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2.
Cell Prolif ; : e12783, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32101357

RESUMO

OBJECTIVES: Cardiac Ca2+ signalling plays an essential role in regulating excitation-contraction coupling and cardiac remodelling. However, the response of cardiomyocytes to simulated microgravity and hypergravity and the effects on Ca2+ signalling remain unknown. Here, we elucidate the mechanisms underlying the proliferation and remodelling of HL-1 cardiomyocytes subjected to rotation-simulated microgravity and 4G hypergravity. MATERIALS AND METHODS: The cardiomyocyte cell line HL-1 was used in this study. A clinostat and centrifuge were used to study the effects of microgravity and hypergravity, respectively, on cells. Calcium signalling was detected with laser scanning confocal microscopy. Protein and mRNA levels were detected by Western blotting and real-time PCR, respectively. Wheat germ agglutinin (WGA) staining was used to analyse cell size. RESULTS: Our data showed that spontaneous calcium oscillations and cytosolic calcium concentration are both increased in HL-1 cells after simulated microgravity and 4G hypergravity. Increased cytosolic calcium leads to activation of calmodulin-dependent protein kinase II/histone deacetylase 4 (CaMKII/HDAC4) signalling and upregulation of the foetal genes ANP and BNP, indicating cardiac remodelling. WGA staining indicated that cell size was decreased following rotation-simulated microgravity and increased following 4G hypergravity. Moreover, HL-1 cell proliferation was increased significantly under hypergravity but not rotation-simulated microgravity. CONCLUSIONS: Our study demonstrates for the first time that Ca2+ /CaMKII/HDAC4 signalling plays a pivotal role in myocardial remodelling under rotation-simulated microgravity and hypergravity.

3.
Sci Rep ; 10(1): 866, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964941

RESUMO

Proton pump inhibitors (PPIs) are used for the long-term treatment of gastroesophageal disorders and the non-prescription medicines for acid reflux. However, there is growing concerns about PPI misuse, overuse and abuse. This study aimed to develop an animal model to examine the effects of long-term use of PPI in vivo. Twenty one Wistar rats were given omeprazole orally or intravenously for 30 days, and caerulein as a positive control. After euthanization, the serum and stool were collected to perform MS-based quantitative analysis of metabolites. We carried out 16S-based profiling of fecal microbiota, assessed the expression of bile acid metabolism regulators and examined the immunopathological characteristics of bile ducts. After long-term PPI exposure, the fecal microbial profile was altered and showed similarity to those observed in high-fat diet studies. The concentrations of several metabolites were also changed in various specimens. Surprisingly, morphological changes were observed in the bile duct, including ductal epithelial proliferation, micropapillary growth of biliary epithelium, focal bile duct stricture formation and bile duct obstruction. These are characteristics of precancerous lesions of bile duct. FXR and RXRα expressions were significantly reduced, which were similar to that observed in cholangiocarcinoma in TCGA and Oncomine databases. We established a novel animal model to examine the effects of long-term use of omeprazole. The gut microbes and metabolic change are consequences of long-term PPI exposure. And the results showed the environment in vivo tends to a high-fat diet. More importantly, we observed biliary epithelial hyperplasia, which is an indicator of a high-fat diet.

4.
Nanotechnology ; 31(17): 175701, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31899907

RESUMO

This manuscript presents a simple, one-step method for the fabrication of micro/nanostructured metal-based superhydrophobic surfaces via electroplating using stacked polycarbonate membranes with nanoscale and microscale pores as a template. The two-tiered mushroom-shaped silver pillar arrays include a top layer composed of nanopillars and a bottom layer composed of T-shaped micropillars. The presence of the re-entrant surface structures with a strong resistance pin the droplets to the cap's ridge and prevent water droplets from penetrating into the valleys of the rough surface, thus resulting in an increase in water contact angle (WCA). Compared with microstructured mushroom-shaped surfaces (WCA = 148°, sliding angle (SA) âˆ¼ 26°) and nanostructured surfaces (WCA = 151.5°, SA âˆ¼ 4.8°), the micro/nanostructured mushroom-shaped pillar arrays (WCA = 154.1°, SA âˆ¼ 2°) exhibit remarkable superhydrophobic properties with high CA and low SA. This new micro/nanostructured surface will have a potential application in metal-based superhydrophobic materials.

5.
J Biol Chem ; 295(11): 3614-3634, 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-31953327

RESUMO

G-protein-gated inwardly-rectifying K+ (GIRK) channels are targets of Gi/o-protein-signaling systems that inhibit cell excitability. GIRK channels exist as homotetramers (GIRK2 and GIRK4) or heterotetramers with nonfunctional homomeric subunits (GIRK1 and GIRK3). Although they have been implicated in multiple conditions, the lack of selective GIRK drugs that discriminate among the different GIRK channel subtypes has hampered investigations into their precise physiological relevance and therapeutic potential. Here, we report on a highly-specific, potent, and efficacious activator of brain GIRK1/2 channels. Using a chemical screen and electrophysiological assays, we found that this activator, the bromothiophene-substituted small molecule GAT1508, is specific for brain-expressed GIRK1/2 channels rather than for cardiac GIRK1/4 channels. Computational models predicted a GAT1508-binding site validated by experimental mutagenesis experiments, providing insights into how urea-based compounds engage distant GIRK1 residues required for channel activation. Furthermore, we provide computational and experimental evidence that GAT1508 is an allosteric modulator of channel-phosphatidylinositol 4,5-bisphosphate interactions. Through brain-slice electrophysiology, we show that subthreshold GAT1508 concentrations directly stimulate GIRK currents in the basolateral amygdala (BLA) and potentiate baclofen-induced currents. Of note, GAT1508 effectively extinguished conditioned fear in rodents and lacked cardiac and behavioral side effects, suggesting its potential for use in pharmacotherapy for post-traumatic stress disorder. In summary, our findings indicate that the small molecule GAT1508 has high specificity for brain GIRK1/2 channel subunits, directly or allosterically activates GIRK1/2 channels in the BLA, and facilitates fear extinction in a rodent model.

6.
Nucleic Acids Res ; 48(1): 86-95, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31777938

RESUMO

Clustering is an essential step in the analysis of single cell RNA-seq (scRNA-seq) data to shed light on tissue complexity including the number of cell types and transcriptomic signatures of each cell type. Due to its importance, novel methods have been developed recently for this purpose. However, different approaches generate varying estimates regarding the number of clusters and the single-cell level cluster assignments. This type of unsupervised clustering is challenging and it is often times hard to gauge which method to use because none of the existing methods outperform others across all scenarios. We present SAME-clustering, a mixture model-based approach that takes clustering solutions from multiple methods and selects a maximally diverse subset to produce an improved ensemble solution. We tested SAME-clustering across 15 scRNA-seq datasets generated by different platforms, with number of clusters varying from 3 to 15, and number of single cells from 49 to 32 695. Results show that our SAME-clustering ensemble method yields enhanced clustering, in terms of both cluster assignments and number of clusters. The mixture model ensemble clustering is not limited to clustering scRNA-seq data and may be useful to a wide range of clustering applications.

7.
Epigenetics ; 15(3): 294-306, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31506003

RESUMO

DNA methylation (DNAm) has a well-established association with age in many tissues, including peripheral blood mononuclear cells (PBMCs). Compared to DNAm, the closely related epigenetic modification known as DNA hydroxymethylation (DNAhm) was much more recently discovered in mammals. Preliminary investigations have observed a positive correlation between gene body DNAhm and cis-gene expression. While some of these studies have observed an association between age and global DNAhm, none have investigated region-specific age-related DNAhm in human blood samples. In this study, we investigated DNAhm and gene expression in PBMCs of 10 young and 10 old, healthy female volunteers. Thousands of regions were differentially hydroxymethylated in the old vs. young individuals in gene bodies, exonic regions, enhancers, and promoters. Consistent with previous work, we observed directional consistency between age-related differences in DNAhm and gene expression. Further, age-related DNAhm and genes with high levels of DNAhm were enriched for immune system processes which may support a role of age-related DNAhm in immunosenescence.

8.
ACS Synth Biol ; 9(1): 26-35, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31825599

RESUMO

There is growing interest in the use of nonmodel microorganisms as hosts for biopharmaceutical manufacturing. These hosts require genomic engineering to meet clinically relevant product qualities and titers, but the adaptation of tools for editing genomes, such as CRISPR-Cas9, has been slow for poorly characterized hosts. Specifically, a lack of biochemical characterization of RNA polymerase III transcription has hindered reliable expression of guide RNAs in new hosts. Here, we present a sequencing-based strategy for the design of host-specific cassettes for modular, reliable, expression of guide RNAs. Using this strategy, we achieved up to 95% gene editing efficiency in the methylotrophic yeast Komagataella phaffii. We applied this approach for the rapid, multiplexed engineering of a complex phenotype, achieving humanized product glycosylation in two sequential steps of engineering. Reliable extension of simple gene editing tools to nonmodel manufacturing hosts will enable rapid engineering of manufacturing strains tuned for specific product profiles and potentially decrease the costs and timelines for process development.

9.
Food Chem Toxicol ; 136: 111092, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31883986

RESUMO

Nano-diamino-tetrac (NDAT), a tetraiodothyroxine deaminated nano-particulated analog, has shown to inhibit expression of pro-inflammatory genes. NDAT inhibits expression of programmed death-ligand 1 (PD-L1). On the other hand, in addition to inhibiting inflammatory effect, the stilbene, resveratrol induces expression of cyclooxygenase-2 (COX-2) and its accumulation. Sequentially, inducible COX-2 complexes with p53 and induces p53-dependent anti-proliferation. In current study, we investigated mechanisms involved in combined treatment of NDAT and resveratrol on anti-proliferation in human oral cancer cells. Both resveratrol and NDAT inhibited expression of pro-inflammatory IL-1ß and TNF-α. They also inhibited expression of CCND1 and PD-L1. Both resveratrol and NDAT induced BAD expression but only resveratrol induced COX-2 expression in both OEC-M1 and SCC-25 cells. Combined treatment attenuated gene expression significantly compared with resveratrol treatment in both cancer cell lines. Resveratrol reduced nuclear PD-L1 accumulation which was enhanced by a STAT3 inhibitor, S31-201 or NDAT suggesting that NDAT may inactivate STAT3 to inhibit PD-L1 accumulation. In the presence of T4, NDAT further enhanced resveratrol-induced anti-proliferation in both cancer cell lines. These findings provide a novel understanding of the inhibition of NDAT in thyroxine-induced pro-inflammatory effect on resveratrol-induced anticancer properties.

10.
Nutrients ; 11(12)2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31817534

RESUMO

Abstract: Pro-inflammatory hormones and cytokines (leptin, tumor necrosis factor (TNF)-α, and interleukin (IL)-6) rise in obesity. Elevated levels of hormones and cytokines are linked with several comorbidities such as diabetes, heart disease, and cancer. The checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) plays an important role in obesity and cancer proliferation. L-thyroxine (T4) and steroid hormones up-regulate PD-L1 accumulation and promote inflammation in cancer cells and diabetics. On the other hand, resveratrol and other herbal medicines suppress PD-L1 accumulation and reduce diabetic effects. In addition, they induce anti-cancer proliferation in various types of cancer cells via different mechanisms. In the current review, we discuss new findings and visions into the antagonizing effects of hormones on herbal medicine-induced anti-cancer properties.

11.
Dalton Trans ; 48(45): 16943-16951, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31687709

RESUMO

1,2-Propanediaminetetraacetic acid (H4pdta = C11H18O8N2) is degraded selectively to 1-methyl-1,2-propanediaminetriacetic acid (H3pd3a = C9H16O6N2) with a yield of 75% at room temperature, while N-(2-hydroxyethyl) ethylenediaminetriacetic acid (H4eed3a = C10H18O7N2) is converted with difficulty to ethylenediaminetriacetic acid (H3ed3a = C8H14O6N2) on peroxotitanates(iv), showing the influence of the uncoordinated leaving group. Various species in the reaction sequence are isolated and fully characterized, including (NH4)[Ti(O2)(Hpdta)]·H2O (1), (NH4)3[Ti(O2)(pdta)H(pdta)(O2)Ti]·7H2O (2), (NH4)[Ti(O2)(pd3a)]·H2O (3) and (NH4)[Ti(O2)(Heed3a)]·H2O (5). Peroxo dimer 2 forms a strong intramolecular hydrogen bond [2.451(3) Å] as an intermediate in the peroxo Ti-pdta system, which results in the absence of a fully deprotonated species of peroxo pdta titanate. A catalytic reaction of the peroxo titanate (NH4)3[Ti(O2)(pdta)H(pdta)(O2)Ti]·7H2O (2) for the conversion of pyridine to pyridine N-oxide shows 94% conversion at 80 °C.

12.
Am J Cancer Res ; 9(8): 1650-1663, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31497348

RESUMO

Liver kinase B1 (LKB1), a serine/threonine kinase, is frequently inactivated in several types of human cancers. To date, inactivation of LKB1 tumor suppressor has rarely been reported in glioblastoma. In this study, we investigated LKB1 status, biological significance, and therapeutic implications in glioblastoma. Loss of LKB1 immunostaining was identified in 8.6% (5/58), while decrease of LKB1 immunostaining was found in 29.3% (17/58) of glioblastoma tissues. Notably, mining TCGA database of LKB1 expression in glioblastoma revealed that lower mRNA level of LKB1 was associated with shorter survival in glioblastoma. We found that knockdown of LKB1 significantly promoted in vitro proliferation, adhesion, invasion, and metformin-induced apoptosis, and simultaneously enhanced activation of ERK and mammalian-target of rapamycin (mTOR) signaling pathways in LKB1-compenent U87 and T98 glioblastoma cells. Moreover, global transcriptional profiling revealed that adhesion and cytoskeletal proteins such as Vinculin, Talin and signaling pathways including focal adhesion kinase (FAK), extracellular martrix (ECM) receptor interaction, and cellular motility were significantly enriched in U87 and T98 glioblastoma cells upon LKB1 knockdown. Additionally, we demonstrated that the enhanced activation of FAK by LKB1 knockdown was dependent on differentially expressed cytoskeletal proteins in these glioblastoma cells. Importantly, we further found that mTOR1 inhibitor rapamycin dominantly inhibited in vitro cellular proliferation, while FAK inhibitor PF-573288 drastically decreased invasion of LKB1-attenuated glioblastoma cells. Therefore, downregulation of LKB1 may contribute to the pathogenesis and malignancy of glioblastoma and may have potential implications for stratification and treatment of glioblastoma patients.

13.
Food Chem Toxicol ; 133: 110808, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499123

RESUMO

The obesity-regulated gene, leptin, is essential for diet. Leptin resistance causes obesity and related diseases. Certain types of diet are able to decrease leptin resistance. However, leptin has been shown to be correlated with inflammation and stimulate proliferation of various cancers. Two synthetic leptin derivatives (mimetics), OB3 and [D-Leu-4]-OB3, show more effective than leptin in reducing obesity and diabetes in mouse models. OB3 inhibits leptin-induced proliferation in ovarian cancer cells. However, effects of these mimetics in hepatocellular carcinoma (HCC) have not been investigated. In the present study, we examined the effects of OB3 and [D-Leu-4]-OB3 on cell proliferation and gene expressions in human HCC cell cultures. In contrast to what was reported for leptin, OB3 and [D-Leu-4]-OB3 reduced cell proliferation in hepatomas. Both OB3 and [D-Leu-4]-OB3 stimulated expression of pro-apoptotic genes. Both compounds also inhibited expressions of pro-inflammatory, proliferative and metastatic genes and PD-L1 expression. In combination with leptin, OB3 inhibited leptin-induced cell proliferation and expressions of pro-inflammation-, and proliferation-related genes. Furthermore, the OB3 peptide inhibited phosphoinositide 3-kinase (PI3K) activation which is essential for leptin-induced proliferation in HCC. These results indicate that OB3 and [D-Leu-4]-OB3 may have the potential to reduce leptin-related inflammation and proliferation in HCC cells.


Assuntos
Proliferação de Células/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Leptina/farmacologia , Fragmentos de Peptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Proteínas Quinases/farmacologia
14.
Dalton Trans ; 48(35): 13388-13395, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31432836

RESUMO

N-Oxido copper(ii) ethylenediaminetetraacetate Na4n[Cu2(edtaO2)2(H2O)4]n·13nH2O (2) (H4edta = ethylenediaminetetraacetic acid, C10H16O8N2) and N-oxido copper(ii) 1,3-propanediaminetetraacetate Na5nOn[Cu2(HpdtaO2)2Cl]n·12.5nH2O (4) (H4pdta = 1,3-propanediaminetetraacetic acid, C11H18O8N2) were obtained from the reactions of copper(ii) edta and pdta respectively with hydrogen peroxide. The copper ions in 2 and 4 are hexa-coordinated by edtaO2 or pdtaO2 ligands, forming 1D chain structures. Further reactions of 2 and 4 at lower pH values result in the isolation of copper(ii) iminodiacetate K[Cu(ida)(H2O)2Cl] (3) (H2ida = iminodiacetate acid, C4H7O4N) and copper(ii) propanediaminediacetate [Cu2(pdda)2]n·nH2O (5) (H2pdda = propanediaminediacetic acid, C7H10O4N2), respectively, which show the selective degradation of ethylenediaminetetraacetate and propanediaminetetraacetate.

15.
Food Chem Toxicol ; 132: 110700, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31356917

RESUMO

Postnatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common plasticizer, is associated with allergy development in childhood, suggesting that DEHP exposure may dysregulate immune response in infants. We investigated whether DEHP exposure in newborns through medical treatment affected the gut microbiota pattern and vaccine response, which are both related to immune development. In this prospective cohort study from May 1, 2016 through July 31, 2017, newborns with respiratory distress who were given intravenous infusions (IVs) were enrolled as the DEHP group, and newborns who did not receive IVs were enrolled as the control group. We excluded patients with perinatal maternal probiotics, vaginal delivery, antibiotic treatment, and exclusive human milk or formula feeding. Of 118 infants, urinary phthalate metabolite analysis revealed that the calculated DEHP concentrations of the newborns treated with IVs (n = 15) were higher than those in the control group (n = 10) (p = 0.0001). DEHP exposure altered bacterial communities both in composition and diversity, particularly decreases in Rothia sp. and Bifidobacterium longum in the DEHP group. Furthermore, DEHP exposure significantly enhanced anti-HBsAg-IgM responses in the DEHP group (p = 0.013). Early-life DEHP exposure alter gut microbiota of newborns and may change their immune responses in later life.


Assuntos
Dietilexilftalato/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Vacinas contra Hepatite B/administração & dosagem , Imunoglobulina M/sangue , Plastificantes/farmacologia , Dietilexilftalato/urina , Feminino , Hidratação , Humanos , Imunoglobulina M/imunologia , Recém-Nascido , Infusões Intravenosas , Masculino , Plastificantes/análise
16.
Food Chem Toxicol ; 132: 110693, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31336132

RESUMO

Thyroid hormone, L-thyroxine (T4), induces inflammatory genes expressions and promotes cancer growth. It also induces expression of the checkpoint programmed death-ligand 1 (PD-L1), which plays a vital role in cancer progression. On the other hand, resveratrol inhibits inflammatory genes expressions. Moreover, resveratrol increases nuclear inducible cyclooxygenase (COX)-2 accumulation, complexes with p53, and induces p53-dependent anti-proliferation. In this study, we investigated the effect of T4 on resveratrol-induced anti-proliferation in oral cancer. T4 increased the expression and cytoplasmic accumulation of PD-L1. Increased expressions of pro-inflammatory genes, interleukin (IL)-1ß and transforming growth factor (TGF)-ß1, were shown to stimulate PD-L1 expression. T4 stimulated pro-inflammatory and proliferative genes expressions, and oral cancer cells proliferation. In contrast, resveratrol inhibited those genes and activated anti-proliferative genes. T4 retained resveratrol-induced COX-2 in cytoplasm and prevented COX-2 nuclear accumulation when resveratrol treated cancer cells. A specific signal transducer and activator of transcription 3 (STAT3) inhibitor, S31-201, blocked T4-induced inhibition and restored resveratrol-induced nuclear COX-2 accumulation. By inhibiting the T4-activated STAT3 signal transduction axis with S31-201, resveratrol was able to sequentially reestablish COX-2/p53-dependent gene expressions and anti-proliferation. These findings provide a novel understanding of the inhibitory effects of T4 on resveratrol-induced anticancer properties via the sequential expression of PD-L1 and inflammatory genes.


Assuntos
Proliferação de Células/efeitos dos fármacos , Citocinas/genética , Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Neoplasias Bucais/patologia , Resveratrol/farmacologia , Tiroxina/farmacologia , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/enzimologia , Ciclo-Oxigenase 2/metabolismo , Humanos , Neoplasias Bucais/metabolismo , Fator de Transcrição STAT3/metabolismo
17.
Opt Express ; 27(6): 9115-9127, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-31052721

RESUMO

Polaritonic slot waveguides have been explored as a means of manipulating nanoscale fields to compete in the race for the sub-diffractional confinement of light. Hexagonal boron nitride (h-BN), when incorporated into hyperbolic-insulator-hyperbolic (HIH) configurations, is a strong contender, with its naturally occurring anisotropy allowing it to strongly confine and enhance local fields. However, while the volumetric phonon polaritons of h-BN have been widely used for these means, its hyperbolic surface phonon polaritons (HSPhPs) or D'yakonov polaritons contain untapped potential and are widely unused. In this paper, we qualitatively discuss the hybridization of fundamental hyperbolic surface phonon polariton modes in an HIH slot waveguide. The resulting symmetric dark, or lower mode, is then used to design a patch antenn, which shows possibilities for applying the familiar microstrip transmission-line approach of antenna design to this HSPhP antenna.

18.
Animals (Basel) ; 9(5)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083431

RESUMO

In this study, we explored the willingness to pay (WTP) for broilers raised under the high welfare system. The interval data model and the ordered probit model were used to investigate the factors that affect consumers' WTP for broiler meat produced by farm animal welfare (FAW), practice. Our results from both methods suggest that socioeconomic characteristics such as education level, income level, gender, and age significantly affect consumers' WTP. The food safety concerns of consumers and perceived consumer effectiveness also influence consumers' WTP. Using the interval data method, we computed the mean and median of the estimated WTP from our survey sample. The mean was 46.7745 New Taiwanese dollar per kilogram. The marginal effects of the different variables are also presented.

20.
Sci Transl Med ; 11(487)2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971451

RESUMO

Reconstruction of the anisotropic structure and proper function of the knee meniscus remains an important challenge to overcome, because the complexity of the zonal tissue organization in the meniscus has important roles in load bearing and shock absorption. Current tissue engineering solutions for meniscus reconstruction have failed to achieve and maintain the proper function in vivo because they have generated homogeneous tissues, leading to long-term joint degeneration. To address this challenge, we applied biomechanical and biochemical stimuli to mesenchymal stem cells seeded into a biomimetic scaffold to induce spatial regulation of fibrochondrocyte differentiation, resulting in physiological anisotropy in the engineered meniscus. Using a customized dynamic tension-compression loading system in conjunction with two growth factors, we induced zonal, layer-specific expression of type I and type II collagens with similar structure and function to those present in the native meniscus tissue. Engineered meniscus demonstrated long-term chondroprotection of the knee joint in a rabbit model. This study simultaneously applied biomechanical, biochemical, and structural cues to achieve anisotropic reconstruction of the meniscus, demonstrating the utility of anisotropic engineered meniscus for long-term knee chondroprotection in vivo.

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