ResearchPad - 22 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Renaissance of Radiotherapy in Intestinal Lymphoma? 10‐Year Efficacy and Tolerance in Multimodal Treatment of 134 Patients: Follow‐up of Two German Multicenter Consecutive Prospective Phase II Trials]]> https://www.researchpad.co/article/elastic_article_6608 This article reports the details of radiation therapy in the therapeutic multimodality approach for treatment of patients with intestinal lymphoma.

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<![CDATA[Intestinal microbes: an axis of functional diversity among large marine consumers]]> https://www.researchpad.co/article/N11c9ff5b-6314-46a5-963a-c9aec1a1f5de Microbes are ubiquitous throughout the world's oceans, yet the manner and extent of their influence on the ecology and evolution of large, mobile fauna remains poorly understood. Here, we establish the intestinal microbiome as a hidden, and potentially important, ‘functional trait’ of tropical herbivorous fishes—a group of large consumers critical to coral reef resilience. Using field observations, we demonstrate that five common Caribbean fish species display marked differences in where they feed and what they feed on. However, in addition to space use and feeding behaviour—two commonly measured functional traits—we find that interspecific trait differences are even more pronounced when considering the herbivore intestinal microbiome. Microbiome composition was highly species specific. Phylogenetic comparison of the dominant microbiome members to all known microbial taxa suggest that microbiomes are comprised of putative environmental generalists, animal-associates and fish specialists (resident symbionts), the latter of which mapped onto host phylogeny. These putative symbionts are most similar to—among all known microbes—those that occupy the intestines of ecologically and evolutionarily related herbivorous fishes in more distant ocean basins. Our findings therefore suggest that the intestinal microbiome may be an important functional trait among these large-bodied consumers.

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<![CDATA[Mobile genomics: tools and techniques for tackling transposons]]> https://www.researchpad.co/article/Nd5da9de4-30ba-4ec8-a08b-86fd66b18c96

Next-generation sequencing approaches have fundamentally changed the types of questions that can be asked about gene function and regulation. With the goal of approaching truly genome-wide quantifications of all the interaction partners and downstream effects of particular genes, these quantitative assays have allowed for an unprecedented level of detail in exploring biological interactions. However, many challenges remain in our ability to accurately describe and quantify the interactions that take place in those hard to reach and extremely repetitive regions of our genome comprised mostly of transposable elements (TEs). Tools dedicated to TE-derived sequences have lagged behind, making the inclusion of these sequences in genome-wide analyses difficult. Recent improvements, both computational and experimental, allow for the better inclusion of TE sequences in genomic assays and a renewed appreciation for the importance of TE biology. This review will discuss the recent improvements that have been made in the computational analysis of TE-derived sequences as well as the areas where such analysis still proves difficult.

This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

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<![CDATA[Constraining classifiers in molecular analysis: invariance and robustness]]> https://www.researchpad.co/article/Nea33803e-a97c-4264-8a61-36afec4e7efb

Analysing molecular profiles requires the selection of classification models that can cope with the high dimensionality and variability of these data. Also, improper reference point choice and scaling pose additional challenges. Often model selection is somewhat guided by ad hoc simulations rather than by sophisticated considerations on the properties of a categorization model. Here, we derive and report four linked linear concept classes/models with distinct invariance properties for high-dimensional molecular classification. We can further show that these concept classes also form a half-order of complexity classes in terms of Vapnik–Chervonenkis dimensions, which also implies increased generalization abilities. We implemented support vector machines with these properties. Surprisingly, we were able to attain comparable or even superior generalization abilities to the standard linear one on the 27 investigated RNA-Seq and microarray datasets. Our results indicate that a priori chosen invariant models can replace ad hoc robustness analysis by interpretable and theoretically guaranteed properties in molecular categorization.

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<![CDATA[Reconciling periodic rhythms of large-scale biological networks by optimal control]]> https://www.researchpad.co/article/Nd3fd2fe7-1722-490f-9f77-9cf9436cd0cd

Periodic rhythms are ubiquitous phenomena that illuminate the underlying mechanism of cyclic activities in biological systems, which can be represented by cyclic attractors of the related biological network. Disorders of periodic rhythms are detrimental to the natural behaviours of living organisms. Previous studies have shown that the state transition from one to another attractor can be accomplished by regulating external signals. However, most of these studies until now have mainly focused on point attractors while ignoring cyclic ones. The aim of this study is to investigate an approach for reconciling abnormal periodic rhythms, such as diminished circadian amplitude and phase delay, to the regular rhythms of complex biological networks. For this purpose, we formulate and solve a mixed-integer nonlinear dynamic optimization problem simultaneously to identify regulation variables and to determine optimal control strategies for state transition and adjustment of periodic rhythms. Numerical experiments are implemented in three examples including a chaotic system, a mammalian circadian rhythm system and a gastric cancer gene regulatory network. The results show that regulating a small number of biochemical molecules in the network is sufficient to successfully drive the system to the target cyclic attractor by implementing an optimal control strategy.

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<![CDATA[Wednesday posters]]> https://www.researchpad.co/article/N19c7ed87-c80c-46f1-bedc-4ddeabe0c3eb ]]> <![CDATA[Thursday posters]]> https://www.researchpad.co/article/N50c37668-91e9-43b8-aadf-3c08854ae4fc ]]> <![CDATA[Hidden patterns of codon usage bias across kingdoms]]> https://www.researchpad.co/article/N34680f65-51e7-4171-99d0-45d58d6a7774

The genetic code is necessarily degenerate with 64 possible nucleotide triplets being translated into 20 amino acids. Eighteen out of the 20 amino acids are encoded by multiple synonymous codons. While synonymous codons are clearly equivalent in terms of the information they carry, it is now well established that they are used in a biased fashion. There is currently no consensus as to the origin of this bias. Drawing on ideas from stochastic thermodynamics we derive from first principles a mathematical model describing the statistics of codon usage bias. We show that the model accurately describes the distribution of codon usage bias of genomes in the fungal and bacterial kingdoms. Based on it, we derive a new computational measure of codon usage bias—the distance D capturing two aspects of codon usage bias: (i) differences in the genome-wide frequency of codons and (ii) apparent non-random distributions of codons across mRNAs. By means of large scale computational analysis of over 900 species across two kingdoms of life, we demonstrate that our measure provides novel biological insights. Specifically, we show that while codon usage bias is clearly based on heritable traits and closely related species show similar degrees of bias, there is considerable variation in the magnitude of D within taxonomic classes suggesting that the contribution of sequence-level selection to codon bias varies substantially within relatively confined taxonomic groups. Interestingly, commonly used model organisms are near the median for values of D for their taxonomic class, suggesting that they may not be good representative models for species with more extreme D, which comprise organisms of medical and agricultural interest. We also demonstrate that amino acid specific patterns of codon usage are themselves quite variable between branches of the tree of life, and that some of this variability correlates with organismal tRNA content.

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<![CDATA[Prediction of polyproline II secondary structure propensity in proteins]]> https://www.researchpad.co/article/N455a20f0-8aef-4ba9-93e2-b6a96b069556

Background: The polyproline II helix (PPIIH) is an extended protein left-handed secondary structure that usually but not necessarily involves prolines. Short PPIIHs are frequently, but not exclusively, found in disordered protein regions, where they may interact with peptide-binding domains. However, no readily usable software is available to predict this state. Results: We developed PPIIPRED to predict polyproline II helix secondary structure from protein sequences, using bidirectional recurrent neural networks trained on known three-dimensional structures with dihedral angle filtering. The performance of the method was evaluated in an external validation set. In addition to proline, PPIIPRED favours amino acids whose side chains extend from the backbone (Leu, Met, Lys, Arg, Glu, Gln), as well as Ala and Val. Utility for individual residue predictions is restricted by the rarity of the PPIIH feature compared to structurally common features. Conclusion: The software, available at http://bioware.ucd.ie/PPIIPRED, is useful in large-scale studies, such as evolutionary analyses of PPIIH, or computationally reducing large datasets of candidate binding peptides for further experimental validation.

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<![CDATA[Revisiting the hypothesis of an energetic barrier to genome complexity between eukaryotes and prokaryotes]]> https://www.researchpad.co/article/N0bd3f347-f06c-4152-b53d-fbf3e5c05574

The absence of genome complexity in prokaryotes, being the evolutionary precursors to eukaryotic cells comprising all complex life (the prokaryote–eukaryote divide), is a long-standing question in evolutionary biology. A previous study hypothesized that the divide exists because prokaryotic genome size is constrained by bioenergetics (prokaryotic power per gene or genome being significantly lower than eukaryotic ones). However, this hypothesis was evaluated using a relatively small dataset due to lack of data availability at the time, and is therefore controversial. Accordingly, we constructed a larger dataset of genomes, metabolic rates, cell sizes and ploidy levels to investigate whether an energetic barrier to genome complexity exists between eukaryotes and prokaryotes while statistically controlling for the confounding effects of cell size and phylogenetic signals. Notably, we showed that the differences in bioenergetics between prokaryotes and eukaryotes were less significant than those previously reported. More importantly, we found a limited contribution of power per genome and power per gene to the prokaryote–eukaryote dichotomy. Our findings indicate that the prokaryote–eukaryote divide is hard to explain from the energetic perspective. However, our findings may not entirely discount the traditional hypothesis; in contrast, they indicate the need for more careful examination.

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<![CDATA[Lymph Node Imaging in Patients with Primary Breast Cancer: Concurrent Diagnostic Tools]]> https://www.researchpad.co/article/Nb602c4c4-063d-42c6-a392-9bd95fb8407e

Abstract

The detection of lymph node metastasis affects the management of patients with primary breast cancer significantly in terms of staging, treatment, and prognosis. The main goal for the radiologist is to determine and detect the presence of metastatic disease in nonpalpable axillary lymph nodes with a positive predictive value that is high enough to initially select patients for upfront axillary lymph node dissection. Features that are suggestive of axillary adenopathy may be seen with different imaging modalities, but ultrasound is the method of choice for evaluating axillary lymph nodes and for performing image‐guided lymph node interventions. This review aims to provide a comprehensive overview of the available imaging modalities for lymph node assessment in patients diagnosed with primary breast cancer.

Implications for Practice

The detection of lymph node metastasis affects the management of patients with primary breast cancer. The main goal for the radiologist is to detect lymph node metastasis in patients to allow for the selection of patients who should undergo upfront axillary lymph node dissection. Features that are suggestive of axillary adenopathy may be seen with mammography, computed tomography, and magnetic resonance imaging, but ultrasonography is the imaging modality of choice for evaluating axillary lymph nodes. A normal axillary lymph node is characterized by a reniform shape, a maximal cortical thickness of 3 mm without focal bulging, smooth margins, and, depending on size, a discernable central fatty hilum.

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<![CDATA[A practical view of fine-mapping and gene prioritization in the post-genome-wide association era]]> https://www.researchpad.co/article/N8e494b47-64da-4604-aa32-679a75731a0f

Over the past 15 years, genome-wide association studies (GWASs) have enabled the systematic identification of genetic loci associated with traits and diseases. However, due to resolution issues and methodological limitations, the true causal variants and genes associated with traits remain difficult to identify. In this post-GWAS era, many biological and computational fine-mapping approaches now aim to solve these issues. Here, we review fine-mapping and gene prioritization approaches that, when combined, will improve the understanding of the underlying mechanisms of complex traits and diseases. Fine-mapping of genetic variants has become increasingly sophisticated: initially, variants were simply overlapped with functional elements, but now the impact of variants on regulatory activity and direct variant-gene 3D interactions can be identified. Moreover, gene manipulation by CRISPR/Cas9, the identification of expression quantitative trait loci and the use of co-expression networks have all increased our understanding of the genes and pathways affected by GWAS loci. However, despite this progress, limitations including the lack of cell-type- and disease-specific data and the ever-increasing complexity of polygenic models of traits pose serious challenges. Indeed, the combination of fine-mapping and gene prioritization by statistical, functional and population-based strategies will be necessary to truly understand how GWAS loci contribute to complex traits and diseases.

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<![CDATA[The amino acid transporter SLC-36.1 cooperates with PtdIns3P 5-kinase to control phagocytic lysosome reformation]]> https://www.researchpad.co/article/Ndbf67ba1-f075-4531-9ced-7a6bcdd2ef63

How lysosomes reform following phagolysosomal digestion of apoptotic cells is poorly understood. Gan et al. reveal that the amino acid transporter SLC-36.1 cooperates with PtdIns3P 5-kinase to control phagocygtic lysosome reformation in Caenorhabditis elegans embryos and autophagic lysosome reformation in adult animals.

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<![CDATA[Responses of apoptosis and matrix metabolism of annulus fibrosus cells to different magnitudes of mechanical tension in vitro]]> https://www.researchpad.co/article/5c94bd6dd5eed0c484613215

Background: Annulus fibrosus (AF) is important to confine disc nucleus pulposus (NP) tissue during mechanical load experience. However, the knowledge on AF cell biology under mechanical load is much limited compared with disc NP. Objective: The present study aimed to investigate responses of apoptosis and matrix metabolism of AF cells to different magnitudes of mechanical tension in vitro. Methods: Rat AF cells were subjected to different magnitudes (5, 10, and 20% elongations at a frequency of 1.0 Hz for 6 h per day) of mechanical tension for 7 days. Control AF cells were cultured without mechanical tension. Cell apoptosis ratio, caspase-3 activity, gene/protein expression of apoptosis-related molecules (Bcl-2, Bax, caspase-3/cleaved caspase-3 and cleaved PARP), matrix macromolecules (aggrecan and collagen I) and matrix metabolism-related enzymes (TIMP-1, TIMP-3, MMP-3, and ADAMTS-4) were analyzed. Results: Compared with 5% tension group and control group, 10 and 20% tension groups significantly increased apoptosis ratio, caspase-3 activity, up-regulated gene/protein expression of Bax, caspase-3/cleaved caspase-3, cleaved PARP, MMP-3, and ADAMTS-4, whereas down-regulated gene/protein expression of Bcl-2, aggrecan, collagen I, TIMP-1, and TIMP-3. No significant difference was found in these parameters apart from Bcl-2 expression between the control group and 5% tension group. Conclusion: High mechanical tension promotes AF cell apoptosis and suppresses AF matrix synthesis compared with low mechanical tension. The present study indirectly indicates how mechanical overload induces disc degeneration through affecting AF biology.

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<![CDATA[The deregulation of STIM1 and store operative calcium entry impaired aortic smooth muscle cells contractility in aortic medial degeneration]]> https://www.researchpad.co/article/5c4b93dad5eed0c48487d17f

Background: Microarray analysis of clinical aortic samples suggested a potential role for stromal interaction molecule 1 (STIM1) in the modulation of aortic medial degeneration (AMD), despite the uncertainty about STIM1 in normal aortic smooth muscle cells (ASMCs). Here, we aimed to explore changes in STIM1 expression in AMD, and the possible mechanisms. Methods: An AMD model was established using auto-delivery of angiotensin II (Ang II) into ApoE−/− mice. We assessed the effects of SKF96365, a STIM1 inhibitor, in AMD model and in vitro cultured ASMCs. Elastic van Gieson (EVG) staining was used to visualize elastic fiber injury. Mitochondria changes were viewed by TEM. Cytoplasmic calcium was quantified by measuring fluo-4 staining in a flow cytometer. Mechanical stretching device was used to mimic stretching that ASMCs experience in vivo. Cell apoptosis was determined by using Annexin V/propidium iodide (PI) staining. The expression of STIM1, contractile related proteins (α-smooth muscle actin (α-SMA), myosin light chain (MLC)), endoplasmic reticulum (ER) stress-related proteins (CHOP, activating transcription factor 6 (ATF-6)) and smad2/3 were assessed by Western blotting, immunohistochemistry (IHC), and immunofluorescence (IF). Results: SKF96365 exacerbated aortic injury in the AMD model. SKF96365 reduced cytoplasmic calcium concentration in ASMCs, caused mitochondrial swelling, and elevated the expression of ATF-6 and CHOP. SKF96365 decreased the expression of MLC and α-SMA in ASMCs, causing them to be vulnerable to mechanical stretch. SKF96365 suppressed smad2/3 activation after treatment with transforming growth factor (TGF) β1 (TGFβ1). Conclusions: STIM1 is indispensable in ASMCs. Interfering with STIM1 exaggerated the AMD process by modulating the expression of contractile proteins, inducing ER stress in ASMCs.

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<![CDATA[MiRNA-575 suppresses angiogenesis by targeting Rab5-MEK-ERK pathway in endothelial cells]]> https://www.researchpad.co/article/5c4b941cd5eed0c48487de14

Hypertension is a major risk factor for the development of atherosclerosis. Increased carotid intima-media thickness (CIMT) is generally considered as an early marker of atherosclerosis. Recently, circulating miRNAs have been implicated both as sensitive biomarkers and key regulators in the development of atherosclerosis. However, the biological functions and molecular regulatory mechanisms for miR-575 on angiogenesis remain unknown. In our study, we first identified up-regulation of circulating miR-575 in plasma of essential hypertensive patients with increased CIMT (iCIMT) compared with those patients with normal CIMT (nCIMT). Furthermore, the overexpression of miR-575 in human umbilical vein endothelial cells (HUVECs) by its mimics significantly inhibited migration and proliferation as well as induction of apoptosis of HUVECs. Inhibition of miR-575 performed the reverse effects of HUVECs. We further suggested Rab5B was the downstream target of miR-575 and knockdown of Rab5B significantly inhibited migration and proliferation of HUVECs. Overexpression of Rab5B largely rescued the miR-575-mediated impairment of angiogenesis processes including: cell proliferation, migration, and apoptosis as well as activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK-ERK) signaling. Therefore, our results uncover a novel role of miR-575 in endothelial cells, implying a potential biomarker and clinical target for atherosclerosis in hypertensive patients.

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<![CDATA[Precision global health and comorbidity: a population-based study of 16 357 people in rural Uganda]]> https://www.researchpad.co/article/5c1acd48d5eed0c484078ada

In low-income countries, complex comorbidities and weak health systems confound disease diagnosis and treatment. Yet, data-driven approaches have not been applied to develop better diagnostic strategies or to tailor treatment delivery for individuals within rural poor communities. We observed symptoms/diseases reported within three months by 16 357 individuals aged 1+ years in 17 villages of Mayuge District, Uganda. Symptoms were mapped to the Human Phenotype Ontology. Comorbidity networks were constructed. An edge between two symptoms/diseases was generated if the relative risk greater than 1, ϕ correlation greater than 0, and local false discovery rate less than 0.05. We studied how network structure and flagship symptom profiles varied against biosocial factors. 88.05% of individuals (14 402/16 357) reported at least one symptom/disease. Young children and individuals in worse-off households—low socioeconomic status, poor water, sanitation, and hygiene, and poor medical care—had dense network structures with the highest comorbidity burden and/or were conducive to the onset of new comorbidities from existing flagship symptoms, such as fever. Flagship symptom profiles for fever revealed self-misdiagnoses of fever as malaria and sexually transmitted infections as a potentially missed cause of fever in individuals of reproductive age. Network analysis may inform the development of new diagnostic and treatment strategies for flagship symptoms used to characterize syndromes/diseases of global concern.

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<![CDATA[Acidic pH promotes nucleus pulposus cell senescence through activating the p38 MAPK pathway]]> https://www.researchpad.co/article/5c15d693d5eed0c484287f25

Background: Nucleus pulposus (NP) cell senescence is an important cellular feature within the degenerative disc. It is known that a very acidic niche exists in the degenerative disc, which participates in regulating disc cell viability and matrix metabolism. Objective: The present study was aimed to investigate the role and potential signaling transduction pathway of an acidic pH in regulating NP cell senescence. Methods: Rat NP cells were cultured in an acidic pH of 7.2 close to that in a healthy disc (Control group) or in an acidic pH of 6.2 close to that in a severe degenerative disc (Experiment group) for 10 days. Additionally, the experimental NP cells were incubated along with the inhibitor SB203580 to analyze the role of p38 MAPK pathway in this process. Results: Compared with the control NP cells, experimental NP cells showed a suppressed cell proliferation potency, an increased G0/G1 phase fraction whereas a decreased S-phase fraction and a declined telomerase activity, an up-regulated expression of senescence-related molecules (p16 and p53), and a down-regulated expression of matrix-related moleucles (aggrecan and collagen II). Further analysis showed that inhibition of the p38 MAPK pathway partly reversed effects of acidic pH of 6.2 on the experimental NP cells. Conclusion: The very acidic niche identified in a severe degenerative disc promotes NP cell senescence through regulating the p38 MAPK pathway. The present study provides a new mechanism that drives NP cell senescence during disc degeneration.

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<![CDATA[Network pharmacology-based identification of major component of Angelica sinensis and its action mechanism for the treatment of acute myocardial infarction]]> https://www.researchpad.co/article/5c15d688d5eed0c484287dd3

Background: To decipher the mechanisms of Angelica sinensis for the treatment of acute myocardial infarction (AMI) using network pharmacology analysis. Methods: Databases were searched for the information on constituents, targets, and diseases. Cytoscape software was used to construct the constituent–target–disease network and screen the major targets, which were annotated with the DAVID (Database for Annotation, Visualization and Integrated Discovery) tool. The cardioprotective effects of Angelica sinensis polysaccharide (ASP), a major component of A. sinensis, were validated both in H9c2 cells subjected to simulated ischemia by oxygen and glucose deprivation and in rats with AMI by ligation of the left anterior coronary artery. Results: We identified 228 major targets against AMI injury for A. sinensis, which regulated multiple pathways and hit multiple targets involved in several biological processes. ASP significantly decreased endoplasmic reticulum (ER) stress-induced cell death both in vitro and in vivo. In ischemia injury rats, ASP treatment reduced infarct size and preserved heart function. ASP enhanced activating transcription factor 6 (ATF6) activity, which improved ER-protein folding capacity. ASP activated the expression of p-AMP-activated protein kinase (p-AMPK) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). Additionally, ASP attenuated levels of proinflammatory cytokines and maintained a balance in the oxidant/antioxidant levels after AMI. Conclusion: In silico analysis revealed the associations between A. sinensis and AMI through multiple targets and several key signaling pathways. Experimental data indicate that ASP protects the heart against ischemic injury by activating ATF6 to ameliorate the detrimental ER stress. ASP’s effects could be mediated via the activation of AMPK-PGC1α pathway.

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<![CDATA[Protective effect of polydatin on radiation-induced injury of intestinal epithelial and endothelial cells]]> https://www.researchpad.co/article/5c15d67cd5eed0c484287bc3

This study aimed to examine the radioprotective effect of polydatin (PD) on crypt and endothelial cells of the small intestines of C57BL/6 mice that received abdominal irradiation (IR). Mice were treated with 6 MV X-ray (20 Gy) abdominal IR at a dose rate of 200 cGy/min. Thirty minutes before or after IR, mice were intraperitoneally injected with PD. The rate of survival of the mice at 30 days after IR was determined. The duodenum (upper small intestine), jejunum (middle small intestine), and ileum (lower small intestine) were collected and subjected to hematoxylin and eosin staining. Tissue sample sections were analyzed through light microscopy, and the lengths of at least 20 intestinal villi were measured in each group; the average number of crypts was obtained from 10 intestinal samples in each group. Microvessel density was assessed using CD31-positive (brown) vascular endothelial cells/cell clusters. FHs74Int cell proliferation was measured using the CCK-8 assay. PD administration (25 mg/kg) before IR was the most effective in prolonging the survival of C57BL/6 mice. PD reduced radiation-induced injury of intestinal villi, prevented loss of crypts, increased intestinal crypt growth, protected against IR-induced intestinal injury, and enhanced the proliferative potential and reduced the apoptosis of FHs74Int cells after IR. Moreover, PD increased small intestinal MVD and reduced the apoptosis of intestinal microvascular endothelial cells in mice after IR. Therefore, PD was found to be able to protect the two types of cells from radiation damage and to thus alleviate radiation-induced injury of small intestine.

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