Increased LACTB2 Expression Regulates Oxidative Phosphorylation and mTORC1 Signaling of Colorectal Cancer.

This study aimed to investigate the mechanisms of LACTB2 in colorectal cancer (CRC). Microarrays and sequencing data of CRC were acquired from UCSC Xena, GTEx, Gene Expression Omnibus, and TCGA. Pooled analysis of the mRNA expression of LACTB2 in CRC was performed using Stata software. The protein expression of LACTB2 in CRC tissues was evaluated by immunohistochemistry. The relationship between immune cell infiltration and LACTB2 expression was investigated using CIBERSORT. The potential signaling pathways and biological mechanisms of LACTB2 were explored using GSEA, KEGG, and GO. Subsequently, further screening of small molecular compounds with potential therapeutic effects on CRC was conducted through the HERB database, followed by molecular docking studies of these compounds with the LACTB2 protein. The integration and analysis of expression data obtained from 2294 CRC samples and 1286 noncancerous colorectal samples showed that LACTB2 was highly expressed in CRC. Immunohistochemistry performed on in-house tissue samples confirmed that LACTB2 protein expression was upregulated in CRC. CIBERSORT revealed lower B cell infiltration levels in the high LACTB2 expression group than in the low expression group. GO, KEGG, and GSEA analyses showed that LACTB2 expression and genes positively correlating with it were mainly related to DNA synthesis and repair, mitochondrial translational elongation and translational termination, phosphorylation, and mTORC1 signaling. Finally, molecular docking simulations confirmed the ability of quercitin to target and bind to LACTB2. This is the first study to demonstrate that LACTB2 is upregulated in CRC. LACTB2 promotes colorectal tumorigenesis and tumor progression.

Design, synthesis, antifungal evaluation and mechanism study of novel norbornene derivatives as potential laccase inhibitors.

BACKGROUND: To discover novel fungicide candidates, five series of novel norbornene hydrazide, bishydrazide, oxadiazole, carboxamide and acylthiourea derivatives (2a-2t, 3a-3f, 4a-4f, 5a-5f and 7a-7f) were designed, synthesized and assayed for their antifungal activity toward seven representative plant fungal pathogens. RESULTS: In the in vitro antifungal assay, some title norbornene derivatives presented good antifungal activity against Botryosphaeria dothidea, Sclerotinia sclerotiorum and Fusarium graminearum. Especially, compound 2b exhibited the best inhibitory activity toward B. dothidea with the median effective concentration (EC50) of 0.17 mg L-1, substantially stronger than those of the reference fungicides boscalid and carbendazim. The in vivo antifungal assay on apples revealed that 2b had significant curative and protective effects, both of which were superior to boscalid. In the preliminary antifungal mechanism study, 2b was able to injure the surface morphology of hyphae, destroy the cell membrane integrity and increase the intracellular reactive oxygen species (ROS) level of B. dothidea. In addition, 2b could considerably inhibit the laccase activity with the median inhibitory concentration (IC50) of 1.02 µM, much stronger than that of positive control cysteine (IC50 = 35.50 µM). The binding affinity and interaction mode of 2b with laccase were also confirmed by molecular docking. CONCLUSION: This study presented a promising lead compound for the study of novel laccase inhibitors as fungicidal agrochemicals, which demonstrate significant anti-B. dothidea activity and laccase inhibitory activity. © 2024 Society of Chemical Industry.

Ring-contracted Artemisinin Derivatives as Novel CDK4/6 Inhibitors: Synthesis and Anti-Breast Cancer Evaluation.

The endoperoxide group of artemisinins is a universally accepted essential group for their anti-cancer effects. In this work, a series of D-ring-contracted artemisinin derivatives were constructed by combining ring-contracted artemisinin core with the fragments of functional heterocyclic molecules or classical CDK4/6 inhibitors to identify more efficacious breast cancer treatment agents. Twenty-six novel hybridized molecules were synthesized and characterized by HRMS, IR, 1H NMR and 13C NMR data. In antiproliferative activities and kinase inhibitory effects assays, we found that the antiproliferative effects of B01 were close to positive controls Palbociclib, with GI50 values of 4.87±0.23 µM and 9.97±1.44 µM towards T47D cells and MDA-MB-436 cells respectively. In addition, the results showed that B01 were the most potent compounds against CDK6/cyclin D3 kinase, with IC50 values of 0.135±0.041 µM, its activity is about 1/3 of the positive control Palbociclib.

Biofortification of different maize cultivars with zinc, iron and selenium by foliar fertilizer applications.

Fertilizer-based biofortification is a strategy for combating worldwide malnutrition of zinc (Zn), iron (Fe) and selenium (Se). Field experiments were conducted to investigate the effects of foliar treatments on concentrations of Zn, Fe, Se, N and bioavailability of Zn and Fe in grains of three maize cultivars grown at three locations. We compared the efficacy of ZnO nanoparticles (ZnO-NPs), Zn complexed chitosan nanoparticles (Zn-CNPs), conventional ZnSO4 and a cocktail solution (containing Zn, Fe and Se). All treatments were foliar-applied at rate of 452 mg Zn L-1, plus urea. Applying ten-fold less Zn (at rate of 45.2 mg Zn L-1) plus urea in the form of ZnO-NPs, Zn-CNPs, or ZnSO4 resulted in no increase, or a negligible increase, in grain Zn concentration compared with deionized water. By contrast, among the different Zn sources plus urea applied by foliar sprays, conventional ZnSO4 was the most efficient in improving grain Zn concentration. Furthermore, foliar application of a cocktail solution effectively improved grain concentrations of Zn, Fe, Se and N simultaneously, without a grain yield trade-off. For example, the average grain concentrations were simultaneously increased from 13.8 to 22.1 mg kg-1 for Zn, from 17.2 to 22.1 mg kg-1for Fe, from 21.4 to 413.5 ug kg-1 for Se and from 13.8 to 14.7 g kg-1 for N by foliar application of a cocktail solution. Because grain yield was significantly negatively correlated with grain nutrient concentrations, the magnitude of increase in grain concentrations of Zn and Fe was most pronounced in the maize cultivar with the lowest grain yield (Zhengdan958 grown in Linyi). Foliar application of a cocktail solution also significantly decreased the phytic acid (PA) concentration, ratios of PA/Fe and PA/Zn in grains, indicating an increased bioavailability of Fe and Zn for human health. In conclusion, we found that a foliar application of a cocktail solution including Zn, Fe, Se and N was most effective for biofortification, but that the grains with the lowest yield contained the greatest concentration of these elements. This finding highlights the need to breed maize varieties that are capable of achieving both high grain yield and high grain nutritional quality to address food security and human health challenges.

MV-CVIB: a microbiome-based multi-view convolutional variational information bottleneck for predicting metastatic colorectal cancer.

Introduction: Imbalances in gut microbes have been implied in many human diseases, including colorectal cancer (CRC), inflammatory bowel disease, type 2 diabetes, obesity, autism, and Alzheimer's disease. Compared with other human diseases, CRC is a gastrointestinal malignancy with high mortality and a high probability of metastasis. However, current studies mainly focus on the prediction of colorectal cancer while neglecting the more serious malignancy of metastatic colorectal cancer (mCRC). In addition, high dimensionality and small samples lead to the complexity of gut microbial data, which increases the difficulty of traditional machine learning models. Methods: To address these challenges, we collected and processed 16S rRNA data and calculated abundance data from patients with non-metastatic colorectal cancer (non-mCRC) and mCRC. Different from the traditional health-disease classification strategy, we adopted a novel disease-disease classification strategy and proposed a microbiome-based multi-view convolutional variational information bottleneck (MV-CVIB). Results: The experimental results show that MV-CVIB can effectively predict mCRC. This model can achieve AUC values above 0.9 compared to other state-of-the-art models. Not only that, MV-CVIB also achieved satisfactory predictive performance on multiple published CRC gut microbiome datasets. Discussion: Finally, multiple gut microbiota analyses were used to elucidate communities and differences between mCRC and non-mCRC, and the metastatic properties of CRC were assessed by patient age and microbiota expression.

Layer-specific strain in patients with cardiac amyloidosis using tissue tracking MR.

Background: Cardiac infiltration is the major predictor of poor prognosis in patients with systemic amyloidosis, thus it becomes of great importance to evaluate cardiac involvement. Purpose: We aimed to evaluate left ventricular myocardial deformation alteration in patients with cardiac amyloidosis (CA) using layer-specific tissue tracking MR. Material and Methods: Thirty-nine patients with CA were enrolled. Thirty-nine normal controls were also recruited. Layer-specific tissue tracking analysis was done based on cine MR images. Results: Compared with the control group, a significant reduction in LV whole layer strain values (GLS, GCS, and GRS) and layer-specific strain values was found in patients with CA (all P < 0.01). In addition, GRS and GLS, as well as subendocardial and subepicardial GLS, GRS, and GCS, were all diminished in patients with CA and reduced LVEF, when compared to those with preserved or mid-range LVEF (all P < 0.05). GCS showed the largest AUC (0.9952, P = 0.0001) with a sensitivity of 93.1% and specificity of 90% to predict reduced LVEF (<40%). Moreover, GCS was the only independent predictor of LV systolic dysfunction (Odds Ratio: 3.30, 95% CI:1.341-8.12, and P = 0.009). Conclusion: Layer-specific tissue tracking MR could be a useful method to assess left ventricular myocardial deformation in patients with CA.

A DNA-based hydrogel for exosome separation and biomedical applications.

Exosomes (EXOs) have been proven as biomarkers for disease diagnosis and agents for therapeutics. Great challenge remains in the separation of EXOs with high-purity and low-damage from complex biological media, which is critical for the downstream applications. Herein, we report a DNA-based hydrogel to realize the specific and nondestructive separation of EXOs from complex biological media. The separated EXOs were directly utilized in the detection of human breast cancer in clinical samples, as well as applied in the therapeutics of myocardial infarction in rat models. The materials chemistry basis of this strategy involved the synthesis of ultralong DNA chains via an enzymatic amplification, and the formation of DNA hydrogels through complementary base-pairing. These ultralong DNA chains that contained polyvalent aptamers were able to recognize and bind with the receptors on EXOs, and the specific and efficient binding ensured the selective separation of EXOs from media into the further formed networked DNA hydrogel. Based on this DNA hydrogel, rationally designed optical modules were introduced for the detection of exosomal pathogenic microRNA, which achieved the classification of breast cancer patients versus healthy donors with 100% precision. Furthermore, the DNA hydrogel that contained mesenchymal stem cell-derived EXOs was proved with significant therapeutic efficacy in repairing infarcted myocardium of rat models. We envision that this DNA hydrogel-based bioseparation system is promising as a powerful biotechnology, which will promote the development of extracellular vesicles in nanobiomedicine.

DeepTPpred: A Deep Learning Approach With Matrix Factorization for Predicting Therapeutic Peptides by Integrating Length Information.

The abuse of traditional antibiotics has led to increased resistance of bacteria and viruses. Efficient therapeutic peptide prediction is critical for peptide drug discovery. However, most of the existing methods only make effective predictions for one class of therapeutic peptides. It is worth noting that currently no predictive method considers sequence length information as a distinct feature of therapeutic peptides. In this article, a novel deep learning approach with matrix factorization for predicting therapeutic peptides (DeepTPpred) by integrating length information are proposed. The matrix factorization layer can learn the potential features of the encoded sequence through the mechanism of first compression and then restoration. And the length features of the sequence of therapeutic peptides are embedded with encoded amino acid sequences. To automatically learn therapeutic peptide predictions, these latent features are input into the neural networks with self-attention mechanism. On eight therapeutic peptide datasets, DeepTPpred achieved excellent prediction results. Based on these datasets, we first integrated eight datasets to obtain a full therapeutic peptide integration dataset. Then, we obtained two functional integration datasets based on the functional similarity of the peptides. Finally, we also conduct experiments on the latest versions of the ACP and CPP datasets. Overall, the experimental results show that our work is effective for the identification of therapeutic peptides.

Influence of different factors on registration error in a 1.5 T MR-guided linac.

Purpose. Accurate image registration is an important step in online image-guided adaptive radiotherapy. The aim of this study was to investigate the effects of different factors on registration accuracy in a magnetic resonance (MR)-guided adaptive radiotherapy workflow.Materials and Methods. A thorax motion phantom was used to obtain computed tomography (CT) simulations in 8 different motion modes and to generate 8 reference plans. Daily pretreatment online MR images were obtained at 5 different positions in each reference plan. Online MR and CT simulations were separately registered using bone structures and the gross tumor volume (GTV) as ROIs, and the image shift distance was recorded by the online treatment planning system. The difference between the shift distance and the real isocentric distance was the registration error. The registration error was analyzed, and the effects of the setup position, motion mode and ROI selection on the registration error were investigated by multivariate analysis of variance.Result. The minimum values of registration error (ΔX, ΔY, ΔZ) were -1.90 mm, -2.70 mm and -2.40 mm, respectively, and the maximum values were 1.70 mm, 4.30 mm and -0.90 mm. ΔY showed the maximum mean standard deviation of 1.25 mm, and ΔZshowed the minimum mean standard deviation of 0.27 mm. The standard deviation of the registration error is largest in the inferior/superior direction. The motion mode of the phantom and ROI selection were significantly correlated with ΔX, ΔY, and ΔZ(p< 0.05).Conclusion. The registration result with the spine as the selected ROI was better than that with the GTV as the ROI. In 1.5 T MR-linac clinical treatment, more attention should be given to patient movement repeatability and to controlling the intrafractional motion as much as possible. It is not recommended to make the GTV-PTV margin expansion less than 2 mm for MR-linac.

In Silico Studies of the Impact of Rotational Errors on Translation Shifts and Dose Distribution in Image-Guided Radiotherapy.

Objective: To compare the 6-dimensional errors of different immobilization devices and body regions based on 3-dimensional cone beam computed tomography for image-guided radiotherapy and to further quantitatively evaluate the impact of rotational corrections on translational shifts and dose distribution based on anthropomorphic phantoms. Materials and Methods: Two hundred ninety patients with cone beam computed tomographies from 3835 fractions were retrospectively analyzed for brain, head & neck, chest, abdomen, pelvis, and breast cases. A phantom experiment was conducted to investigate the impact of rotational errors on translational shifts using cone beam computed tomography and the registration system. For the dosimetry study, pitch rotations were simulated by adjusting the breast bracket by ±2.5°. Roll and yaw rotations were simulated by rotating the gantry and couch in the planning system by ±3.0°, respectively. The original plan for the breast region was designed in the computed tomography image space without rotation. With the same planning parameters, the original plan was transplanted into the image space with different rotations for dose recalculation. The effect of these errors on the breast target and organs at risk was assessed by dose-volume histograms. Results: Most of the mean rotational errors in the breast region were >1°. A single uncorrected yaw of 3° caused a change of 2.9 mm in longitudinal translation. A phantom study for the breast region demonstrated that when the pitch rotations were -2.5° and 2.5° and roll and yaw were both 3°, the reductions in the planning target volumes-V50 Gy were 20.07% and 29.58% of the original values, respectively. When the pitch rotation was +2.5°, the left lung V5 Gy and heart Dmean were 7.49% and 165.76 Gy larger, respectively, than the original values. Conclusions: Uncorrected rotations may cause changes in the values and directions of translational shifts. Rotational corrections may improve the patient setup and dose distribution accuracy.

Loss of the receptors ER, PR and HER2 promotes USP15-dependent stabilization of PARP1 in triple-negative breast cancer.

Poly(ADP-ribose) polymerase 1 (PARP1) is essential for the progression of several types of cancers. However, whether and how PARP1 is stabilized to promote genomic stability in triple-negative breast cancer (TNBC) remains unknown. Here, we demonstrated that the deubiquitinase USP15 interacts with and deubiquitinates PARP1 to promote its stability, thereby stimulating DNA repair, genomic stability and TNBC cell proliferation. Two PARP1 mutations found in individuals with breast cancer (E90K and S104R) enhanced the PARP1-USP15 interaction and suppressed PARP1 ubiquitination, thereby elevating the protein level of PARP1. Importantly, we found that estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) inhibited USP15-mediated PARP1 stabilization through different mechanisms. ER bound to the USP15 promoter to suppress its expression, PR suppressed the deubiquitinase activity of USP15, and HER2 abrogated the PARP1-USP15 interaction. The specific absence of these three receptors in TNBC results in high PARP1 levels, leading to increases in base excision repair and female TNBC cell survival.

Computational prediction and characterization of cell-type-specific and shared binding sites.

MOTIVATION: Cell-type-specific gene expression is maintained in large part by transcription factors (TFs) selectively binding to distinct sets of sites in different cell types. Recent research works have provided evidence that such cell-type-specific binding is determined by TF's intrinsic sequence preferences, cooperative interactions with co-factors, cell-type-specific chromatin landscapes and 3D chromatin interactions. However, computational prediction and characterization of cell-type-specific and shared binding sites is rarely studied. RESULTS: In this article, we propose two computational approaches for predicting and characterizing cell-type-specific and shared binding sites by integrating multiple types of features, in which one is based on XGBoost and another is based on convolutional neural network (CNN). To validate the performance of our proposed approaches, ChIP-seq datasets of 10 binding factors were collected from the GM12878 (lymphoblastoid) and K562 (erythroleukemic) human hematopoietic cell lines, each of which was further categorized into cell-type-specific (GM12878- and K562-specific) and shared binding sites. Then, multiple types of features for these binding sites were integrated to train the XGBoost- and CNN-based models. Experimental results show that our proposed approaches significantly outperform other competing methods on three classification tasks. Moreover, we identified independent feature contributions for cell-type-specific and shared sites through SHAP values and explored the ability of the CNN-based model to predict cell-type-specific and shared binding sites by excluding or including DNase signals. Furthermore, we investigated the generalization ability of our proposed approaches to different binding factors in the same cellular environment. AVAILABILITY AND IMPLEMENTATION: The source code is available at: https://github.com/turningpoint1988/CSSBS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Mechanisms of Chinese Medicine in Gastroesophageal Reflux Disease Treatment: Data Mining and Systematic Pharmacology Study.

OBJECTIVE: To identify specific Chinese medicines (CMs) that may benefit patients with gastroesophageal reflux disease (GERD), and explore the action mechanism. METHODS: Domestic and foreign literature on the treatment of GERD with CMs was searched and selected from China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and PubMed from October 1, 2011 to October 1, 2021. Data from all eligible articles were extracted to establish the database of CMs for GERD. Apriori algorithm of data mining techniques was used to analyze the rules of herbs selection and core Chinese medicine formulas were identified. A system pharmacology approach was used to explore the action mechanism of these medicines. RESULTS: A total of 278 prescriptions for GERD were analyzed, including 192 CMs. Results of Apriori algorithm indicated that Evodiae Fructus and Coptidis Rhizoma were the highest confidence combination. A total of 32 active ingredients and 66 targets were screened for the treatment of GERD. Enrichment analysis showed that the mechanisms of action mainly involved pathways in cancer, fluid shear stress and atherosclerosis, advanced glycation end product (AGE), the receptor for AGE signaling pathway in diabetic complications, bladder cancer, and rheumatoid arthritis. CONCLUSION: Evodiae Fructus and Coptidis Rhizoma are the core drugs in the treatment of GERD and the potential mechanism of action of these medicines includes potential target and pathways.

Effect of exercise training on cardiac mitochondrial respiration, biogenesis, dynamics, and mitophagy in ischemic heart disease.

Objective: Cardiac mitochondrial dysfunction was found in ischemic heart disease (IHD). Hence, this study determined the effects of exercise training (ET) on cardiac mitochondrial respiration and cardiac mitochondrial quality control in IHD. Methods: A narrative synthesis was conducted after searching animal studies written in English in three databases (PubMed, Web of Science, and EMBASE) until December 2020. Studies that used aerobic exercise as an intervention for at least 3 weeks and had at least normal, negative (sedentary IHD), and positive (exercise-trained IHD) groups were included. The CAMARADES checklist was used to check the quality of the included studies. Results: The 10 included studies (CAMARADES score: 6-7/10) used swimming or treadmill exercise for 3-8 weeks. Seven studies showed that ET ameliorated cardiac mitochondrial respiratory function as manifested by decreased reactive oxygen species (ROS) production and increased complexes I-V activity, superoxide dismutase 2 (SOD2), respiratory control ratio (RCR), NADH dehydrogenase subunits 1 and 6 (ND1/6), Cytochrome B (CytB), and adenosine triphosphate (ATP) production. Ten studies showed that ET improved cardiac mitochondrial quality control in IHD as manifested by enhanced and/or controlled mitochondrial biogenesis, dynamics, and mitophagy. Four other studies showed that ET resulted in better cardiac mitochondrial physiological characteristics. Conclusion: Exercise training could improve cardiac mitochondrial functions, including respiration, biogenesis, dynamics, and mitophagy in IHD. Systematic review registration: https://www.crd.york.ac.uk/prospero/ display_record.php?RecordID=226817, identifier: CRD42021226817.

A cohesin-associated gene score may predict immune checkpoint blockade in hepatocellular carcinoma.

Stromal antigen 1 (STAG1), a component of cohesion, is overexpressed in various cancers, but it is unclear whether it has a role in the transcriptional regulation of hepatocellular carcinoma (HCC). To test this hypothesis, here, we screened global HCC datasets and performed multiscale embedded gene co-expression network analysis to identify the potential functional modules of differentially expressed STAG1 co-expressed genes. The putative transcriptional targets of STAG1 were identified using chromatin immunoprecipitation followed by high-throughput DNA sequencing. The cohesin-associated gene score (CAGS) was quantified using the The Cancer Genome Atlas HCC cohort and single-sample gene set enrichment analysis. Distinct cohesin-associated gene patterns were identified by calculating the euclidean distance of each patient. We assessed the potential ability of the CAGS in predicting immune checkpoint blockade (ICB) treatment response using IMvigor210 and GSE78220 cohorts. STAG1 was upregulated in 3313 HCC tissue samples compared with 2692 normal liver tissue samples (standard mean difference = 0.54). A total of three cohesin-associated gene patterns were identified, where cluster 2 had a high TP53 mutated rate and a poor survival outcome. Low CAGS predicted a significant survival advantage but presaged poor immunotherapy response. Differentially expressed STAG1 co-expression genes were enriched in the mitotic cell cycle, lymphocyte activation, and blood vessel development. PDS5A and PDGFRA were predicted as the downstream transcriptional targets of STAG1. In summary, STAG1 is significantly upregulated in global HCC tissue samples and may participate in blood vessel development and the mitotic cell cycle. A cohesin-associated gene scoring system may have potential to predict the ICB response.

Macrophage Membrane-Derived Biomimetic Nanoparticles for Treatment of Cytokine Release Syndrome.

Cytokine release syndrome (CRS) is a severe complication of infectious diseases like Coronavirus disease 2019 (COVID-19) that cause serious damage to public health. Currently, supportive therapy is still the main therapeutic strategy exists for CRS treatment. Here, we show the potential of macrophage membrane-derived biomimetic nanoparticles for CRS treatment. By fusing macrophage membrane on the surface of the PLGA nano core, we constructed biomimetic nanoparticles that inherited the membrane receptors from the "parental" macrophages, enabling the neutralization of CRS-related cytokines. We compared three types of macrophage membranes to screen out more effective biomimetic nanoparticles for CRS treatment. Our results show that M0 macrophage membrane-derived biomimetic nanoparticles could neutralize pro-inflammatory cytokines involved in CRS to the greatest extent and reduce organ damage in a mouse model.

Effect of Body Size Change on Off-Center Cervical Point and Face Doses in Patients Undergoing Nasopharyngeal Carcinoma Radiotherapy.

Nasopharyngeal carcinoma (NPC) is a clinically multiple malignant tumor. At present, with the increase in the infection rate of Epstein-Barr virus, the incidence of nasopharyngeal carcinoma is also increasing day by day. To explore the effect of body size change on off-center cervical point and face doses in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy, in total, 100 patients with NPC from January 2019 to May 2020 in our hospital were selected for retrospective analysis, and they all received intensity-modulated radiation therapy. Bodyweight, horizontal longitudinal diameter of the odontoid process, longitudinal diameter of the third cervical spine, maximum radiation dose, and average radiation dose of normal organs in the first and last treatments were assessed, and the correlation between normal organ irradiation dose and body size was analyzed. Bodyweight, horizontal longitudinal diameter of the odontoid process, and longitudinal diameter of the third cervical spine in the last treatment were lower than those in the first treatment, with a statistically significant difference. There was no statistically significant difference in the maximum normal organ irradiation dose to the left eyeball, right eyeball, left crystalline lens, right crystalline lens, and maximum irradiation dose to optic nerve between the last treatment and the first treatment. In the last treatment, the maximum dose to the left parotid gland, right parotid gland, spinal cord, and brain stem was higher than that in the first treatment. The average irradiation dose to the left eye bulb, right eye bulb, left lens, right lens, optic nerve in the last treatment, and that in the first treatment showed no significant difference. The average dose to the left parotid gland, right parotid gland, spinal cord, and brain stem in the last treatment was higher than that in the first treatment. The irradiation dose to the left parotid gland, right parotid gland, spinal cord, and brain stem was significantly negatively correlated with body weight, horizontal longitudinal diameter of the odontoid process, and longitudinal diameter of the third cervical spine. After NPC radiotherapy, the body size of patients can change, which can have different effects on irradiation doses. Therefore, the target area and dose should be corrected during treatment to ensure the efficacy and safety of the treatment.

Acanthoic acid, unique potential pimaradiene diterpene isolated from Acanthopanax koreanum Nakai (Araliaceae): A review on its pharmacology, molecular mechanism, and structural modification.

Acanthoic acid (AA) is a pimaradiene diterpene isolated from the root bark of Acanthopanax koreanum Nakai (Araliaceae) with a wide range of pharmacological activities, including anti-cancer, anti-inflammatory, anti-diabetes, liver protection, gastrointestinal protection, and cardiovascular protection. In addition, AA promotes its pharmacological effects by targeting liver X receptors (LXRs), nuclear factor-kappa B (NF-κB), Toll-Like Receptor 4 (TLR4) and IL-1 receptor-associated kinase (IRAK) signaling pathways, or AMP-activated protein kinase (AMPK) signaling pathway, etc. Also, some studies focus on the structural modification of AA to improve its pharmacological activities. The review summarizes the pharmacological activities, molecular mechanism, and the structural modification of AA, which might supply information for the development of AA in the future.

Modulation of interleukin-36 based inflammatory feedback loop through the hepatocyte-derived IL-36R-P2X7R axis improves steatosis in alcoholic steatohepatitis.

BACKGROUND AND PURPOSE: Interleukin-36 is induced by proinflammatory cytokines and promotes inflammatory responses, creating an IL-36-based inflammation loop. Although hepatocytes, produce IL-36 responses to drug-induced liver injury, little is known about the mechanistic role of IL-36 signalling during the progression of alcoholic steatohepatitis (ASH). Regarding IL-36/IL-36R and P2X7R coregulating the inflammatory response, we elucidated that modulation of IL-36R-P2X7R-TLR axis affected hepatocyte steatosis as well as the IL-36-based inflammatory feedback loop that accompanies the onset of ASH. EXPERIMENTAL APPROACH: C57BL/6J mice were subjected to either chronic-plus-binge ethanol feeding or acute gavage with multiple doses of ethanol to establish ASH, followed by pharmacological inhibition or genetic silencing of IL-36R and P2X7R. AML12 cells or mouse primary hepatocytes were stimulated with alcohol, LPS plus ATP or Poly(I:C) plus ATP, followed by silencing of IL-36γ, IL-36R or P2X7R. KEY RESULTS: P2X7R and IL-36R deficiency blocked the inflammatory loop, specifically initiated by IL-36 cytokines, in hepatocytes of mice suffering from ASH. Pharmacological inhibition to P2X7R or IL-36R alleviated lipid accumulation and inflammatory response in ASH. IL-36R was indispensable for P2X7R modulated NLRP3 inflammasome activation in ASH, and IL-36 led to a vicious cycle of P2X7R-driven inflammation in alcohol-treated hepatocytes. TLR ligands promoted IL-36γ production in hepatocytes, based on synergism with P2X7R. CONCLUSIONS AND IMPLICATIONS: Blockade of IL-36 based inflammatory feedback loop, via IL-36R-P2X7R-TLRs-modulated NLRP3 inflammasome activation, circumvented steatosis and inflammation that accompanies the onset of ASH, suggesting that targeting IL-36 can serve as a novel therapeutic approach to combat ASH.

Mucosal bacterial dysbiosis in patients with nodular lymphoid hyperplasia in the terminal ileum.

BACKGROUND: Nodular lymphoid hyperplasia (NLH) in the small intestine is a rare benign lesion characterized by multiple small nodules on the intestinal surface. Patients with terminal ileal NLH may experience long-term abdominal pain, diarrhea, and abdominal distension, among other symptoms. Supplementation with probiotics could mitigate these symptoms. NLH is linked to the immune system, and it may result from accumulation of plasma-cell precursors due to a maturational defect during the development of B lymphocytes. The intestinal microbiome plays an essential role in the immune system. Thus, we speculate that the gut flora plays a key role in terminal ileal NLH. AIM: To explore the correlation between intestinal flora and terminal ileal NLH. METHODS: We collected mucosal biopsy samples that were obtained via colonoscopy from 15 patients with terminal ileal NLH (the test group) and 15 normal subjects (the control group). We subsequently performed 16S-rRNA gene amplicon sequencing of these samples, and the results were evaluated using alpha diversity, beta diversity and microbial composition analyses. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States was used to predict the metabolic pathways and orthologous groups according to the Kyoto Encyclopedia of Genes and Genomes database. RESULTS: Compared with the control group, the terminal ileal NLH group showed an increased alpha diversity (P < 0.05). The overall intestinal microbiota in the NLH group was significantly different from that of the control group (P < 0.05), implying that there was the dysbiosis in the terminal ileal NLH patients. The relative abundance of phylum Bacteroidetes was significantly lower in the NLH group, while that of Patescibacteria and Campilobacterota was significantly higher. The genus Bacteroides was the dominant gut microbiota in both groups, but its abundance was significantly lower in the test group than it was in the control group. Conversely, the relative abundances of Haemophilus, Streptococcus, Pseudomonas, Actinomyces, TM7X, Fusobacterium nucleatum, Parvimonas, Granulicatella, Helicobacter, and the [Eubacterium] nodatum group were significantly higher in the test group than they were in the control group. In addition, several altered metabolic pathways, orthologous groups, and modules were found. For example, the Peptidoglycan biosynthesis and Aminoacyl tRNA biosynthesis were both increased in the test group. CONCLUSION: Maintaining the microbial balance and supplementing targeted protective bacteria could improve symptoms and potentially reduce the risk of lymphoma transformation in patients with terminal ileal NLH.