The Correlation Between Peripheral Blood Micro-Ribonucleic Acid Expression Level and Personality Disorder in Patients with Schizophrenia.

Objective: Schizophrenia patients often have personality disorders; schizophrenia patients with personality disorders are more difficult to treat and have a worse prognosis. Early identification of this group of patients and early intervention can achieve better prognosis. Therefore, it is very important to explore effective biomarkers and early diagnosis for the prognosis of schizophrenia. The primary purpose of this paper is to explore the relationship between plasma miRNA expression level and personality disorder with schizophrenia. Methods: Gene microarrays in miRNA files were employed, and the plasma of peripheral blood of 82 schizophrenic patients and 43 healthy control subjects were examined. Real-time reverse transcription polymerase chain reaction detection were performed to explore the results. Spearman correlation analysis was used to analyze the correlation between expression level of miRNAs and Personality Diagnosis Questionnaire-4 score. Results: The results showed that miR-1273d, miR-1303, miR-3064-5p, miR-3131, miR-3687, miR-4428, miR-4725-3p, and miR-5096 were up-regulated in schizophrenic patients. Compared to healthy control subjects, the difference was statistically significant (P < .05). Schizophrenic patients with schizoid, paranoid, schizotypal, and obsessive compulsive traits had negative correlation with miR-1303, miR-3131, miR-4428, and miR-5096 expression level (r = -0.40 to -0.62, P < .05); there were no significant differences in the other miRNAs. Correlation with other personality traits was not significant (P > .05). The stepwise regression analysis indicated that miR-5096, miR-3131, and miR-1273d have a significant predictive effect on the schizoid trait (P < .01). MiR-4428 and miR-1303 had a significant predictive effect on the schizotypal trait (P < .01). MiR-5096, miR-4428, and miR-4725-3P had a significant predictive effect on the paranoid trait (P < .05). MiR-4428, miR-1303, and miR-5096 had a significant predictive effect on the obsessive compulsive trait (P < .05). Conclusion: The expression levels of miR-1273d, miR-1303, miR-3064-5p, miR-3131, miR-3687, miR-4428, miR-4725-3p, and miR-5096 were up-regulated in the peripheral blood of patients with schizophrenia, and these miRNAs are expected to be diagnostic biomarkers for accurate diagnosis of schizophrenia. The expression levels of miR-1303, miR-3131, miR-1273d, miR-4428, miR-4725-3p, and miR-5096 have significant predictive effects on personality disorder in schizophrenia.

BUB1 Promotes Gemcitabine Resistance in Pancreatic Cancer Cells by Inhibiting Ferroptosis.

The development of chemotherapy resistance severely limits the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer (PC), and the dysregulation of ferroptosis is a crucial factor in the development of chemotherapy resistance. BUB1 Mitotic Checkpoint Serine/Threonine Kinase (BUB1) is highly overexpressed in PC patients and is closely associated with patient prognosis. However, none of the literature reports the connection between BUB1 and ferroptosis. The molecular mechanisms underlying GEM resistance are also not well understood. Therefore, this study first established the high expression levels of BUB1 in PC patients, then explored the role of BUB1 in the process of ferroptosis, and finally investigated the mechanisms by which BUB1 regulates ferroptosis and contributes to GEM resistance in PC cells. In this study, downregulation of BUB1 enhanced the sensitivity of PC cells to Erastin, and inhibited cell proliferation and migration. Mechanistically, BUB1 could inhibit the expression levels of Neurofibromin 2 (NF2) and MOB kinase activator 1 (MOB1), and promote Yes-associated protein (YAP) expression, thereby inhibiting ferroptosis and promoting GEM resistance in PC cells. Furthermore, the combination of BUB1 inhibition with GEM exhibited a synergistic therapeutic effect. These findings reveal the mechanisms underlying the development of GEM chemotherapy resistance based on ferroptosis and suggest that the combined use of BUB1 inhibitors may be an effective approach to enhance GEM efficacy.

Effect of Regular Aerobic Exercise on Cognitive Function, Depression Level and Regulative Role of Neurotrophic Factor: A Prospective Cohort Study in the Young and the Middle-Aged Sample.

Purpose: Mild cognitive impairment (MCI) and depressive disorder (DD), which are associated with unhealthy lifestyles, are prevalent worldwide. This study aimed to investigate the effects of regular aerobic exercise on cognitive function, depression, and the regulatory role of neurotrophic growth factors for providing scientific basis in preventing MCI and DD in healthy individuals. Patients and Methods: Eighty members of the fitness center and 80 community residents were recruited, who were administered by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Patient Health Questionnaire (PHQ-9). Brain-derived neurotrophic factor (BDNF) and glial cell-line-derived neurotrophic factor (GDNF) in the peripheral blood were detected by enzyme-linked immunosorbent assay (ELISA). Results: The RBANS and other factor scores, except for visuospatial abilities, were higher and PHQ-9 scores were lower in the study group than in the control group. The concentrations of BDNF and GDNF in the study group were higher than those in the control group. RBANS and its factor scores positively and PHQ-9 negatively correlated with BDNF and GDNF levels. Finally, multiple regression analysis showed that BDNF, as a predictor of RBANS, could explain 59.90% of its variance and that GDNF was a predictor of PHQ-9 could explain 12.30% of the variance. Conclusion: Regular aerobic exercise can improve cognitive function and depressive symptoms by increasing the BDNF and GDNF levels.

The polysaccharides from seeds of Glycyrrhiza uralensis ameliorate metabolic disorders and restructure gut microbiota in type 2 diabetic mice.

T2D and its complications are significant threats to human health and are among the most concerning metabolic diseases worldwide. Previous studies have revealed that Glycyrrhiza uralensis polysaccharide extract (GUP) exhibits remarkable antioxidant capabilities and inhibits alpha-glucosidase activity. However, whether GUP improves glycemic control in T2D is unknown. This study aims to investigate the effects of GUP on glucose and lipid metabolism as well as the intestinal microbiota in HFD/STZ-induced T2D. The results demonstrated that GUP could significantly ameliorate hyperglycemia, insulin resistance, oxidative stress, and reduce liver lipid levels in T2D mice. Furthermore, it also enhanced the integrity of the intestinal barrier in T2D mice by reducing the levels of pro-inflammatory cytokines and serum LPS levels. Interestingly, GUP treatment significantly lowered serum creatinine and urea nitrogen levels, mitigating renal function deterioration and interstitial fibrosis. Additionally, GUP intervention increased the α diversity of gut microbiota, promoting beneficial species like Akkermansia, Lactobacillus, Romboutsia and Faecalibaculum, while decreasing harmful ones such as Bacteroides, Escherichia-Shigella, and Clostridium sensu stricto 1 in T2D mice. Overall, this study highlights the potential of GUP in alleviating complications and enhancing intestinal health in T2D mice, providing valuable insights into dietary strategies for diabetes control and overall health improvement.

Micro(nano)plastics in marine medaka: Entry pathways and cardiotoxicity with triphenyltin.

The simultaneous presence of micro(nano)plastics (MNPs) and pollutants represents a prevalent environmental challenge that necessitates understanding their combined impact on toxicity. This study examined the distribution of 5 µm (PS-MP5) and 50 nm (PS-NP50) polystyrene plastic particles during the early developmental stages of marine medaka (Oryzias melastigma) and assessed their combined toxicity with triphenyltin (TPT). Results showed that 2 mg/L PS-MP5 and PS-NP50 could adhere to the embryo surface. PS-NP50 can passively enter the larvae and accumulate predominantly in the intestine and head, while PS-MP5 cannot. Nonetheless, both types can be actively ingested by the larvae and distributed in the intestine. 2 mg/L PS-MNPs enhance the acute toxicity of TPT. Interestingly, high concentrations of PS-NP50 (20 mg/L) diminish the acute toxicity of TPT due to their sedimentation properties and interactions with TPT. 200 µg/L PS-MNPs and 200 ng/L TPT affect complement and coagulation cascade pathways and cardiac development of medaka larvae. PS-MNPs exacerbate TPT-induced cardiotoxicity, with PS-NP50 exhibiting stronger effects than PS-MP5, which may be related to the higher adsorption capacity of NPs to TPT and their ability to enter the embryos before hatching. This study elucidates the distribution of MNPs during the early developmental stages of marine medaka and their effects on TPT toxicity, offering a theoretical foundation for the ecological risk assessment of MNPs.

KAN0438757, a novel PFKFB3 inhibitor, prevent the progression of severe acute pancreatitis via the Nrf2/HO-1 pathway in infiltrated macrophage.

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.

MaxCLK: discovery of cancer driver genes via maximal clique and information entropy of modules.

MOTIVATION: Cancer is caused by the accumulation of somatic mutations in multiple pathways, in which driver mutations are typically of the properties of high coverage and high exclusivity in patients. Identifying cancer driver genes has a pivotal role in understanding the mechanisms of oncogenesis and treatment. RESULTS: Here, we introduced MaxCLK, an algorithm for identifying cancer driver genes, which was developed by an integrated analysis of somatic mutation data and protein-protein interaction (PPI) networks and further improved by an information entropy index. Tested on pancancer and single cancers, MaxCLK outperformed other existing methods with higher accuracy. About pancancer, we predicted 154 driver genes and 787 driver modules. The analysis of co-occurrence and exclusivity between modules and pathways reveals the correlation of their combinations. Overall, our study has deepened the understanding of driver mechanism in PPI topology and found novel driver genes. AVAILABILITY AND IMPLEMENTATION: The source codes for MaxCLK are freely available at https://github.com/ShandongUniversityMasterMa/MaxCLK-main.

Effects of Health-Promoting Lifestyle on Late-Onset Depression in Older Adults: Mediating Effect of Meaning in Life and Interleukin-6 (IL-6).

Purpose: Late-onset depression (LOD) with poor treatment response has high incidence and mortality in the China's aged people, this study aims to explore the correlation between health-promoting lifestyle, meaning in life, interleukin-6 (IL-6) and LOD for providing scientific basis of LOD prevention and rehabilitation. Patients and Methods: A total of 496 LOD patients (study group) and healthy older adults (control group) were enrolled and investigated by using the Health-promoting lifestyle Profile-II, revised (HPLP-IIR), Meaning in Life Questionnaire-Chinese Version (MLQ-C), and Hamilton Depression Scale (HAMD). The interleukin-6 (IL-6) in the circulating blood was detected by utilizing ELISA kit. Results: The results showed that the scores of all factors in HPLP-IIR and MLQ were significantly lower and IL-6 level was higher in the study group than the control group. Scores of most factors in HPLP-IIR and MLQ negatively and IL-6 positively correlated with scores of subscales and total HAMD score. Meaning in life and IL-6 partially mediated the relationship between health-promoting lifestyles and depression severity in the study group, with the mediating effect explains 15.76% and 22.64% of the total effect, respectively. Conclusion: Health-promoting lifestyles, meaning in life, and IL-6 are predictors of LOD, and an unhealthy lifestyle could induce LOD through the mediating effect of meaning in life and IL-6 in older adults.

Effects of Treatment with Probiotics on Cognitive Function and Regulatory Role of Cortisol and IL-1ß in Adolescent Patients with Major Depressive Disorder.

The aim of this study was to investigate the effects of probiotics on cognitive function and the regulation of cortisol and IL-1ß in adolescents with depression. All 180 participants were randomly assigned to a study group (treated with probiotics combined with sertraline hydrochloride) and a control group (treated with sertraline hydrochloride). The repetitive Neuropsychological State Test (RBANS) and Hamilton Depression Scale (HAMD) were administered to MDD patients. The levels of serum cortisol and IL-1ß were detected using an ELISA kit. Except for speech function, factors including immediate memory, visual span, attention function, delayed memory, and the RBANS in the study group were significantly higher than those in the control group. The levels of cortisol and interleukin-1ß in the study group were significantly downregulated compared to those in the control group. Except for speech function, the cortisol level was negatively correlated with the RBANS total score and other factors in the study group. Interleukin-1ß was also negatively correlated with the RBANS total score and each factor score. Cortisol and interleukin-1ß were predictors of the RBANS total score, which explained 46.80% of the variance. Cortisol had significant predictive effects on attention function and delayed memory, and interleukin-1ß had significant predictive effects on visual span and speech function. It could be concluded that probiotics could improve cognitive function in adolescents with depression by regulating cortisol and IL-1ß levels.

Differentiation value of miR-26b for major depressive disorder, schizophrenia, generalized anxiety disorder.

Introduction: First episode and drug naive schizophrenia (SZ) patients comorbid with major depressive episode and generalized anxiety disorder (GAD) comorbid with major depressive disorder (MDD) are common in clinical practice, overlapping symptomatology during first presentation of MDD, SZ and GAD challenged the diagnostic process. Materials and Methods: This study aimed to investigate the differentiation value of peripheral microRNA-26b expression in 52 patients of MDD, SZ, and GAD, respectively, and 52 controls. Quantitative real-time reverse transcription polymerase chain reaction was used to further verify aberrant miRNAs of previous identified in MDD and investigate expression level of these peripheral miRNAs in SZ and GAD. Results: The expression levels of miR-26b and miR-4743 were significantly upregulated and of miR-4498, miR-4485, and miR-1972 had no significant difference. There were no significant differences of expression levels of miR-26b, miR-4498, miR-4485, and miR-1972 except miR-4743 between SZ patients and control group and of miR-26b, miR-1972, miR-4498, and miR-4485 between GAD group and the controls. The receiver operating characteristic (ROC) curve of miR-26b in MDD patients showed that its sensitivity and specificity for diagnosis were 0.540 and 0.830, respectively, with the area under curve (AUC) being 0.728; the ROC of miR-26b for SZ and MDD differentiation showed that its sensitivity and specificity were 0.580 and 0.710, respectively, with AUC being 0.631; the ROC of miR-26b for GAD and MDD differentiation suggested that sensitivity and specificity were 0.560 and 0.750, respectively, with AUC being 0.637. Conclusion: MiR-26b might have potential value of differentiation biomarker for MDD, SZ, and GAD.

Histone lysine methyltransferase SMYD3 promotes oral squamous cell carcinoma tumorigenesis via H3K4me3-mediated HMGA2 transcription.

BACKGROUND: Epigenetic dysregulation is essential to the tumorigenesis of oral squamous cell carcinoma (OSCC). SET and MYND domain-containing protein 3 (SMYD3), a histone lysine methyltransferase, is implicated in gene transcription regulation and tumor development. However, the roles of SMYD3 in OSCC initiation are not fully understood. The present study investigated the biological functions and mechanisms involved in the SMYD3-mediated tumorigenesis of OSCC utilizing bioinformatic approaches and validation assays with the aim of informing the development of targeted therapies for OSCC. RESULTS: 429 chromatin regulators were screened by a machine learning approach and aberrant expression of SMYD3 was found to be closely associated with OSCC formation and poor prognosis. Data profiling of single-cell and tissue demonstrated that upregulated SMYD3 significantly correlated with aggressive clinicopathological features of OSCC. Alterations in copy number and DNA methylation patterns may contribute to SMYD3 overexpression. Functional experimental results suggested that SMYD3 enhanced cancer cell stemness and proliferation in vitro and tumor growth in vivo. SMYD3 was observed to bind to the High Mobility Group AT-Hook 2 (HMGA2) promoter and elevated tri-methylation of histone H3 lysine 4 at the corresponding site was responsible for transactivating HMGA2. SMYD3 also was positively linked to HMGA2 expression in OSCC samples. Furthermore, treatment with the SMYD3 chemical inhibitor BCI-121 exerted anti-tumor effects. CONCLUSIONS: Histone methyltransferase activity and transcription-potentiating function of SMYD3 were found to be essential for tumorigenesis and the SMYD3-HMGA2 is a potential therapeutic target in OSCC.

Injectable, self-healable and antibacterial multi-responsive tunicate cellulose nanocrystals strengthened supramolecular hydrogels for wound dressings.

Wound dressing with an improved structural and functional recapitulation of damaged organs, efficient self-healing and antibacterial properties that can well integrate with tissue are urgently needed in wound management. Supramolecular hydrogels confer control over structural properties in a reversible, dynamic and biomimetic fashion. Herein, a kind of injectable, self-healing and antibacterial supramolecular hydrogel with multi-responses were fabricated by mixing phenylazo-terminated Pluronic F127, quaternized chitosan-graft-cyclodextrin and polydopamine coated tunicate cellulose nanocrystals under physiological conditions. By exploiting the photoisomerization of azobenzene under different wavelengths, a supramolecular hydrogel featuring a changing crosslink density of network was obtained. The corporation of polydopamine coated tunicate cellulose nanocrystals strengthens the hydrogel network with Schiff base bonds and hydrogen bonds, which avoids complete gel-sol transition. The inherent antibacterial property, drug release behavior, self-healing ability, hemostatic performance and biocompatibility were investigated to confirm superiority in wound healing. Moreover, the curcumin loaded hydrogel (Cur-hydrogel) showed multi-responsive release profiles (light, pH, and temperature). A full-thickness skin defect model was built to confirm that Cur-hydrogels significantly accelerated wound healing rate with better granulation tissue thickness and collagen disposition. Overall, the novel photo-responsive hydrogel with coherent antibacterial property has great potential in the healthcare of wound healing.

Design and synthesis of boron-containing ALK inhibitor with favorable in vivo efficacy.

ALK is an attractive therapeutic target for the treatment of non-small cell lung cancer. As an emerging element in medicinal chemistry, boron has achieved great success in the discovery of antitumor drugs and antibacterial agents. Through construction of a BCC (boron-containing compound) compound library and broad kinase screening, we found the ALK inhibitor hit compound 10a. Structural optimization by CADD and isosterism revealed that lead compound 10k has improved activity (ALKL1196M IC50 = 8.4 nM, NCI-H2228 cells IC50 = 520 nM) and better in vitro metabolic stability (human liver microsomes, T1/2 = 238 min). Compound 10k showed good in vivo efficacy in a nude mouse NCI-H2228 lung cancer xenograft model with a TGI of 52 %. Molecular simulation analysis results show that the hydroxyl group on the oxaborole forms a key hydrogen bond with Asn1254 or Asp1270, and this binding site provides a new idea for drug design. This is the first publicly reported lead compound for a boron-containing ALK inhibitor.

Identification of Prognosis-Related Molecular Subgroups and Construction of a Prognostic Prediction Model Using Immune-Related Genes in Pancreatic Cancer.

Background: Pancreatic cancer patients with similar clinicopathological status exhibit substantially different therapeutic responses, which might be caused by the vast molecular heterogeneity of tumors. In this study, we attempted to identify specific molecular subgroups and construct a prognostic prediction model based on the expression level of immune-related genes in pancreatic cancer. The transcriptome profiling, single nucleotide variation, copy number variation, clinicopathological information, and follow-up data of pancreatic cancer patients were obtained from The Cancer Genome Atlas database. Thereafter, the immune-related genes with prognostic significance were identified for further consensus cluster analysis. The molecular characteristics and clinicopathological information were compared between the identified subgroups, and a weighted correlation network analysis was performed to identify the hub genes associated with the subgroups. Finally, the prognostic prediction model based on immune-related genes was established using the least absolute shrinkage and selection operator (LASSO) analysis. Results: A total of 67 immune-relevant genes with prognostic significance were selected and used for the consensus cluster analysis. The total samples were divided into two groups, C1 and C2. The subgroup C1 had a significantly worse prognosis than C2, as well as lower levels of immune cell infiltration, which indicate an immunosuppressed state. The mutational rate of the cancer-related genes including KRAS, TP53, and RNF43 was higher in the C1 subgroup. The C1 subgroup was associated with more advanced tumor grade and T stage and with higher mortality. Using LASSO regression, we developed a prognostic prediction model based on the expression levels of 19 immune-related genes, which we validated in three external data sets. In addition, we identified four potential therapeutic and prognostic biomarkers (TNNT1, KCNN4, SH2D3A, and PHLDA2). Conclusion: We identified two novel molecular subgroups of pancreatic cancer and developed a prognostic prediction model based on the expression levels of immune-related genes, which could be used in a clinical setting and could aid in unraveling the molecular processes leading to the development of pancreatic cancer.

Function of Foxl2 and Dmrt1 proteins during gonadal differentiation in the olive flounder Paralichthys olivaceus.

Study on fish sex differentiation is important both from academic and practical aspects. Foxl2 and Dmrt1 are important transcription factors that should be involved in fish gonadal differentiation, but there is still no direct evidence to clarify their protein functions. Olive flounder Paralichthys olivaceus, an important mariculture fish in China, Japan, and Korea, shows sex-dimorphic growth. In this study, the Foxl2 and Dmrt1 proteins were detected in granulosa cells of the ovary and Sertoli cells of the testis, respectively, showing significant sex-dimorphic expression patterns. Then, bioactive high-purity Foxl2 and Dmrt1 recombinant proteins were obtained in vitro. Furthermore, effects of the recombinant Foxl2 and Dmrt1 during gonadal differentiation period were evaluated by intraperitoneal injection in juvenile fish. Compared with the control group, the male rate in the Dmrt1 group increased from 0 % to 82 %, showing for the first time in fish that the recombinant Dmrt1 could alter the sex phenotype. In addition, transcription levels of cyp19a and its transcription factors also changed after the recombinant Foxl2 and Dmrt1 injection. These findings reveal that Foxl2 and Dmrt1 are vital regulators for fish gonadal differentiation by regulating cyp19a expression, and also provide a new approach for sex control in fish aquaculture.

Spatial analysis of global Bitcoin mining.

Bitcoin mining is not only the fundamental process to maintain Bitcoin network, but also the key linkage between the virtual cryptocurrency and the physical world. A variety of issues associated with it have been raised, such as network security, cryptoasset management and sustainability impacts. Investigating Bitcoin mining from a spatial perspective will provide new angles and empirical evidence with respect to extant literature. Here we explore the spatial distribution of Bitcoin mining through bottom-up tracking and geospatial statistics. We find that mining activity has been detected at more than 6000 geographical units across 139 countries and regions, which is in line with the distributed design of Bitcoin network. However, in terms of computing power, it has demonstrated a strong tendency of spatial concentration and association with energy production locations. We also discover that the spatial distribution of Bitcoin mining is dynamic, which fluctuates with diverse patterns, according to economic and regulatory changes.

Role of ferroptosis in gastrointestinal tumors: From mechanisms to therapies.

Ferroptosis is an iron-dependent nonapoptotic regulated cell death, which is mainly caused by an abnormal increase in lipid oxygen free radicals and an imbalance in redox homeostasis. Recently, ferroptosis has been shown to have implications in various gastrointestinal cancers, such as gastric carcinoma, hepatocellular carcinoma, and pancreatic cancer. This review summarises the latest research on ferroptosis, its mechanism of action, and its role in the progression of different gastrointestinal tumors to provide more information regarding the prevention and treatment of these tumors.

Sitagliptin activates the p62-Keap1-Nrf2 signalling pathway to alleviate oxidative stress and excessive autophagy in severe acute pancreatitis-related acute lung injury.

Acute lung injury (ALI) is a complication of severe acute pancreatitis (SAP). Sitagliptin (SIT) is a DPP4 inhibitor that exerts anti-inflammatory and antioxidant effects; however, its mechanism of action in SAP-ALI remains unclear. In this study, we investigated the effects of SIT on SAP-ALI and the specific pathways involved in SAP-induced lung inflammation, including oxidative stress, autophagy, and p62-Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) signalling pathways. Nrf2 knockout (Nrf2-/-) and wild-type (WT) mice were pre-treated with SIT (100 mg/kg), followed by caerulein and lipopolysaccharide (LPS) administration to induce pancreatic and lung injury. BEAS-2B cells were transfected with siRNA-Nrf2 and treated with LPS, and the changes in inflammation, reactive oxygen species (ROS) levels, and autophagy were measured. SIT reduced histological damage, oedema, and myeloperoxidase activity in the lung, decreased the expression of pro-inflammatory cytokines, and inhibited excessive autophagy and ROS production via the activation of the p62-Keap1-Nrf2 signalling pathway and promotion of the nuclear translocation of Nrf2. In Nrf2-knockout mice, the anti-inflammatory effect of SIT was reduced, resulting in ROS accumulation and excessive autophagy. In BEAS-2B cells, LPS induced ROS production and activated autophagy, further enhanced by Nrf2 knockdown. This study demonstrates that SIT reduces SAP-ALI-associated oxidative stress and excessive autophagy through the p62-Keap1-Nrf2 signalling pathway and nuclear translocation of Nrf2, suggesting its therapeutic potential in SAP-ALI.

Understanding the Effects of Metabolites on the Gut Microbiome and Severe Acute Pancreatitis.

Acute pancreatitis (AP) is an inflammatory disease of the pancreas. The severity is classified as mild (MAP), moderately severe (MSAP), or severe (SAP). In patients with SAP, organ dysfunction can occur in the early stage of the disease course, accompanied by secondary infection, with a mortality rate of 36%-50%. In the late stage SAP, infection-related complications caused by pancreatic necrotic tissue and peripancreatic effusion are the main causes of death in patients. Dysbacteriosis of intestinal microflora, barrier dysfunction of intestinal mucosa, and translocation of enteric bacteria are considered to be the main causes of infection of pancreatic necrotic tissue and peripancreatic effusion. During the past few years, increasing attention has been paid to the metabolic activities of intestinal microflora in SAP, which plays an important role in the metabolic activities of the human body. This review is aimed at bringing together the most recent findings and advances regarding the gut microbial community and associated gut microbial community metabolites and illustrating the role of these metabolites in disease progression in severe acute pancreatitis. We hope that this review will provide new ideas and schemes for the treatment of SAP in the clinical settings.

Modeling coupling dynamics between the transmission, intervention of COVID-19 and economic development.

Current explosive outbreak of the novel coronavirus (COVID-19) pandemic is posing serious threats to public health and economics around the world. To clarify the coupling mechanism between this disease and economic development, a new dynamical system is established by ordinary differential equations (ODEs). It is theoretically proved that the basic reproduction number is a nonlinear combination of parameters regarding disease transmission, intervention and economy effect, which totally determines the stability of the disease-free and endemic equilibria. Further analyses indicate the existence of interaction and mutual restraint among transmissibility, quarantine and economics, in which (1) COVID-19 would cause a long-term impact on halting economic progress; (2) strong coupling of COVID-19 and economics would easily trigger disease outbreak, cause more human infections and alleviate the intervention effects of quarantine; and (3) there exists optimal strategy of time-varying quarantine for disease control and economic development. It is highlighted that adaptive isolation (rather than constant isolation) of at-risk population (rather than random individuals) is highly effective in reducing morbidity at the cost of least economic loss.