Rosa canina extract relieves methylation alterations of pancreatic genes in STZ-induced diabetic rats : Gene methylation in diabetic rats treated with an extract.

BACKGROUND: Diabetes is a chronic metabolic disease that affects many parts of the body. Considering diabetes as a beta cells' defect and loss, the focus is on finding mechanisms and compounds involved in stimulating the function and regeneration of pancreatic ß-cells. DNA methylation as an epigenetic mechanism plays a pivotal role in the ß-cells' function and development. Considering the regenerative and anti-diabetic effects of Rosa canina extract, this study aimed to assess the methylation levels of Pdx-1, Pax-4, and Ins-1 genes in diabetic rats treated with Rosa Canina extract. METHODS AND RESULTS: Streptozotocin-induced diabetic rats were used to evaluate the frequency of Pdx-1, Pax-4, and Ins-1 gene methylation. Treatment groups were exposed to Rosa canina as spray-dried and decoction extracts. Following blood glucose measurement, pancreatic DNA was extracted and bisulfited. Genes' methylation was measured using MSP-PCR and qRT-PCR techniques. Oral administration of Rosa canina extracts significantly reduced blood sugar levels in diabetic rats compared to the control group. The methylation levels of the Pdx-1, Pax-4, and Ins-1 genes promoter in streptozotocin-induced diabetic rats increased compared to the control rats while, the treatment of diabetic rats with Rosa canina extracts, spray-dried samples especially, led to a decreased methylation in these genes. CONCLUSION: The results of this study showed that Rosa canina extract as a spray-dried sample could be effective in treating diabetes by regulating the methylation of genes including Pdx-1, Pax-4, and Ins-1 involved in the activity and regeneration of pancreatic islet cells.

Dexmedetomidine's Effects on the Livers and Kidneys of Rats with Pancreatic Ischemia-Reperfusion Injury.

Objective: Pancreatic surgeries inherently cause ischemia-reperfusion (IR) injury, affecting not only the pancreas but also distant organs. This study was conducted to explore the potential use of dexmedetomidine, a sedative with antiapoptotic, anti-inflammatory, and antioxidant properties, in mitigating the impacts of pancreatic IR on kidney and liver tissues. Methods: A total of 24 rats were randomly divided into four groups: control (C), dexmedetomidine (D), ischemia reperfusion (IR), and dexmedetomidine ischemia reperfusion (D-IR). Pancreatic ischemia was induced in the IR and D-IR groups. Dexmedetomidine was administered intraperitoneally to the D and D-IR groups. Liver and kidney tissue samples were subjected to microscopic examinations after hematoxylin and eosin staining. The levels of thiobarbituric acid reactive substances (TBARS), aryllesterase (AES), catalase (CAT), and glutathione S-transferase (GST) enzyme activity were assessed in liver and kidney tissues. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine were measured. Results: A comparison of the groups revealed that the IR group exhibited significantly elevated TBARS (p < 0.0001), AES (p = 0.004), and CAT enzyme activity (p < 0.0001) levels in the liver and kidney compared to groups C and D. Group D-IR demonstrated notably reduced histopathological damage (p < 0.05) and low TBARS (p < 0.0001), AES (p = 0.004), and CAT enzyme activity (p < 0.0001) in the liver and kidney as well as low AST and ALT activity levels (p < 0.0001) in the serum compared to the IR group. Conclusion: The preemptive administration of dexmedetomidine before pancreatic IR provides significant protection to kidney and liver tissues, as evidenced by the histopathological and biochemical parameters in this study. The findings underscored the potential therapeutic role of dexmedetomidine in mitigating the multiorgan damage associated with pancreatic surgeries.

Evaluation of the combination of black rice bran ethanol extract and glimepiride in reducing blood glucose and protecting kidney, liver and pancreatic cells.

Long-lasting hyperglycemia can potentially cause damage to organs such as the kidneys, liver and pancreas. Glimepiride (GLIM), as a drug of choice in the treatment of diabetes mellitus (DM), has the risk of decreasing the functioning of organs such as the kidneys, liver and pancreas. Black rice bran ethanol extract (EEBRB) with antioxidant content has been shown to protect the kidney, liver and pancreas organs. The aim of this study was to establish the effect of EEBRB on lowering fasting blood glucose (FBG) and protecting several organs after GLIM administration in alloxan (ALX)-induced hyperglycemic rats. A total of 20 rats were divided into 4 groups and treated for 21 days treatments using following preparations: normal control (NC), diabetic group (DC), GLIM 1 mg/ kgBW and combination of glimepiride 1mg/kgBW and EEBRB 50 mg/KgBW (GLBR). The results showed that the GLBR was able to lower blood glucose levels back to normal (<126 mg/dL) and protect kidney, liver and pancreas cells by increasing the amount in normal cells.

Antidiabetic Effect of Fig Seed Oil in Rats with Diabetes Induced by Streptozotocin.

The anti-diabetic effect of Ficus carica (Fig) seed oil was investigated. 4 groups with 6 rats in each group were used in the experiment as control, diabetes (45 mg/kg streptozotocin), fig seed oil (FSO) (6 mL/ kg/day/rat by gavage) and diabetes+FSO groups. Glucose, urea, creatinine, ALT, AST, GSH, AOPP and MDA analyses were done. Pancreatic tissues were examined histopathologically. When fig seed oil was given to the diabetic group, the blood glucose level decreased. In the diabetes+FSO group, serum urea, creatinine, AOPP, MDA levels and ALT and AST activities decreased statistically significantly compared to the diabetes group, while GSH levels increased significantly, histopathological, immunohistochemical, and immunofluorescent improvements were observed. It has been shown for the first time that FSO has positive effects on blood glucose level and pancreatic health. It can be said that the protective effect of fig seed oil on tissues may be due to its antioxidant activity.

Vitamin B6 ameliorates acute pancreatitis by suppressing the caspase3 signaling pathway.

BACKGROUND: Acute pancreatitis (AP) is a prevalent exocrine inflammatory disorder of the pancreas characterized by pancreatic inflammation and injury to acinar cells. Vitamin B6 (VB6) is a vital nutrient that plays a significant role in preserving human health and has anti-inflammatory and anti-apoptotic effects. METHODS: This study aimed to explore the potential pancreatic protective effects of VB6 in mitigating pancreatic inflammation and apoptosis induced by taurocholate sodium (TLCS) in an AP model and to assess the underlying mechanism of action. AP was induced in Sprague‒Dawley (SD) rats through TLCS administration and lipopolysaccharide (LPS)-treated AR42J cells, followed by treatment with VB6. RESULTS: Various parameters associated with AP were assessed in both plasma and pancreatic tissues. VB6 has been shown to ameliorate the severity of AP through various mechanisms. It effectively reduces the levels of serum amylase, lipase, and inflammatory factors, thereby mitigating histological injury to the pancreas. Moreover, VB6 inhibited pancreatic apoptosis by downregulating bax expression and up-regulating Bcl2 expression in TLCS-treated rats. Additionally, VB6 suppressed the expression of caspase3. The anti-inflammatory and anti-apoptotic effects of VB6 observed in LPS-treated AR42J cells are consistent with those observed in a rat model of AP. CONCLUSIONS: These results suggest that VB6 exerts anti-inflammatory and anti-apoptotic effects through inhibition of the caspase3 signaling pathway and has a protective effect against AP.

Hesperidin, vanillic acid, and sinapic acid attenuate atorvastatin-induced mitochondrial dysfunction via inhibition of mitochondrial swelling and maintenance of mitochondrial function in pancreas isolated mitochondria.

It has been reported that lipophilic statins such as atorvastatin can more readily penetrate into ß-cells and reach the mitochondria, resulting in mitochondrial dysfunction, oxidative stress, decrease in insulin release. Many studies have shown that natural products can protect mitochondrial dysfunction induced by drug in different tissue. We aimed to explore mitochondrial protection potency of hesperidin, vanillic acid, and sinapic acid as natural compounds against mitochondrial dysfunction induced by atorvastatin in pancreas isolated mitochondria. Mitochondria were isolated form rat pancreas and directly treated with toxic concentration of atorvastatin (500 µM) in presence of various concentrations hesperidin, vanillic acid, and sinapic acid (1, 10, and 100 µM) separately. Mitochondrial toxicity parameters such as the reactive oxygen species (ROS) formation, succinate dehydrogenases (SDH) activity, mitochondrial swelling, depletion of glutathione (GSH), mitochondrial membrane potential (MMP) collapse, and malondialdehyde (MDA) production were measured. Our findings demonstrated that atorvastatin directly induced mitochondrial toxicity at concentration of 500 µM and higher in pancreatic mitochondria. Except MDA, atorvastatin caused significantly reduction in SDH activity, mitochondrial swelling, ROS formation, depletion of GSH, and collapse of MMP. While, our data showed that all three protective compounds at low concentrations ameliorated atorvastatin-induced mitochondrial dysfunction with the increase of SDH activity, improvement of mitochondrial swelling, MMP collapse and mitochondrial GSH, and reduction of ROS formation. We can conclude that hesperidin, vanillic acid, and sinapic acid can directly reverse the toxic of atorvastatin in rat pancreas isolated mitochondria, which may be beneficial for protection against diabetogenic-induced mitochondrial dysfunction in pancreatic ß-cells.

Rhei Radix et Rhizoma and its anthraquinone derivatives: Potential candidates for pancreatitis treatment.

BACKGROUND: Pancreatitis is a common exocrine inflammatory disease of the pancreas and lacks specific medication currently. Rhei Radix et Rhizoma (RR) and its anthraquinone derivatives (AQs) have been successively reported for their pharmacological effects and molecular mechanisms in experimental and clinical pancreatitis. However, an overview of the anti-pancreatitis potential of RR and its AQs is limited. PURPOSE: To summarize and analyze the pharmacological effects of RR and its AQs on pancreatitis and the underlying mechanisms, and discuss their drug-like properties and future perspectives. METHODS: The articles related to RR and its AQs were collected from the Chinese National Knowledge Infrastructure, Wanfang data, PubMed, and the Web of Science using relevant keywords from the study's inception until April first, 2024. Studies involving RR or its AQs in cell or animal pancreatitis models as well as structure-activity relationship, pharmacokinetics, toxicology, and clinical trials were included. RESULTS: Most experimental studies are based on severe acute pancreatitis rat models and a few on chronic pancreatitis. Several bioactive anthraquinone derivatives of Rhei Radix et Rhizoma (RRAQs) exert local protective effects on the pancreas by maintaining pancreatic acinar cell homeostasis, inhibiting inflammatory signaling, and anti-fibrosis, and they improve systemic organ function by alleviating intestinal and lung injury. Pharmacokinetic and toxicity studies have revealed the low bioavailability and wide distribution of RRAQs, as well as hepatotoxicity and nephrotoxicity. However, there is insufficient research on the clinical application of RRAQs in pancreatitis. Furthermore, we propose effective strategies for subsequent improvement in terms of balancing effectiveness and safety. CONCLUSION: RRAQs can be developed as either candidate drugs or novel lead structures for pancreatitis treatment. The comprehensive review of RR and its AQs provides references for optimizing drugs, developing therapies, and conducting future studies on pancreatitis.

Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress ß-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.

Anti-Hyperglycemic Effect of the Brown Slime Cap Mushroom Chroogomphus rutilus (Agaricomycetes) Crude Polysaccharide In Vitro and In Vivo.

The prevalence of diabetes is increasing worldwide, and it is very important to study new hypoglycemic active substances. In this study, we investigated the hypoglycemic effect of Chroogomphus rutilus crude polysaccharide (CRCP) in HepG2 cells and streptozotocin-induced diabetic mice. A glucose consumption experiment conducted in HepG2 cells demonstrated the in vitro hypoglycemic activity of CRCP. Furthermore, CRCP exhibited significant hypoglycemic effects and effectively ameliorated insulin resistance in insulin resistant HepG2 cells. In high-fat diet and streptozotocin-induced diabetic mice, after 4 weeks of CRCP administration, fasting blood glucose, fasting serum insulin, triglyceride, total cholesterol, low-density lipoprotein cholesterol, glutamate transaminase, alanine transaminase, and insulin resistance index significantly decreased, while high-density lipoprotein cholesterol and insulin sensitivity index (ISI) were markedly increased. Moreover, hematoxylin-eosin (HE) staining and immunofluorescence labeling of tissue sections indicated that CRCP attenuated the pathological damage of liver and pancreas in diabetic mice. These results indicate that CRCP is a potential hypoglycemic agent.

Melatonin ameliorates multiorgan injuries induced by severe acute pancreatitis in mice by regulating the Nrf2 signaling pathway.

Severe acute pancreatitis (SAP) is a complicated inflammatory reaction that impacts the pancreas, often resulting in damage to numerous organs. This disorder encompasses a range of processes such as inflammation, oxidative stress, and pancreatitis. The hormone melatonin (MT) is primarily secreted by the pineal gland and plays a crucial role in mitigating inflammation, countering the harmful effects of free radicals, and regulating oxidative stress. The aim of this research was to investigate the potential protective impact and the underlying mechanism of melatonin in mice afflicted with SAP. The biochemical and histological assessments unequivocally demonstrated that melatonin effectively inhibited necrosis, infiltration, edema and cell death in pancreatic tissues, thereby suppressing acute pancreatitis. Notably, melatonin also alleviated the consequent harm to distant organs, notably the lungs, liver, and kidneys. Furthermore, both preventive and therapeutic administration of melatonin prompted nuclear factor E2-related factor 2 (Nrf2) activation followed by Nrf2 target gene expression. Nrf2 initiates the activation of antioxidant genes, thereby providing defense against oxidative stress. Conversely, Nrf2 reduction may contribute to impaired antioxidant protection in SAP. The beneficial impact of Nrf2 on antioxidants was absent in Nrf2-knockout mice, leading to the accumulation of LDH and exacerbation of cell death. This deterioration in both pancreatitis and injuries in distant organs intensified significantly. The results indicate that melatonin has an enhanced ability to protect against multiorgan damage caused by SAP, which is accomplished through the increase in Nrf2 expression. Additionally, Nrf2 initiates the activation of antioxidant genes that offer defense against cell death.

Improving the anti-diabetic and anti-hyperlipidemic activities of extra virgin olive oil by the incorporation of diallyl sulfide.

Development of novel functional foods is trending as one of the hot topics in food science and food/beverage industries. In the present study, the anti-diabetic, anti-hyperlipidemic and histo-protective effects of the extra virgin olive oil (EVOO) enriched with the organosulfur diallyl sulfide (DAS) (DAS-rich EVOO) were evaluated in alloxan-induced diabetic mice. The ingestion of EVOO (500µL daily for two weeks) attenuated alloxan-induced elevated glucose, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), urea and creatinine. It also normalized the levels of triglycerides (TG), total cholesterols (TC), low-density lipoprotein-cholesterol (LDL-c) and their consequent atherogenic index of plasma (AIP) in diabetic animals. Additionally, EVOO prevented lipid peroxidation (MDA) and reduced the level of hydrogen peroxide (H2O2) in diabetic animals. Concomitantly, it enhanced the activity of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), reducing thereby tissue oxidative stress injury. The overall histologic (pancreas, liver, and kidney) alterations were also improved after EVOO ingestion. The manifest anti-diabetic, lipid-lowering and histo-protective properties of EVOO were markedly potentiated with DAS-rich EVOO suggesting possible synergistic interactions between DAS and EVOO lipophilic bioactive ingredients. Overall, EVOO and DAS-rich EVOO show promise as functional foods and/or adjuvants for the treatment of diabetes and its complications.

Co-exposure to PVC microplastics and cadmium induces oxidative stress and fibrosis in duck pancreas.

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.

Persistent metabolic toxicities following developmental exposure to hexafluoropropylene oxide trimer acid (HFPO-TA): Roles of peroxisome proliferator activated receptor gamma.

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.

Liproxstatin-1 attenuates acute hypertriglyceridemic pancreatitis through inhibiting ferroptosis in rats.

Ferroptosis is closely associated with inflammatory diseases, including acute pancreatitis (AP); however, the involvement of ferroptosis in hypertriglyceridemic pancreatitis (HTGP) remains unclear. In the present study, we aimed to explore the relationship between lipid metabolism and ferroptosis in HTGP and the alleviating effect of liproxstatin-1 (Lip-1) in vivo. This study represents the first exploration of lipid metabolism and endoplasmic reticulum stress (ERS) in HTGP, targeting ferroptosis as a key factor in HTGP. Hypertriglyceridemia (HTG) was induced under high-fat diet conditions. Cerulein was then injected to establish AP and HTGP models. Lip-1, a specific ferroptosis inhibitor, was administered before the induction of AP and HTGP in rats, respectively. Serum triglyceride, amylase, inflammatory factors, pathological and ultrastructural structures, lipid peroxidation, and iron overload indicators related to ferroptosis were tested. Moreover, the interaction between ferroptosis and ERS was assessed. We found HTG can exacerbate the development of AP, with an increased inflammatory response and intensified ferroptosis process. Lip-1 treatment can attenuate pancreatic injury by inhibiting ferroptosis through lipid metabolism and further resisting activations of ERS-related proteins. Totally, our results proved lipid metabolism can promote ferroptosis in HTGP by regulating ACSL4/LPCAT3 protein levels. Additionally, ERS may participate in ferroptosis via the Bip/p-EIF2α/CHOP pathway, followed by the alleviating effect of Lip-1 in the rat model.

Insufficient secretion of pancreatic FGF21 is the toxicological mechanism and therapeutic target of asparaginase-associated pancreatitis.

Asparaginase-associated pancreatitis (AAP) is a severe and potentially life-threatening drug-induced pancreas targeted toxicity in the combined chemotherapy of acute lymphoblastic leukemia among children and adolescents. The toxicological mechanism of AAP is not yet clear, and there are no effective preventive and treatment measures available clinically. Fibroblast growth factor 21 (FGF21) is a secretory hormone that regulates lipid, glucose, and energy metabolism balance. Acinar tissue is the main source of pancreatic FGF21 protein and plays an important role in maintaining pancreatic metabolic balance. In this study, we found that the decrease of FGF21 in pancreas is closely related to AAP. Pegaspargase (1 IU/g) induces widespread edema and inflammatory infiltration in the pancreas of rats/mice. The specific expression of FGF21 in the acinar tissue of AAP rats was significantly downregulated. Asparaginase caused dysregulation of the ATF4/ATF3/FGF21 axis in acinar tissue or cells, and thus mediated the decrease of FGF21. It greatly activated ATF3 in the acinar, which competed with ATF4 for the Fgf21 promoter, thereby inhibiting the expression of FGF21. Pharmacological replacement of FGF21 (1 mg/kg) or PERK inhibitors (GSK2656157, 25 mg/kg) can significantly mitigate the pancreatic tissue damage and reduce markers of inflammation associated with AAP, representing potential strategies for the prevention and treatment of AAP.

Rhizoma Alismatis Decoction improved mitochondrial dysfunction to alleviate SASP by enhancing autophagy flux and apoptosis in hyperlipidemia acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas, especially hyperlipidemia acute pancreatitis (HLAP) is the third leading cause of acute pancreatitis which is more severe with a greater incidence of persistent multiorgan failure. HLAP inflicts injury upon the organelles within the acinar cell, particularly mitochondria, the endolysosomal-autophagy system, and is accompanied by senescence-associated secretory phenotype (SASP). RAD, only two consists of Rhizoma Alismatis and Atractylodes macrocephala Rhizoma, which is best known for its ability to anti-inflammatory and lipid-lowering. Nevertheless, the mechanism by which RAD alleviates HLAP remains obscure, necessitating further investigation. PURPOSE: The study aimed to assess the effects of the RAD on HLAP and to elucidate the underlying mechanism in vivo and in vitro, offering a potential medicine for clinical treatment for HLAP. STUDY DESIGN AND METHODS: C57BL/6 mice with hyperlipidemia acute pancreatitis were induced by HFD and CER, then administrated with RAD. AR42J were stimulated by cerulein or conditioned medium and then cultured with RAD. Serums were analyzed to evaluate potential pancreas and liver damage. Furthermore, tissue samples were obtained for histological, and protein investigations by H&E, Oil red staining, and Western blot. In addition, western blot and immunofluorescent staining were utilized to estimate the effect of RAD on mitochondrial function, autophagy flux, and SASP. RESULTS: In vivo, RAD considerably alleviated systemic inflammation while attenuating TC, TG, AMY, LPS, inflammatory cytokines, histopathology changes, oxidative damage, mitochondrial fission, and autophagy markers in HLAP mice. Impaired autophagy flux and mitochondrial dysfunction resulted in a significant enhancement of NLRP3 and IL-1ß in the pancreas. RAD could reverse these changes. In vitro, RAD significantly restored mitochondrial membrane potential and oxidative phosphorylation levels. RAD decreased Beclin-1 and LC3-II expression and increased LAMP-1 and Parkin-Pink expression, which showed that RAD significantly ameliorated HLAP-induced damage to the mitochondria function by suppressing mitochondrial oxidative damage and enhancing autophagy flux and mitophagy to remove the damaged mitochondria. In addition, we found that RAD could up-regulate the expression of BAX, and Bad and down-regulate the expression of p16, and p21, indicating that RAD could promote damaged cell apoptosis and alleviate SASP. CONCLUSIONS: This study revealed that RAD ameliorates mitochondrial function to alleviate SASP through enhancing autophagy flux, mitophagy, and apoptosis which provided a molecular basis for the advancement and development of protection strategies against HLAP.

Inflammation and Acinar Cell Dual-Targeting Nanomedicines for Synergistic Treatment of Acute Pancreatitis via Ca2+ Homeostasis Regulation and Pancreas Autodigestion Inhibition.

Severe acute pancreatitis (AP) is a life-threatening pancreatic inflammatory disease with a high mortality rate (∼40%). Existing pharmaceutical therapies in development or in clinical trials showed insufficient treatment efficacy due to their single molecular therapeutic target, poor water solubility, short half-life, limited pancreas-targeting specificity, etc. Herein, acid-responsive hollow mesoporous Prussian blue nanoparticles wrapped with neutrophil membranes and surface modified with the N,N-dimethyl-1,3-propanediamine moiety were developed for codelivering membrane-permeable calcium chelator BAPTA-AM (BA) and trypsin activity inhibitor gabexate mesylate (Ga). In the AP mouse model, the formulation exhibited efficient recruitment at the inflammatory endothelium, trans-endothelial migration, and precise acinar cell targeting, resulting in rapid pancreatic localization and higher accumulation. A single low dose of the formulation (BA: 200 µg kg-1, Ga: 0.75 mg kg-1) significantly reduced pancreas function indicators to close to normal levels at 24 h, effectively restored the cell redox status, reduced apoptotic cell proportion, and blocked the systemic inflammatory amplified cascade, resulting in a dramatic increase in the survival rate from 58.3 to even 100%. Mechanistically, the formulation inhibited endoplasmic reticulum stress (IRE1/XBP1 and ATF4/CHOP axis) and restored impaired autophagy (Beclin-1/p62/LC3 axis), thereby preserving dying acinar cells and restoring the cellular "health status". This formulation provides an upstream therapeutic strategy with clinical translation prospects for AP management through synergistic ion homeostasis regulation and pancreatic autodigestion inhibition.

Incretins Beyond the Pancreas: Exploring the Impact of GIP and GLP-1/2 on Bone Remodeling.

Incretin hormones, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 and 2 (GLP-1, 2), belong to the group of gastrointestinal hormones. Their actions occur through interaction with GIP and GLP-1/2 receptors, which are present in various target tissues. Apart from their well-established roles in pancreatic function and insulin regulation, incretins elicit significant effects that extend beyond the pancreas. Specifically, these hormones stimulate osteoblast differentiation and inhibit osteoclast activity, thereby promoting bone anabolism. Moreover, they play a pivotal role in bone mineralization and overall bone quality and function, making them potentially therapeutic for managing bone health. Thus, this review provides a summary of the crucial involvement of incretins in bone metabolism, influencing both bone formation and resorption processes. While existing evidence is persuasive, further studies are necessary for a comprehensive understanding of the therapeutic potential of incretins in modifying bone health.

Developmental programming: Testosterone excess masculinizes female pancreatic transcriptome and function in sheep.

Hyperandrogenic disorders, such as polycystic ovary syndrome, are often associated with metabolic disruptions such as insulin resistance and hyperinsulinemia. Studies in sheep, a precocial model of translational relevance, provide evidence that in utero exposure to excess testosterone during days 30-90 of gestation (the sexually dimorphic window where males naturally experience elevated androgens) programs insulin resistance and hyperinsulinemia in female offspring. Extending earlier findings that adverse effects of testosterone excess are evident in fetal day 90 pancreas, the end of testosterone treatment, the present study provides evidence that transcriptomic and phenotypic effects of in utero testosterone excess on female pancreas persist after cessation of treatment, suggesting lasting organizational changes, and induce a male-like phenotype in female pancreas. These findings demonstrate that the female pancreas is susceptible to programmed masculinization during the sexually dimorphic window of fetal development and shed light on underlying connections between hyperandrogenism and metabolic homeostasis.

Interleukin-22 Alleviates Caerulein-Induced Acute Pancreatitis by Activating AKT/mTOR Pathway.

BACKGROUND: Acute pancreatitis (AP) is one of the most common acute abdominal disorders; due to the lack of specific treatment, the treatment of acute pancreatitis, especially serious acute pancreatitis (SAP), is difficult and challenging. We will observe the changes of Interleukin -22 levels in acute pancreatitis animal models, and explore the mechanism of Interleukin -22 in acute pancreatitis. OBJECTIVE: This study aims to assess the potential protective effect of Interleukin -22 on caerulein-induced acute pancreatitis and to explore its mechanism. METHODS: Blood levels of amylase and lipase and Interleukin -22 were assessed in mice with acute pancreatitis. In animal model and cell model of caerulein-induced acute pancreatitis, the mRNA levels of P62 and Beclin-1 were determined using PCR, and the protein expression of P62, LC3-II, mTOR, AKT, p-mTOR, and p-AKT were evaluated through Western blot analysis. RESULTS: Interleukin -22 administration reduced blood amylase and lipase levels and mitigated tissue damage in acute pancreatitis mice model. Interleukin -22 inhibited the relative mRNA levels of P62 and Beclin-1, and the Interleukin -22 group showed a decreased protein expression of LC3-II and P62 and the phosphorylation of the AKT/mTOR pathway. Furthermore, we obtained similar results in the cell model of acute pancreatitis. CONCLUSION: This study suggests that Interleukin -22 administration could alleviate pancreatic damage in caerulein-induced acute pancreatitis. This effect may result from the activation of the AKT/mTOR pathway, leading to the inhibition of autophagy. Consequently, Interleukin -22 shows potential as a treatment.