Search

Sedum sarmentosum Bunge possesses excellent anti-inflammatory properties and was used in the treatment of inflammatory diseases. The aim of the present study was to investigate the efficiency of Sedum sarmentosum Bunge extract (SSBE) on severe acute pancreatitis-associated (SAP-associated) acute lung injury (ALI) in rats and to explore the underlying mechanisms. Here, we used a sodium taurocholate-induced SAP rat model to determine the role of SSBE in ALI. During the course of pancreatitis, the expressions of phosphorylated phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt) and nuclear factor-kappa B (NF-κB) p65 in the lungs were upregulated. Meanwhile, a parallel increase in the levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the lungs was observed after the induction of SAP. Treatment with SSBE significantly reduced the expression of p-Akt and p-p65 in the lungs and attenuated the severity of SAP-associated ALI compared to the SAP group at 12 h and 24 h. In summary, this study showed that SSBE has beneficial effects on SAP-associated ALI, probably through the PI3-K/Akt signaling pathways by suppressing the NF-κB activities. [ABSTRACT FROM AUTHOR]

The activation of hepatic stellate cells ( HSCs) is a prominent event in liver fibrogenesis. However, how HSCs are activated in the hypoxic microenvironment remains unclear. Here, we found that hypoxia increased autophagy in rat HSCs. Moreover, hypoxia induced an elevation of the intracellular calcium concentration ([Ca2+]i), which was abolished by the cytosolic Ca2+ chelator or the phospholipase C ( PLC)-specific inhibitor. Furthermore, hypoxia-induced autophagy involved the calcium-dependent activation of the 5ʹ-adenosine monophosphate-activated protein kinase ( AMPK)-mammalian target of rapamycin ( mTOR) and protein kinase C-theta ( PKCθ) pathways. In addition, hypoxia-mediated activation of HSCs depended on autophagy. Our results suggest that autophagy induction via the calcium-dependent AMPK- mTOR and PKCθ pathways might lead to the activation of HSCs during hypoxic stress. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the pancreatic exocrine function in a canine model and to analyze the changes in organelles of pancreatic acinar cells during the early stage of acute pancreatitis (AP). AP was induced by retrograde injection of 5% sodium taurocholate (0.5 ml/kg) into the main pancreatic duct of dogs. The induction of AP resulted in serum hyperamylasemia and a marked reduction of amylase activity in the pancreatic fluid (PF). The pancreatic exocrine function was markedly decreased in subjects with AP compared with the control group. After the induction of AP, histological examination showed acinar cell edema, cytoplasmic vacuolization, fibroblasts infiltration, and inflammatory cell infiltration in the interstitium. Electron micrographs after the induction of AP revealed that most of the rough endoplasmic reticulum (RER) were dilated and that some of the ribosomes were no longer located on the RER. The mitochondria were swollen, with shortened and broken cristae. The present study demonstrated, in a canine model, a reduced volume of PF secretion with decreased enzyme secretion during the early stage of AP. Injury of mitochondria and dilatation and degranulation of RER may be responsible for the reduced exocrine function in AP. Furthermore, the present model and results may be useful for researching novel therapeutic measures in AP. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the potential applicability and the underlying mechanisms of flavokawain C, a natural compound derived from kava extracts, in liver cancer treatment. Methods: Drug distribution experiment used to demonstrate the preferential tissues enrichment of flavokawain C. Cell proliferation, apoptosis and migration effect of flavokawain C were determined by MTT, colony formation, EdU staining, cell adhesion, transwell, flow cytometry and western blot assay. The mechanism was explored by comet assay, immunofluorescence assay, RNA-seq-based Kyoto encyclopedia of genes and genomes analysis, molecular dynamics, bioinformatics analysis and western blot assay. The anticancer effect of flavokawain C was further confirmed by xenograft tumor model. Results: The studies first demonstrated the preferential enrichment of flavokawain C within liver tissues in vivo. The findings demonstrated that flavokawain C significantly inhibited proliferation and migration of liver cancer cells, induced cellular apoptosis, and triggered intense DNA damage along with strong DNA damage response. The findings from RNA-seq-based KEGG analysis, molecular dynamics, bioinformatics analysis, and western blot assay mechanistically indicated that treatment with flavokawain C notably suppressed the FAK/PI3K/AKT signaling pathway in liver cancer cells. This effect was attributed to the induction of gene changes and the binding of flavokawain C to the ATP sites of FAK and PI3K, resulting in the inhibition of their phosphorylation. Additionally, flavokawain C also displayed the strong capacity to inhibit Huh-7-derived xenograft tumor growth in mice with minimal adverse effects. Conclusions: These findings identified that flavokawain C is a promising anticancer agent for liver cancer treatment. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is a non-infectious pancreatic enzyme-induced disorder, a life-threatening inflammatory condition that can cause multi-organ dysfunction, characterized by high morbidity and mortality. Several therapies have been employed to target this disorder; however, few happen to be effectively employable even in the early phase. PFKFB3(6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) is a critical regulator of glycolysis and is upregulated under inflammatory, mitogenic, and hypoxia conditions. Essential information on the targeting of the inflammatory pathway will present the termination of the disorder and recovery. Herein we investigated the protective function of KAN0438757, a potent inhibitor of PFKFB3, and its mechanism of impeding AP induced in mice. KAN0438757 was confirmed to activate the Nrf2/HO-1 inflammatory signaling pathways in response to caerulein induced acute pancreatitis (CAE-AP) and fatty acid ethyl ester induced severe acute pancreatitis (FAEE-SAP). Additionally, KAN0438757 alleviated the inflammatory process in infiltrated macrophage via the Nrf2/HO-1 inflammatory signaling pathway and demonstrated a significant effect on the growth of mice with induced AP. And more importantly, KAN0438757 displayed negligible toxicity in vivo. Taken together our data suggest KAN0438757 directly suppresses the inflammatory role of PFKFB3 and induces a protective role via the Nrf2/HO-1 pathway, which could prove as an excellent therapeutic platform for SAP amelioration. [Display omitted] • KAN0438757 alleviated the inflammatory process in infiltrated macrophages. • KAN0438757 demonstrates negligible toxicity in vivo. • KAN0438757 suppresses the inflammatory role of PFKFB3. • KAN0438757 induces a protective role via the Nrf2/HO-1 pathway. [ABSTRACT FROM AUTHOR]

This work introduces a novel multifunctional system called UPIPF (upconversion‐polydopamine‐indocyanine‐polyethylene‐folic) for upconversion luminescent (UCL) imaging of cancer cells using near‐infrared (NIR) illumination. The system demonstrates efficient inhibition of human hepatoma (HepG2) cancer cells through a combination of NIR‐triggered photodynamic therapy (PDT) and enhanced photothermal therapy (PTT). Initially, upconversion nanoparticles (UCNP) are synthesized using a simple thermal decomposition method. To improve their biocompatibility and aqueous dispersibility, polydopamine (PDA) is introduced to the UCNP via a ligand exchange technique. Indocyanine green (ICG) molecules are electrostatically attached to the surface of the UCNP‐polydopamine (UCNP@PDAs) complex to enhance the PDT and PTT effects. Moreover, polyethylene glycol (PEG)‐modified folic acid (FA) is incorporated into the UCNP‐polydopamine‐indocyanine‐green (UCNP@PDA‐ICGs) nanoparticles to enhance their targeting capability against cancer cells. The excellent UCL properties of these UCNP enable the final UCNP@PDA‐ICG‐PEG‐FA nanoparticles (referred to as UPIPF) to serve as a potential candidate for efficient anticancer drug delivery, real‐time imaging, and early diagnosis of cancer cells. Furthermore, the UPIPF system exhibits PDT‐assisted PTT effects, providing a convenient approach for efficient cancer cell inhibition (more than 99% of cells are killed). The prepared UPIPF system shows promise for early diagnosis and simultaneous treatment of malignant cancers. [ABSTRACT FROM AUTHOR]

Ferroptosis driven by the iron‐dependent accumulation of lipid peroxides and subsequent oxidative damage of biological membranes has shown great potential in the treatment of various diseases, especially cancer. However, suffering from the lack of safe and efficient delivery strategies for the unstable ferrous ions (Fe2+), the therapeutic efficacy induced by ferroptosis is always unsatisfactory. Herein, a protein‐based nanocomposite (Protein‐Gold Hybrid Materials‐Red, PGHM‐R) is designed as both an Fe2+ stabilizer and a carrier for the safe and efficient delivery of Fe2+ to hepatoma cells. The conspicuous feature of ferroptosis, such as downregulation of GPX4 and FTH1, upregulation of ASCL4 and NOX1, as well as mitochondrial deformation, is observed in PGHM‐R‐Fe‐treated hepatoma cells, which demonstrate that PGHM‐R‐Fe can effectively trigger ferroptosis of hepatoma cells. More importantly, systematic in vivo therapeutic outcomes demonstrate the low side effects and the high tumor‐inhibiting ratio of 58% of PGHM‐R‐Fe in the tumor model of hepatocellular carcinoma‐bearing mice. This novel strategy for inducing the ferroptosis of cancer cells based on utilizing protein to deliver Fe2+ holds great potential in the clinical applications of ferroptosis‐based therapy. [ABSTRACT FROM AUTHOR]

Summary: Acute pancreatitis (AP), an inflammatory disorder of the pancreas with a high hospitalization rate, frequently leads to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). However, therapeutic targets for effective treatment and early intervention of AP are still urgently required to be identified. Here, we have observed that the expression of pancreatic lincRNA‐EPS, a long intergenic non‐coding RNA, is dynamically changed during both caerulein‐induced AP (Cer‐AP) and sodium taurocholate‐induced severe AP (NaTc‐SAP). The expression pattern of lincRNA‐EPS is negatively correlated with the typical inflammatory genes such as IL‐6, IL‐1β, CXCL1, and CXCL2. Further studies indicate that knockout of lincRNA‐EPS aggravates the pathological symptoms of AP including more induction of serum amylase and lipase, severe edema, inflammatory cells infiltration and acinar necrosis in both experimental AP mouse models. Besides these intrapancreatic effects, lincRNA‐EPS also protects against tissue damages in the extra‐pancreatic organs such as lung, liver, and gut in the NaTc‐SAP mouse model. In addition, we have observed more serum pro‐inflammatory cytokines TNF‐α and IL‐6 in the lincRNA‐EPS‐/‐ NaTc‐SAP mice and more extracellular HMGB1 around injured acinar cells in the pancreas from lincRNA‐EPS‐/‐ NaTc‐SAP mice, compared with their respective controls. Pharmacological inhibition of NF‐κB activity by BAY11‐7082 significantly abolishes the suppressive effect of lincRNA‐EPS on TLR4 ligand‐induced inflammatory genes in macrophages. Our study has described a protective role of lincRNA‐EPS in alleviating AP and SAP, outlined a novel pathway that lincRNA‐EPS suppresses HMGB1‐NF‐κB‐dependent inflammatory response in pancreatic macrophages and provided a potential therapeutic target for SAP. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is a clinically common acute inflammatory disease in digestive system, leading to systemic inflammatory response syndrome (SIRS) and severe acute pancreatitis (SAP). It was reported that PINK1/PARK2 dependent mitophagy played an important role in various inflammatory diseases. However, its role in AP has not been elucidated. Herein, we explore the effect of mitophagy in the pathogenesis of AP. Firstly, we established cerulein-induced AP group and arginine-induced SAP group based on wild, PINK1-/- and PARK2-/- mice. Pancreatic samples were harvested for further investing the mitochondrial dynamics, mitophagy alterations, NLRP3 inflammatory pathway etc. Furthermore, peripheral blood mononuclear cells from SAP patients were collected to examine the expression of mitophagy-related indicators. Additionally, the interrelationship between mitophagy and NLRP3 inflammasome was also explored in AP. It was confirmed that mitochondria were damaged in both AP and SAP models. The expressions of PINK1, PARK2 and mitochondrial autophagosomes were elevated in wild AP group, which were decreased in SAP group over time. Similarly, the expressions of PINK1 and PAKR2 in peripheral blood mononuclear cells were significantly lower in SAP patients. Besides, in PINK1-/- and PARK2-/- mice AP groups, more pronounced inflammatory infiltration, increased apoptotic and necrotic levels and upregulated NLRP3 inflammasome pathway were detected. After injection with MCC950, NLRP3 inflammasome production was notably reduced in PINK1-/-and PARK2-/-mice, which effectively alleviated the pancreatic damage and inflammatory cell infiltration. Our study suggested that mitochondrial dysfunction activated PINK1/PARK2-mediated mitophagy in AP, while mitophagy was impaired in SAP. PINK1-/- and PARK2-/- mice were more sensitive to onset of SAP and the deficiency of mitophagy could lead to the formation of NLRP3 inflammasome. [Display omitted] • Mitochondria were damaged in both AP and SAP models. • The expressions of mitochondrial autophagosomes were decreased in SAP group over time. • PINK1-/- and PARK2-/- mice AP groups had more pronounced inflammatory infiltration. • The deficiency of mitophagy could lead to the formation of NLRP3 inflammasome. • MCC950 could reduce NLRP3 inflammasome production in PINK1-/-and PARK2-/- AP mice. [ABSTRACT FROM AUTHOR]

Objective: Investigate the therapeutic effect of regional arterial infusion (RAI) with Aspirin-Triggered Lipoxin A4 (ATL) in experimental severe acute pancreatitis (SAP) in rats. Materials and Methods: SAP was induced by injection of 5% sodium taurocholate into the pancreatic duct. Rats with SAP were treated with ATL (the ATL group) or physiological saline (the SAP group) infused via the left gastric artery 30 min after injection of sodium taurocholate. The sham group was subjected to the same surgical procedure, though without induction of SAP. Serum levels of amylase, phospholipase A2 (PLA2), interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) were measured at 12 and 24 h after induction of SAP. Ascitic fluid, the pancreatic index (wet weight ratio) and myeloperoxidase (MPO) levels in the pancreas were determined and histopathological findings were evaluated. The expression of intercellular adhesion molecule-1 (ICAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1), NF-κB p65, and heme oxygenase-1 (HO-1) in the pancreas were estimated by immunofluorescence and western blot, respectively. Results: ATL rats had lower serum levels of TNF-α, IL-1β, and IL-6 (P<0.01), PLA2 (P<0.05), and amylase levels (P<0.05) studied as compared with the SAP group. The pancreatic index in the ATL group decreased only at 24 h as compared with the SAP group (P<0.05). The histopathological findings and MPO levels in the pancreas significantly decreased in the ATL group as compared to the SAP group (P<0.05 and P<0.01, respectively). Immunofluorescence and western blot showed that ATL attenuated the expression of NF-κB p65, ICAM-1 and PECAM-1 in the pancreas, and increased the expression of HO-1 in SAP animals. Conclusions: We demonstrated that RAI with ATL attenuated the severity of experimental SAP, maybe achieved by improving the expression of HO-1, and down-regulating the NF-κB signaling pathway, with decreased expression of ICAM-1 and PECAM-1 and reduced generation of pro-inflammatory cytokines. [ABSTRACT FROM AUTHOR]