Abstract
Severe acute pancreatitis (SAP) is often associated with pulmonary inflammation leading to acute lung injury. Daphnetin, a natural coumarin derivative, has been reported to exert ...anti-inflammatory effects. Here, we explored the effect and possible mechanism of daphnetin in a mouse model of SAP-associated lung injury induced by an intraperitoneal injection of
l
-arginine. The severity of pancreatic and lung injury is determined by histology and its score. Immunostaining of inflammatory and apoptotic cells was used to demonstrate lung tissue inflammation and apoptosis; ELISA analysis of serum and tissue cytokine levels; and western blotting and immunohistochemical staining for the activated Janus kinase 2 (JAK2)–signal transducer and activator of transcription protein 3 (STAT3) signalling pathway in lung tissues. Daphnetin pretreatment significantly reduced SAP-induced pancreatic and lung tissue damage, reduced interleukin-6 and tumour necrosis factor-α concentrations in both serum and lung tissues, reduced serum amylase and myeloperoxidase activities, and reduced macrophage (CD11b) and neutrophil (Ly6G) infiltration and cell apoptosis in the lung tissue. Moreover, SAP-induced phosphorylation of JAK2 and STAT3 in the lung tissue was also significantly diminished by the daphnetin pretreatment. These results indicated that daphnetin reduces SAP-associated lung tissue damage, likely by inhibiting the activation of JAK2–STAT3 signalling.
This study sought to investigate the biological effects of specific MIF inhibitor, ISO-1, on the proliferation, migration and invasion of PANC-1 human pancreatic cells in vitro, and on tumour growth ...in a xenograft tumour model in vivo. The effect of ISO-1 on PANC-1 cell proliferation was examined using CCK-8 cell proliferation assay. The effect of ISO-1 on collective cell migration and recolonization of PANC-1 cells was evaluated using the cell-wound closure migration assay. The effect of ISO-1 on the migration and invasion of individual PANC-1 cells in a 3-dimensional environment in response to a chemo-attractant was investigated through the use of Transwell migration/invasion assays. Quantitative real time PCR and western blot analyses were employed to investigate the effects of ISO-1 on MIF, NF-κB p65 and TNF-α mRNA and protein expression respectively. Finally, a xenograft tumor model in BALB/c nude mice were used to assess the in vivo effects of ISO-1 on PANC-1-induced tumor growth. We found high expression of MIF in pancreatic cancer tissues. We demonstrated that ISO-1 exerts anti-cancer effects on PANC-1 cell proliferation, migration and invasion in vitro, and inhibited PANC-1 cell-induced tumour growth in xenograft mice in vivo. Our data suggests that ISO-1 and its derivative may have potential therapeutic applications in pancreatic cancer.
The present study investigates whether paraquat (PQ) regulates polarization of alveolar macrophages through glycolysis and promotes the occurrence of acute lung injury in rats. In vivo, the PQ ...intraperitoneal injection was used to construct a model of acute lung injury in rats. In vitro, the study measured the effect of different concentrations of PQ on the viability of the alveolar macrophages, and explored the polarization and glycolysis metabolism of alveolar macrophages at different time points after PQ intervention. Compared with the normal control (NC) group, the lung pathological damage in rats increased gradually after PQ poisoning, reaching a significant degree at 48 h after poisoning. The PQ-poisoned rat serum showed increased expressions of interleukin-6 (IL-6), tumor necrosis factor- α (TNF-α), and M1 macrophage marker, iNOS, while the expression of interleukin-10 (IL-10) and M2 macrophage marker, Arg1, decreased. The toxic effect of PQ on alveolar macrophages was dose- and time-dependent. Compared with the NC group, IL-6 and TNF-α in the cell supernatant gradually increased after PQ intervention, while the IL-10 content gradually decreased. The PQ intervention in alveolar macrophages increased the expression of intracellular glycolysis rate-limiting enzyme pyruvate kinase isozymes M1/M2 (PKM1/M2), lactate, lactate/pyruvate ratio, and the polarization of alveolar macrophage towards M1. Inhibition of cellular glycolysis significantly reduced the PQ-induced alveolar macrophage polarization to M1 type. Thus, PQ induced increased polarization of lung macrophages toward M1 and decreased polarization toward M2, promoting acute lung injury. Therefore, it can be concluded that PQ regulates the polarization of alveolar macrophages through glycolysis.
Paraquat promotes acute lung injury by increasing M1 polarization and decreasing M2 polarization of alveolar macrophages. Display omitted
•Lung macrophage polarization is associated with acute lung injury caused by paraquat poisoning.•Paraquat can induce alveolar macrophages to increase polarization toward M1 type and decrease polarization toward M2 type.•PQ regulates the polarization of the alveolar macrophage through glycolysis.
A two-dimensional directional modulation (DM) tech-nology with dual-mode orbital angular momentum (OAM) beam is proposed for physical-layer security of the relay unmanned aerial vehicle (UAV) ...tracking transmission. The elevation and azimuth of the vortex beam are modulated into the constellation, which can form the digital waveform with the encoding modula-tion. Since the signal is direction-dependent, the modulated waveform is purposely distorted in other directions to offer a security technology. Two concentric uniform circular arrays (UCAs) with different radii are excited to generate dual vortex beams with orthogonality for the composite signal, which can increase the demodulation difficulty. Due to the phase propaga-tion characteristics of vortex beam, the constellation at the desired azimuth angle will change continuously within a wave-length. A desired single antenna receiver can use the propaga-tion phase compensation and an opposite helical phase factor for the signal demodulation in the desired direction. Simulations show that the proposed OAM-DM scheme offers a security approach with direction sensitivity transmission.
•In the context of C57/BL6, a MIF knockout mouse model was constructed for study.•After the expression of MIF was inhibited, it can improve pancreatic injury in acute pancreatitis.
Macrophage ...migration inhibitory factor (MIF) is an important pro-inflammatory cytokine implicated in sepsis, rheumatoid arthritis and other diseases. However, the role of MIF in acute pancreatitis (AP) remains unclear. This study aims to explore the role of MIF in the pathogenesis of AP using MIF−/− mice (referred to as KO) and the biological effects of pharmacological inhibition of MIF in l-arginine induced AP.
AP was induced in C57BL/6 wild-type (referred to as WT) and KO mice by administration of l-arginine. The severity of AP was assessed by serum analysis of amylase and lipase, and of these pro-inflammatory cytokines TNF-α and IL-1β. Histological hematoxylin and eosin (H&E) and immunohistochemical staining of pancreatic tissues were examined for inflammation and expression of pro-inflammatory mediators. We also investigated the biological effects of pharmacological inhibition of MIF activity using ISO-1((S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester).
At 72 h after the induction of AP with l-arginine, significantly lower levels of serum amylase, lipase, TNF-α, and IL-1β were observed in KO mice when compared with WT controls. Histological examination further showed protective effects against pancreatic tissue damage and inflammation, with pancreatic expression of TNF-α, IL-1β and NF-κB p65 markedly reduced. Pharmacological inhibition of MIF activity with ISO-1 markedly mirrored the protective effect seen in the KO AP model providing further evidence that MIF is involved in the pathogenesis of AP.
Our data provided strong evidence for the participation of MIF in the pathogenesis of AP and subsequent inflammatory response. The genetic ablation of MIF or its inhibition with pharmacological agents significantly ameliorated the severity of AP.
Purpose
Significant results of randomized controlled trials (RCTs) should be properly weighed. This study adopted fragility index (FI) to evaluate the robustness of significant dichotomous outcomes ...from RCTs on coronavirus disease 2019 (COVID-19) treatment.
Materials and methods
ClinicalTrials.gov and PubMed were searched from inception to July 31, 2021. FIs were calculated and their distribution was depicted. FI’s categorical influential factors were analyzed. Spearman correlation coefficient (
r
s
) was reported for the relationship between FI and the continuous characteristics of RCTs.
Results
Fifty RCTs with 120 outcomes in 7869 patients were included. The FI distribution was abnormal with median 3 (interquartile range 1–7, P = 0.0001). The FIs and robustness were affected by the outcomes of interest, various patient populations, and interventions (T = 18.215,16.667, 23.107; P = 0.02,0.0001, 0.001, respectively). A cubic relationship between the FIs and absolute difference of events between groups with R square of 0.848 (T = 215.828, P = 0.0001, R square = 0.865) was observed. A strong negative logarithmic relationship existed between FI and the P value with R square = – 0.834.
Conclusion
The robustness of significant dichotomous outcomes of COVID-19 treatments was fragile and affected by the outcomes of interest, patients, interventions, P value, and absolute difference of events between the groups. FI was an useful quantitative metric for the binary significant outcomes on COVID-19 treatments.
Registration
PROSPERO (CRD42021272455).
Background
The coronavirus disease 2019 (COVID-19) pandemic as well as the subsequent prevention and control measures is like a quasi-experiment intervention that might have changed the features of ...emergency hospitalizations. Mortality is high in patient hospitalization due to emergency respiratory diseases (ERD). Therefore, we compared the characteristics of these patients before and during the pandemic. Exploring this issue might contribute to decision-making of emergency management when most of the resources and attention has been devoted to combat COVID-19.
Methods
This study was a retrospective observational cohort study. All emergency hospitalizations due to ERD from January 1, 2019 to December 31, 2020 in a tertiary hospital in China were included. Data including patients’ age, sex, and clinical outcomes were extracted. Air quality was collected from the official online platform. Clinical characteristics were compared and odds ratios were calculated.
Results
The ERD hospitalization rate was lower in 2020 than in 2019 (6.4 vs. 4.3%,
χ
2
= 55.449,
P
= 0.000) with a 50.65% reduction; however, the patients were older in 2020 than in 2019 (
P
= 0.000) with a higher proportion of admission to the intensive care unit (ICU) (46 vs. 33.5%,
χ
2
= 20.423,
P
= 0.000) and a longer ICU stay (
P
= 0.000). The overall intubation rate, hospital mortality, and rate of discharge due to ineffective treatment in 2020 were higher than those in 2019 (15.6 vs. 8%,
χ
2
= 18.578,
P
= 0.000; 4.2 vs. 1.1%,
χ
2
= 4.122,
P
= 0.000; 5.5 vs. 2.4%,
χ
2
= 8.93,
P
= 0.000, respectively). The logistic regression analysis indicated hospitalizations due to ERD were mainly associated with PM2.5 and sulfur dioxide on the day, and on the 4th and 5th days before admission (
P
= 0.034 and 0.020, 0.021 and 0.000, 0.028, and 0.027, respectively) in 2019. However, in 2020, the relationship between parameters of air quality and hospitalization changed.
Conclusion
The COVID-19 pandemic has changed the characteristics of emergency hospitalization due to ERD with a larger proportion of severe patients and poorer prognosis. The effect of air quality on emergencies were weakened. During the COVID-19 pandemic, it is necessary to pay more attention to the non-COVID-19 emergency patients.
Acute pancreatitis (AP) is a common emergency of the digestive system and serious cases can develop into severe acute pancreatitis (SAP), which ortality rates up to 30%. Sirtuin4 (SIRT4) is a member ...of the sirtuin family, and plays a key role in inflammation and oxidative stress. However, the potential role of SIRT4 in SAP has yet to be elucidated. In the present study, we found that the expression level of SIRT4 in human AP was downregulated by screening a public database, suggesting that SIRT4 may play a role in AP. Subsequently, we used L-arginine (L-Arg) to induce SAP in SIRT4 knockout (SIRT4_KO) and SIRT4 overexpression (AAV_SIRT4) mice. The results showed that the pancreatic tissue injury and related lung and kidney injury were serious in SIRT4_KO mice after SAP induction, but were significantly reduced in AAV_SIRT4 mice. More importantly, we found that the levels of antioxidant factors GSH and SOD were decreased in SIRT4_KO mice, and the production of oxidative products and lipid peroxidation markers was increased, suggesting that SIRT4 was involved in inflammation and oxidative stress during SAP. Further studies showed that the absence or overexpression of SIRT4 affected the expression level of Hypoxia-inducible factor-1α (HIF-1α) after SAP induction, and regulated the expression of ferroptosis related proteins by mediating HIF-1α/HO-1 pathway. Collectively, our study revealed that SIRT4 plays a protective role in SAP by regulating the HIF-1α/HO-1 pathway to inhibit ferroptosis.
Background:
Hepatic ischemia–reperfusion (I/R) injury is a major complication leading to surgical failures in liver resection, transplantation, and hemorrhagic shock. The role of cytokine macrophage ...migration inhibitory factor (MIF) in hepatic I/R injury is unclear.
Methods:
We examined changes of MIF expression in mice after hepatic I/R surgery and hepatocytes challenged with hypoxia–reoxygenation (H/R) insult. Subsequently, MIF global knock-out mice and mice with adeno-associated-virus (AAV)-delivered MIF overexpression were subjected to hepatic I/R injury. Hepatic histology, the inflammatory response, apoptosis and oxidative stress were monitored to assess liver damage. The molecular mechanisms of MIF function were explored
in vivo
and
in vitro
.
Results:
MIF was significantly upregulated in the serum whereas decreased in liver tissues of mice after hepatic I/R injury. MIF knock-out effectively attenuated I/R -induced liver inflammation, apoptosis and oxidative stress
in vivo
and
in vitro
, whereas MIF overexpression significantly aggravated liver injury.
Via
RNA-seq analysis, we found a significant decreased trend of MAPK pathway in MIF knock-out mice subjected hepatic I/R surgery. Using the apoptosis signal-regulating kinase 1 (ASK1) inhibitor NQDI-1 we determined that, mechanistically, the protective effect of MIF deficiency on hepatic I/R injury was dependent on the suppressing of the ASK1-JNK/P38 signaling pathway. Moreover, we found MIF inhibitor ISO-1 alleviate hepatic I/R injury in mice.
Conclusion:
Our results confirm that MIF deficiency suppresses the ASK1-JNK/P38 pathway and protects the liver from I/R -induced injury. Our findings suggest MIF as a novel biomarker and therapeutic target for the diagnosis and treatment of hepatic I/R injury.
Acute pancreatitis is a common acute inflammatory abdominal disease. When acute pancreatitis progresses to severe acute pancreatitis (SAP), it can lead to systemic inflammation and even multiple ...organ failure. Thioredoxin-interacting protein (TXNIP) is an important protein involved in redox reactions of the inflammatory response. However, the specific role of TXNIP in SAP remains unclear. In this study, we investigated the role of thioredoxin interacting protein (TXNIP) in acute pancreatitis when induced by high doses of arginine. We found that pancreatic damage and the inflammatory response associated with acute pancreatitis were largely restrained in TXNIP knock-out mice but were enhanced in mice overexpressing TXNIP. Interestingly, the phosphorylation of p38, JNK, and ASK1 diminished in TXNIP-KO mice with pancreatitis in comparison with wild-type mice. The role of oxidative stress in SAP was explored in two models: TXNIP and AVV-TXNIP. TXNIP knockdown or the inhibition of ASK1 by gs-4997 abrogated the increase in p-p38, p-JNK, and p-ASK1 in AR42J cells incubated with L-Arg. The administration of gs-4997 to mice with pancreatitis largely reduced the upregulation of IL-6, IL-1β, TNF-α, and MCP-1. Systemic inflammatory reactions and injury in the lungs and kidneys were assessed in TXNIP-KO and AVV-TXNIP mice with expected outcomes. In conclusion, TXNIP is a novel mediator of SAP and exerts action by regulating inflammatory responses and oxidative stress via the ASK1-dependent activation of the JNK/p38 pathways. Thus, targeting TXNIP may represent a promising approach to protect against SAP.
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