Sargassum polysaccharide attenuates osteoarthritis in rats and is associated with the up-regulation of the ITGß1-PI3K-AKT signaling pathway.

Background: Osteoarthritis (OA) presents a formidable challenge, characterized by as-yet-unclear mechanical intricacies within cartilage and the dysregulation of bone homeostasis. Our preliminary data revealed the encouraging potential of a Sargassum polysaccharide (SP), in promoting chondrogenesis. The aim of our study is to comprehensively assess the therapeutic effects of SP on OA models and further elucidate its potential mechanism. Methods: The protective effects of SP were initially evaluated in an inflammation-induced human chondrocyte (C28) cell model. CCK-8 assays, Alcian blue staining, RT-qPCR and Western blotting were used to verify the chondrogenesis of SP in vitro. To assess the efficacy of SP in vivo, surgically induced medial meniscus destabilization (DMM) OA rats underwent an 8-week SP treatment. The therapeutic effects of SP in OA rats were comprehensively evaluated using X-ray imaging, micro-computed tomography (µ-CT), histopathological analysis, as well as immunohistochemical and immunofluorescent staining. Following these assessments, we delved into the potential signaling pathways of SP in inflammatory chondrocytes utilizing RNA-seq analysis. Validation of these findings was conducted through RT-qPCR and western blotting techniques. Results: SP significantly enhance the viability of C28 chondrocytes, and increased the secretion of acidic glycoproteins. Moreover, SP stimulated the expression of chondrogenic genes (Aggrecan, Sox9, Col2a1) and facilitated the synthesis of Collagen II protein in C28 inflammatory chondrocytes. In vivo experiments revealed that SP markedly ameliorated knee joint stenosis, alleviated bone and cartilage injuries, and reduced the histopathological scores in the OA rats. µ-CT analysis confirmed that SP lessened bone impairments in the medial femoral condyle and the subchondral bone of the tibial plateau, significantly improving the microarchitectural parameters of the subchondral bone. Histopathological analyses indicated that SP notably enhanced cartilage quality on the surface of the tibial plateau, leading to increased cartilage thickness and area. Immunohistochemistry staining and immunofluorescence staining corroborated these findings by showing a significant promotion of Collagen II expression in OA joints treated with SP. RNA-seq analysis suggest that SP's effects were mediated through the regulation of the ITGß1-PI3K-AKT signaling axis, thereby stimulating chondrogenesis. Verification through RT-qPCR and Western blot analyses confirmed that SP significantly upregulated the expression of ITGß1, p110δ, AKT1, ACAN, and Col2a1. Notably, knock-down of ITGß1 using siRNA in C28 chondrocytes inhibited the expression of ITGß1, p110δ, AKT1, and ACAN. However, these inhibitory effects were not completely reversed by supplemental SP intervention. Conclusions: In summary, our findings reveal that SP significantly enhances chondrogenesis both in vitro and in vivo, alleviating OA progression both in bone and cartilage. The observed beneficial effects are intricately linked to the activation of the ITGß1-PI3K-AKT signaling axis. The translational potential of this article: Our research marks the first instance unveiling the advantageous effects and underlying mechanisms of SP in OA treatment. With its clinical prospects, SP presents compelling new evidence for the advancement of a next-generation polysaccharide drug for OA therapy.

Skinned Motion Retargeting with Preservation of Body Part Relationships.

Motion retargeting is an active research area in computer graphics and animation, allowing for the transfer of motion from one character to another, thereby creating diverse animated character data. While this technology has numerous applications in animation, games, and movies, current methods often produce unnatural or semantically inconsistent motion when applied to characters with different shapes or joint counts. This is primarily due to a lack of consideration for the geometric and spatial relationships between the body parts of the source and target characters. To tackle this challenge, we introduce a novel spatially-preserving Skinned Motion Retargeting Network (SMRNet) capable of handling motion retargeting for characters with varying shapes and skeletal structures while maintaining semantic consistency. By learning a hybrid representation of the character's skeleton and shape in a rest pose, SMRNet transfers the rotation and root joint position of the source character's motion to the target character through embedded rest pose feature alignment. Additionally, it incorporates a differentiable loss function to further preserve the spatial consistency of body parts between the source and target. Comprehensive quantitative and qualitative evaluations demonstrate the superiority of our approach over existing alternatives, particularly in preserving spatial relationships more effectively.

Effects of C and Al Alloying on Constitutive Model Parameters and Hot Deformation Behavior of Medium-Mn Steels.

Single-pass isothermal hot compression tests on four medium-Mn steels with different C and Al contents were conducted using a Gleeble-3500 thermal simulation machine at varying deformation temperatures (900-1150 °C) and strain rates (0.01-5 s-1). Based on friction correction theory, the friction of the test stress-strain data was corrected. On this basis, the Arrhenius constitutive model of experimental steels considering Al content and strain compensation and hot processing maps of different experimental steels at a strain of 0.9 were established. Moreover, the effects of C and Al contents on constitutive model parameters and hot processing performance were analyzed. The results revealed that the increase in C content changed the trend of the thermal deformation activation energy Q with the true strain. The Q value of 2C7Mn3Al increased by about 50 KJ/mol compared with 7Mn3Al at a true strain greater than 0.4. In contrast, increasing the Al content from 0 to 1.14 wt.% decreased the activation energy of thermal deformation in the true strain range of 0.4-0.9. Continuing to increase to 3.30 wt.% increased the Q of 7Mn3Al over 7Mn by about 65 KJ/mol over the full strain range. In comparison, 7Mn1Al exhibited the best hot processing performance under the deformation temperature of 975-1125 °C and strain rate of 0.2-5 s-1. This is due to the addition of C element reduces the δ-ferrite volume fraction, which leads to the precipitation of κ-carbides and causes the formation of microcracks; an increase in Al content from 0 to 1.14 wt.% reduces the austenite stability and improves the hot workability, but a continued increase in the content up to 3.30 wt.% results in the emergence of δ-ferrite in the microstructure, which slows down the austenite DRX and not conducive to the hot processing performance.

Hypofunction of macrophage chemotaxis contributes to defective efficacy of herceptin in HER2-positive breast cancer patients.

Breast cancer was considered as a kind of prone breast tumors with the complicated pathological mechanisms and diverse clinical classifications. In the clinical treatments of HER2-positive tumor patients, HER2 monoclonal antibodies, such as Herceptin, have shown well-defined therapeutic effects. Nevertheless, due to the heterogeneity of breast cancers, drug resistance inevitably appeared during the application of Herceptin. In order to fully understand the immune tolerance status of the tumor microenvironment in the population of sensitive and insensitive patients, this study carried out a series of studies through Luminex cytokines assay, clinicopathological analysis, immunofluorescence, and PCR. The results confirmed that in clinical samples sensitive to Herceptin, there were a large number of macrophages, and the protein expression levels and in situ expression of macrophage-related chemokines and inflammatory mediators are significantly higher than drug-resistant tumor samples. Further studies found that T cell function has a low correlation with tumor growth, and there are obvious obstacles in the process of peripheral blood immune cells entering the tumor microenvironment. In summary, this study provided clues for understanding the clinical drug resistance of HER2 monoclonal antibody and the clinical rational use of drugs and combination drugs.

In Situ Metal-Oxygen-Hydrogen Modified B-Tio2 @Co2 P-X S-Scheme Heterojunction Effectively Enhanced Charge Separation for Photo-assisted Uranium Reduction.

Photo-assisted uranium reduction from uranium mine wastewater is expected to overcome the competition between impurity ions and U(VI) in the traditional process. Here, B-TiO2 @Co2 P-X S-scheme heterojunction with metal-oxygen-hydrogen (M-O-H) is developed insitu modification for photo-assisted U(VI) (hexavalent uranium) reduction. Relying on the DFT calculation and Hard-Soft-Acid-Base (HSAB) theory, the introduction of metal-oxygen-hydrogen (M-O-H, hard base) metallic bonds in the B-TiO2 @Co2 P-X is found to enhance the hydrophilicity and the capture capability for uranyl ion (hard acid). Accordingly, B-TiO2 @Co2 P-500 hybrid nanosheets exhibit excellent U(VI) reduction ability (>98%) in the presence of competing ions. By self-consistent energy band calculations and in-situ KPFM spectral analysis, the formation of the internal electric field between B-TiO2 and Co2 P at the heterojunction is proven, offering a strong driving force and atomic transportation highway for accelerating the S-scheme charge carriers directed migration and promoting the photocatalytic reduction of uranium. This work provides a valuable route to explore the functionally modified photocatalyst with high-efficiency photoelectron separation for U(VI) reduction.

Effect of Deformation Conditions on Strain-Induced Precipitation of 7Mo Super-Austenitic Stainless Steel.

Strain-induced precipitation (SIP) behaviors of 7Mo super-austenitic stainless steel (SASS) under various deformation conditions were studied by stress relaxation tests. The research demonstrates that sigma phases are the primary SIP phases of 7Mo SASS. Generally, SIP is mainly distributed in granular shape at the boundaries of deformed grains or recrystallized grains, as well as around the deformed microstructure, such as deformation twin layers/matrix interfaces. The variation of deformation parameters can lead to changes in microstructure, therefore influencing the distribution of SIP. For instance, with the temperature increases, the SIP distribution gradually evolves from deformed grain boundaries to recrystallized grain boundaries. The average size of SIP increases with increasing temperature and strain, as well as decreasing strain rate. The SIP content also increases with increasing strain and decreasing strain rate, while exhibiting an initial rise followed by a decline with increasing temperature, reaching its maximum value at 850 °C. The presence of SIP can promote recrystallization by particle-induced nucleation (PSN) mechanism during the hot deformation process. Moreover, the boundaries of these recrystallized grains can also serve as nucleation sites for SIP, therefore promoting SIP. This process can be simplified as SIP→PSNRecrystallization→Nucleation sitesSIP. With the increase in holding time and the consumption of stored energy, the process gradually slows down, leading to the formation of a multi-layer structure, namely SIPs/Recrystallized grains/SIPs structure. Moreover, SIP at recrystallized grain boundaries can hinder the growth of recrystallized grains. Through this study, a comprehensive understanding of the SIP behaviors in 7Mo SASS under different deformation conditions has been achieved, as well as the interaction between SIP and recrystallization. This finding provides valuable insights for effective control or regulation of SIP and optimizing the hot working processes of 7Mo SASS.

Taphonomic experiments reveal authentic molecular signals for fossil melanins and verify preservation of phaeomelanin in fossils.

Melanin pigments play a critical role in physiological processes and shaping animal behaviour. Fossil melanin is a unique resource for understanding the functional evolution of melanin but the impact of fossilisation on molecular signatures for eumelanin and, especially, phaeomelanin is not fully understood. Here we present a model for the chemical taphonomy of fossil eumelanin and phaeomelanin based on thermal maturation experiments using feathers from extant birds. Our results reveal which molecular signatures are authentic signals for thermally matured eumelanin and phaeomelanin, which signatures are artefacts derived from the maturation of non-melanin molecules, and how these chemical data are impacted by sample preparation. Our model correctly predicts the molecular composition of eumelanins in diverse vertebrate fossils from the Miocene and Cretaceous and, critically, identifies direct molecular evidence for phaeomelanin in these fossils. This taphonomic framework adds to the geochemical toolbox that underpins reconstructions of melanin evolution and of melanin-based coloration in fossil vertebrates.

Preservation of corneous ß-proteins in Mesozoic feathers.

Fossil proteins are valuable tools in evolutionary biology. Recent technological advances and better integration of experimental methods have confirmed the feasibility of biomolecular preservation in deep time, yielding new insights into the timing of key evolutionary transitions. Keratins (formerly α-keratins) and corneous ß-proteins (CBPs, formerly ß-keratins) are of particular interest as they define tissue structures that underpin fundamental physiological and ecological strategies and have the potential to inform on the molecular evolution of the vertebrate integument. Reports of CBPs in Mesozoic fossils, however, appear to conflict with experimental evidence for CBP degradation during fossilization. Further, the recent model for molecular modification of feather chemistry during the dinosaur-bird transition does not consider the relative preservation potential of different feather proteins. Here we use controlled taphonomic experiments coupled with infrared and sulfur X-ray spectroscopy to show that the dominant ß-sheet structure of CBPs is progressively altered to α-helices with increasing temperature, suggesting that (α-)keratins and α-helices in fossil feathers are most likely artefacts of fossilization. Our analyses of fossil feathers shows that this process is independent of geological age, as even Cenozoic feathers can comprise primarily α-helices and disordered structures. Critically, our experiments show that feather CBPs can survive moderate thermal maturation. As predicted by our experiments, analyses of Mesozoic feathers confirm that evidence of feather CBPs can persist through deep time.

Nestin Expression and the Survival of Patients With Digestive Tract Cancers: A Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Several cancers have been associated with poor prognoses based on nestin, a confirmed marker of cancer stem cells. However, there is conflicting evidence regarding the prognostic value of tumor nestin expression in patients with digestive tract cancers. An investigation of the association between nestin and survival in patients with digestive tract cancers was performed in this meta-analysis. MATERIALS AND METHODS: Meta-analyses were conducted using PubMed, Embase, and Web of Science databases to search for cohort studies. We analyzed the data using a random-effects model that incorporates differences between studies. RESULTS: The pooled analysis showed a negative association between nestin expression and overall survival (hazard ratio: 1.38, 95% CI: 1.11 to 1.72, P = .004, I2 = 68%) and disease-free survival (hazard ratio: 1.48, 95% CI: 1.12 to 1.96, P = .005, I2 = 56%). Subgroup analysis showed that nestin expression was associated with poorer overall survival in gastric cancer (hazard ratio: 1.46, P < .001) and liver cancer (hazard ratio: 2.05, P < .001) patients, but not in colorectal cancer (hazard ratio: 1.03, P = .89) or pancreatic cancer (hazard ratio: 0.96, P = .80) patients. Further subgroup analysis showed a consistent association between nestin expression and poor overall survival in Asian and non-Asian studies, and in studies with univariate and multivariate regression models. CONCLUSION: To sum up, the presence of high nestin expression in digestive tract cancer patients is associated with poorer survival, particularly in patients with gastric and liver cancers.

The Optimized Homogenization Process of Cast 7Mo Super Austenitic Stainless Steel.

Super austenitic stainless steels are expected to replace expensive alloys in harsh environments due to their superior corrosion resistance and mechanical properties. However, the ultra-high alloy contents drive serious segregation in cast steels, where the σ phase is difficult to eliminate. In this study, the microstructural evolution of 7Mo super austenitic stainless steels under different homogenization methods was investigated. The results showed that after isothermal treatment for 30 h at 1250 °C, the σ phase in steels dissolved, while the remelting morphologies appeared at the phase boundaries. Therefore, the stepped solution heat treatment was further conducted to optimize the homogenized microstructure. The samples were heated up to 1220 °C, 1235 °C and 1250 °C with a slow heating rate, and held at these temperatures for 2 h, respectively. The elemental segregation was greatly reduced without incipient remelting and the σ phase was eventually reduced to less than 0.6%. A prolonged incubation below the dissolution temperature will lead to a spontaneous compositional adjustment of the eutectic σ phase, resulting in uphill diffusion of Cr and Mn, and reducing the homogenization efficiency of ISHT, which is avoided by SSHT. The hardness reduced from 228~236 Hv to 220~232 Hv by adopting the cooling process of "furnace cooling + water quench". In addition, the study noticed that increasing the Ce content or decreasing the Mn content can both refine the homogenized grain size and accelerate diffusion processes. This study provides a theoretical and experimental basis for the process and composition optimization of super austenitic stainless steels.

A holistic model for melt electrowritten three-dimensional structured materials based on residual charge.

The printing accuracy of polymer melt electrowriting is adversely affected by the residual charge entrapped within the fibers, especially for three-dimensional (3D) structured materials or multilayered scaffolds with small interfiber distances. To clarify this effect, an analytical charge-based model is proposed herein. The electric potential energy of the jet segment is calculated considering the amount and distribution of the residual charge in the jet segment and the deposited fibers. As the jet deposition proceeds, the energy surface assumes different patterns, which constitute different modes of evolution. The manner in which the various identified parameters affect the mode of evolution are represented by three charge effects, including the global, local, and polarization effect. Based on these representations, typical modes of energy surface evolution are identified. Moreover, the lateral characteristic curve and characteristic surface are advanced to analyze the complex interplay between fiber morphologies and residual charge. Different parameters contribute to this interplay either by affecting residual charge, fiber morphologies, or the three charge effects. To validate this model, the effects of lateral location and grid number (i.e., number of fibers printed in each direction) on the fiber morphologies are investigated. Moreover, the "fiber bridging" phenomenon in parallel fiber printing is successfully explained. These results help to comprehensively understand the complex interplay between the fiber morphologies and the residual charge, thus furnishing a systematic workflow to improve printing accuracy.

Low-Dose IL-2 Attenuated Depression-like Behaviors and Pathological Changes through Restoring the Balances between IL-6 and TGF-ß and between Th17 and Treg in a Chronic Stress-Induced Mouse Model of Depression.

Microglia activation, increased IL-6 and decreased TGF-ß were found in depressed patients or in animal models of depression. IL-6 enhances T helper 17 cell differentiation, thereby causing an imbalance between Th17 and Treg cells, which induces neuroinflammation and neuronal dysfunction. However, whether imbalances between IL-6 and TGF-ß and between Th17 and Treg occur in depression and whether depression can be improved upon restoring these imbalances are unknown. Treg promoter IL-2 (1500UI/0.1 mL/day) was used to treat a mouse model of depression induced by chronic unpredictable mild stress (CUMS). The behavior and concentrations of IL-6, TGF-ß, Th17, IL-17A, IL-17Rc, Treg-related factors (helios and STAT5), astrocyte A1 phenotype S100ß, microglia M1 phenotype Iba-1, indoleamine-2,3-dioxygenase (IDO) enzyme, corticosterone (CORT) and neurotransmitters were evaluated. When compared to controls, CUMS reduced sucrose preference, the number of entries into and the time spent in the open arms of the elevated plus maze and the exploration in the "open field", while it increased the immobility time in tail suspension, which was ameliorated by IL-2 treatment. RoRα, S100ß, IL-17A, IL-17Rc, IL-6, Iba-1, IDO enzyme and CORT concentrations were significantly increased, and Helios, FoxP3+, STAT5 and TGF-ß were significantly decreased by CUMS, which were significantly attenuated by IL-2 when compared to the CUMS group. The NE, DA and 5-HT contents and those of their metabolites were decreased by CUMS, which returned to control levels after IL-2 treatment. The study demonstrated that imbalances between IL-6 and TGF-ß and between Th17and Treg occurred in the hippocampus of the depression model. IL-2 attenuated depression- and anxiety-like behaviors and normalized the neurotransmitter concentration and the activity of the IDO enzyme, astrocytes and microglia through restoring both balances, but it did not decrease the CORT concentration.

Tensile Properties and Microstructure Evolutions of Low-Density Duplex Fe-12Mn-7Al-0.2C-0.6Si Steel.

An austenite-ferrite duplex low-density steel (Fe-12Mn-7Al-0.2C-0.6Si, wt%) was designed and fabricated by cold rolling and annealing at different temperatures. The tensile properties, microstructure evolution, deformation mechanism and stacking fault energy (SFE) of the steel were systemically investigated at ambient temperature. Results show two phases of fine equiaxed austenite and coarse band-like δ-ferrite in the microstructure of the steel. With increasing annealing temperature, the yield and tensile strengths decrease while the total elongation increases. At initial strains, the deformation is mainly concentrated in the fine austenite and grain boundaries of the coarse δ-ferrite, and the interior of the coarse δ-ferrite gradually deforms with further increase in the strain to 0.3. No twinning-induced plasticity (TWIP) or transformation-induced plasticity (TRIP) occurred during the tensile deformation. Considering element segregation and two-phase proportion, the chemical composition of austenite was measured more precisely. The SFE of the austenite is 39.7 mJ/m2, and the critical stress required to produce deformation twins is significantly higher than the maximum flow stress of the steel.

Numerical analysis on the effects of microfluidic-based bioprinting parameters on the microfiber geometrical outcomes.

The application of microfluidics technology in additive manufacturing is an emerging approach that makes possible the fabrication of functional three-dimensional cell-laden structured biomaterials. A key challenge that needs to be addressed using a microfluidic-based printhead (MBP) is increasing the controllability over the properties of the fabricated microtissue. Herein, an MBP platform is numerically simulated for the fabrication of solid and hollow microfibers using a microfluidic channel system with high level of controllability over the microfiber geometrical outcomes. Specifically, the generation of microfibers is enabled by studying the effects of microfluidic-based bioprinting parameters that capture the different range of design, bioink material, and process parameter dependencies as numerically modeled as a multiphysics problem. Furthermore, the numerical model is verified and validated, exhibiting good agreement with literature-derived experimental data in terms of microfiber geometrical outcomes. Additionally, a predictive mathematical formula that correlates the dimensionless process parameters with dimensionless geometrical outcomes is presented to calculate the geometrical outcomes of the microfibers. This formula is expected to be applicable for bioinks within a prescribed range of the density and viscosity value. The MBP applications are highlighted towards precision fabrication of heterogeneous microstructures with functionally graded properties to be used in organ generation, disease modeling, and drug testing studies.

Effect of RNA Interference Inhibiting the Expression of the FUBP1 Gene on Biological Function of Gastric Cancer Cell Line SGC7901.

BACKGROUND: The research aimed to observe the effect of gene silencing on the proliferation, migration, cell cycle, apoptosis, and other biological functions of human gastric cancer cells with RNA interference inhibiting the expression of the far upstream element-binding protein 1 (FUBP1) in the gastric cancer cell line SGC7901. METHODS: The shRNA lentivirus vector of the target gene FUBP1 was constructed to transfect the gastric cancer cell line SGC7901. The qRT-PCR and western blot assays were used to detect the expression levels of FUBP1 mRNA and protein in the gastric cancer cells. The CCK-8 assay was used to detect the proliferation of gastric cancer cells. The cell scratch assay and the transwell assays were used to detect the migration of gastric cancer cells. Flow cytometry was used to detect cell cycle distribution and apoptosis. RESULTS: The shRNA lentiviral vector of FUBP1 was successfully transfected into the gastric cancer cell line SGC7901, and could effectively reduce the expression of mRNA and protein of FUBP1. The silencing of FUBP1 could inhibit the gastric cancer cell proliferation and affect the distribution of the cell cycle, resulting in S-phase arrest and cell growth inhibition. However, FUBP1 silencing has no significant effect on cell apoptosis and migration. CONCLUSIONS: The expression of FUBP1 can be inhibited specifically and effectively by RNA interference technology, which can significantly affect the biological function of the gastric cancer cell line SGC7901.

Isoginkgetin treatment attenuated lipopolysaccharide-induced monoamine neurotransmitter deficiency and depression-like behaviors through downregulating p38/NF-κB signaling pathway and suppressing microglia-induced apoptosis.

BACKGROUND: Microglia activation-induced neuroinflammation may contribute to the etiology of depression. Podocarpus nagi containing high concentration of isoginkgetin could effectively treat mental diseases in ancient times. However, the therapeutic role, peculiarly in the brain-immune modulation in depression is still unclear. This study aimed to determine effects of isoginkgetin on lipopolysaccharide (LPS)-induced depression-like changes. Furthermore, its modulation on the p38/nuclear factor-kappa B (NF-κB) pathway in LPS-activated microglia was evaluated. METHODS: Adult Kunming mice were intraperitoneally injected vehicle or isoginkgetin (4 mg/kg) daily for 14 days before saline or LPS (0.83 mg/kg) administration. Depression-like behavior, neurotransmitter levels, and markers of neuroinflammation were determined. Isoginkgetin effect on LPS-induced microglial activation was then assessed in BV2 cells. Finally, conditioned medium (CM) derived from isoginkgetin-treated BV2 cells was co-cultured with SH-SY5Y cells for 24 h. Cell viability and apoptosis were evaluated. RESULTS: LPS significantly induced helplessness and anxiety, which were associated with decreased 5-HT, noradrenaline, and dopamine concentrations. Meanwhile, LPS increased microglia M1 hallmark Iba1 expression and serum interleukin (IL)-1ß concentration. These changes were attenuated by isoginkgetin treatment. In vitro, isoginkgetin markedly suppressed the production of IL-1ß, IL-6, tumor necrosis factor-alpha, cyclooxygenase-2, inducible nitric oxide, and reactive oxygen species, which are released from LPS-stimulated BV2 cells. More interestingly, CM from isoginkgetin-treated BV2 cells significantly alleviated SH-SY5Y cell apoptosis and restored cell viability compared to LPS-treated group through the inhibition of p38/NF-κB signaling pathway. CONCLUSION: These data demonstrate that isoginkgetin is an effective therapeutic agent for depression-like behaviors and neuropathological changes via potent anti-inflammatory property.

Bone marrow mesenchymal stem cell-derived exosomes promote rotator cuff tendon-bone healing by promoting angiogenesis and regulating M1 macrophages in rats.

BACKGROUND: Rotator cuff tears (RCTs) often require reconstructive surgery. Tendon-bone healing is critical for the outcome of rotator cuff reconstruction, but the process of tendon-bone healing is complex and difficult. Mesenchymal stem cells (MSCs) are considered to be an effective method to promote tendon-bone healing. MSCs have strong paracrine, anti-inflammatory, immunoregulatory, and angiogenic potential. Recent studies have shown that MSCs achieve many regulatory functions through exosomes. The purpose of this study was to explore the role of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) in tendon-bone healing. METHODS: Our study found that BMSC-Exos promote the proliferation, migration, and angiogenic tube formation of human umbilical vein endothelial cells (HUVECs). The mechanism by which BMSC-Exos achieve this may be through the regulation of the angiogenic signaling pathway. In addition, BMSC-Exos can inhibit the polarization of M1 macrophages and inhibit the secretion of proinflammatory factors by M1 macrophages. After rotator cuff reconstruction in rats, BMSC-Exos were injected into the tail vein to analyze their effect on the rotator cuff tendon-bone interface healing. RESULTS: It was confirmed that BMSC-Exos increased the breaking load and stiffness of the rotator cuff after reconstruction in rats, induced angiogenesis around the rotator cuff endpoint, and promoted growth of the tendon-bone interface. CONCLUSION: BMSC-Exos promote tendon-bone healing after rotator cuff reconstruction in rats by promoting angiogenesis and inhibiting inflammation.

Protective Effect of Pravastatin on Myocardial Ischemia Reperfusion Injury by Regulation of the miR-93/Nrf2/ARE Signal Pathway.

PURPOSE: This research intended to study the mechanism of pravastatin in myocardial ischemia reperfusion (I/R) injury. PATIENTS AND METHODS: Altogether 70 male rats were selected and grouped into Sham operation group (Sham group), ischemia reperfusion group (I/R group), pravastatin pretreatment group (I/R+P group), I/R+miR-93-mimics, I/R+P+miR-93-mimics, I/R+Nrf2 siRNA, and I/R+P+Nrf2 siRNA group. The myocardial function of each group was detected. RESULTS: Myocardial I/R injury could lead to abnormal myocardial enzyme activity, inflammatory reaction and oxidative stress. However, pravastatin could significantly inhibit the activity of myocardial enzymes, alleviate inflammatory reaction and inhibit oxidative stress reaction, thus playing a protective role. Furthermore, cell experiments showed that pravastatin can alleviate the injury of H9C2 myocardial cells caused by I/R, inhibit the apoptosis of myocardial cells, and lead to a significant reduction in pro-apoptotic genes Bax, caspase-3 and caspase-9 transcription levels, an obvious increase in anti-apoptotic gene Bcl-2, and an increase in cell activity. After I/R induced injury, miR-93 level was significantly up-regulated and Nrf2 level was down-regulated. Over-expression of miR-93 or inhibition of Nrf2 expression would lead to further aggravation of I/R myocardial injury, increase the apoptosis rate of cells and decrease the activity of myocardial cells. Pravastatin administration could inhibit miR-93, activate and promote Nrf2 in myocardial tissue, and promote protein expression of downstream regulatory genes HO-1 and NQO1. In the I/R model, pravastatin was given. Over-expression of miR-93 or silencing Nrf2 could reverse the therapeutic effect of pravastatin on I/R. CONCLUSION: Pravastatin acts as a protector on myocardial ischemia reperfusion injury by regulating miR-93/Nrf2/ARE signaling pathway.