Impacts of pancreatic exocrine insufficiency on gut microbiota. / èƒ°è ºå¤–åˆ†æ³ŒåŠŸèƒ½ä¸å ¨å¯¹è‚ é“å¾®ç”Ÿç‰©ç¾¤çš„å½±å“.

Pancreatic exocrine insufficiency (PEI) can be induced by various kinds of diseases, including chronic pancreatitis, acute pancreatitis, and post-pancreatectomy. The main pathogenetic mechanism of PEI involves the decline of trypsin synthesis, disorder of pancreatic fluid flow, and imbalance of secretion feedback. Animal studies have shown that PEI could induce gut bacterial overgrowth and dysbiosis, with the abundance of Lactobacillus and Bifidobacterium increasing the most, which could be partially reversed by pancreatic enzyme replacement therapy. Clinical studies have also confirmed the association between PEI and the dysbiosis of gut microbiota. Pancreatic exocrine secretions and changes in duodenal pH as well as bile salt malabsorption brought about by PEI may affect and shape the abundance and composition of gut microbiota. In turn, the gut microbiota may impact the pancreatic exocrine acinus through potential bidirectional crosstalk. Going forward, more and higher-quality studies are needed that focus on the mechanism underlying the impact of PEI on the gut microbiota.

A photoelectrochemical aptasensor based on double Z-scheme α-Fe2O3/MoS2/Bi2S3 ternary heterojunction for sensitive detection of circulating tumor cells.

A novel photoelectrochemical (PEC) aptasensor based on a dual Z-scheme α-Fe2O3/MoS2/Bi2S3 ternary heterojunction for the ultrasensitive detection of circulating tumor cells (CTCs) was developed. The α-Fe2O3/MoS2/Bi2S3 nanocomposite was prepared via a step-by-step route, and the photoproduced electron/hole transfer path was speculated by conducting trapping experiments of reactive species. α-Fe2O3/MoS2/Bi2S3-modified electrodes exhibited greatly enhanced photocurrent under visible light due to the double Z-scheme charge transfer process, which met the requirement of the PEC sensor for detecting larger targets. After the aptamer was conjugated on the photoelectrode through chitosan (CS) and glutaraldehyde (GA), when MCF-7 cells were presented and captured, the photocurrent of the PEC biosensing system decreased due to steric hindrance. The current intensity had a linear relationship with the logarithm of MCF-7 cell concentration ranging from 10 to 1×105 cells mL-1, with a low detection limit of 3 cell mL-1 (S/N = 3). The dual Z-scheme α-Fe2O3/MoS2/Bi2S3 ternary heterojunction-modified PEC aptasensor exhibited high sensitivity and excellent specificity and stability. Additionally, MCF-7 cells in human serum were determined by this PEC aptasensor, exhibiting great potential as a promising tool for clinical detection.

Abiotic Methane Production Driven by Ubiquitous Non-Fenton-Type Reactive Oxygen Species.

Abiotic CH4 production driven by Fenton-type reactive oxygen species (ROS) has been confirmed to be an indispensable component of the atmospheric CH4 budget. While the chemical reactions independent of Fenton chemistry to ROS are ubiquitous in nature, it remains unknown whether the produced ROS can drive abiotic CH4 production. Here, we first demonstrated the abiotic CH4 production at the soil-water interface under illumination. Leveraging this finding, polymeric carbon nitrides (CNx) as a typical analogue of natural geobattery material and dimethyl sulfoxide (DMSO) as a natural methyl donor were used to unravel the underlying mechanisms. We revealed that the ROS, photocatalytically produced by CNx, can oxidize DMSO into CH4 with a high selectivity of 91.5 %. Such an abiotic CH4 production process was further expanded to various non-Fenton-type reaction systems, such as electrocatalysis, pyrocatalysis and sonocatalysis. This work provides insights into the geochemical cycle of abiotic CH4, and offers a new route to CH4 production via integrated energy development.

Incidence, distribution, disease spectrum, and genetic deficits of congenital heart defects in China: implementation of prenatal ultrasound screening identified 18,171 affected fetuses from 2,452,249 pregnancies.

BACKGROUND: Congenital heart defects (CHDs) are the most common birth defects. Assessment of the incidence, distribution, disease spectrum, and genetic deficits of fetal CHDs in China is urgently needed. METHODS: A national echocardiography screening program for fetal CHDs was implemented in 92 prenatal screening-diagnostic centers in China. FINDINGS: A total of 18,171 fetal CHD cases were identified from 2,452,249 pregnancies, resulting in 7·4/1,000 as the national incidence rate of fetal CHD. The incidences of fetal CHD in the six geographical regions, the southern, central, eastern, southwestern, northern, and northwestern, were 7·647 (CI: 7·383-7·915), 7·839 (CI: 7·680-8·000), 7·647 (CI: 7·383-7·915), 7·562 (CI: 7·225-7·907), 5·618 (CI: 5·337-5·906), and 4·716 (CI: 4·341-5·108), respectively, per 1,000 pregnancies. Overall, ventricular septal defect was the most common fetal CHD, accounting for 17.04% of screened pregnancies nationwide, and tetralogy of Fallot, the most common anomaly in the major defect of fetal CHD, was the second most common, accounting for 9.72%. A total of 76.24% cases of fetal CHD were found to be an isolated intracardiac single defect. The remaining 23.76% of cases of fetal CHD had multiple heart defects. Among all extracardiac malformations, the central nervous system (CNS) was the most common tissue with extracardiac anomalies associated with CHD, accounting for 22.89% of fetal CHD cases. Chromosomal karyotyping identified trisomy 18 as the most common chromosomal abnormality in fetal CHD. We also documented that CHD-containing syndromes could be identified with a comprehensive approach integrating prenatal ultrasound, MRI, pathological autopsy, and cytogenetics and molecular genetics. CONCLUSION: Implementation of prenatal echocardiography as a practically feasible platform to screen fetal CHD will reduce the financial and emotional burden of CHD, which may facilitate intrauterine and neonatal intervention of CHD.

Acupuncture Pretreatment Reduces Skeletal Muscle Inflammatory Response in EIMD Rats by Activating cGAS-STING-NF-κB Signaling Pathway.

Acupuncture pretreatment (AP) has a good skeletal muscle protective effect. The present study investigated whether acupuncture pretreatment could improve ultrastructural changes and skeletal muscle inflammation in exercising skeletal muscle injury. Eighty-eight male SD rats were randomly divided into a blank group (C), an exercise group (E), and an acupuncture pretreatment group (AP). Among them, the E and AP groups were divided into five subgroups of 0h, 12h, 24h, 48h, and 72h according to the extraction time after exercise, with 11 groups and eight rats in each group. The study involved simulating skeletal muscle injury caused by intermittent downhill running centrifugal exercise. The researchers used various methods to observe changes in mitochondrial structure and cGAS-STING-NF-κB p65 protein content of classical inflammatory response signaling pathway. These methods included transmission electron microscopy to observe skeletal muscle, Western Blot to detect changes in protein content, and reverse transcription polymerase chain reaction (RT-qPCR method) to detect cytoplasmic mtDNA gene fragment ND1, D-LOOP and cGAS-STING- NF-κB p65 protein RNA. The aim was to investigate the changes in NF-κB p65 protein RNA. Changes in NF-κB p65 protein RNA content and mtDNA gene fragment ND1 and D-LOOP content; changes in serum IL-8 and IFN-ß content were detected by enzyme-linked immunosorbent assay (ELISA); WB, RT-qPCR, ELISA assays aimed to study the skeletal muscle injury and mitochondrial structural damage in group E relationship skeletal muscle tissue level, cytoplasmic mtDNA fragment gene ND1, and D-LOOP content in skeletal muscle tissue of group E. In comparison to group C, the levels of cGAS-STING-NF-κB p65 protein expression and mRNA, and the serum levels of IL-8 and IFN-ß were significantly higher in group E . However, the acupuncture pretreatment group (AP) reduced the extent of damage to skeletal muscle mitochondria and the levels of cytoplasmic mtDNA fragment genes ND1 and D-LOOP. Also, the high expression of cGAS-STING-NF-κB p65 protein, mRNA, and the levels of IL-8 and IFN-ß were inhibited in the AP group. The results indicated that AP ameliorated exercise-induced skeletal muscle injury and reduced skeletal muscle inflammation produced after centrifugal exercise. This was achieved by inhibiting the overexpression of the cGAS-STING-NF-κB signaling pathway.

[Current status and trend of acupuncture-moxibustion for myofascial pain syndrome: a visual analysis of knowledge graph based on CiteSpace and VOSviewer].

Bibliometric and scientific knowledge graph methods were used to analyze the research status and hot spots of acupuncture-moxibustion in treatment of myofascial pain syndrome (MPS) and explore its development trend. The articles of both Chinese and English versions relevant to MPS treated by acupuncture-moxibustion were searched in CNKI, VIP, Wanfang, SinoMed and WOS from the database inception to March 20, 2023. Using Excel2016, CiteSpace6.2.R2 and VOSviewer1.6.18, the visual analysis was conducted by means of the cooperative network, keyword co-occurrence, keyword timeline, keyword emergence, etc. From Chinese databases and WOS database, 910 Chinese articles and 300 English articles were included, respectively. The annual publication volume showed an overall rising trend. Literature output of English articles was concentrated in Spain, China, and the United States, of which, there was less cross-regional cooperation. In the keyword analysis, regarding acupuncture-moxibustion therapy, Chinese articles focused on "acupuncture", "electroacupuncture" and "acupotomy"; while, "dry needling" and "injection" were dominated for English one. Clinical study was the current hot spot in Chinese databases, in comparison, the randomized controlled double-blind clinical trial was predominant in WOS. Both Chinese and English articles were limited in the report of mechanism research. The cooperation among research teams should be strengthened to conduct comparative research, dose-effect research and effect mechanism research with different methods of acupuncture-moxibustion involved so that the evidences can be provided for deeper exploration.

A controllable surface etching strategy for MOF-derived porous ZnCo2O4@ZnO/Co3O4 oxides and their sensing properties.

Here, we report a surface etching strategy for the controllable synthesis of metal-organic framework (MOF)-derived ZnCo2O4@ZnO/Co3O4 oxides. Different from previous studies, ZnCo-glycolate (ZnCo-gly) spheres acted as sacrificial templates to provide Zn2+ and Co2+ ions, which coordinated with 2-MeIm to form Zeolitic Imidazolate Frameworks (ZIFs) on the surface of ZnCo-gly. A series of characterizations were employed to clarify the evolution of the surface etching strategy. Interestingly, the ZIF thickness of the ZnCo-gly surface could be controlled by adjusting the reaction time. After calcination, p-n heterojunctions were formed between the MOF-derived ZnO and Co3O4, which made it show excellent selectivity to methanal gas.

Acinous cell AR42J-derived exosome miR125b-5p promotes acute pancreatitis exacerbation by inhibiting M2 macrophage polarization via PI3K/AKT signaling pathway.

BACKGROUND: The incidence rate of acute pancreatitis (AP), which is a pathophysiological process with complex etiology, is increasing globally. miR-125b-5p, a bidirectional regulatory miRNA, is speculated to exhibit anti-tumor activity. However, exosome-derived miR-125b-5p in AP has not been reported. AIM: To elucidate the molecular mechanism of exosome-derived miR-125b-5p promoting AP exacerbation from the perspective of the interaction between immune cells and acinar cells. METHODS: Exosomes derived from AR42J cells were isolated and extracted in active and inactive states by an exosome extraction kit, and were verified via transmission electron microscopy, nanoparticle tracking analysis, and western blotting. RNA sequencing assay technology was used to screen differentially expressed miRNAs in active and inactive AR42J cell lines, and bioinformatics analysis was used to predict downstream target genes of miR-125b-5p. The expression level of miR-125b-5p and insulin-like growth factor 2 (IGF2) in the activated AR42J cell line and AP pancreatic tissue were detected by quantitative real-time polymerase chain reaction and western blots. The changes in the pancreatic inflammatory response in a rat AP model were detected by histopathological methods. Western Blot was used to detect the expression of IGF2, PI3K/AKT signaling pathway proteins, and apoptosis and necrosis related proteins. RESULTS: miR-125b-5p expression was upregulated in the activated AR42J cell line and AP pancreatic tissue, while that of IGF2 was downregulated. In vitro experiments confirmed that miR-125b-5p could promote the death of activated AR42J cells by inducing cell cycle arrest and apoptosis. In addition, miR-125b-5p was found to act on macrophages to promote M1 type polarization and inhibit M2 type polarization, resulting in a massive release of inflammatory factors and reactive oxygen species accumulation. Further research found that miR-125b-5p could inhibit the expression of IGF2 in the PI3K/AKT signaling pathway. Additionally, in vivo experiments revealed that miR-125b-5p can promote the progression of AP in a rat model. CONCLUSION: miR-125b-5p acts on IGF2 in the PI3K/AKT signaling pathway and promotes M1 type polarization and inhibits M2 type polarization of macrophage by inhibiting IGF2 expression, resulting in a large release of pro-inflammatory factors and an inflammatory cascade amplification effect, thus aggravating AP.

IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling.

BACKGROUND: Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia. In addition to systemic immune/inflammatory effects in response to tumor progression, tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss. However, the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood. METHODS: The yki -gut tumors were induced in fruit flies. Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3 (IGFBP-3) treated cells. Immunoblotting was used to display phenotypes of tumor cells and adipocytes. Quantitative polymerase chain reaction (qPCR) analysis was carried out to examine the gene expression levels such as Acc1 , Acly , and Fasn et al . RESULTS: In this study, it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes. IGFBP-3, which is highly expressed in cachectic tumor cells, antagonized insulin/IGF-like signaling (IIS) and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes. Conditioned medium from cachectic tumor cells, such as Capan-1 and C26 cells, contained excessive IGFBP-3 that potently induced lipolysis in adipocytes. Notably, neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes. Furthermore, cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS, ensuring their escape from IGFBP-3-associated growth suppression. Finally, cachectic tumor-derived ImpL2, the IGFBP-3 homolog, also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila . Most importantly, IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients, especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients. CONCLUSION: Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.

An examination of causal associations and shared risk factors for diabetes and cardiovascular diseases in the East Asian population: A Mendelian randomization study.

Background: One of the major contributors to disability and mortality among diabetics is cardiovascular disease (CVD), with coronary artery disease (CAD) as the most prevalent type. However, previous studies have provided controversial evidence linking diabetes to other types of CVDs, such as atrial fibrillation (AF). In addition, the risk factors that predispose people to the risk of diabetes and its complications differ across ethnicities, but the disease risk profiles in the East Asian population have been less investigated. Methods: The causal association between type 2 diabetes (T2D) and two types of CVDs (i.e., AF and CAD) in the East Asian population was first studied using Mendelian randomization (MR) analyses. Next, we examined the causal effect of 49 traits on T2D and CAD to identify their separate and shared risk factors in East Asians. A causal mediation analysis was performed to examine the role of T2D in mediating the relationship between the identified shared risk factors and CAD. Results: T2D was causally associated with CAD, but not AF, in East Asians. A screening of the risk factors indicated that six and 11 traits were causally associated with T2D and CAD, respectively, with suggestive levels of evidence. Alkaline phosphatase (ALP) was the only trait associated with both T2D and CAD, as revealed by the univariable MR analyses. Moreover, the causal association between ALP and CAD no longer existed after adjusting T2D as a covariable in the causal mediation study. Conclusion: Our study highlights the risk profiles in the East Asian population, which is important in formulating targeted therapies for T2D and CVDs in East Asians.

Predictive Risk Factors of Pancreatic Exocrine Insufficiency Developed After Acute Pancreatitis: A Retrospective Cohort Study.

Purpose: The aim of this study was to compare the clinical characteristics of acute pancreatitis (AP) patients between those who developed pancreatic exocrine insufficiency (PEI) and those who did not, and to investigate the predictive factors of PEI. Patients and Methods: From October 1st 2019 to July 30th 2021, AP patients admitted at our center were included. The fecal elastase-1 assay was adopted for PEI diagnosis. The clinical characteristics, treatments, and outcomes between the patients with and without PEI were analyzed. Results: In total, 63 males and 42 females were included. There were 27 patients with mild AP, 54 with moderately severe AP, and 24 with severe AP. The median modified computed tomography severity index (MCTSI) was 6.000(4.000, 8.000). During the follow-up, 38 patients developed PEI after AP. The univariate analysis showed that higher ASA grade (P = 0.006), more severe AP (P = 0.000), the presence of multiple organ dysfunction syndrome (P = 0.030), higher MCTSI (P = 0.000), the development of infected pancreatic necrosis (P = 0.002) and local complications (P = 0.000), higher levels of triacylglycerol (P = 0.022), video-assisted retroperitoneal debridement intervention (P = 0.015), and longer intensive care unit stay (P = 0.044) were correlated with PEI development. Furthermore, the logistic regression analyses showed that MCTSI during hospitalization is an independent risk factor for PEI development during the AP recovery period. Conclusion: ASA grade, severity of AP, multiple organ dysfunction syndrome, MCTSI, infected pancreatic necrosis, local complications, higher levels of triacylglycerol, video-assisted retroperitoneal debridement intervention, and longer intensive care unit stay were potentially associated with PEI development during the AP recovery period. High MCTSI was independently associated with the development of PEI during the AP recovery period, which may help alert to the possibility of PEI to help with its early detection and treatment.

Identification of critical prognosis signature associated with lymph node metastasis of stomach adenocarcinomas.

Lymph node metastasis (LNM) is an important factor affecting the prognosis of patients with gastric adenocarcinoma (STAD), which is the most common malignancy of the human digestive system. Current detection techniques have limited sensitivity and specificity, and there is a lack of effective biomarkers to screen for LNM. Therefore, it is critical to screen for biomarkers that predict LNM in STAD. Gene expression differential analysis (false discovery rate < 0.05, |log2Fold change| ≥1.5) was performed on 102 LNM samples, 224 non-LNM samples, and 29 normal gastric tissue samples from The Cancer Genome Atlas (TCGA) STAD dataset, and 269 LNM-specific genes (DEGs) were obtained. Enrichment analysis showed that LNM-specific genes functioned mainly in cytokine-cytokine receptor interactions, calcium signaling, and other pathways. Ten DEGs significantly associated with overall survival in STAD patients were screened by multivariate Cox regression, and an LNM-based 10-mRNA prognostic signature was established (Logrank P < 0.0001). This 10-mRNA signature was well predicted in both the TCGA training set and the Gene Expression Omnibus validation dataset (GSE84437) and was associated with survival in patients with LNM or advanced-stage STAD. Using Kaplan-Meier survival, receiver operating characteristic curve, C-index analysis, and decision curve analysis, the 10-mRNA signature was found to be a more effective predictor of prognosis in STAD patients than the other two reported models (P < 0.0005). Protein-protein interaction network and gene set enrichment analysis of the 10-mRNA signature revealed that the signature may affect the expression of multiple biological pathways and related genes. Finally, the expression levels of prognostic genes in STAD tissues and cell lines were verified using qRT-PCR, Western blot, and the Human Protein Atlas database. Taken together, the prognostic signature constructed in this study may become an indicator for clinical prognostic assessment of LNM-STAD and provide a new strategy for future targeted therapy.

Shared Decision-Making in Hemophilic Arthropathy Rehabilitation: A Qualitative Study.

Purpose: To probe into the needs and barriers underlying patients' participation in shared decision-making related to rehabilitation nursing for hemophilic arthropathy. Patients and Methods: The phenomenological research approach was adopted to conduct a series of semi-structured, in-depth interviews with 15 patients with hemophilic arthropathy undergoing rehabilitative treatments, 10 caregivers, and 7 healthcare providers from a hemophilia treatment center in Shanxi province, China. Colaizzi's seven-step method of data analysis was applied to organize, analyze, and extract the themes from the interview materials. Results: Three main themes emerged from the analysis: the status quo of the healthcare system (insufficient decision support systems and mismatch between healthcare providers' and patients' resources), circumstances of provider-patient interactions (lack of information exchange and unbalanced power structure between healthcare providers and patients), and patient-related factors influencing participation in decision-making (lack of self-efficacy, personal characteristics, family and social decision support, and attitude toward participation in decision-making). Conclusion: Participation in rehabilitation decision-making among patients with hemophilic arthropathy is affected by multiple barriers. Healthcare professionals should improve their understanding of shared decision-making, offer patients active guidance on participating in the decision-making process, prioritize their affective needs, and formulate professional and effective solutions to support shared decision-making as early as possible.

Characteristics and Incidence of Colon Complication in Necrotizing pancreatitis: A Propensity Score-Matched Study.

Objective: To clarify the incidence of colonic complications in patients with NP and their impact on prognosis. Methods: The clinical data of NP patients admitted to the Department of General Surgery of Xuanwu Hospital, Capital Medical University from January 2014 to December 2020 were retrospectively analyzed. Patients were grouped according to the presence or absence of colonic complications, and the clinical prognosis of the two groups was analyzed after matching using a 1:1 propensity score, The primary study endpoint was patient mortality during hospitalization. Data are reported as median (range) or percentage of patients (%). Results: A total of 306 patients with NP were included in this study, and the incidence of colonic complications was 12.4%, including 15 cases of colonic obstruction, 17 cases of colonic fistula, and 9 cases of colonic hemorrhage. Before matching, patients in the colonic group had severe admissions and poor clinical outcomes (P<0.05). After matching, the baseline data and clinical characteristics at admission were comparable between the two groups of patients. In terms of clinical outcomes, although the mortality was similar in the two groups (P>0.05), but patients in the colonic group were more likely to have multiorgan failure, length of nutrition support, number of minimally invasive interventions, number of extra-pancreatic infections, length of ICU stay and total length of stay were significantly higher than those of patients in the group without colonic complications (P<0.05). During long-term follow-up, patients in the colonic group were more likely to develop recurrent pancreatitis. Conclusion: About 12.4% of NP patients developed colonic complications, and after PSM it was found that colonic complications only led to a longer hospital stay and an increased number of clinical interventions in NP patients and did not increase the mortality.

Identification of key microRNAs in exosomes derived from patients with the severe acute pancreatitis.

OBJECTIVE: Exosomes have been identified as important carriers of various genetic materials, including microRNAs (miRNAs). Increasing evidence indicates that the course of severe acute pancreatitis (SAP) is associated with miRNAs transported by exosomes. We aimed to identify the signature miRNAs as biomarkers of SAP. METHODS: We obtained exosomes from the SAP patients' blood. After separation, purification, and identification, we performed high-throughput sequencing and screened the differentially expressed(DE) miRNAs in the exosomes. Bioinformatics analysis was performed to identified the target genes of the miRNAs and the pathways enriched based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, and selected the key miRNAs related to SAP. Total RNA was extracted from patient serum exosomes to detect the expression levels of the selected miRNAs in exosomes of three experimental groups (mild -, moderately severe -, and severe AP) and a control group, using Real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: 272 DE miRNAs were identified between SAP and control group. Using bioinformatics analysis, we determined that the functions of the target genes were enriched in six signaling pathways including focal adhesion. Based on this, seven candidate signature miRNAs were selected: miR-603, miR-548ad-5p, miR-122-5p, miR-4477a, miR-192-5p, miR-215-5p, and miR-583. The RT-qPCR results of the seven miRNAs in the SAP group were consistent with the sequencing results. CONCLUSION: Exosome-derived miR-603, miR-548ad-5p, miR-122-5p, miR-4477a, miR-192-5p, miR-215-5p, miR-583 are positively correlated with SAP, which might provide new insights into the pathogenesis of SAP and serve as the biomarkers of SAP.

BL-918, a small-molecule activator of ULK1, induces cytoprotective autophagy for amyotrophic lateral sclerosis therapy.

Amyotrophic lateral sclerosis (ALS) is one of the most common fatal neurodegenerative diseases in adults. ALS pathogenesis is associated with toxic SOD1 aggregates generated by mutant SOD1. Since autophagy is responsible for the clearance of toxic protein aggregates including SOD1 aggregates, autophagy induction has been considered as a potential strategy for treating ALS. Autophagic signaling is initiated by unc-51 like autophagy activating kinase 1 (ULK1) complex. We previously identified that BL-918 as a specific ULK1 activator, which exerted cytoprotective effect against Parkinson's disease in vitro and in vivo. In this study we investigated whether BL-918 exerted a therapeutic effect against ALS, and characterized its pharmacokinetic profile in rats. In hSODG93A-NSC34 cells, treatment with BL-918 (5, 10 µM) dose-dependently induced ULK1-dependent autophagy, and eliminated toxic SOD1 aggregates. In SODG93A mice, administration of BL-918 (40, 80 mg/kg, b.i.d., i.g.) dose-dependently prolonged lifespan and improved the motor function, and enhanced the clearance of SOD1 aggregates in spinal cord and cerebral cortex through inducing autophagy. In the pharmacokinetic study conducted in rats, we found BL-918 and its 2 metabolites (M8 and M10) present in spinal cord and brain; after intragastric and intravenous administration, BL-918 reached the highest blood concentration compared to M8 and M10. Collectively, ULK1 activator BL-918 displays a therapeutic potential on ALS through inducing cytoprotective autophagy. This study provides a further clue for autophagic dysfunction in ALS pathogenesis.

The Correlation Between the HEAD-US-C Score and HJHS in Hemophilic Arthropathy of the Knee.

OBJECTIVES: We aimed to discuss the correlation between the Hemophilia Early Detection Ultrasound in China (HEAD-US-C) score and the Hemophilia Joint Health Score version 2.1 (HJHS 2.1) of the knee joint in patients with hemophilia. METHODS: We included 70 male patients with hemophilia admitted to The Second Hospital of Shanxi Medical University; the patients' bilateral knee joints were evaluated using the HEAD-US-C score and HJHS. We analyzed factors influencing hemophilia arthropathy of the knee and examined the correlation between the HEAD-US-C score and HJHS. RESULTS: The joint injury severity was positively correlated with age and the number of bleeds (P < .001). Further, the HEAD-US-C score and HJHS differed according to the severity (both P < .001), but not type (P = .163 and P = .283, respectively), of hemophilia. There was a significant correlation between the HEAD-US-C score and HJHS (P < .001). CONCLUSIONS: Overall, all joint lesions observed on ultrasound corresponded to clinical joint functional abnormalities. Therefore, the HEAD-US-C is important for hemophilic arthropathy evaluation and is useful in explaining abnormal joint function.

Effect of acupuncture pretreatment on inflammatory response of exercise-induced skeletal muscle damage in rats based on TLR9/MyD88/NF-κB signaling pathway. / 基于TLR9/MyD88/NF­κBä¿¡å·é€šè·¯æŽ¢è®¨é’ˆåˆºé¢„å¤„ç†å¯¹è¿åŠ¨æ€§éª¨éª¼è‚ŒæŸä¼¤å¤§é¼ ç‚Žæ€§ååº”çš„å½±å“.

OBJECTIVES: To observe the effects of acupuncture pretreatment on toll-like receptor 9/myeloid differentiation factor 88/nuclear factor-κB (TLR9/MyD88/NF-κB) signaling pathway and inflammatory response in the rats with exercise-induced skeletal muscle damage (EIMD) and explore the underlying mechanism of this pretreatment for EIMD. METHODS: A total of 88 male SD rats were randomly divided into a blank group (8 rats), a model group (40 rats) and an acupuncture pretreatment group (40 rats). In the model group and the acupuncture pretreatment group, 5 subgroups were randomized according to the sampling time of 0, 12, 24, 48 and 72 h of modeling, with 8 rats in each one, respectively. Before modeling, in the acupuncture pretreatment group, acupuncture was delivered at bilateral "Zusanli" (ST 36) and "Guanyuan" (CV 4) for 20 min, once daily for consecutive 7 days. By one-time intermittent downhill centrifugal exercise on animal experimental treadmill, EIMD model was established in the model group and the acupuncture pretreatment group. The ultrastructure of gastrocnemius muscle was observed under transmission electron microscope. The levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the serum were detected by ELISA. The protein and mRNA expression of TLR9, MyD88 and NF-κB p65 in the gastrocnemius tissue of rats was detected by the Western blot and real-time PCR, respectively. RESULTS: Compared with the blank group, the gastrocnemius ultrastructure in the model group showed the damage of different degrees, with myofilaments disarranged and twisted, mitochondria obviously swollen and mitochondrial crista partially defected. Compared with the model group, the injury was mild, most of muscle fibers were arranged neatly and the number of mitochondria increased remarkably in the acupuncture pretreatment group. Compared with the blank group, in the model group, the serum IL-6 levels increased at 0, 12, 24 and 48 h after modeling in the rats (P<0.01), and TNF-α levels were elevated at each time point after modeling (P<0.05, P<0.01). In the acupuncture pretreatment group, the serum IL-6 levels were reduced at 12, 24 and 48 h after modeling (P<0.01, P<0.05), and the TNF-α levels decreased at 24, 48 and 72 h after modeling (P<0.01) when compared with those in the model group at the same time points separately. The serum IL-6 and TNF-α levels ascended and then tended to decline in the model group and the acupuncture pretreatment group. Compared with the blank group, the protein and mRNA expression of TLR9 and NF-κB p65 in the gastrocnemius tissue increased at 12, 24, 48 and 72 h after modeling (P<0.01, P<0.05), and the protein and mRNA expression levels of MyD88 in the gastrocnemius tissue at each time point after modeling were elevated (P<0.05, P<0.01) in the model group. When compared with the model group at the same time points, in the acupuncture pretreatment group, the protein expression of TLR9 in the gastrocnemius tissue decreased at 12, 24, 48 and 72 h after modeling (P<0.05, P<0.01), and the mRNA expression of TLR9 was declined at 24, 48 and 72 h after modeling (P<0.01, P<0.05); the protein and mRNA expression of MyD88 in the gastrocnemius decreased at 24, 48 and 72 h after modeling (P<0.01, P<0.05), and that of NF-κB p65 was reduced at 24 h and 48 h after modeling (P<0.01). The protein and mRNA expression of TLR9, MyD88 and NF-κB p65 in the gastrocnemius tissue showed a trend of decrease after increase in the model group and the acupuncture pretreatment group. CONCLUSIONS: Acupuncture pretreatment can alleviate exercise-induced skeletal muscle damage, which may be related to modulating the expression of TLR9/MyD88/NF-κB signaling pathway to inhibit the inflammatory response.

Risk Factors and Outcomes of Multidrug-Resistant Bacteria Infection in Infected Pancreatic Necrosis Patients.

Objective: The incidence of acute pancreatitis (AP) is increasing. Twenty percent of AP patients with developing necrotizing pancreatitis (NP), while ~40-70% of NP patients develop potentially fatal infectious complications. When patients are suspected or confirmed infected pancreatic necrosis (IPN), antibiotics should be administered timeously to control the infection, but long-term use of antibiotics can lead to multidrug-resistant bacteria (MDRB) infection and eventually to increased mortality. Our study aimed to determine the incidence of MDRB infection and evaluate the risk factors for MDRB infection in IPN patients. Methods: Clinical data of IPN patients admitted to the general surgery department of Xuanwu Hospital of Capital Medical University between January 1, 2014, and December 31, 2021, were retrospectively analyzed. Results: IPN patients (n = 267) were assigned to MDRB infection (n = 124) and non-MDRB infection (n = 143) groups. On admission, patients in the MDRB group had a higher modified computer tomography severity index (CTSI) score (P < 0.05), pancreatic necrosis degree, and PCT level (P < 0.05) than those in the non-MDRB group, and the prognosis of patients in MDRB group was poor. The most common gram-negative bacteria were Acinetobacter baumannii (n = 117), the most common gram-positive bacteria were Enterococcus faecium (n = 98), and the most common fungal infection was Candida albicans (n = 47). Multivariable analysis showed that complications of EPI (OR: 4.116, 95% CI: 1.381-12.271, P = 0.011), procalcitonin (PCT) level at admission (OR: 2.728, 95% CI: 1.502-4.954, P = 0.001), and degree of pancreatic necrosis (OR: 2.741, 95% CI: 1.109-6.775, P = 0.029) were independent risk factors for MDRB infection in IPN patients. Conclusion: We identified common infectious strains and risk factors for MDRB infection in IPN patients.

Prognostic biomarkers of pancreatic cancer identified based on a competing endogenous RNA regulatory network.

Background: Pancreatic cancer is an insidious and heterogeneous malignancy with poor prognosis that is often locally unresectable. Therefore, determining the underlying mechanisms and effective prognostic indicators of pancreatic cancer may help optimize clinical management. This study was conducted to develop a prognostic model for pancreatic cancer based on a competing endogenous RNA (ceRNA) network. Methods: We obtained transcriptomic data and corresponding clinicopathological information of pancreatic cancer samples from The Cancer Genome Atlas (TCGA) database (training set). Based on the ceRNA interaction network, we screened candidate genes to build prediction models. Univariate Cox regression analysis was performed to screen for genes associated with prognosis, and least absolute shrinkage and selection operator (LASSO) regression analysis was conducted to construct a predictive model. A receiver operating characteristic (ROC) curve was drawn, and the C-index was calculated to evaluate the accuracy of the prediction model. Furthermore, we downloaded transcriptomic data and related clinical information of pancreatic cancer samples from the Gene Expression Omnibus database (validation set) to evaluate the robustness of our prediction model. Results: Eight genes (ANLN, FHDC1, LY6D, SMAD6, ACKR4, RAB27B, AUNIP, and GPRIN3) were used to construct the prediction model, which was confirmed as an independent predictor for evaluating the prognosis of patients with pancreatic cancer through univariate and multivariate Cox regression analysis. By plotting the decision curve, we found that the risk score model is an independent predictor has the greatest impact on survival compared to pathological stage and targeted molecular therapy. Conclusions: An eight-gene prediction model was constructed for effectively and independently predicting the prognosis of patients with pancreatic cancer. These eight genes identified show potential as diagnostic and therapeutic targets.