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Abstract Backgrounds Progranulin (PGRN) is a growth factor-like molecule with diverse roles in homeostatic and pathogenic processes including the control of immune and inflammatory responses. Pathogenic inflammation is a hallmark of systemic lupus erythematosus (SLE) and elevated serum levels of PGRN has been evaluated as a biomarker of disease activity in SLE. However, the role of PGRN in SLE has not been fully investigated. This study is aimed to determine the potential involvements of PGRN in SLE. Methods Wild type (WT) and PGRN knockout (PGRN-/-) C57BL/6 mice received intraperitoneal injection of pristane for induction of a murine model of SLE. Sera were collected every biweekly and levels of anti-dsDNA antibody, IgG, and inflammatory factors were measured. Mice were sacrificed 5 months later and the renal lesions, as well as the proportions of T cell subtypes in the spleen were analyzed. Results Following exposure to pristane, PGRN-/- mice generated significantly lower levels of anti-dsDNA antibody and IgG relative to WT mice. PGRN-/- mouse kidneys had less IgG and collagen deposition compared with WT mice after pristane injection. Conclusion The results indicate that PGRN participates in inflammatory response and renal damage in pristane induced SLE models, suggesting that PGRN mediates the onset of SLE.

Estrogen deficiency is considered the most important cause of postmenopausal osteoporosis. However, the underlying mechanism is still not completely understood. In this study, progranulin (PGRN) was isolated as a key regulator of bone mineral density in postmenopausal women through high throughput proteomics screening. In addition, PGRN-deficient mice exhibited significantly lower bone mass than their littermates in an ovariectomy-induced osteoporosis model. Furthermore, estrogen-mediated inhibition of osteoclastogenesis and bone resorption as well as its protection against ovariectomy-induced bone loss largely depended on PGRN. Mechanistic studies revealed the existence of a positive feedback regulatory loop between PGRN and estrogen signaling. In addition, loss of PGRN led to the reduction of estrogen receptor α, the important estrogen receptor involved in estrogen regulation of osteoporosis, through enhancing its degradation via K48-linked ubiquitination. These findings not only provide a previously unrecognized interplay between PGRN and estrogen signaling in regulating osteoclastogenesis and osteoporosis but may also present a new therapeutic approach for the prevention and treatment of postmenopausal osteoporosis by targeting PGRN/estrogen receptor α.

Abstract Background Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

China is rich in mineral resources, and problems of goaf formed in the process of resource exploitation are serious obstacle to the development of China's economic, so it is of great significance for the assessment and management of goafs. This paper introduces emerging dung beetle optimizer (DBO) algorithm and establishes DBO-BP (back-propagation) model, at the same time, it is compared with a series of heuristic algorithms coupled with BP neural network models: PSO (particle swarm optimization) - BP model, WOA (whale optimization algorithm) - BP model, and SSA (sparrow search algorithm) - BP model. Then they are applied to evaluate the hazard of goafs, the result shows that the DBO-BP model gets the highest train set accuracy, which is at least 2.7 % higher than other models, while the DBO-BP model obtains the highest test set accuracy, meanwhile its effectiveness and stability have also been proven. Finally we apply the established DBO-BP model to evaluate the hazard of the tungsten mine goaf of Yaogangshan in Hunan Province, and its excellent practicability was confirmed. This paper may provide a reference for the solution of nonlinear engineering problems.

Introductions: Excessive mechanical stress is closely associated with cell death in various conditions. Exposure of chondrocytes to excessive mechanical loading leads to a catabolic response as well as exaggerated cell death. Ferroptosis is a recently identified form of cell death during cell aging and degeneration. However, it's potential association with mechanical stress remains to be illustrated. Objectives: To identify whether excessive mechanical stress can cause ferroptosis. To explore the role of mechanical overloading in chondrocyte ferroptosis. Methods: Chondrocytes were collected from loading and unloading zones of cartilage in patients with osteoarthritis (OA), and the ferroptosis phenotype was analyzed through transmission electron microscope and microarray. Moreover, the relationship between ferroptosis and OA was analyzed by GPX4-conditional knockout (Col2a1-CreERT: GPX4flox/flox) mice OA model and chondrocytes cultured with high strain mechanical stress. Furthermore, the role of Piezo1 ion channel in chondrocyte ferroptosis and OA development was explored by using its inhibitor (GsMTx4) and agonist (Yoda1). Additionally, chondrocyte was cultured in calcium-free medium with mechanical stress, and ferroptosis phenotype was tested. Results: Human cartilage and mouse chondrocyte experiments revealed that mechanical overloading can induce GPX4-associated ferroptosis. Conditional knockout of GPX4 in cartilage aggravated experimental OA process, while additional treatment with ferroptosis suppressor protein (FSP-1) and coenzyme Q10 (CoQ10) abated OA development in GPX4-CKO mice. In mouse OA model and chondrocyte experiments, inhibition of Piezo1 channel activity increased GPX4 expression, attenuated ferroptosis phenotype and reduced the severity of osteoarthritis. Additionally, high strain mechanical stress induced ferroptosis damage in chondrocyte was largely abolished by blocking calcium influx through calcium-free medium. Conclusions: Our findings show that mechanical overloading induces ferroptosis through Piezo1 activation and subsequent calcium influx in chondrocytes, which might provide a potential target for OA treatment.

Diabetes mellitus is a group of chronic diseases characterized by high blood glucose levels. Diabetic patients have a higher risk of sustaining osteoporotic fractures than non-diabetic people. The fracture healing is usually impaired in diabetics, and our understanding of the detrimental effects of hyperglycemia on fracture healing is still inadequate. Metformin is the first-line medicine for type 2 diabetes (T2D). However, its effects on bone in T2D patients remain to be studied. To assess the impacts of metformin on fracture healing, we compared the healing process of closed-wound fixed fracture, non-fixed radial fracture, and femoral drill-hole injury models in the T2D mice with and without metformin treatment. Our results demonstrated that metformin rescued the delayed bone healing and remolding in the T2D mice in all injury models. In vitro analysis indicated that compromised proliferation, osteogenesis, chondrogenesis of the bone marrow stromal cells (BMSCs) derived from the T2D mice were rescued by metformin treatment when compared to WT controls. Furthermore, metformin could effectively rescue the impaired detrimental lineage commitment of BMSCs isolated from the T2D mice in vivo as assessed by subcutaneous ossicle formation of the BMSC implants in recipient T2D mice. Moreover, the Safranin O staining of cartilage formation in the endochondral ossification under hyperglycemic condition significantly increased at day 14 post-fracture in the T2D mice receiving metformin treatment. The chondrocyte transcript factors SOX9 and PGC1α, important to maintain chondrocyte homeostasis, were both significantly upregulated in callus tissue isolated at the fracture site of metformin-treated MKR mice on day 12 post-fracture. Metformin also rescued the chondrocyte disc formation of BMSCs isolated from the T2D mice. Taken together, our study demonstrated that metformin facilitated bone healing, more specifically bone formation and chondrogenesis in T2D mouse models.

The effect of pullulanase enzymatic hydrolysis on the physicochemical properties of granular kudzu starch was studied. The gelatinization property, content of resistant starch, thermal characteristic, morphology, particle size, crystal structure and molecular structure of kudzu starch (KS) and enzymatic hydrolysis kudzu starch (EHKS) were determined by rapid viscosity analyzer (RVA), differential scanning calorimetry (DSC), polarizing microscope, scanning electron microscope (SEM), laser particle sizer, fourier transform infrared spectrometer (FTIR) and X-ray diffraction (XRD), respectively. The results showed that after the enzymatic hydrolysis of KS, its peak viscosity and breakdown value decreased by 28.33% and 94.69%, respectively, while the trough viscosity, final viscosity and setback value increased by 12.53%, 12.47% and 12.37%, respectively. And the content of resistant starch increased from 1.29% to 4.60%. After the enzymatic hydrolysis of KS, its polarized cross still existed, but the granules expanded and the particles size became large. And the surface layer was peeled off. DSC endothermic peak of modified starch shifts to high temperature region, but its endothermic enthalpy decreased. The enzymatic hydrolysis promoted the formation of short-range ordered structure of starch molecules. After the enzymatic hydrolysis of KS, its relative crystallinity decreased from 37.31% to 29.10%.

Abstract Abdominal aortic aneurysm (AAA) is a lethal cardiovascular disease, and there is no proven drug treatment for this condition. In this study, by using the Connectivity Map (CMap) approach, we explored naringenin, a naturally occurring citrus flavonoid, as a putative agent for inhibiting AAA. We then validated the prediction with two independent mouse models of AAA, calcium phosphate (CaPO4)-induced C57BL/6J mice and angiotensin II-infused ApoE−/− mice. Naringenin effectively blocked the formation of AAAs and the progression of established AAAs. Transcription factor EB (TFEB) is the master regulator of lysosome biogenesis. Intriguingly, the protective role of naringenin on AAA was abolished by macrophage-specific TFEB depletion in mice. Unbiased interactomics, combined with isothermal titration calorimetry (ITC) and cellular thermal shift assays (CETSAs), further revealed that naringenin is directly bound to 14-3-3 epsilon blocked the TFEB-14-3-3 epsilon interaction, and therefore promoted TFEB nuclear translocation and activation. On one hand, naringenin activated lysosome-dependent inhibition of the NLRP3 inflammasome and repressed aneurysmal inflammation. On the other hand, naringenin induced TFEB-dependent transcriptional activation of GATA3, IRF4, and STAT6 and therefore promoted reparative M2 macrophage polarization. In summary, naturally derived naringenin or macrophage TFEB activation shows promising efficacy for the treatment of AAA.

To investigate the effects and mechanisms of irisin, a newly discovered myokine, in cartilage development, osteoarthritis (OA) pathophysiology and its therapeutic potential for treating OA we applied the following five strategical analyses using (1) murine joint tissues at different developmental stages; (2) human normal and OA pathological tissue samples; (3) experimental OA mouse model; (4) irisin gene knockout (KO) and knock in (KI) mouse lines and their cartilage cells; (5) in vitro mechanistic experiments. We found that Irisin was involved in all stages of cartilage development. Both human and mouse OA tissues showed a decreased expression of irisin. Intra-articular injection of irisin attenuated ACLT-induced OA progression. Irisin knockout mice developed severe OA while irisin overexpression in both irisin KI mice and intraarticular injection of irisin protein attenuated OA progression. Irisin inhibited inflammation and promoted anabolism in chondrogenic ADTC5 cells. Proliferative potential of primary chondrocytes from KI mice was found to be enhanced, while KO mice showed an inhibition under normal or inflammatory conditions. The primary chondrocytes from irisin KI mice showed reduced expression of inflammatory factors and the chondrocytes isolated from KO mice showed an opposite pattern. In conclusion, it is the first time to show that irisin is involved in cartilage development and OA pathogenesis. Irisin has the potential to ameliorate OA progression by decreasing cartilage degradation and inhibiting inflammation, which could lead to the development of a novel therapeutic target for treating bone and cartilage disorders including osteoarthritis.

Beta cell dysfunction and reduction in beta cell mass are hallmark events in the pathogenesis of diabetes mellitus. We identify focal adhesion protein Kindlin-2 as a key factor that controls insulin synthesis and secretion and beta cell mass by modulating MafA and beta-catenin proteins in pancreatic beta cells.

BackgroundCartilage defects account for substantial economic and humanistic burdens and pose a significant clinical problem. The efficacy of clinical approaches to cartilage repair is often inadequate, in part, owing to the restricted proliferative capacity of chondrocytes. Molecules have the capacity to promote the differentiation of multipotent mesenchymal stem cells into chondrocytes and may also gain the ability to repair the damaged cartilage.ObjectiveThis study aimed to investigate the role of Atsttrin (progranulin-derived engineered protein) in cartilage repair as well as the signaling pathway involved.MethodsPrimary and mesenchymal stem cell lines were used for the micromass culture. A murine cartilage defect model was used to determine the role of Atsttrin in cartilage repair in vivo. Real-time polymerase chain reaction and Western blot analysis were used to monitor the effect of Atsttrin on the transcriptional and protein levels, respectively, of key anabolic and catabolic signaling molecules.ResultsAtsttrin stimulated chondrogenesis in vitro and accelerated cartilage repair in vivo. In addition, Atsttrin-mediated cartilage repair occurred primarily through tumor necrosis factor receptor 2-initiated Akt signaling and downstream JunB transcription factor.ConclusionAtsttrin might serve as a promising therapeutic modality for cartilage regeneration.

Deformation and failure of freeze-thawed rocks under dynamic loads are of practical meaning in studying the stability of slopes and tunnels in cold regions. The rock failure process is essentially actuated by the transfer and transformation of energy. In this paper, the energy dissipation characteristics and failure patterns of freeze-thawed granite under dynamic loads were investigated. A split Hopkinson pressure bar (SHPB) system was used to conduct the experiments on semicircular bend (SCB) specimens subjected to 30, 60, 90, and 120 freeze-thaw (F-T) cycles. The results found that the incident energy, reflected energy, and dissipation energy were loading rate-dependent, while the transmitted energy was not correlated with the loading rate. The reflected energy accounted for the largest proportion (greater than 60%) of the incident energy. In addition, the energy reflection rate (ERR) decreased when the loading rate or porosity increased, whereas the energy dissipation rate increased when the loading rate or porosity increased. A model was established to predict the ERR and EDR evolution. Finally, the failure patterns of freeze-thawed granite under dynamic loads demonstrated that a higher loading rate caused a change in failure patterns, whereas a larger porosity led to greater fragmentation in the specimens.

Rock materials used as building stone and construction materials are usually subjected to the corrosion of hydro-chemical solutions. To investigate the effect of chemical corrosion on the change of pore structure and mechanical properties of sandstones, the nuclear magnetic resonance (NMR) technique was used for the measurement of porosity and T2 spectrum distribution. Series of triaxial compression tests with the confining pressure of 0, 5, 10, and 20 MPa were then conducted for rock specimens treated with chemical corrosions. The test results revealed that, compared with the rock specimens in their natural state, after chemical corrosion the porosity increased, the T2 spectrum distribution was broadened successively, and the pore structure became more complex with the fractal dimension increasing. The proportions of pores with different sizes were various with the change of chemical solutions and the immersion time. Moreover, under a certain confining pressure, the peak strength, elastic modulus, internal friction angle, and cohesion of sandstone after chemical corrosions decreased, but the corresponding peak strain increased. A chemical damage variable was proposed based on the porosity of sandstone and the order of effect of chemical solutions on pore structure and mechanical properties of sandstone was obtained as H2SO4 solution > NaOH solution > distilled water. Finally, a decay model considering both of chemical damage and confining pressure was established to predict the triaxial compressive strength of sandstone treated with chemical corrosion.

To investigate the variation in the characteristics of rock microstructure after cyclic dynamic disturbances, a split Hopkinson pressure bar (SHPB) was used to carry out cyclic dynamic impact tests on granite, and the P-wave velocity was used as the characteristic parameter representing the microstructural change. Using the nuclear magnetic resonance (NMR) technique, the porosity and the T2 distribution of rock samples were obtained. The results show that, after the cyclic dynamic disturbance, the P-wave velocity within the rock specimen decreases but rebounds with time. At the elastic phase, when the axial loading increases, the P-wave velocity declines. The T2 limit is shortened, and the cyclic dynamic disturbance process promotes the formation of small pores and decreases the size and quantity of large pores. After the cyclic dynamic disturbance, the porosity of the rock samples was reduced.