Biomechanical effects of the medial meniscus horizontal tear and the resection strategy on the rabbit knee joint under resting state: finite element analysis.

The biomechanical changes following meniscal tears and surgery could lead to or accelerate the occurrence of osteoarthritis. The aim of this study was to investigate the biomechanical effects of horizontal meniscal tears and different resection strategies on a rabbit knee joint by finite element analysis and to provide reference for animal experiments and clinical research. Magnetic resonance images of a male rabbit knee joint were used to establish a finite element model with intact menisci under resting state. A medial meniscal horizontal tear was set involving 2/3 width of a meniscus. Seven models were finally established, including intact medial meniscus (IMM), horizontal tear of the medial meniscus (HTMM), superior leaf partial meniscectomy (SLPM), inferior leaf partial meniscectomy (ILPM), double-leaf partial meniscectomy (DLPM), subtotal meniscectomy (STM), and total meniscectomy (TTM). The axial load transmitted from femoral cartilage to menisci and tibial cartilage, the maximum von Mises stress and the maximum contact pressure on the menisci and cartilages, the contact area between cartilage to menisci and cartilage to cartilage, and absolute value of the meniscal displacement were analyzed and evaluated. The results showed that the HTMM had little effect on the medial tibial cartilage. After the HTMM, the axial load, maximum von Mises stress and maximum contact pressure on the medial tibial cartilage increased 1.6%, 1.2%, and 1.4%, compared with the IMM. Among different meniscectomy strategies, the axial load and the maximum von Mises stress on the medial menisci varied greatly. After the HTMM, SLPM, ILPM, DLPM, and STM, the axial load on medial menisci decreased 11.4%, 42.2%, 35.4% 48.7%, and 97.0%, respectively; the maximum von Mises stress on medial menisci increased 53.9%, 62.6%, 156.5%, and 65.5%, respectively, and the STM decreased 57.8%, compared to IMM. The radial displacement of the middle body of the medial meniscal was larger than any other part in all the models. The HTMM led to few biomechanical changes in the rabbit knee joint. The SLPM showed minimal effect on joint stress among all resection strategies. It is recommended to preserve the posterior root and the remaining peripheral edge of the meniscus during surgery for an HTMM.

Medial meniscus posterior root tears and partial meniscectomy significantly increase stress in the knee joint during dynamic gait.

PURPOSE: As a simple and invasive treatment, arthroscopic medial meniscal posterior horn resections (MMPHRs) can relieve the obstructive symptoms of medial meniscus posterior root tears (MMPRTs) but with the risk of aggravating biomechanical changes of the joint. The aim of this study was to analyze dynamic simulation of the knee joint after medial meniscus posterior root tear and posterior horn resection. METHODS: This study established static and dynamic models of MMPRTs and MMPHRs on the basis of the intact medial meniscus model (IMM). In the finite element analysis, the three models were subjected to 1000 N axial static load and the human walking gait load defined by the ISO14243-1 standard to evaluate the influence of MMPRTs and MMPHRs on knee joint mechanics during static standing and dynamic walking. RESULTS: In the static state, the load ratio of the medial and lateral compartments remained nearly constant (2:1), while in the dynamic state, the load ratio varied with the gait cycle. After MMPHRs, at 30% of the gait cycle, compared with the MMPRTs condition, the maximum von Mises stress of the lateral meniscus (LM) and the lateral tibial cartilage (LTC) were increased by 166.0% and 50.0%, respectively, while they changed by less than 5% during static analysis. The maximum von Mises stress of the medial meniscus (MM) decreased by 55.7%, and that of the medial femoral cartilage (MFC) increased by 53.5%. CONCLUSION: After MMPHRs, compared with MMPRTs, there was no significant stress increase in articular cartilage in static analysis, but there was a stress increase and concentration in both medial and lateral compartments in dynamic analysis, which may aggravate joint degeneration. Therefore, in clinical treatments, restoring the natural structure of MMPRTs is first recommended, especially for physically active patients.

Intra-Articular Biomechanical Changes of the Meniscus and Ligaments During Stance Phase of Gait Circle after Different Anterior Cruciate Ligament Reconstruction Surgical Procedures: A Finite Element Analysis.

OBJECTIVE: The debate on the superiority of single- or double-bundle for anterior cruciate ligament reconstruction has not ceased. The comparative studies on intra-articular biomechanics after different surgical reconstructions are rare. This study is to evaluate the biomechanical stress distribution intra-knee after single- and double-bundle anterior cruciate ligament reconstruction by three-dimensional finite element analysis, and to observe the change of stress concentration under the condition of vertical gradient loads. METHODS: In this study, magnetic resonance imaging data were extracted from patients and healthy controls for biomechanical analysis. Patients included in the three models were matched in age and sex. The strength and distribution of induced stresses were analyzed in two frequently used procedures, anatomical single-bundle anterior cruciate ligament reconstruction and anatomical double-bundle anterior cruciate ligament reconstruction, using femoral-graft-tibial system under different loads, to mimic a post-operation mechanical motion. The three-dimensional finite-element models for normal ligament and two surgical methods were applied. A vertical force simulating daily walking was performed on the models to assess the interfacial stresses and displacements of intra-articular tissues and ligaments. The evaluation results mainly included the stress of each part of ligament and meniscus. The stress values of different parts of three models were extracted and compared. RESULTS: The stress of ligament/graft at femoral side of three finite-element models was significantly higher than at tibial side, while the highest level was observed in single-bundle reconstruction finite-element model. With the increase of force, the maximum stress in the medial (7.1-7.1 MPa) and lateral (4.9-7.4 MPa) meniscus of single-bundle reconstruction finite-element model shifted from the anterior horn to the central area (p = 0.0161, 0.0479, respectively). The stress was shown to be at a lower level at femoral side and posterior cruciate ligament of intra-knee in two reconstruction finite-element models than that in normal finite-element models, while presented higher level at the tibial side than normal knee (p = 0.3528). The displacement of the femoral side and intra-knee areas in reconstruction finite-element models was greater than that in normal finite-element model (p = 0.0855). CONCLUSION: Compared with the single-bundle technique, the graft of double-bundle anterior cruciate ligament reconstruction has better stress dissipation effect and can prevent postoperative meniscus tear more effectively.

Huangbai Liniment Ameliorates Skin Inflammation in Atopic Dermatitis.

Atopic dermatitis (AD), also known as atopic eczema, is one of the most common skin diseases and is characterized by allergic skin inflammation, redness, and itchiness and is associated with a hyperactivated type 2 immune response. The leading causes of AD include an imbalance in the immune system, genetic predisposition, or environmental factors, making the development of effective pharmacotherapies complex. Steroids are widely used to treat AD; however, they provide limited efficacy in the long term and can lead to adverse effects. Thus, novel treatments that offer durable efficacy and fewer side effects are urgently needed. Here, we investigated the therapeutic potential of Huangbai Liniment (HB), a traditional Chinese medicine, using an experimental AD mouse model, following our clinical observations of AD patients. In both AD patient and the mouse disease model, HB significantly improved the disease condition. Specifically, patients who received HB treatment on local skin lesions (3-4 times/day) showed improved resolution of inflammation. Using the 1-Chloro-2,4-dinitrobenzene (DNCB)-induced AD model in BALB/c mice, we observed that HB profoundly alleviated severe skin inflammation and relieved the itching. The dermatopathological results showed markedly reversed skin inflammation with decreased epidermal thickness and overall cellularity. Correspondingly, HB treatment largely decreased the mRNA expression of proinflammatory cytokines, including IL-1ß, TNF-α, IL-17, IL-4, and IL-13, associated with declined gene expression of IL-33, ST2, and GATA3, which are connected to the type 2 immune response. In addition, HB restored immune tolerance by promoting regulatory T (TREG) cells and inhibiting the generation of TH1, TH2, and TH17 cells in vitro and in the DNCB-induced AD mouse model. For the first time, we demonstrate that HB markedly mitigates skin inflammation in AD patients and the DNCB-induced AD mouse model by reinvigorating the T cell immune balance, shedding light on the future development and application of novel HB-based therapeutics for AD.

The comparative studies on the magnetic relaxation behaviour of the axially-elongated pentagonal-bipyramidal dysprosium and erbium ions in similar one-dimensional chain structures.

A family of cyano-bridged 3d-4f 1D chain compounds, {RE[TM(CN)6(2-PNO)5]}·(H2O)4 {RE = YIII, TM = [FeIII]LS (1); RE = DyIII, TM = CoIII (3); RE = ErIII, TM = [FeIII]LS (4), CoIII (5); 2-PNO = 2-picoline-N-oxide} and {RE[TM(CN)6(2-PNO)5]} {RE = DyIII, TM = [FeIII]LS (2)}, were synthesized and characterized. Single-crystal X-ray diffraction studies reveal that compounds 1 and 3-5 are isostructural, while compound 2 has a similar 1D chain structure with a different chain to chain arrangement. An axially-elongated pentagonal bipyramidal (D5h) coordination geometry is formed with five 2-PNO ligands in the equatorial plane and two [TM(CN)6]3- on the apical sites around the rare earth ions in these compounds. A comparison of the magnetic relaxation behaviour in detail reveals that it is more favorable for the Er (4 and 5) than the Dy analogues (2 and 3) to exhibit SIM properties in this axially-elongated D5h coordination environment. Under zero dc field, ac susceptibility measurements show that the Dy analogues have no magnetic relaxation behaviour, while the Er analogues exhibit frequency dependence despite the strong QTM effect. Under a 1 kOe dc field, the Er analogues generally show 1-2 orders of magnitude longer relaxation time at each selected temperature and a higher relaxation energy barrier than the Dy analogues. And the RECo compounds (3 and 5) show a more suppressed QTM effect than the corresponding REFe (2 and 4) compounds, which may be ascribed to the elimination of the fluctuation field from the neighbouring [FeIII]LS ions. The ab initio calculations indicate the misplacement between the orientation of the main magnetic axis and the structural axis in the Dy analogues, and the relative consistency in the Er analogues, which should be the source of the Er analogues showing better SIM properties than the Dy analogues.

Chemically defined and xeno-free culture condition for human extended pluripotent stem cells.

Extended pluripotent stem (EPS) cells have shown great applicative potentials in generating synthetic embryos, directed differentiation and disease modeling. However, the lack of a xeno-free culture condition has significantly limited their applications. Here, we report a chemically defined and xeno-free culture system for culturing and deriving human EPS cells in vitro. Xeno-free human EPS cells can be long-term and genetically stably maintained in vitro, as well as preserve their embryonic and extraembryonic developmental potentials. Furthermore, the xeno-free culturing system also permits efficient derivation of human EPS cells from human fibroblast through reprogramming. Our study could have broad utility in future applications of human EPS cells in biomedicine.

A novel near-infrared optical and redox-active receptor for the multi-model detection of Hg2+ in water and living cells.

A key issue for constructing optical and redox-active receptors is how to conjugate a specific sensing kernel with a multi-signal-responsive system to carry out multi-feature analysis. Mercury is considered to be highly toxic to human health and ecological security. In this work, we present a novel near-infrared optical and redox-active receptor that can sense Hg2+ at ppb level in aqueous media via multi-model monitors with a low detection limit of 8.4 × 10-9 M (1.68 ppb). This receptor features a visible detection, 'off-on' fluorescence response, and efficient electrochemistry assessment, as well as pH-insensitivity to Hg2+ with high sensitivity. In view of its marked near-infrared emission and fluorescence enhancement, we successfully applied this receptor to visualize Hg2+ in live cells. Furthermore, a possible sensing model was established and rationalized with theoretical studies.

Luteolin, an aryl hydrocarbon receptor ligand, suppresses tumor metastasis in vitro and in vivo.

Estrogen receptor (ER)­negative breast tumors are associated with low survival rates, which is related to their ability to grow and metastasize into distal organs. The aryl hydrocarbon receptor (AhR), a ligand­activated transcription factor that is involved in several biological processes, is a promising anti­metastatic target. Luteolin, a non­toxic naturally occurring plant flavonoid with diverse biological activities, has been demonstrated to be effective against certain types of cancer, and has also been described as a ligand of AhR. In the present study, various cancer cell lines were first investigated following treatment with luteolin, and luteolin exhibited the lowest IC50 in MDA­MB­231 cells. Then, the efficiency of luteolin in suppressing the metastasis of ER­negative breast cancer in vitro was assessed. MDA­MB­231 cells were treated with luteolin in vitro. Subsequently, MTT assay and flow cytometry were used to detect cell viability, the cell cycle and apoptosis, and a Transwell assay was used to evaluate cell invasion. In addition, reverse transcription­semi­quantitative PCR and western blot were performed to detect the mRNA and protein expression levels of matrix metalloproteinase (MMP)­2 and MMP­9. In addition, the number of surface tumor nodules was measured in vivo, in mice bearing B16­F10 tumors, following treatment with luteolin. Luteolin inhibited the viability and induced the apoptosis of MDA­MB­231 cells, which was accompanied by cell cycle arrest. This was associated with a decrease in the expression of the pro­metastatic markers C­X­C chemokine receptor type 4 (CXCR4), MMP­2 and MMP­9, which was reversed by AhR inhibition. Furthermore, it was identified that luteolin could inhibit the metastasis in a B16F10 mouse xenograft model, and the levels of MMP­9, MMP­2 and CXCR4 were significantly decreased in the lung tissues isolated from tumor­bearing nude mice following luteolin treatment. In conclusion, luteolin is a potential molecule for inhibiting breast cancer invasion and metastasis, which could have promising clinical applications.

The differential magnetic relaxation behaviours of slightly distorted triangular dodecahedral dysprosium analogues in a type of cyano-bridged 3d-4f zig-zag chain compounds.

A class of cyano-bridged 3d-4f zig-zag chain compounds, {RE[TM(CN)6] (PNO)2(H2O)4}·(H2O) {RE = YIII, TM = [FeIII]LS (1); RE = DyIII, TM = [FeIII]LS (2), CoIII (3)}, have been synthesized and characterized by single-crystal X-ray diffraction. The rare earth ions in these compounds are situated in a slightly distorted triangular dodecahedral (D2d) coordination environment. The magnetic properties of compounds 1-3 have been comparatively studied in detail. Under a zero dc field, the temperature dependence of ac susceptibility measurements for YFe (1) indicates the absence of magnetic relaxation stemming from the single anisotropic [FeIII]LS ion. The dysprosium analogue DyFe (2) shows only magnetic relaxation behavior with a prominent QTM effect, while DyCo (3) exhibits SIM properties not completely covered by QTM, with an extracted energy barrier of 73 K under a zero dc field. The ab initio calculations indicate that both compounds 2 and 3 are SMMs with well-behaved magnetic relaxation properties primarily from the individual DyIII ion. Therefore, the different magnetic behaviors exhibited by compound 2 compared to 3 may be ascribed to the stronger QTM effect caused by the extra weak interaction of [FeIII]LS ions in 2 as a fluctuating transverse field around the DyIII ion. The QTM effect for both 2 and 3 is suppressed under an applied dc field with an effective energy barrier of 134 and 150 K, respectively. Compared with compound 2, the higher extracted Ueff/kB and χ''(T) peak temperature for 3 should be further attributed to its slightly higher single-ion axiality as calculated and the elimination of the transverse field from the [FeIII]LS ion.

Elimination of senescent cells by ß-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice.

Cellular senescence, a persistent state of cell cycle arrest, accumulates in aged organisms, contributes to tissue dysfunction, and drives age-related phenotypes. The clearance of senescent cells is expected to decrease chronic, low-grade inflammation and improve tissue repair capacity, thus attenuating the decline of physical function in aged organisms. However, selective and effective clearance of senescent cells of different cell types has proven challenging. Herein, we developed a prodrug strategy to design a new compound based on the increased activity of lysosomal ß-galactosidase (ß-gal), a primary characteristic of senescent cells. Our prodrug SSK1 is specifically activated by ß-gal and eliminates mouse and human senescent cells independently of senescence inducers and cell types. In aged mice, our compound effectively cleared senescent cells in different tissues, decreased the senescence- and age-associated gene signatures, attenuated low-grade local and systemic inflammation, and restored physical function. Our results demonstrate that lysosomal ß-gal can be effectively leveraged to selectively eliminate senescent cells, providing a novel strategy to develop anti-aging interventions.

Near-infrared and metal-free tetra(butylamino)phthalocyanine nanoparticles for dual modal cancer phototherapy.

Synergistic phototherapy combining photodynamic therapy (PDT) and photothermal therapy (PTT) based on near-infrared (NIR) dyes using a single light source offers the opportunity to treat diseases at deep locations. In this study, we reported human serum albumin (HSA)-involving tetra(butylamino)phthalocyanine (Pc)-based nanomaterials of HSA-α-Pc and HSA-ß-Pc as highly efficient dual-phototherapy agents, namely 1(4),8(11),15(18),22(25)-tetra(butylamino)phthalocyanine (α-Pc) and 2(3),9(10),16(17),23(24)-tetra(butylamino)phthalocyanine (ß-Pc). Both HSA-α-Pc and HSA-ß-Pc showed excellent photothermal effects under a single NIR (808 nm) laser irradiation due to the S 1 fluorescence emission quenching of Pcs. Compared to HSA-ß-Pc, HSA-α-Pc exhibited better singlet oxygen generation ability and its highly efficient PDT/PTT dual-phototherapy was also well evidenced via in vitro and vivo experiments under a single 808 nm laser irradiation. Overall, this approach would be viable for the fabrication of more new Pc-based metal-free nano agents for PDT/PTT synergistic phototherapy upon a single NIR light source.

Potential of myricetin to restore the immune balance in dextran sulfate sodium-induced acute murine ulcerative colitis.

OBJECTIVES: Myricetin is a bioactive compound in many edible plants with anti-inflammatory and anticarcinogenic activity. The current study aimed to determine the protective effects and mechanism of myricetin against ulcerative colitis (UC). METHODS: Myricetin was orally administered at doses of 40 and 80 mg/kg to C57BL/6 mice with UC induced using dextran sulfate sodium. The disease-associated index and colon length were determined at the end of the experiment, the proportion of Treg, Th1 and Th17 was analysed by cytometry, and cytokines were detected using ELISA. KEY FINDINGS: Myricetin (80 mg/kg) ameliorated the severity of inflammation in acute UC and significantly improved the condition. Myricetin (80 mg/kg) elevated the levels of IL-10 and transforming growth factor ß. In addition, the proportion of regulatory T cells significantly increased in mice in the myricetin treatment group. CONCLUSIONS: Taking together, these results suggest that myricetin exhibits significant protective effects against UC and it could be used as a potential treatment for UC.

Surface Decorated Porphyrinic Nanoscale Metal-Organic Framework for Photodynamic Therapy.

Nanocrystallization of organic molecular photosensitizers (PSs) by means of NMOF platforms has been demonstrated to be a promising approach to build up highly efficient PDT therapeutics. We report herein a new UiO-66 type of NMOF-based PS (UiO-66-TPP-SH), which is generated from UiO-66 NMOF and S-ethylthiol ester monosubstituted metal free porphyrin (TPP-SH) via a facile postsynthetic approach under mild conditions. The obtained NMOF (size less than 150 nm) with surface-decorated porphyrinic PS can not only retain MOF crystallinity, structural feature, and size, but also exhibit highly efficient singlet oxygen generation. Compared to the interior-located porphyrinic NMOF, UiO-66-TPP-SH shows significantly higher photodynamic activity and more efficient PDT tumor treatment.