A computationally efficient gradient-enhanced healing model for soft biological tissues.

Soft biological tissues, such as arterial tissue, have the ability to grow and remodel in response to damage. Computational method plays a critical role in understanding the underlying mechanisms of tissue damage and healing. However, the existing healing model often requires huge computation time and it is inconvenient to implement finite element simulation. In this paper, we propose a computationally efficient gradient-enhanced healing model that combines the advantages of the gradient-enhanced damage model, the homeostatic-driven turnover remodeling model, and the damage-induced growth model. In the proposed model, the evolution of healing-related parameters can be solved explicitly. Additionally, an adaptive time increment method is used to further reduce computation time. The proposed model can be easily implemented in Abaqus, requiring only a user subroutine UMAT. The effectiveness of proposed model is verified through a semi-analytical example, and the influence of the variables in the proposed model is investigated using uniaxial tension and open-hole plate tests. Finally, the long-term development of aneurysms is simulated to demonstrate the potential applications of the proposed model in real biomechanical problems.

Antidepressant effect of the novel histone deacetylase-5 inhibitor T2943 in a chronic restraint stress mouse model.

Depression is a prevalent and debilitating psychiatric illness. However, the antidepressant drugs currently prescribed are only effective in a limited group of patients. Histone modifications mediated by histone acetylation are considered to play an important role in the pathogenesis and treatment of depression. Recent studies have revealed that histone deacetylase inhibitors may be involved in the pathogenesis of depression and the underlying mechanism of the antidepressant therapeutic action. Here, we first conducted virtual screening of histone deacetylase-5 (HDAC5) inhibitors against HDAC5, a target closely related to depression, and identified compound T2943, further verifying its inhibitory effect on enzyme activities in vitro. After stereotaxic injection of T2943 into the hippocampus of mice, the antidepressant effect of T2943 was evaluated using behavioral experiments. We also used different proteomic and molecular biology analyses to determine and confirm that T2943 promoted histone 3 lysine 14 acetylation (H3K14ac) by inhibiting HDAC5 activity. Following the overexpression of adenoviral HDAC5 in the hippocampus of mice and subsequent behavioral analyses, we confirmed that T2943 exerts antidepressant effects by inhibiting HDAC5 activity. Our findings highlight the efficacy of targeting HDAC5 to treat depression and demonstrate the potential of using T2943 as an antidepressant.

Sensitivity analysis of the mechanical properties on atherosclerotic arteries rupture risk with an artificial neural network method.

Considering the differences between individuals, in this paper, an uncertainty analysis model for predicting rupture risk of atherosclerotic arteries is established based on a back-propagation artificial neural network. The influence of isotropy and anisotropy on the rupture risk of atherosclerotic arteries is analyzed, and the results demonstrate the effectiveness of the artificial neural network in predicting the rupture risk. Moreover, the rupture risk of atherosclerotic arteries at different inflation sizes are simulated. This study contributes to a better understanding of the underlying mechanisms of atherosclerotic arteries rupture and promotes the advancement of artificial neural networks in atherosclerosis research.

Cloning and characterization of AMP-activated protein kinase genes in Daphnia pulex: Modulation of AMPK gene expression in response to polystyrene nanoparticles.

Energy metabolism is essential for almost all organisms. At the molecular level, adenosine monophosphate activated protein kinase (AMPK) plays a vital role in cellular energy homeostasis. Its molecular characterization in invertebrates, including Daphnia pulex, and the understanding of its role in response to environmental contaminants is limited. In this study, three subunits of AMPK (AMPKα, ß, and γ) were cloned in D. pulex, and assigned the GenBank accession numbers MT536758, MT536759, and MT536760, respectively. Their full lengths were 2,000, 1,384, and 2594 bp, respectively, and contained open reading frames of 526, 274, and 580 amino acids, respectively. Bioinformatic analysis revealed that the three AMPK subunits all have features representative of the AMPK superfamily, and were correspondingly clustered with each orthologue branch. The three AMPK subunit genes, AMPKα, ß, and γ, had the highest similarity to those of other organisms at 82%, 94%, and 71%, respectively. Nanoplastics significantly increased AMPKα expression, but decreased that of AMPKß and γ. These results identified AMPKα, ß, and γ in D. pulex, and showed that they all encode proteins with conserved functional domains. This study provides basic information on how three types of AMPK in aquatic organisms respond to environmental contaminants.

Novel glucose-lowering drugs for non-alcoholic fatty liver disease.

BACKGROUND: The efficacy of novel glucose-lowering drugs in treating non-alcoholic fatty liver disease (NAFLD) is unknown. AIM: To evaluate the efficacy of glucose-lowering drugs dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors in treating NAFLD and to perform a comparison between these treatments. METHODS: Electronic databases were systematically searched. The inclusion criteria were: Randomized controlled trials comparing DPP-4 inhibitors, GLP-1 RAs, or SGLT2 inhibitors against placebo or other active glucose-lowering drugs in NAFLD patients, with outcomes of changes in liver enzyme [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] from baseline. RESULTS: Nineteen studies were finally included in this meta-analysis. Compared with placebo or other active glucose-lowering drug treatment, treatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors all led to a significant decrease in ALT change and AST change from baseline. The difference between the DPP-4 inhibitor and SGLT2 inhibitor groups in ALT change was significant in favor of DPP-4 inhibitor treatment (P < 0.05). The trends of reduction in magnetic resonance imaging proton density fat fraction and visceral fat area changes were also observed in all the novel glucose-lowering agent treatment groups. CONCLUSION: Treatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors resulted in improvements in serum ALT and AST levels and body fat composition, indicating a beneficial effect in improving liver injury and reducing liver fat in NAFLD patients.

STAT1-induced regulation of lncRNA ZFPM2-AS1 predicts poor prognosis and contributes to hepatocellular carcinoma progression via the miR-653/GOLM1 axis.

Long noncoding RNAs (lncRNAs) have drawn growing attention owing to their important effects in various tumors, including hepatocellular carcinoma (HCC). Recently, a newly identified lncRNA, ZFPM2 antisense RNA 1 (ZFPM2-AS1), was reported to serve as an oncogene in gastric cancer. However, its function in tumors remains largely unknown. In this study, we identified ZFPM2-AS1 as a novel HCC-related lncRNA, which was observed to be distinctly upregulated in HCC tissues and associated with shorter overall survival. Luciferase reporter and chromatin immunoprecipitation assays suggested that overexpression of ZFPM2-AS1 was induced by STAT1. Functional investigations suggested that the inhibition of ZFPM2-AS1 suppressed cell proliferation, metastasis, cell cycle progression while accelerated cell apoptosis. Mechanistic studies showed that there were two binding sites of miR-653 within the sequence of ZFPM2-AS1 and the levels of ZFPM2-AS1 were negatively correlated with miR-653. In addition, ZFPM2-AS1 could reverse the suppressor effects of miR-653 on the proliferation and metastasis of HCC cells by the modulation of GOLM1, a target gene of miR-653. To conclude, we provided a better understanding of the interaction mechanism between ZFPM2-AS-miR-653-GOLM1 axis, which may help develop prognostic biomarkers and therapeutic target for HCC.

Sensitivity analysis of non-local damage in soft biological tissues.

Computational modeling can provide insight into understanding the damage mechanisms of soft biological tissues. Our gradient-enhanced damage model presented in a previous publication has shown advantages in considering the internal length scales and in satisfying mesh independence for simulating damage, growth and remodeling processes. Performing sensitivity analyses for this model is an essential step towards applications involving uncertain patient-specific data. In this paper, a numerical analysis approach is developed. For that we integrate two existing methods, that is, the gradient-enhanced damage model and the surrogate model-based probability analysis. To increase the computational efficiency of the Monte Carlo method in uncertainty propagation for the nonlinear hyperelastic damage analysis, the surrogate model based on Legendre polynomial series is employed to replace the direct FEM solutions, and the sparse grid collocation method (SGCM) is adopted for setting the collocation points to further reduce the computational cost in training the surrogate model. The effectiveness of the proposed approach is illustrated by two numerical examples, including an application of artery dilatation mimicking to the clinical problem of balloon angioplasty.

LncRNA SNHG4 Attenuates Inflammatory Responses by Sponging miR-449c-5p and Up-Regulating STAT6 in Microglial During Cerebral Ischemia-Reperfusion Injury.

BACKGROUND: Inflammatory response mediated by microglia plays a key role in cerebral ischemia-reperfusion injury. This study intends to probe the role of lncRNA SNHG4 in regulating the inflammatory response of the microglia during cerebral ischemia reperfusion. MATERIALS AND METHODS: Blood samples and cerebrospinal fluid samples were collected from acute cerebral infarction (ACI) patients and healthy controls. The middle cerebral artery occlusion (MCAO) models were constructed with rats. LPS induction and oxygen-glucose deprivation methods were respectively applied to simulate the activation of microglia in vitro. qRT-PCR was employed to determine the expressions of SNHG4, miR-449c-5p and related inflammatory factors in vivo and in vitro. The inflammatory responses of the microglia subject to the varied expressions of SNHG4 and miR-449c-5p were detected. Luciferase assays were conducted to verify the crosstalk involving SNHG4, miR-449c-5p and STAT6. RESULTS: Compared with the control group, the expression of SNHG4 derived from the samples of ACI patients and the microglia of MCAO group were remarkably down-regulated, but the expression of miR-449c-5p was dramatically up-regulated. Overexpression of SNHG4 and knock-down of miR-449c-5p could inhibit the expression of pro-inflammatory cytokine in the microglia and promote the expression of anti-inflammatory factors. Meanwhile, the phospho-STAT6 was up-regulated, whereas the knock-down of SNHG4 and over-expression of miR-449c-5p in microglia had the opposite effects. Luciferase assay confirmed that SNHG4 could target miR-449c-5p, while miR-449c-5p could target STAT6. CONCLUSION: SNHG4 can regulate STAT6 and repress inflammation by adsorbing miR-449c-5p in microglia during cerebral ischemia-reperfusion injury.

TNF­α promotes the malignant transformation of intestinal stem cells through the NF­κB and Wnt/ß­catenin signaling pathways.

Cancer stem cells are responsible for tumorigenesis, progression, recurrence and metastasis. Intestinal stem cells (ISCs) are regarded as the origin of intestinal neoplasia. Inflammation also serves an important role in intestinal neoplasia. To explore the molecular mechanisms underlying the inflammation­mediated induction of intestinal tumorigenesis, the present study investigated the function of tumor necrosis factor (TNF)­α in the malignant transformation of ISCs. NCM460 spheroid (NCM460s) cells with higher expression of stem cell genes, such as Oct4, Nanog, Sox2 and Lgr5, and with a higher ratio of CD133+, were obtained from NCM460 cells in serum­free medium. TNF­α accelerated cell proliferation, migration and invasion, induced chemotherapy resistance and the epithelial­mesenchymal transition. NF­κB and Wnt/ß­catenin pathways were activated in TNF­α­induced inflammatory responses, leading to the nuclear translocation of p65 and ß­catenin, as well as promoter activity of NF­κB and TCF/LEF transcription factors. It was further demonstrated that TNF­α­induced activation of the NF­κB and Wnt/ß­catenin signaling pathways, as well as the upregulation of proinflammatory cytokines, were significantly suppressed by p65­knockdown. Notably, PDTC, an inhibitor of NF­κB signaling, reversed TNF­α­induced activation of the NF­κB and Wnt/ß­catenin pathways. A similar role was observed for IWP­2, an inhibitor of Wnt/ß­catenin signaling. Collectively, these results demonstrated that the NF­κB and Wnt/ß­catenin pathways were activated to promote TNF­α­induced malignant transformation of ISCs, in which these two pathways cross­regulated each other.

Postretrieval Microinjection of Baclofen Into the Agranular Insular Cortex Inhibits Morphine-Induced CPP by Disrupting Reconsolidation.

Environmental cues associated with drug abuse are powerful mediators of drug craving and relapse in substance-abuse disorders. Consequently, attenuating the strength of cue-drug memories could reduce the number of factors that cause drug craving and relapse. Interestingly, impairing cue-drug memory reconsolidation is a generally accepted strategy aimed at reducing the intensity of cues that trigger drug-seeking and drug-taking behaviors. In addition, the agranular insular cortex (AI) is an important component of the neural circuits underlying drug-related memory reconsolidation. GABAB receptors (GABABRs) are potential targets for the treatment of addiction, and baclofen (BLF) is the only prototypical GABAB agonist available for application in clinical addiction treatment. Furthermore, ΔFosB is considered a biomarker for the evaluation of potential therapeutic interventions for addiction. Here, we used the morphine-induced conditioned place preference (CPP) paradigm to investigate whether postretrieval microinjections of BLF into the AI could affect reconsolidation of drug-reward memory, reinstatement of CPP, and the level of ΔFosB in mice. Our results showed that BLF infused into the AI immediately following morphine CPP memory retrieval, but not 6 h postretrieval or following nonretrieval, could eliminate the expression of a morphine CPP memory. This effect persisted in a morphine-priming-induced reinstatement test, suggesting that BLF in the AI was capable of preventing the reconsolidation of the morphine CPP memory. Our results also showed that the elimination of morphine CPP memory was associated with reduced morphine-associated ΔFosB expression in the longer term. Taken together, the results of our research provide evidence to support that GABABRs in the AI have an important role in drug-cue memory reconsolidation and further our understanding of the role of the AI in drug-related learning and memory.

[Amentoflavone inhibits inflammation of mouse BV-2 microglia cells induced by lipopolysaccharide].

Objective To investigate the block effect of amentoflavone (AF) on the inflammation of mouse BV-2 microglial cells induced by lipopolysaccharide (LPS). Methods BV-2 microglial cells were treated with AF at different concentrations, and cell viability was determined by CCK-8 assay to get the AF concentration that had no effect on the cell viability. BV-2 microglia cells were pretreated with 10 mol/L AF, and 1 hour later, 1.0 g/mL LPS was used to induce inflammatory response in the BV-2 microglial cells. Real-time quantitative PCR was performed to detect the gene expression of interleukin 1ß (IL-1ß), tumor necrosis factor α (TNF-α), cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS). The protein expression of COX2 and iNOS were measured by Western blot analysis. Immunofluorescence staining was used to observe the location and expression of COX2 and iNOS. Results CCK-8 showed that 10 mol/L AF did not affect the viability in BV-2 microglial cells. The treatment of 1.0 g/mL LPS could significantly up-regulate the mRNA expression of IL-1ß, TNF-α, COX2, iNOS, and the protein expression of COX2 and iNOS. Compared with the only LPS treatment, 10 mol/L AF pretreatment markedly decreased the elevated gene and protein expression induced by LPS. In addition, AF significantly inhibited the expression of COX2 and iNOS, and less microglial cells were activated. Conclusion AF can inhibit the inflammation of BV-2 microglial cells induced by LPS.

[TNF-α activates PI3K/AKT pathway to promote proliferation of SW620Lgr5+ colon cancer stem cells].

Objective To investigate the role of PI3K/AKT pathway in the proliferation of SW620Lgr5+ colon cancer stem cells (CSCs) in inflammatory environment. Methods The expression level of Lgr5 in SW620, SW480, HT29 and HCT116 human colon cancer cells were analyzed by Western blot analysis. SW620 cells were selected to analyze the proportion of Lgr5+ cells by fluorescence activated cell sorting (FACS). The cells were cultured in serum-free medium (SFM) to form spheroid cells. Furthermore, Lgr5+ CSCs were isolated from the spheroid cells by FACS system. The biological characteristics of Lgr5+ CSCs were assessed by the colony formation assay and 5-FU chemotherapy sensitivity assay. The inflammatory microenvironment of Lgr5+ CSCs was established with TNF-α and the optimum conditions of TNF-α were analyzed using CCK-8 assay. CSCs were treated with PI3K/AKT pathway inhibitor MK2206. The experimental cells were divided into a blank control group, MK2206 group, TNF-α group and TNF-α combined with MK2206 group. The cell proliferation and apoptosis of each group were detected by colony formation assay and annexin V-FITC/PI double labeling assay. Finally, Western blot analysis was used to analyze the protein expression of AKT, phospho-AKT(p-AKT), GSK-3ß and p-GSK-3ß. Results The expression of Lgr5 in the SW620 cells was significantly higher than that in the other colon cancer cells. FACS showed 6.9% of SW620 cells were Lgr5+. After cultured in SFM, the proportion of Lgr5+ in SW620 spheroid cells increased to 34.5%. The proliferation ability and drug resistance were significantly enhanced in SW620Lgr5+ CSCs compared with SW620 cells. The treatment of 1 ng/mL TNF-α for 24 hours promoted the most remarkably increase of the viability of SW620Lgr5+ CSCs. Compared with the control group, TNF-α significantly increased the colony forming ability of SW620Lgr5+ CSCs. MK2206 statistically decreased the colony forming ability of SW620Lgr5+ CSCs, and increased its apoptosis rate. In addition, MK2206 significantly decreased the colony forming ability of SW620Lgr5+ CSCs compared with the TNF-α treatment group. TNF-α treatment increased the phosphorylation of AKT and GSK-3ß in SW620Lgr5+ CSCs, but the phosphorylation was inhibited by MK2206. Conclusion TNF-α activates PI3K/AKT pathway to promote the proliferation of SW620Lgr5+ CSCs.

The novel estrogen receptor GPER1 decreases epilepsy severity and susceptivity in the hippocampus after status epilepticus.

The steroid hormone 17ß-estradiol (estrogen) exerts neuroprotective effects in several types of neurological disorders including epilepsy. The novel G protein-coupled estrogen receptor 1 (GPER1), also called GPR30, mediates the non-genomic effects of 17ß-estradiol. However, the specific role of GPER1 in status epilepticus (SE) remains unclear. In this report, we evaluated the effects of GPER1 on the hippocampus during SE and the underlying mechanism was studied. Our results revealed that pilocarpine-induced GPER1-KD epileptic rats exhibited a shorter latency to generalized convulsions and strikingly elevated seizure severity. Additionally, the electroencephalographic seizure activity also corresponded to these results. Fast-Fourier analysis indicated an enhancement of power in the theta and alpha bands during SE in GPER1-KD rats. In addition, epilepsy-induced pathological changes were dramatically exacerbated in GPER1-KD rats, including neuron damage and neuroinflammation in hippocampus. GPER1 might be associated with the susceptibility to and severity of epileptic seizures. In summary, our results suggested that GPER1 plays a neuroprotective role in SE, and might be a candidate target for epilepsy therapy.

GABAergic neurons in the insular cortex play an important role in cue-morphine reward memory reconsolidation.

AIMS: There have been recent reports that reconsolidation-based interventions attenuate drug reward memories in rodents. The insular cortex (IC) is an essential part of neural circuits that underlie cue-drug memory reconsolidation. GABAergic interneurons in the IC are a potent control on network excitability and play an important role in the inhibitory mediation of reward circuits. However, the function of GABAergic neurons in the IC for memory reconsolidation remains unclear; therefore, we conducted this study to clarify this. MAIN METHODS: We applied morphine-induced conditioned place preference (mCPP) paradigm and pharmacogenetic techniques to study the mediation effect of GABAergic neurons in the IC on mCPP reconsolidation. Moreover, we preliminarily explored the possible mechanisms of mediating GABAergic neurons in the IC involved in mCPP reconsolidation by assessing Arc and Erg-1 protein levels in the IC. KEY FINDINGS: We found that post-retrieval immediate activation of GABAergic neurons in the IC impaired mCPP reconsolidation. In addition, this effect was not reversed by a priming morphine injection. Further, post-retrieval inhibition and non-retrieval excitation of GABAergic neurons in the IC had no effect on mCPP. SIGNIFICANCE: Taken together, our findings suggest that GABAergic neurons in the IC are closely involved in mCPP reconsolidation. Specifically, their excitation could eliminate established mCPP and prevent the relapse risk by disruption of the reconsolidation. The underlying molecular biological mechanisms could involve reduced Arc and Erg-1 levels.

Three-dimensional numerical simulation of soft-tissue wound healing using constrained-mixture anisotropic hyperelasticity and gradient-enhanced damage mechanics.

Healing of soft biological tissues is the process of self-recovery or self-repair after injury or damage to the extracellular matrix (ECM). In this work, we assume that healing is a stress-driven process, which works at recovering a homeostatic stress metric in the tissue by replacing the damaged ECM with a new undamaged one. For that, a gradient-enhanced continuum healing model is developed for three-dimensional anisotropic tissues using the modified anisotropic Holzapfel-Gasser-Ogden constitutive model. An adaptive stress-driven approach is proposed for the deposition of new collagen fibres during healing with orientations assigned depending on the principal stress direction. The intrinsic length scales of soft tissues are considered through the gradient-enhanced term, and growth and remodelling are simulated by a constrained-mixture model with temporal homogenization. The proposed model is implemented in the finite-element package Abaqus by means of a user subroutine UEL. Three numerical examples have been achieved to illustrate the performance of the proposed model in simulating the healing process with various damage situations, converging towards stress homeostasis. The orientations of newly deposited collagen fibres and the sensitivity to intrinsic length scales are studied through these examples, showing that both have a significant impact on temporal evolutions of the stress distribution and on the size of the damage region. Applications of the approach to carry out in silico experiments of wound healing are promising and show good agreement with existing experiment results.

Mass spectrometry-based metabolomics in health and medical science: a systematic review.

Metabolomics is the study of the investigation of small molecules derived from cellular and organism metabolism, which reflects the outcomes of the complex network of biochemical reactions in living systems. As the most recent member of the omics family, there has been notable progress in metabolomics in the last decade, mainly driven by the improvement in mass spectrometry (MS). MS-based metabolomic strategies in modern health and medical science studies provide innovative tools for novel diagnostic and prognostic approaches, as well as an augmented role in drug development, nutrition science, toxicology, and forensic science. In the present review, we not only introduce the application of MS-based metabolomics in the above fields, but also discuss the MS analysis technologies commonly used in metabolomics and the application of metabolomics in precision medicine, and further explore the challenges and perspectives of metabolomics in the field of health and medical science, which are expected to make a little contribution to the better development of metabolomics.

REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-ß pathway.

Anaplastic thyroid cancer (ATC) is the most aggressive human thyroid malignancy, characterized by dedifferentiation and resistance to radioiodine therapy. The underlying mechanisms regulating ATC dedifferentiation are largely unknown. Here, we show that REGγ, a noncanonical proteasome activator highly expressed in ATC, is an important regulator of differentiation in ATC cells. Ablation of REGγ significantly restored expression of thyroid-specific genes, enhanced iodine uptake, and improved the efficacy of 131I therapy in ATC xenograft models. Mechanistically, REGγ directly binds to the TGF-ß signaling antagonist Smad7 and promotes its degradation, leading to the activation of the TGF-ß signal pathway. With gain- and loss-of-function studies, we demonstrate that Smad7 is an important mediator for the REGγ function in ATC cell dedifferentiation, which is supported by expression profiles in human ATC tissues. It seems that REGγ impinges on repression of thyroid-specific genes and promotion of tumor malignancy in ATC cells by activating the TGF-ß signal pathway via degradation of Smad7. Thus, REGγ may serve as a novel therapeutic target for allowing radioiodine therapy in anaplastic thyroid cancer patients with poor prognosis.

Gradient-enhanced continuum models of healing in damaged soft tissues.

Healing of soft biological tissue is the process of self-recovering or self-repairing the injured or damaged extracellular matrix (ECM). Healing is assumed to be stress-driven, with the objective of returning to a homeostatic stress metrics in the tissue after replacing the damaged ECM with new undamaged one. However, based on the existence of intrinsic length scales in soft tissues, it is thought that computational models of healing should be non-local. In the present study, we introduce for the first time two gradient-enhanced constitutive healing models for soft tissues including non-local variables. The first model combines a continuum damage model with a temporally homogenized growth model, where the growth direction is determined according to local principal stress directions. The second one is based on a gradient-enhanced healing model with continuously recoverable damage variable. Both models are implemented in the finite-element package Abaqus by means of a user subroutine UEL. Three two-dimensional situations simulating the healing process of soft tissues are modeled numerically with both models, and their application for simulation of balloon angioplasty is provided by illustrating the change of damage field and geometry in the media layer throughout the healing process.

Stochastic analysis of a heterogeneous micro-finite element model of a mouse tibia.

Finite element (FE) analysis can be used to predict bone mechanical environments that can be used for many important applications, such as the understanding of bone mechano-regulation mechanisms. However, when defining the FE models, uncertainty in bone material properties may lead to marked variations in the predicted mechanical environment. The aim of this study is to investigate the influence of uncertainty in bone material property on the mechanical environment of bone. A heterogeneous FE model of a mouse tibia was created from micro computed tomography images. Axial compression loading was applied, and all possible bone density-modulus relationships were considered through stochastic analysis. The 1st and 3rd principal strains (ε1 and ε3) and the strain energy density (SED) were quantified in the tibial volume of interest (VOI). The bounds of ε1, ε3, and SED were determined by the bounds of the density-modulus relationship; the bone mechanical environment (ε1, ε3, and SED) and the bone density-modulus relationship exhibit the same trend of change; the relative percentage differences caused by bone material uncertainty are up to 28%, 28%, and 21% for ε1, ε3, and SED, respectively. These data provide guidelines on the adoption of bone density-modulus relationship in heterogeneous FE models.