver and kidney) and significantly lower degree of malon dialdehyde accumulation in the liver (but not the heart, lung and kidney). Oxandrolone-treated mice showed a significant attenuation of the burn-induced elevation in circulating alkaline aminotransferase and amylase levels, while blood urea nitrogen and creatinine levels remained unaffected, indicative of protective effects of the anabolic hormone against burn-induced hepatic and pancreatic (but not renal) functional impairment. Multiple burn-induced inflammatory mediators (TNF-α, IL-1α, IL-1β, IL-4, IL-6, IL-10, IL-12, IP-10, G-CSF, GM-CSF and interferon-γ) were significantly lower in the plasma of oxandrolone-treated animals after burn injury than in the plasma of controls subjected to burns. Finally, oxandrolone significantly accelerated burn wound healing. We conclude that oxandrolone improves organ function, modulates the systemic inflammatory response and accelerates wound healing in a murine model of burn injury., (Copyright © 2018 Elsevier Ltd and ISBI. All rights reserved.)

Syntrophins are a family of proteins forming membrane-anchored scaffolds and serving as adaptors for various transmembrane and intracellular signaling molecules. To understand the physiological roles of β1 syntrophin, one of the least characterized members, we generated mouse models to eliminate β1 syntrophin specifically in the endocrine or exocrine pancreas. β1 syntrophin is dispensable for the morphology and function of insulin-producing β cells. However, mice with β1 syntrophin deletion in exocrine acinar cells exhibit increased severity of cerulein-induced acute pancreatitis. Reduced expression of cystic fibrosis transmembrane conductance regulator and dilation of acinar lumen are potential predisposition factors. During the disease progression, a relative lack of autophagy is associated with deficiencies in both actin assembly and endoplasmic reticulum nucleation. Our findings reveal, for the first time, that β1 syntrophin is a critical regulator of actin cytoskeleton and autophagy in pancreatic acinar cells and is potently protective against cerulein-induced acute pancreatitis., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

In the modern world, type-2 diabetes mellitus has become a leading public healthcare problem, due to major risks of morbidity and mortality. Prevalence has increased significantly in recent decades. Treatment involves oral hypoglycemic agents or insulin replacement therapy. Development is ongoing for cell-based diabetes therapies using stem cells with the potential to differentiate into insulin-producing cells (IPCs): embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and stem cells from adult pancreas, liver, central nervous system, bone marrow and adipose tissue. Successful induction of iPSCs, however, depends on the quantity and quality of available stem cells and the development of adapted protocols determining the environment of extrinsic factors and involvement of small molecules. Validating such new cell therapies must be founded on this experimental rationale., (Copyright © 2019 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Chronic pancreatitis is characterized by pancreatic fibrosis, associated with excessive activation of pancreatic stellate cells (PSCs) and increased expression of transforming growth factor-β1 (TGF-β1). Recently, our studies have shown that autophagy inhibitor could inhibit PSCs activation and reduce collagen secretion. Saikosaponin d (SSd), the major active component of bupleurum falcatum (a medicinal plant), has anti-fibrosis effects in liver. However, it is unclear whether SSd has a role in pancreatic fibrosis. This study aimed to investigate the effect of SSd on the autophagy and activation of PSCs in vivo and in vitro. In vivo, a rat chronic pancreatitis model was induced by intravenous injection of dibutyltin dichloride. SSd was administered at a dose of 2.0 mg/kg body weight per day by gavage. After 4 weeks, the pancreas was collected for histological and molecular analysis. In vitro, PSCs were isolated and cultured for treatment with different dosages of SSd. The results showed that SSd inhibited PSCs autophagy and activation while also reducing extracellular matrix (ECM) formation and pancreatic damage. SSd inhibited autophagy through activating the PI3K/Akt/mTOR pathway. SSd also promoted degradation of ECM with an increasing ratio of MMPs/TIMPs and suppressed the TGF-β1/Smads pathway. From these results, we concluded that SSd prevents pancreatic fibrosis by reducing autophagy of PSCs through PI3K/Akt/mTOR pathway, which has crosstalk with the TGF-β1/Smads pathway., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Acute pancreatitis (AP) is a severe and frequently lethal disorder, but the precise mechanisms are not well understood and there is lack of effective drugs. Therefore, our study examined the in vivo intervention effects of genistein and elucidated its mechanism in acute experimental pancreatitis models. We used cerulein or taurocholate to induce acute pancreatitis (AP) in Sprague-Dawley rats with prior genistein treatment. Histological examination of the pancreas was performed and the expression of unfolded protein response (UPR) components and apoptotic mediators like caspase 12 and c-Jun N-terminal protein kinase (JNK) were measured. The amount of apoptosis in pancreatic acinar cells was also determined. Our studies found that the severity of cerulein- or taurocholate-induced AP was rescued by prior genistein treatment. Genistein stimulated the activation of multiple endoplasmic reticulum (ER) stress-related regulators like GRP78, PERK, eIF2α, and upregulated the expression of the apoptotic genes, caspase 12 and CHOP. Moreover, TUNEL assays showed that genistein treatment promoted acinar cell apoptosis. Taken together, we speculated that ER stress-associated apoptotic pathways in AP are induced by genistein, which showed cytoprotective capacity in the exocrine pancreas. These data suggest novel therapeutic strategies that employ genistein in the prevention of AP., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Increasing evidence shows that the endoplasmic reticulum (ER) stress is an early event that injures pancreatic acinar cells and contributes to the pathogenesis of acute pancreatitis. In the present work we sought to establish whether atrial natriuretic peptide (ANP) alleviated ER stress in rats with cerulein-induced pancreatitis. The major components of the unfolded protein response (UPR) and their downstream effectors were assessed by immunoblotting or fluorimetry and the ultrastructure of ER evaluated by electron transmission microscopy. Cross-talk with autophagy was evaluated by beclin-1 expression. ANP reduced binding immunoglobulin protein (Bip) expression (UPR major controller) which under non-stress conditions keeps inactive the stress sensor proteins: protein kinase-like ER kinase (PERK), inositol-requiring enzyme-1 (IRE1) and activating transcription factor 6 (ATF6). Although ANP did not change PERK expression it decreased p-eIF2α and enhanced downstream effector CHOP, suggesting that ANP stimulates ER-dependent apoptosis. In accordance, ANP also decreased Bcl2 expression and enhanced proapoptotic proteins Bax and Bak. The atrial peptide enhanced ATF6 expression and although it did not affect IRE1/sXBP1 signaling, it increased caspase-2 activity, also involved in ER-dependent apoptosis. Furthermore, ANP decreased beclin-1 expression. The ultrastructure of the RE revealed decreased swelling and conserved ribosomes in the presence of ANP. Present findings support that ANP alleviates ER stress in acute pancreatitis by modulating the three branches of the UPR and stimulates ER-dependent apoptosis. Gaining insights into the modulation of ER stress may help to develop specific therapeutic strategies for acute pancreatitis and/or medical interventions at risk of its developing like endoscopic retrograde cholangiopancreatography., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: Pancreatic stellate cells (PSCs) play a critical role in the development of pancreatic fibrosis. Any agents that can affect PSC activation could become potential candidates for treating pancreatic fibrosis. FTY720 can attenuate chronic pancreatic fibrosis by suppressing T-cell infiltration, but its effect on PSCs remains unknown. This study was conducted to investigate the effects of FTY720 on PSC activation in cultured rat PSCs., Main Methods: The viability of PSCs after FTY720 treatment was detected by MTT. Cell proliferation and migration analysis was performed using the iCELLigence System and a Transwell assay. Cell apoptosis was assessed by flow cytometry, western blot and an activity assay. The mitochondrial membrane potential (MMP) was assessed by JC-1 staining. The expression of α-SMA, collagen I, fibronectin, Beclin-1, Atg5, P62 and LC3B were analysed by immunofluorescence, quantitative real-time PCR and western blot. Rapamycin and phenformin hydrochloride were used to determine whether FTY720 inhibits PSC autophagy by the AMPK/mTOR pathway., Key Findings: FTY720 supressed PSC viability, proliferation and migration. FTY720 inhibited PSC activation, induced PSC apoptosis and supressed PSC autophagy. We also confirmed that FTY720 inhibited PSC autophagy via the AMPK/mTOR pathway., Significance: Our results indicated that FTY720 inhibited PSC activation by promoting cell apoptosis and inhibiting PSC autophagy by suppressing AMPK and activating the mTOR pathway. These findings may explain the therapeutic mechanisms of FTY720 in treating pancreatic fibrosis and further suggest that targeting autophagy and the related signalling pathways may provide new strategies for the treatment of pancreatic fibrosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The efficiency of human butyrylcholinesterase (BChE) as a stoichiometric bioscavenger of nerve agents is well established. However, wide use is currently limited by production and purification costs. Aiming at identifying an alternative human protein bioscavenger, we looked for an original scaffold candidate by virtual screening of the Protein Data Bank for functional similarity using the "Surfing the Molecules" software (sumo-pbil.ibcp.fr) and a search model based on the BChE active site topology. Besides the expected acetylcholinesterase and butyrylcholinesterase, we identified a set of bile salt activated lipases structures, among which the human pancreatic lipase (hBAL) that shares 34% identity with BChE. We produced the recombinant enzyme in mammalian cells, purified it, and measured the inhibition constants for paraoxon and surrogates of VX, sarin and tabun. We solved the X-ray structure of apo hBAL and conjugates with paraoxon and the surrogates at resolutions in the 2-Å range. These structures allow the assessment of hBAL for scavenging nerve agents. They revealed that hBAL has inverted stereoselectivity for the surrogates of nerve agent compared to human cholinesterases. We observed a remarkable flip of the catalytic histidine driven by the chelation of Zn 2+ . Dealkylation of the conjugate, aka aging, was solely observed for paraoxon., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Injection localized amyloidosis is one of the most prevalent disorders in type II diabetes mellitus (TIIDM) patients relying on insulin injections. Previous studies have reported that nanoparticles can play a role in the amyloidogenic process of proteins. Hence, the present study deals with the effect of zinc oxide nanoparticles (ZnONP) on the amyloidogenicity and cytotoxicity of insulin., Methods: ZnONP is synthesised and characterized using XRD, Zeta Sizer, UV-Visible spectroscope and TEM. The characterization is followed by ZnONP interaction with insulin, which is studied employing fluorescence spectroscopes, isothermal titration calorimetry and molecular dynamics simulations. The interaction leads insulin conformational rearrangement into amyloid-like fibril, which is studied using thioflavin T dye binding assay, circular dichroism spectroscopy and TEM, followed by cytotoxicity propensity using Alamar Blue dye reduction assay., Results: Insulin has very weak interaction with ZnONP interface. Insulin at studied concentration forms amorphous aggregates at physiological pH, whereas in presence of ZnONP interface amyloid-like fibrils are formed. While the amyloid-like fibrils are cytotoxic to MIN6 and THP-1 cell lines, insulin and ZnONP individual solutions and their fresh mixtures enhance the cells proliferation., Conclusions: The presence of ZnONP interface enhances insulin fibrillation at physiological pH by providing a favourable template for the nucleation and growth of insulin amyloids., General Significance: The studied protein-nanoparticle system from protein conformational dynamics point of view throws caution over nanoparticle use in biological applications, especially in vivo applications, considering the amyloidosis a very slow but non-curable degenerative disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)