Exploring the microRNA-mRNA regulatory network associated with solasonine in bladder cancer.

Background: Solasonine has been demonstrated to exert an inhibitory effect on bladder cancer (BC), but the potential mechanisms remain unclear. Therefore, the aim of this study is to explore the association between microRNAs (miRNAs)-mediated regulation and the anti-tumor activities of solasonine in BC. Methods: MiRNA sequencing was performed to identify the differentially expressed microRNAs (DE-miRNAs) associated with solasonine in BC cells. Functional enrichment analyses of the DE-miRNAs activated and inhibited by solasonine were then conducted. The DE-miRNAs with prognostic value for BC and those differentially expressed in the BC samples were subsequently identified as the hub DE-miRNAs. After identifying the messenger RNAs (mRNAs) that were targeted by the hub DE-miRNAs and those differentially expressed in the BC samples, a protein-protein interaction analysis was performed to identify the core downstream genes, which were then used to construct a solasonine-miRNA-mRNA regulatory network. Results: A total of 27 activated and 19 inhibited solasonine-mediated DE-miRNAs were identified that were found to be associated with several tumor-related biological functions and pathways. After integrating the results of the survival analysis and expression assessment, the following nine hub DE-miRNAs were identified: hsa-miR-127-3p, hsa-miR-450b-5p, hsa-miR-99a-5p, hsa-miR-197-3p, hsa-miR-423-3p, hsa-miR-4326, hsa-miR-625-3p, hsa-miR-625-5p, and hsa-miR-92a-3p. The DE-mRNAs targeted by the hub DE-miRNAs were predicted, and 30 core downstream genes were used to construct the solasonine-miRNA-mRNA regulatory network. miR-450b-5p was shown to be associated with the most mRNAs in this network, which suggests that it plays a crucial role in the solasonine-mediated anti-BC effect. Conclusions: A regulatory network, including solasonine, miRNAs, and mRNAs related to BC, was constructed. This network provides extensive insights into the molecular regulatory mechanisms that underlie the anti-cancer efficacy of solasonine in BC.

Thermostability-assisted limited proteolysis-coupled mass spectrometry for capturing drug target proteins and sites.

BACKGROUND: Identifying drug-binding targets and their corresponding sites is crucial for drug discovery and mechanism studies. Limited proteolysis-coupled mass spectrometry (LiP-MS) is a sophisticated method used for the detection of compound and protein interactions. However, in some cases, LiP-MS cannot identify the target proteins due to the small structure changes or the lack of enrichment of low-abundant protein. To overcome this drawback, we developed a thermostability-assisted limited proteolysis-coupled mass spectrometry (TALiP-MS) approach for efficient drug target discovery. RESULTS: We proved that the novel strategy, TALiP-MS, could efficiently identify target proteins of various ligands, including cyclosporin A (a calcineurin inhibitor), geldanamycin (an HSP90 inhibitor), and staurosporine (a kinase inhibitor), with accurately recognizing drug-binding domains. The TALiP protocol increased the number of target peptides detected in LiP-MS experiments by 2- to 8-fold. Meanwhile, the TALiP-MS approach can not only identify both ligand-binding stability and destabilization proteins but also shows high complementarity with the thermal proteome profiling (TPP) and machine learning-based limited proteolysis (LiP-Quant) methods. The developed TALiP-MS approach was applied to identify the target proteins of celastrol (CEL), a natural product known for its strong antioxidant and anti-cancer angiogenesis effect. Among them, four proteins, MTHFD1, UBA1, ACLY, and SND1 were further validated for their strong affinity to CEL by using cellular thermal shift assay. Additionally, the destabilized proteins induced by CEL such as TAGLN2 and CFL1 were also validated. SIGNIFICANCE: Collectively, these findings underscore the efficacy of the TALiP-MS method for identifying drug targets, elucidating binding sites, and even detecting drug-induced conformational changes in target proteins in complex proteomes.

Performance of ChatGPT on Chinese Master's Degree Entrance Examination in Clinical Medicine.

BACKGROUND: ChatGPT is a large language model designed to generate responses based on a contextual understanding of user queries and requests. This study utilised the entrance examination for the Master of Clinical Medicine in Traditional Chinese Medicine to assesses the reliability and practicality of ChatGPT within the domain of medical education. METHODS: We selected 330 single and multiple-choice questions from the 2021 and 2022 Chinese Master of Clinical Medicine comprehensive examinations, which did not include any images or tables. To ensure the test's accuracy and authenticity, we preserved the original format of the query and alternative test texts, without any modifications or explanations. RESULTS: Both ChatGPT3.5 and GPT-4 attained average scores surpassing the admission threshold. Noteworthy is that ChatGPT achieved the highest score in the Medical Humanities section, boasting a correct rate of 93.75%. However, it is worth noting that ChatGPT3.5 exhibited the lowest accuracy percentage of 37.5% in the Pathology division, while GPT-4 also displayed a relatively lower correctness percentage of 60.23% in the Biochemistry section. An analysis of sub-questions revealed that ChatGPT demonstrates superior performance in handling single-choice questions but performs poorly in multiple-choice questions. CONCLUSION: ChatGPT exhibits a degree of medical knowledge and the capacity to aid in diagnosing and treating diseases. Nevertheless, enhancements are warranted to address its accuracy and reliability limitations. Imperatively, rigorous evaluation and oversight must accompany its utilization, accompanied by proactive measures to surmount prevailing constraints.

Associations between postoperative anaemia and unplanned readmission to hospital after major surgery: a retrospective cohort study†.

BACKGROUND: Anaemia following major surgery may be associated with unplanned readmission to hospital. However, the severity-response relationship between the degree of anaemia at discharge and the risk of unplanned readmission is poorly defined. We aimed to describe the severity-response relationship between haemoglobin concentration at the time of discharge and the risk of unplanned readmission in a cohort of patients undergoing different types of major surgery. METHODS: We performed a retrospective cohort study in a single tertiary health service, including all patients who underwent major surgery (orthopaedic, abdominal, cardiac or thoracic) between 1 May 2011 and 1 February 2022. The primary outcome was unplanned readmission to hospital in the 90 days following discharge after the index surgical procedure. These complex, non-linear relationships were modelled with restricted cubic splines. RESULTS: We identified 22,134 patients and included 14,635 in the primary analysis, of whom 1804 (12%) experienced at least one unplanned readmission. The odds of unplanned readmission rose when the discharge haemoglobin concentration was < 100 g.l-1 (p < 0.001). On subgroup analysis, the haemoglobin threshold below which odds of readmission began to increase appeared to be higher in patients undergoing emergency surgery (110 g.l-1; p < 0.001) compared with elective surgery. Declining discharge haemoglobin concentration was associated with increased odds ratios (95%CI) of unplanned readmission in patients undergoing orthopaedic (1.08 (1.01-1.15), p = 0.03), abdominal (1.13 (1.07-1.19), p < 0.001) and thoracic (1.12 (1.01-1.24), p = 0.03) procedures, but not cardiac surgery (1.09 (0.99-1.19), p = 0.07). CONCLUSIONS: Our findings suggest that a haemoglobin concentration < 100 g.l-1 following elective procedures and < 110 g.l-1 following emergency procedures, at the time of hospital discharge after major surgery, was associated with unplanned readmission. Future interventional trials that aim to treat postoperative anaemia and reduce unplanned readmission should include patients with discharge haemoglobin below these thresholds.

Effect of various different pretreatment methods on infrared combined hot air impingement drying behavior and physicochemical properties of strawberry slices.

In current work, the effect of freezing (F), ultrasound (U), and freeze- ultrasound (FU) pretreatment on infrared combined with hot air impingement drying kinetics, cell ultrastructure, enzyme activity, and physicochemical properties of strawberry slices were explored. Results showed that FU pretreatment enhanced cell membrane permeability via forming micropores, altered water status by transforming bound water into free water and thus promoted moisture diffusivity and decreased drying time by 50% compared to the control group. FU pretreatment also extensively decreased pectin methylesterase enzyme activity and maintained quality. The contents of total phenols, anthocyanins, vitamin C, antioxidant activity, and a* value of dried strawberries pretreated by FU were extensively increased compared to the control group. U and FU pretreatments were beneficial for retaining aromatic components and organic sulfides according to e-nose analyses. The findings indicate that FU is a promising pretreatment technique as it enhances drying process and quality of strawberry slices.

A novel therapy for intractable chronic cough.

Two cases of intractable chronic cough improved significantly with humidified high flow therapy (HHFT). A 59-year-old woman with Primary Sjogren's disease and interstitial lung disease, was trialled on a Fisher and Paykel myAIRVO™ system. She reported sustained benefits of uninterrupted sleep and increased socialization with tapering use of HHFT. A 67-year-old woman with idiopathic pulmonary fibrosis also benefited from the use of myAIRVO™. She had relentless cough with minimal movement, and nocturnal cough causing fragmented sleep. Her cough subsided considerably with continuous HHFT, but recurred without. Both patients reported significant reductions in the cough visual analogue scale. The mechanisms by which HHFT improve intractable cough may include reducing airway dryness, inhibition of neutrophil inflammation and mucus obstruction, and splinting of the airways. HHFT significantly improved cough and health-related quality of life in two patients with interstitial lung disease. Further research is warranted to explore the role of domiciliary HHFT.

Deep learning model based on multi-lesion and time series CT images for predicting the benefits from anti-HER2 targeted therapy in stage IV gastric cancer.

OBJECTIVE: To develop and validate a deep learning model based on multi-lesion and time series CT images in predicting overall survival (OS) in patients with stage IV gastric cancer (GC) receiving anti-HER2 targeted therapy. METHODS: A total of 207 patients were enrolled in this multicenter study, with 137 patients for retrospective training and internal validation, 33 patients for prospective validation, and 37 patients for external validation. All patients received anti-HER2 targeted therapy and underwent pre- and post-treatment CT scans (baseline and at least one follow-up). The proposed deep learning model evaluated the multiple lesions in time series CT images to predict risk probabilities. We further evaluated and validated the risk score of the nomogram combining a two-follow-up lesion-based deep learning model (LDLM-2F), tumor markers, and clinical information for predicting the benefits from treatment (Nomo-LDLM-2F). RESULTS: In the internal validation and prospective cohorts, the one-year AUCs for Nomo-LDLM-2F using the time series medical images and tumor markers were 0.894 (0.728-1.000) and 0.809 (0.561-1.000), respectively. In the external validation cohort, the one-year AUC of Nomo-LDLM-2F without tumor markers was 0.771 (0.510-1.000). Patients with a low Nomo-LDLM-2F score derived survival benefits from anti-HER2 targeted therapy significantly compared to those with a high Nomo-LDLM-2F score (all p < 0.05). CONCLUSION: The Nomo-LDLM-2F score derived from multi-lesion and time series CT images holds promise for the effective readout of OS probability in patients with HER2-positive stage IV GC receiving anti-HER2 therapy. CRITICAL RELEVANCE STATEMENT: The deep learning model using baseline and early follow-up CT images aims to predict OS in patients with stage IV gastric cancer receiving anti-HER2 targeted therapy. This model highlights the spatiotemporal heterogeneity of stage IV GC, assisting clinicians in the early evaluation of the efficacy of anti-HER2 therapy. KEY POINTS: • Multi-lesion and time series model revealed the spatiotemporal heterogeneity in anti-HER2 therapy. • The Nomo-LDLM-2F score was a valuable prognostic marker for anti-HER2 therapy. • CT-based deep learning model incorporating time-series tumor markers improved performance.

Baohuoside I suppresses the NLRP3 inflammasome activation via targeting GPER to fight against Parkinson's disease.

BACKGROUND: Accumulating evidence indicates the crucial role of microglia-mediated inflammation and the NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis in the pathogenesis of Parkinson's disease (PD). Baohuoside I, a natural flavonoid extracted from Herba Epimedii, has been shown to possess anti-inflammatory effects, but its potential neuroprotective effects and mechanism against PD have not been documented. STUDY DESIGN AND METHODS: The anti-inflammatory effects of Baohuoside I were evaluated by LPS-induced BV2 cells or primary microglia isolated from wide type or G protein-coupled estrogen receptor (GPER) gene knockout mice. The underlying mechanism related to GPER-mediated NLRP3 inflammasome inhibition was further explored using LPS-induced GPER+/+ or GPER-/- mouse models of PD. The neuroprotective effects of Baohuoside I were detected through western blot analysis, real-time PCR, molecular docking, mouse behavioral tests, immunofluorescence, and immunohistochemistry. RESULTS: Baohuoside I significantly alleviated LPS-induced neuroinflammation by inhibiting the activation of NF-κB signal and the increase of pyroptosis levels as evidenced by the downregulated expression of pyroptosis-related proteins (NLRP3, ASC, pro-Caspase-1, IL-1ß) in microglia cells. Intragastric administration of Baohuoside I protected against LPS-induced motor dysfunction and loss of dopaminergic neurons, reduced pro-inflammatory cytokines expressions, and inhibited microglial (Iba-1) and astrocyte (GFAP) activation in the nigrostriatal pathway in LPS-induced mouse model of PD. Pretreatment with GPER antagonist G15 in microglia cells or GPER gene deletion in mice significantly blocked the inhibitory effects of Baohuoside I on LPS-induced neuroinflammation and activation of the NLRP3/ASC/Caspase-1 pathway. Molecular docking further indicated that Baohuoside I might bind to GPER directly with a binding energy of -10.4 kcal/mol. CONCLUSION: Baohuoside I provides neuroprotective effects against PD by inhibiting the activation of the NF-κB signal and NLRP3/ASC/Caspase-1 pathway. The molecular target for its anti-inflammatory effects is proved to be GPER in the PD mouse model. Baohuoside I may be a valuable anti-neuroinflammatory agent and a drug with well-defined target for the treatment of PD.

The METTL3-m6A-YTHDC1-AMIGO2 axis contributes to cell proliferation and migration in esophageal squamous cell carcinoma.

The upregulation of methyltransferase-like 3 (METTL3) has been associated with the progression of esophageal cancer. However, METTL3-induced N6-methyladenosine (m6A) alterations on the downstream target mRNAs in esophageal squamous cell carcinoma (ESCC) are not yet fully understood. Our study revealed that silencing METTL3 resulted in a significant decrease in ESCC cell proliferation and metastasis in vitro and in vivo. Additionally, the adhesion molecule with Ig like domain 2 (AMIGO2) was identified as a potential downstream target of both METTL3 and YTH Domain-Containing Protein 1 (YTHDC1) in ESCC cells. Functionally, AMIGO2 augmented the malignant behaviors of ESCC cells in vitro and in vivo, and its overexpression can rescue the inhibition of the proliferation and migration in ESCC cells induced by METTL3 or YTHDC1 knockdown. Furthermore, our findings revealed that knockdown of METTL3 decreased m6A modification in the 5'-untranslated regions (5'UTR) of AMIGO2 precursor mRNA (pre-mRNA), and YTHDC1 interacted with AMIGO2 pre-mRNA to regulate AMIGO2 expression by modulating the splicing process of AMIGO2 pre-mRNA in ESCC cells. These findings highlighted a novel role of the METTL3-m6A-YTHDC1-AMIGO2 axis in regulating ESCC cell proliferation and motility, suggesting its potential as a therapeutic target for ESCC.

IP3R2-mediated Ca2+ release promotes LPS-induced cardiomyocyte pyroptosis via the activation of NLRP3/Caspase-1/GSDMD pathway.

Pyroptosis plays a crucial role in sepsis, and the abnormal handling of myocyte calcium (Ca2+) has been associated with cardiomyocyte pyroptosis. Specifically, the inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is a Ca2+ release channel in the endoplasmic reticulum (ER). However, the specific role of IP3R2 in sepsis-induced cardiomyopathy (SIC) has not yet been determined. Thus, this study aimed to investigate the underlying mechanism by which IP3R2 channel-mediated Ca2+ signaling contributes to lipopolysaccharide (LPS)-induced cardiac pyroptosis. The SIC model was established in rats by intraperitoneal injection of LPS (10 mg/kg). Cardiac dysfunction was assessed using echocardiography, and the protein expression of relevant signaling pathways was analyzed using ELISA, RT-qPCR, and western blot. Small interfering RNAs (siRNA) and an inhibitor were used to explore the role of IP3R2 in neonatal rat cardiomyocytes (NRCMs) stimulated by LPS in vitro. LPS-induced NLRP3 overexpression and GSDMD-mediated pyroptosis in the rats' heart. Treatment with the NLRP3 inhibitor MCC950 alleviated LPS-induced cardiomyocyte pyroptosis. Furthermore, LPS increased ATP-induced intracellular Ca2+ release and IP3R2 expression in NRCMs. Inhibiting IP3R activity with xestospongin C (XeC) or knocking down IP3R2 reversed LPS-induced intracellular Ca2+ release. Additionally, inhibiting IP3R2 reversed LPS-induced pyroptosis by suppressing the NLRP3/Caspase-1/GSDMD pathway. We also found that ER stress and IP3R2-mediated Ca2+ release mutually regulated each other, contributing to cardiomyocyte pyroptosis. IP3R2 promotes NLRP3-mediated pyroptosis by regulating ER Ca2+ release, and the mutual regulation of IP3R2 and ER stress further promotes LPS-induced pyroptosis in cardiomyocytes.

Magnetite-boosted syntrophic conversion of acetate to methane during thermophilic anaerobic digestion.

Using a batch thermophilic anaerobic system established with 60 mL serum bottles, the mechanism on how microbial enrichments obtained from magnetite-amended paddy soil via repeated batch cultivation affected methane production from acetate was investigated. Magnetite-amended enrichments (MAEs) can improve the methane production rate rather than the methane yield. Compared with magnetite-unamended enrichments, the methane production rate in MAE was improved by 50%, concomitant with the pronounced electrochemical response, high electron transfer capacity, and fast acetate degradation. The promoting effects might be ascribed to direct interspecies electron transfer facilitated by magnetite, where magnetite might function as electron conduits to link the acetate oxidizers (Anaerolineaceae and Peptococcaceae) with methanogens (Methanosarcinaceae). The findings demonstrated the potential application of MAE for boosting methanogenic performance during thermophilic anaerobic digestion.

Engineering High-Performance Hypergolic Propellant by Synergistic Contribution of Metal-Organic Framework Shell and Aluminum Core.

Hypergolicity is a highly desired characteristic for hybrid rocket engine-based fuels because it eliminates the need for a separate ignition system. Introducing hypergolic additives into conventional fuels through physical mixing is a feasible approach, but achieving highly reliable hypergolic ignition and energy release remains a major challenge. Here, the construction of core-shell Al@metal organic framework (MOF) heterostructures is reported as high-performance solid hypergolic propellants. Upon contact with the liquid oxidizer the uniformly distributed hypergolic MOF (Ag-MOF) shell can induce the ignition of hypergolic-inert fuel Al, resulting in Al combustion. Such a synthetic strategy is demonstrated to be favorable in hotspot generation and heat transfer relative to a simple physical mixture of Al/Ag-MOF, thus producing shorter ignition delay times and more efficient combustion. Thermal reactivity study indicated that the functionalization of the Ag-MOF shell changes the energy release process of the inner Al, which is accompanied by a thermite reaction. The synergistic effect of implantation of hypergolic MOF and high energy Al contributes to high specific impulses of 230-270 s over a wide range of oxidizer-to-fuel ratios.

Recent advances in promising drugs for primary prevention of gastroesophageal variceal bleeding with cirrhotic portal hypertension.

BACKGROUND: Gastroesophageal variceal bleeding is one of the most severe complications of patients with cirrhosis. Although primary prevention drugs, including non-selective ß-blockers, have effectively reduced the incidence of bleeding, their efficacy is limited due to side effects and related contraindications. With recent advances in precision medicine, precise drug treatment provides better treatment efficacy. DATA SOURCES: Literature search was conducted in PubMed, MEDLINE and Web of Science for relevant articles published up to May 2022. Information on clinical trials was obtained from https://clinicaltrials.gov/ and http://www.chictr.org.cn/. RESULTS: The in-depth understanding of the pathogenesis and advances of portal hypertension has enabled the discovery of multiple molecular targets for promising drugs. According to the site of action, these drugs could be classified into four classes: intrahepatic, extrahepatic, both intrahepatic and extrahepatic targets and others. All these classes of drugs offer advantages over traditional treatments in prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension. CONCLUSIONS: This review classified and summarized the promising drugs, which prevent gastroesophageal variceal bleeding by targeting specific markers of pathogenesis of portal hypertension, demonstrating the significance of using the precision medicine strategy to discover and develop promising drugs for the primary prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.

A molecular networking-assisted automatic database screening strategy for comprehensive annotation of small molecules in complex matrices.

Liquid chromatography-tandem with high-resolution mass spectrometry (LCHRMS) has proven challenging for annotating multiple small molecules within complex matrices due to the complexities of chemical structure and raw LCHRMS data, as well as limitations in previous literatures and reference spectra related to those molecules. In this study, we developed a molecular networking assisted automatic database screening (MN/auto-DBS) strategy to examine the combined effect of MS1 exact mass screening and MS2 similarity analysis. We compiled all previously reported compounds from the relevant literatures. With the development of a Python software, the in-house database (DB) was created by automatically calculating the m/z and data from experimental MS1 hits were rapid screened with DB. We then performed a feature-based molecular network analysis on the auto-MS2 data for supplementary identification of unreported compounds, including clustered FBMN and annotated GNPS compounds. Finally, the results from both strategies were merged and manually curated for correct structural assignment. To demonstrate the applicability of MN/auto-DBS, we selected the Huangqi-Danshen herb pair (HD), commonly used in prescriptions or patent medicines to treat diabetic nephropathy and cerebrovascular disease. A total of 223 compounds were annotated, including 65 molecules not previously reported in HD, such as aromatic polyketides, coumarins, and diarylheptanoids. Using MN/auto-DBS, we can profile and mine a wide range of complex matrices for potentially new compounds.

Pneumorrhachis secondary to exacerbation of asthma: A case report and literature review.

Pneumorrhachis is defined by the presence of air within the spinal cord. Spontaneous pneumorrhachis secondary to exacerbation of asthma is rare, and its management is rarely discussed. We present a case of spontaneous pneumorrhachis in the context of a viral exacerbation of asthma, followed by a systematic literature review of all available cases of pneumorrhachis in asthma exacerbation. A total of 25 case studies reported pneumorrhachis in 28 asthma patients, all of whom presented with concomitant pneumomediastinum. Investigation and exclusion for other potential aetiologies of pneumorrhachis such as trauma or infection occurred to varying extents and may depend on clinical presentation and degree of suspicion. No other contributing aetiologies were demonstrated in this review, and no patients required specific intervention for pneumorrhachis. Whilst pneumorrhachis is generally benign, management should revolve around standard care of asthma exacerbation, attention to potentially life-threatening differential diagnoses, and supportive care.

The Role of Polaronic States on the Spin Dynamics in Solution-Processed Two-Dimensional Layered Perovskite with Different Layer Thickness.

2D lead halide perovskites (LHPs) show strong excitonic and spin-orbit coupling effects, generating a facile spin injection. Besides, they possess a polaron character due to the soft crystal lattice, which can prolong the spin lifetime, making them favorable materials for spintronic applications. Here, the spin dynamics of 2D PEA2 PbI4 (MAPbI3 )n -l thin films with different layers by temperature- and pump fluence-dependent circularly polarization-resolved transient absorption (TA) measurements is studied. These results indicate that the spin depolarization mechanism is gradually converted from the Maialle-Silva-Sham (MSS) mechanism to the polaronic states protection mechanism with the layer number increasing from = 1 to 3, which is determined by the interplay between the strength of Coulomb exchange interaction and the strength of polaronic effect. While for ≥ 4, the Elliot-Yafet (EY) impurities mechanism is proposed, in which the formed polaronic states with free charge carriers no longer play the protective role.

Irisin inhibits neutrophil extracellular traps formation and protects against acute pancreatitis in mice.

INTRODUCTION: Irisin is a newly discovered myokine which links exercise to inflammation and inflammation-related diseases through macrophage regulation. However, the effect of irisin on the activity of inflammation related immune cells (such as neutrophils) has not been clearly described. OBJECTIVES: The objective of our study was to explore the effect of irisin on the neutrophil extracellular traps (NETs) formation. METHODS: Phorbol-12-myristate-13-acetate (PMA) was used to construct a classic neutrophil inflammation model that was used to observe the formation of NETs in vitro. We studied the effect of irisin on NETs formation and its regulation mechanism. Subsequently, acute pancreatitis (AP) was used to verify the protective effect of irisin in vivo, which was an acute aseptic inflammatory response disease model closely related to NETs. RESULTS: Our study found that addition of irisin significantly reduced the formation of NETs via regulation of the P38/MAPK pathway through integrin αVß5, which might be the one of key pathways in NETs formation, and which could theoretically offset the immunoregulatory effect of irisin. Systemic treatment with irisin reduced the severity of tissue damage common in the disease and inhibited the formation of NETs in pancreatic necrotic tissue of two classical AP mouse models. CONCLUSION: The findings confirmed for the first time that irisin could inhibit NETs formation and protect mice from pancreatic injury, which further elucidated the protective effect of exercise on acute inflammatory injury.

Discovery of effective combination from Renshen-Fuzi herbal pair against heart failure by spectrum-effect relationship analysis and zebrafish models.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional herbal pair Ginseng Radix et Rhizoma (roots and rhizomes of Panax ginseng C.A. Mey, Renshen in Chinese) and Aconiti Lateralis Radix Praeparata (lateral roots of Aconitum carmichaelii Debeaux, Fuzi in Chinese), composition of two traditional Chinese medicinal herbs, has been widely used in traditional Chinese medicine formula, in which Shenfu decoction has been used clinically in China for the treatment of heart failure at present. AIM OF THE STUDY: Although the ginsenosides and aconite alkaloids have been proven as the essential bioactive components in Renshen-Fuzi herbal pair, the exact composition of effective components to combat heart failure are still unclear. Therefore, spectrum-effect relationship analysis was performed to reveal its effective combination for anti-heart failure effect. MATERIALS AND METHODS: Firstly, the chemical constituents of Renshen-Fuzi herbal pair were identified using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). The 39 major compounds in Renshen-Fuzi with five different compatibility ratios were simultaneously quantified using ultra high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UHPLC-QQQ MS/MS). Subsequently, zebrafish models induced by verapamil hydrochloride were constructed and four heart failure-related indexes were selected for pharmacodynamic evaluation of Renshen-Fuzi. To analyze the spectrum-effect relationships, partial least squares regression (PLSR) models were established among the contents of 39 compounds in Renshen-Fuzi with each pharmacodynamic index. According to the contribution of each compound to the whole efficacy, 12 compounds were finally screened out as the effective combination. RESULTS: A total of 157 chemical compounds of Renshen-Fuzi herbal pair were identified, in which 39 components were simultaneously determined. The pharmacological effects indicated that Renshen-Fuzi with 1:2 ratio exhibited the best effect based on zebrafish model, which could improve cardiac output and blood flow velocity and inhibit pericardial enlargement and venous blood stasis significantly. A combination of 9 ginsenosides and 3 aconite alkaloids based on a component-efficacy modeling by PLSR was screened, and exerted approximately equivalent pharmacological effects compared with Renshen-Fuzi herbal pair. CONCLUSIONS: Our findings elucidated the effective combination of Renshen-Fuzi herbal pair that has been used in clinic for the treatment of heart failure, which could also promote the pharmacological research and quality control of their formula such as Shenfu decoction.

Associations of subcutaneous fat area and Systemic Immune-inflammation Index with survival in patients with advanced gastric cancer receiving dual PD-1 and HER2 blockade.

BACKGROUND: Systemic Immune-inflammation Index (SII) and body composition parameters are easily assessed, and can predict overall survival (OS) in various cancers, allowing early intervention. This study aimed to assess the correlation between CT-derived body composition parameters and SII and OS in patients with advanced gastric cancer receiving dual programmed death-1 (PD-1) and human epidermal growth factor receptor 2 (HER2) blockade. MATERIALS AND METHODS: This retrospective study enrolled patients with advanced gastric cancer treated with dual PD-1 and HER2 blockade from March 2019 to June 2022. We developed a deep learning model based on nnU-Net to automatically segment skeletal muscle, subcutaneous fat and visceral fat at the third lumbar level, and calculated the corresponding Skeletal Muscle Index, skeletal muscle density, subcutaneous fat area (SFA) and visceral fat area. SII was computed using the formula that total peripheral platelet count×neutrophil/lymphocyte ratio. Univariate and multivariate Cox regression analysis were used to determine the associations between SII, body composition parameters and OS. RESULTS: The automatic segmentation deep learning model was developed to efficiently segment body composition in 158 patients (0.23 s/image). Multivariate Cox analysis revealed that high SII (HR=2.49 (95% CI 1.54 to 4.01), p<0.001) and high SFA (HR=0.42 (95% CI 0.24 to 0.73), p=0.002) were independently associated with OS, whereas sarcopenia was not an independent prognostic factor for OS (HR=1.41 (95% CI 0.86 to 2.31), p=0.173). In further analysis, patients with high SII and low SFA had worse long-term prognosis compared with those with low SII and high SFA (HR=8.19 (95% CI 3.91 to 17.16), p<0.001). CONCLUSION: Pretreatment SFA and SII were significantly associated with OS in patients with advanced gastric cancer. A comprehensive analysis of SII and SFA may improve the prognostic stratification of patients with gastric cancer receiving dual PD-1 and HER2 blockade.