PRMT7-Dependent Transcriptional Activation of Hmgb2 Aggravates Severe Acute Pancreatitis by Promoting Acsl1-Induced Ferroptosis.

Severe acute pancreatitis (SAP) is a highly fatal abdominal emergency, and its association with protein arginine methyltransferase 7 (PRMT7), the sole known type III enzyme responsible for the monomethylation of arginine residue, remains unexplored. In this study, we observe an increase in the PRMT7 levels in the pancreas of SAP mice and Cerulein-LPS-stimulated AR42J cells. Overexpression of Prmt7 exacerbated pancreatic damage in SAP, while the inhibition of PRMT7 improved SAP-induced pancreatic damage. Furthermore, PRMT7 overexpression promoted inflammation, oxidative stress, and ferroptosis during SAP. Mechanically, PRMT7 catalyzed monomethylation at histone H4 arginine 3 (H4R3me1) at the promoter region of high mobility group proteins 2 (HMGB2), thereby enhancing its transcriptional activity. Subsequently, HMGB2 facilitated Acyl CoA synthase long-chain family member 1 (ACSL1) transcription by binding to its promoter region, resulting in the activation of ferroptosis. Inhibition of PRMT7 effectively alleviated ferroptosis in Cerulein-LPS-induced AR42J cells by suppressing the HMGB2-ACSL1 pathway. Overall, our study reveals that PRMT7 plays a crucial role in promoting SAP through its regulation of the HMGB2-ACSL1 pathway to accelerate ferroptosis.

METTL14 depletion ameliorates ferroptosis in severe acute pancreatitis by increasing the N6-methyladenosine modification of ACSL4 and STA1.

Methyltransferase-like 14 (METTL14) is implicated in the regulation of various inflammatory disorders. However, its function and molecular mechanism in severe acute pancreatitis (SAP) remains unrevealed. Here we reported an increase in METTL14 in the pancreas of SAP mice and cerulein-LPS-treated AR42J cells. METTL14 depletion reversed inflammatory response and ferroptosis by reducing the expression of SAT1 (spermidine/spermine N1-acetyltransferase 1) and ACSL4 (acyl-CoA synthetase long chain family member 4) in an m6A-dependent manner. IGF2BP2 (insulin like growth factor 2 mRNA binding protein 2) could recognize m6A-modified SAT1 and ACSL4 mRNA and enhance their stability. Moreover, METTL14 depletion ameliorated pancreatic injury, inflammation, and ferroptosis induced by SAP. METTL14 overexpression aggravated SAP by promoting ferroptosis in vivo. Therefore, these results demonstrated that METTL14-induced ferroptosis promoted the progression of SAP, and targeting METTL14 or ferroptosis could be a potential strategy for the prevention and treatment of SAP.

Hypothermia may reduce mortality and improve neurologic outcomes in adult patients treated with VA-ECMO: A systematic review and meta-analysis.

BACKGROUND: VA-ECMO can greatly reduce mortality in critically ill patients, and hypothermia attenuates the deleterious effects of ischemia-reperfusion injury. We aimed to study the effects of hypothermia on mortality and neurological outcomes in VA-ECMO patients. METHODS: A systematic search of the PubMed, Embase, Web of Science, and Cochrane Library databases was performed from the earliest available date to 31 December 2022. The primary outcome was discharge or 28-day mortality and favorable neurological outcomes in VA-ECMO patients, and the secondary outcome was bleeding risk in VA-ECMO patients. The results are presented as odds ratios (ORs) and 95% confidence intervals (CIs). Based on the heterogeneity assessed by the I2 statistic, meta-analyses were performed using random or fixed-effects models. GRADE methodology was used to rate the certainty in the findings. RESULTS: A total of 27 articles (3782 patients) were included. Hypothermia (33-35 °C) lasting at least 24 h can significantly reduce discharge or 28-day mortality (OR, 0.45; 95% CI, 0.33-0.63; I2 = 41%) and significantly improve favorable neurological outcomes (OR, 2.08; 95% CI, 1.66-2.61; I2 = 3%) in VA-ECMO patients. Additionally, there was no risk associated with bleeding (OR, 1.15; 95% CI, 0.86-1.53; I2 = 12%). In our subgroup analysis according to in-hospital or out-of-hospital cardiac arrest, hypothermia reduced short-term mortality in both VA-ECMO-assisted in-hospital (OR, 0.30; 95% CI, 0.11-0.86; I2 = 0.0%) and out-of-hospital cardiac arrest (OR, 0.41; 95% CI, 0.25-0.69; I2 = 52.3%). Out-of-hospital cardiac arrest patients assisted by VA-ECMO for favorable neurological outcomes were consistent with the conclusions of this paper (OR, 2.10; 95% CI, 1.63-2.72; I2 = 0.5%). CONCLUSIONS: Our results show that mild hypothermia (33-35 °C) lasting at least 24 h can greatly reduce short-term mortality and significantly improve favorable short-term neurologic outcomes in VA-ECMO-assisted patients without bleeding-related risks. As the grade assessment indicated that the certainty of the evidence was relatively low, hypothermia as a strategy for VA-ECMO-assisted patient care may need to be treated with caution.

Environment-mediated entropic uncertainty in charging quantum batteries.

We studied the dynamics of entropic uncertainty in Markovian and non-Markovian systems during the charging of open quantum batteries (QBs) mediated by a common dissipation environment. In the non-Markovian regime, the battery is almost fully charged efficiently, and the strong non-Markovian property is beneficial for improving the charging power. In addition, the results show that the energy storage is closely related to the couplings of the charger-reservoir and battery-reservoir; that is, the stronger coupling of a charger reservoir improves energy storage. In particular, entanglement is required to obtain the most stored energy and is accompanied by the least tight entropic bound. Interestingly, it was found that the tightness of the entropic bound can be considered as a good indicator of the energy transfer in different charging processes, and the complete energy transfer always corresponds to the tightest entropic bound. Our results provide insight into the optimal charging efficiency of QBs during practical charging.

MicroRNA-361-5p Aggravates Acute Pancreatitis by Promoting Interleukin-17A Secretion via Impairment of Nuclear Factor IA-Dependent Hes1 Downregulation.

This study set out to explore the potential role of microRNA-361-5p (miR-361-5p) in acute pancreatitis through regulation of interleukin-17A (IL-17A). We first identified the expression of miR-361-5p, IL-17A, nuclear factor IA (NFIA), and hes family bHLH transcription factor 1 (Hes1) in serum samples collected from patients with acute pancreatitis, caerulein-induced mice, and a Th17 cell model. The predicted binding of miR-361-5p to NFIA was confirmed in vitro. Gain- and loss-of-function assays of miR-361-5p and NFIA were employed to elucidate their effects on acute pancreatitis. miR-361-5p promoted Th17 cells to secrete IL-17A and then aggravated acute pancreatitis. miR-361-5p directly targeted NFIA by binding to its promoter region, leading to its downregulation. Overexpression of NFIA reduced Hes1 expression and rescued the promoting effect of miR-361-5p on IL-17A secretion. In summary, miR-361-5p enhances IL-17A secretion from Th17 cells and thus aggravates acute pancreatitis by targeting NFIA and upregulating Hes1.

TNFAIP3-upregulated RIP3 exacerbates acute pancreatitis via activating NLRP3 inflammasome.

Acute pancreatitis (AP) is an inflammatory disease of the pancreas. Accumulating studies have revealed the involvement of tumor necrosis factor alpha-induced protein 3 (TNFAIP3) in the progression of AP. Here, the current study was conducted to elucidate the role of TNFAIP3 and the underlying molecular mechanisms on the progression of AP. The in vivo animal model and in vitro cell model of AP were generated by retrograde injection of sodium taurocholate and stimulation of cerulein into AR42J cells, respectively. Relationships among TNFAIP3, receptor interacting protein 3 (RIP3) and nod-like receptor protein 3 (NLRP3) were predicted on bioinformatics websites and verified by co-immunoprecipitation. AR42J cells were transfected with overexpressing plasmid or shRNA to study the effects of TNFAIP3/RIP3/NLRP3 axis on cell proliferation and apoptosis, secretion of inflammatory cytokines and production of ROS. The effect of TNFAIP3/RIP3/NLRP3 axis in AP was further confirmed in vivo. High expression of TNFAIP3 was observed in AP pancreatic tissues and AP cell model. TNFAIP3 increased RIP phosphorylation through deubiquitination. RIP activated the NLRP3 inflammasome. Silencing of TNFAIP3 or RIP3T led to elevated proliferation and inhibited apoptosis in AR42J cells, accompanied by decreased inflammatory cytokine levels and ROS production. The protective role of inhibited TNFAIP3 in AP was confirmed evidenced by reduced levels of AMY, LIPA, and ROS in vivo. Collectively, overexpressed TNFAIP3 could contribute to the progression of AP by activating RIP3/NLRP3 axis, providing a potential therapeutic target for AP treatment.

FBXO10 prevents chronic unpredictable stress-induced behavioral despair and cognitive impairment through promoting RAGE degradation.

AIMS: Depression is one of the leading causes of disability worldwide. The receptor for advanced glycosylation end products (RAGE) is closely related to chronic stress and is a target of F-box protein O10 (FBXO10) which promotes the degradation of RAGE by ubiquitination. Here, we explored the role of FBXO10 and RAGE in chronic unpredictable stress (CUS)-induced behavioral despair, cognitive impairment, neuroinflammation, and the polarization microglia. METHODS: Male C57BL/6 mice with or without infusion of viral in the medial prefrontal cortex (PFC) were subjected to CUS. Then the mice were exposed to forced swim test, sucrose consumption test, novelty-suppressed feeding test, and temporal object recognition task to assess the behavioral despair and cognitive impairment. Inflammatory cytokines and the neurotrophic factor brain-derived neurotrophic factor (BDNF) levels in PFC were assessed by enzyme-linked immunosorbent assay. Immunofluorescence and immunohistochemistry staining were performed to observe the activation and phenotypic transformation of microglia in PFC. LPS-induced cell model was constructed to explore the effect of FBXO10/RAGE axis in the polarization of microglia in vitro. RESULTS: FBXO10 promoted RAGE degradation by ubiquitination in BV2 cells. FBXO10 protein levels were reduced whereas RAGE protein levels were enhanced in CUS mice. FBXO10 overexpression or RAGE knockdown inhibited proinflammatory cytokine release, promoted BDNF expression, mitigated the depressive-like and cognitive impairment behaviors, and affected the polarization of microglia induced by CUS exposure. FBXO10/RAGE axis promoted the polarization of microglia from the M1 to the M2 phenotype in vitro. Moreover, p38 MAPK and NF-κΒ were identified to be the downstream effect factors for FBXO10/RAGE axis. CONCLUSIONS: FBXO10 administration prevents CUS-induced behavioral despair, cognitive impairment, neuroinflammation, and the polarization of microglia through decreasing the accumulation of RAGE, p38 MAPK, and NF-κΒ, suggesting potential therapeutic strategies for the prevention and treatment of depression.

Elevation of miR-146a Inhibits BTG2/BAX Expression to Ameliorate Postoperative Cognitive Dysfunction Following Probiotics (VSL#3) Treatment.

It has been reported that the gut microbiome modulates postoperative cognitive dysfunction (POCD), and that administration of probiotics (VSL#3) may effectively relieve POCD. In this study, we aimed to identify the underlying mechanism of VSL#3 in POCD. A mouse model of POCD was constructed in adult male C57BL/6 mice, which were then treated with VSL#3. VSL#3 exerted a protective role against POCD and resultant neuronal apoptosis. The expression of miR-146a was found to be downregulated in hippocampal tissues of POCD mice, while VSL#3 could restore its expression. Loss- and gain-function approaches were conducted to determine the roles of microRNA (miR)-146a, B-cell translocation gene 2 (BTG2), and Bcl-2-associated X protein (Bax) in post-operative effects on cognitive function and neuronal apoptosis. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured to determine oxidative stress in brain tissue. The dual-luciferase reporter gene assay identified that miR-146a could target BTG2 and negatively regulate its expression. BTG2 knockdown suppressed neuronal apoptosis and contributed to shortened time of latency, prolonged time of mice spent in the target quadrant, and reduced oxidative stress through downregulating Bax expression. Finally, VSL#3 treatment upregulated the expression of miR-146a to block BTG2/Bax axis and consequently inhibited neuronal apoptosis and reduced oxidative stress in POCD mice. Taken together, the study suggested that miR-146a-mediated suppression of BTG2/Bax contributed to the protective role of probiotics treatment against POCD.