A static magnetic field enhances the repair of osteoarthritic cartilage by promoting the migration of stem cells and chondrogenesis.

Objective: To investigate the therapeutic effects of static magnetic field (SMF) and its regulatory mechanism in the repair of osteoarthritic cartilage. Methods: Fourteen-week-old female C57BL/6 mice were randomly divided into the sham operation group and the osteoarthritis (OA) groups with and without SMF application. SMF was applied at 200 â€‹mT for two consecutive weeks. Changes in knee cartilage were examined by histomorphometry, and the chondrogenesis and migration of endogenous stem cells were assessed. The expression of SRY-related protein 9 (SOX9), Collagen type II (COL2), matrix metallopeptidase 13 (MMP13), stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4), Piezo1 and other genes was evaluated, and the mechanism of SMF's action was tested using the CXCR4 inhibitor, AMD3100, and Piezo1 siRNA. Results: SMF significantly decreased the OARSI scores after induction of OA. SMF was beneficial to chondrogenesis by elevating SOX9. In the OA mouse model, an increase in MMP13 with a decrease in COL2 led to the destruction of the cartilage extracellular matrix, which was suppressed by SMF. SMF promoted the migration of cartilage-derived stem/progenitor cells and bone marrow-derived mesenchymal stem cells (MSCs). It increased SDF-1 and CXCR4, while the CXCR4 inhibitor significantly suppressed the beneficial effects of SMF. The application of Piezo1 siRNA inhibited the SMF-induced increase of CXCR4. Conclusion: SMF enhanced chondrogenesis and improved cartilage extracellular matrices. It activated the Piezo1-mediated SDF-1/CXCR4 regulatory axis and promoted the migration of endogenous stem cells. Collectively, it attenuated the pathological progression of cartilage destruction in OA mice. The Translational potential of this article: The findings in this study provided convincing evidence that SMF could enhance cartilage repair and improve OA symptoms, suggesting that SMF could have clinical value in the treatment of OA.

Mechanical Loading Promotes the Migration of Endogenous Stem Cells and Chondrogenic Differentiation in a Mouse Model of Osteoarthritis.

Osteoarthritis (OA) is a major health problem, characterized by progressive cartilage degeneration. Previous works have shown that mechanical loading can alleviate OA symptoms by suppressing catabolic activities. This study evaluated whether mechanical loading can enhance anabolic activities by facilitating the recruitment of stem cells for chondrogenesis. We evaluated cartilage degradation in a mouse model of OA through histology with H&E and safranin O staining. We also evaluated the migration and chondrogenic ability of stem cells using in vitro assays, including immunohistochemistry, immunofluorescence, and Western blot analysis. The result showed that the OA mice that received mechanical loading exhibited resilience to cartilage damage. Compared to the OA group, mechanical loading promoted the expression of Piezo1 and the migration of stem cells was promoted via the SDF-1/CXCR4 axis. Also, the chondrogenic differentiation was enhanced by the upregulation of SOX9, a transcription factor important for chondrogenesis. Collectively, the results revealed that mechanical loading facilitated cartilage repair by promoting the migration and chondrogenic differentiation of endogenous stem cells. This study provided new insights into the loading-driven engagement of endogenous stem cells and the enhancement of anabolic responses for the treatment of OA.

Retrospective case-control study on screening risk factors of antibiotic-associated encephalopathy in patients with chronic kidney disease.

OBJECTIVE: The renal excretion function of patients with chronic kidney disease (CKD) is reduced, and the nervous system toxic reactions of antibiotics are prone to occur. The purpose of this study is to screen out some risk factors for patients with CKD to suffer from antibiotic-associated encephalopathy (AAE). DESIGN: A case-control study. SETTING: A tertiary hospital in China. PARTICIPANTS: The medical records of patients who were hospitalised for CKD and infectious diseases in our hospital from January 2010 to December 2019. All patients used antibiotics to treat infectious diseases during hospitalisation. All patients were divided into two groups according to whether they developed AAE during hospitalisation. The patients with CKD without AAE were selected as the control group (n=120), and the patients with CKD with AAE were regarded as the AAE group (n=102). INTERVENTIONS: This study systematically analysed its clinical manifestations, laboratory examinations, prognosis, etc, and summarised the risk factors related to AAE in patients with CKD. PRIMARY OUTCOME: Screening risk factors of AAE in patients with CKD. RESULTS: Logistic regression analysis showed that coronary heart disease, as well as abnormal indicators of haemoglobin, albumin, uric acid and blood phosphorus were independent risk factors for patients with CKD with AAE (OR values were 4.137, 0.963, 0.849, 0.996 0.161, respectively, all p<0.05). The case fatality rate (Pearson χ2=7.524, p=0.006), rehospitalisation rate (Pearson χ2=6.187, p=0.013) and treatment costs (t=-8.44, p<0.001) in encephalopathy group are significantly higher than the control group. CONCLUSIONS: Patients with CKD with AAE will increase the case fatality rate and cause poor prognosis. Coronary heart disease, as well as decreased levels of haemoglobin, albumin, uric acid, and blood phosphorus are independent risk factors for patients with CKD with AAE. Timely intervention of these risk factors may reduce the incidence of AAE and improve the prognosis.

Functionalized PAMAM-based Nanoformulation for Targeted Delivery of 5-Fluorouracil in Hepatocellular Carcinoma.

BACKGROUND: The efficacy of a traditional anticancer drug is challenged by adverse effects of the drug, including its nonspecific bio-distribution, short half-life, and side effects. Dendrimer-based targeted drug delivery system has been considered a promising strategy to increase targeting ability and reduce adverse effects of anti-cancer drugs. OBJECTIVE: This study analyzed the feasibility of whether the anticancer drug 5-fluorouracil (5-FU) could be delivered by functionalized fifth-poly(amidoamine) (PAMAM) with the peptide WP05 and the acetic anhydride to the liver cancer cells, reducing the toxicity of the PAMAM and improving the targeting property of 5-FU during delivery. METHODS: The functionalized PAMAM-based nanoformulation (WP05-G5.0NHAC-FUA) was fabricated through an amide condensation reaction to improve the therapeutic efficacy of 5-Fluorouracil (5-FU) in hepatocellular carcinoma (HCC). The physicochemical structure, particle size, zeta potential, stability, and in vitro release characteristics of WP05-G5.0NHAC-FUA were evaluated. In addition, the targeting, biocompatibility, anti-proliferation, and anti-migration of WP05-G5.0NHAC-FUA were investigated. The anti-tumor effect of WP05-G5.0NHAC-FUA in vivo was evaluated by constructing xenograft tumor models of human hepatoma cells (Bel-7402) implanted in nude mice. RESULTS: The resultant WP05-G5.0NHAC-FUA displayed spherical-like nanoparticles with a size of 174.20 ± 3.59 nm. Zeta potential and the drug loading of WP05-G5.0NHAC-FUA were 5.62 ± 0.41mV and 28.67 ± 1.25%, respectively. Notably, the optimized 5-FU-loaded formulation showed greater cytotoxicity with an IC50 of 30.80 ± 4.04 µg/mL than free 5-FU (114.93 ± 1.43 µg/mL) in Bel-7402 cancer liver cells, but a significantly reduced side effect relative to free 5-FU in L02 normal liver cells. In vivo animal study further confirmed efficient tumor accumulation and enhanced therapeutic efficiency. CONCLUSION: The developed nanoformulation is a promising platform for the targeting delivery of 5-FU and provides a promising solution for improving the efficacy of hepatocellular carcinoma chemotherapy.

Knee Loading Enhances the Migration of Adipose-Derived Stem Cells to the Osteoarthritic Sites Through the SDF-1/CXCR4 Regulatory Axis.

Osteoarthritis (OA) is a whole joint disorder that is characterized by cartilage damage and abnormal remodeling of subchondral bone. Injecting adipose-derived stem cells (ASCs) into the knee joint cavity can assist in repairing osteoarthritic joints, but their ability to migrate to the damaged site is limited. Our previous studies have shown that knee loading can improve the symptoms of OA, but the effect and mechanism of knee loading on the migration of ASCs in OA remain unclear. We employed a mouse model of OA in the knee and applied knee loading (1 N at 5 Hz for 6 min/day for 2 weeks) after the intra-articular injection of ASCs. The cartilage and subchondral bone repair were assessed by histopathological analysis. Immunofluorescence assays were also used to analyze the migration of ASCs. Using cell cultures, we evaluated the migration of ASCs using the transwell migration and wound healing assays. In vivo experiments showed that knee loading promoted the migration of ASCs, increased the local SDF-1 level, and accelerated the repair of the OA-damaged sites. Mechanistically, the observed effects were blocked by the SDF-1/CXCR4 inhibitor. The in vitro results further revealed that knee loading promoted the migration of ASCs and the inhibition of SDF-1/CXCR4 significantly suppressed the beneficial loading effect. The results herein suggested that the migration of ASCs was enhanced by knee loading through the SDF-1/CXCR4 regulatory axis, and mechanical loading promoted the joint-protective effect of ASCs.

Mechanical loading mitigates osteoarthritis symptoms by regulating the inflammatory microenvironment in a mouse model.

Osteoarthritis (OA) is one of the most common chronic diseases, in which inflammatory responses in the articular cavity induce chondrocyte apoptosis and cartilage degeneration. While mechanical loading is reported to mitigate synovial inflammation, the mechanism and pathways for the loading-driven improvement of OA symptoms remain unclear. In this study, we evaluated the loading effects on M1/M2 polarization of synovial macrophages via performing histology, cytology, and molecular analyses. In the OA group, the cell layer of the synovial lining was enlarged with an increase in cell density. Also, M1 macrophages were polarized and proinflammatory cytokines were increased. In contrast, in the OA group with mechanical loading, cartilage degradation was reduced and synovial inflammation was alleviated. Notably, the M1 macrophages were diminished by mechanical loading, while M2 macrophages were increased. Furthermore, mechanical loading decreased the levels of proinflammatory cytokines, such as interleukin-1 beta and tumor necrosis factor-α, and suppressed PI3K/AKT/NF-κB signaling. Taken together, this study demonstrates that mechanical loading changes the ratio of M1 and M2 macrophages via regulation of PI3K/AKT/NF-κB signaling and provides cartilage protection in the mouse OA model.

Loading-driven PI3K/Akt signaling and erythropoiesis enhanced angiogenesis and osteogenesis in a postmenopausal osteoporosis mouse model.

Bone vasculature influences osteogenesis and haematopoiesis in the bone microenviroment. Mechanical loading has been shown to stimulate the formation of osteogenesis-related type H vessels in an ovariectomy (OVX)-induced osteoporosis mouse model. To determine the loading-driven mechanism of angiogenesis and the formation of type H vessels in bone, we evaluated the roles of PI3K/Akt signaling and erythropoiesis in the bone marrow. The daily application of mechanical loading (1 N at 5 Hz for 6 min/day) for 2 weeks on OVX mice inhibited osteoclast activity, associated with an increase in the number of osteoblasts and trabecular volume ratio. Mechanical loading enhanced bone vasculature and vessel formation, as well as PI3K/Akt phosphorylation and erythropoiesis in the bone marrow. Notably, LY294002, an inhibitor of PI3K signaling, blocked the tube formation by endothelial progenitor cells, as well as their migration and wound healing. The conditioned medium, derived from erythroblasts, also promoted the function of HUVECs with elevated levels of VEGF, CD31, and Emcn. Collectively, this study demonstrates that mechanical loading prevents osteoporotic bone loss by promoting angiogenesis and type H vessel formation. This load-driven preventing effect is in part mediated by PI3K/Akt signaling and erythropoiesis in the bone marrow.

Mechanical loading attenuates breast cancer-associated bone metastasis in obese mice by regulating the bone marrow microenvironment.

Breast cancer, a common malignancy for women, preferentially metastasizes to bone and obesity elevates the chance of its progression. While mechanical loading can suppress obesity and tumor-driven osteolysis, its effect on bone-metastasized obese mice has not been investigated. Here, we hypothesized that mechanical loading can lessen obesity-associated bone degradation in tumor-invaded bone by regulating the fate of bone marrow-derived cells. In this study, the effects of mechanical loading in obese mice were evaluated through X-ray imaging, histology, cytology, and molecular analyses. Tumor inoculation to the tibia elevated body fat composition, osteolytic lesions, and tibia destruction, and these pathologic changes were stimulated by the high-fat diet (HFD). However, mechanical loading markedly reduced these changes. It suppressed osteoclastogenesis by downregulating receptor activator of nuclear factor Kappa-B ligand and cathepsin K and promoted osteogenesis, which was associated with the upregulation of OPG and downregulation of C/enhancer-binding protein alpha and proliferator-activated receptor gamma for adipogenic differentiation. Furthermore, it decreased the levels of tumorigenic genes such as Rac1, MMP9, and interleukin 1ß. In summary, this study demonstrates that although a HFD aggravates bone metastases associated with breast cancer, mechanical loading significantly protected tumor-invaded bone by regulating the fate of bone marrow-derived cells. The current study suggests that mechanical loading can provide a noninvasive, palliative option for alleviating breast cancer-associated bone metastasis, in particular for obese patients.

Mechanical loading stimulates bone angiogenesis through enhancing type H vessel formation and downregulating exosomal miR-214-3p from bone marrow-derived mesenchymal stem cells.

Exosomes are important transporters of miRNAs, which play varying roles in the healing of the bone fracture. Angiogenesis is one of such critical events in bone healing, and we previously reported the stimulatory effect of mechanical loading in vessel remodeling. Focusing on type H vessels and exosomal miR-214-3p, this study examined the mechanism of loading-driven angiogenesis. MiRNA sequencing and qRT-PCR revealed that miR-214-3p was increased in the exosomes of the bone-losing ovariectomized (OVX) mice, while it was significantly decreased by knee loading. Furthermore, compared to the OVX group, exosomes, derived from the loading group, promoted the angiogenesis of endothelial cells. In contrast, exosomes, which were transfected with miR-214-3p, decreased the angiogenic potential. Notably, knee loading significantly improved the microvascular volume, type H vessel formation, and bone mineral density and contents, as well as BV/TV, Tb.Th, Tb.N, and Tb.Sp. In cell cultures, the overexpression of miR-214-3p in endothelial cells reduced the tube formation and cell migration. Collectively, this study demonstrates that knee loading promotes angiogenesis by enhancing the formation of type H vessels and downregulating exosomal miR-214-3p.

Phosphorylation of eIF2α signaling pathway attenuates obesity-induced non-alcoholic fatty liver disease in an ER stress and autophagy-dependent manner.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder and frequently exacerbates in postmenopausal women. In NAFLD, the endoplasmic reticulum (ER) plays an important role in lipid metabolism, in which salubrinal is a selective inhibitor of eIF2α de-phosphorylation in response to ER stress. To determine the potential mechanism of obesity-induced NAFLD, we employed salubrinal and evaluated the effect of ER stress and autophagy on lipid metabolism. Ninety-five female C57BL/6 mice were randomly divided into five groups: standard chow diet, high-fat (HF) diet, HF with salubrinal, HF with ovariectomy, and HF with ovariectomy and salubrinal. All mice except for SC were given HF diet. After the 8-week obesity induction, salubrinal was subcutaneously injected for the next 8 weeks. The expression of ER stress and autophagy markers was evaluated in vivo and in vitro. Compared to the normal mice, the serum lipid level and adipose tissue were increased in obese mice, while salubrinal attenuated obesity by blocking lipid disorder. Also, the histological severity of hepatic steatosis and fibrosis in the liver and lipidosis was suppressed in response to salubrinal. Furthermore, salubrinal inhibited ER stress by increasing the expression of p-eIF2α and ATF4 with a decrease in the level of CHOP. It promoted autophagy by increasing LC3II/I and inhibiting p62. Correlation analysis indicated that lipogenesis in the development of NAFLD was associated with ER stress. Collectively, we demonstrated that eIF2α played a key role in obesity-induced NAFLD, and salubrinal alleviated hepatic steatosis and lipid metabolism by altering ER stress and autophagy through eIF2α signaling.

Knee loading repairs osteoporotic osteoarthritis by relieving abnormal remodeling of subchondral bone via Wnt/ß-catenin signaling.

Osteoporotic osteoarthritis (OPOA) is a common bone disease mostly in the elderly, but the relationship between Osteoporotic (OP) and osteoarthritis (OA) is complex. It has been shown that knee loading can mitigate OA symptoms. However, its effects on OPOA remain unclear. In this study, we characterized pathological linkage of OP to OA, and evaluated the effect of knee loading on OPOA. We employed two mouse models (OA and OPOA), and conducted histology, cytology, and molecular analyses. In the OA and OPOA groups, articular cartilage was degenerated and Osteoarthritis Research Society International score was increased. Subchondral bone underwent abnormal remodeling, the differentiation of bone marrow mesenchymal stem cells (BMSCs) to osteoblasts and chondrocytes was reduced, and migration and adhesion of pre-osteoclasts were enhanced. Compared to the OA group, the pathological changes of OA in the OPOA group were considerably aggravated. After knee loading, however, cartilage degradation was effectively prevented, and the abnormal remodeling of subchondral bone was significantly inhibited. The differentiation of BMSCs was also improved, and the expression of Wnt/ß-catenin was elevated. Collectively, this study demonstrates that osteoporosis aggravates OA symptoms. Knee loading restores OPOA by regulating subchondral bone remodeling, and may provide an effective method for repairing OPOA.

Enhanced Thermoelectric Performance of Zr1-xTaxNiSn Half-Heusler Alloys by Diagonal-Rule Doping.

Although Sb doping is regarded as the most effective method to regulate the carrier concentration within the optimum range for ZrNiSn-based half-Heusler (HH) alloys, the resulting thermal conductivity remains high. Hence, the aim of this study was to investigate the effect of "diagonal-rule" doping; that is, the Zr site was displaced by Ta, which can simultaneously enhance the electrical conductivity and reduce the lattice thermal conductivity. The solid-solubility limit of Ta in the ZrNiSn matrix was determined to be x = 0.04. The highest ZT, 0.72, was achieved at 923 K for Zr0.98Ta0.02NiSn. In addition, ZTavg increased by 10.2% for Zr0.98Ta0.02NiSn compared with that for ZrNiSn0.99Sb0.01 at 873 K, which was mainly attributed to the reduced lattice thermal conductivity of Zr0.98Ta0.02NiSn. These results suggest that Ta doping is more effective than Sb doping in ZrNiSn-based HH alloys. In addition, the microhardness of Zr1-xTaxNiSn was substantially improved with increasing Ta content and was also much higher than that of other traditional thermoelectric materials.

eIF2α signaling regulates autophagy of osteoblasts and the development of osteoclasts in OVX mice.

Bone loss in postmenopausal osteoporosis is induced chiefly by an imbalance of bone-forming osteoblasts and bone-resorbing osteoclasts. Salubrinal is a synthetic compound that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). Phosphorylation of eIF2α alleviates endoplasmic reticulum (ER) stress, which may activate autophagy. We hypothesized that eIF2α signaling regulates bone homeostasis by promoting autophagy in osteoblasts and inhibiting osteoclast development. To test the hypothesis, we employed salubrinal to elevate the phosphorylation of eIF2α in an ovariectomized (OVX) mouse model and cell cultures. In the OVX model, salubrinal prevented abnormal expansion of rough ER and decreased the number of acidic vesiculars. It regulated ER stress-associated signaling molecules such as Bip, p-eIF2α, ATF4 and CHOP, and promoted autophagy of osteoblasts via regulation of eIF2α, Atg7, LC3, and p62. Salubrinal markedly alleviated OVX-induced symptoms such as reduction of bone mineral density and bone volume fraction. In primary bone-marrow-derived cells, salubrinal increased the differentiation of osteoblasts, and decreased the formation of osteoclasts by inhibiting nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Live cell imaging and RNA interference demonstrated that suppression of osteoclastogenesis is in part mediated by Rac1 GTPase. Collectively, this study demonstrates that ER stress-autophagy axis plays an important role in OVX mice. Bone-forming osteoblasts are restored by maintaining phosphorylation of eIF2α, and bone-resorbing osteoclasts are regulated by inhibiting NFATc1 and Rac1 GTPase.

Ankle loading ameliorates bone loss from breast cancer-associated bone metastasis.

Breast cancer is a serious health problem that preferentially metastasizes to bone. We have previously shown that bone loss can be prevented by mechanical loading, but the efficacy of ankle loading for metastasis-linked bone loss has not been investigated. This study showed that body weight was decreased after inoculation of tumor cells, but ankle loading restored a rapid weight loss. The nonloading group exhibited a decrease in bone volume/tissue volume (BV/TV), trabecular thickness, and trabecular number (all P < 0.01) as well as an increase in trabecular separation (P < 0.001). However, ankle loading improved those changes (all P < 0.05). Furthermore, although the nonloading group increased the tumor bearing as well as expression of IL-8 and matrix metalloproteinase 9, ankle loading decreased them. Induction of tumor in the bone elevated the osteoclast number (P < 0.05) as well as the levels of nuclear factor of activated T-cells cytoplasmic 1, NF-κB ligand, cathepsin K, and serum tartrate-resistant acid phosphatase type 5b, but ankle loading reduced osteoclast activity and those levels (all P < 0.05). Tumor bearing was positively correlated with the osteoclast number (P < 0.01) and negatively correlated with BV/TV and the osteoblast number (both P < 0.01). Collectively, these findings demonstrate that ankle loading suppresses tumor growth and osteolysis by inhibiting bone resorption and enhancing bone formation.-Yang, S., Liu, H., Zhu, L., Li, X., Liu, D., Song, X., Yokota, H., Zhang, P. Ankle loading ameliorates bone loss from breast cancer-associated bone metastasis.

Wnt3a involved in the mechanical loading on improvement of bone remodeling and angiogenesis in a postmenopausal osteoporosis mouse model.

Osteoporosis is a major health problem, making bones fragile and susceptible to fracture. Previous works showed that mechanical loading stimulated bone formation and accelerated fracture healing. Focusing on the role of Wnt3a (wingless/integrated 3a), this study was aimed to assess effects of mechanical loading to the spine, using ovariectomized (OVX) mice as a model of osteoporosis. Two-week daily application of this novel loading (4 N, 10 Hz, 5 min/d) altered bone remodeling with an increase in Wnt3a. Spinal loading promoted osteoblast differentiation, endothelial progenitor cell migration, and tube formation and inhibited osteoclast formation, migration, and adhesion. A transient silencing of Wnt3a altered the observed loading effects. Spinal loading significantly increased bone mineral density, bone mineral content, and bone area per tissue area. The loaded OVX group showed a significant increase in the number of osteoblasts and reduction in osteoclast surface/bone surface. Though expression of osteoblastic genes was increased, the levels of osteoclastic genes were decreased by loading. Spinal loading elevated a microvascular volume as well as VEGF expression. Collectively, this study supports the notion that Wnt3a-mediated signaling involves in the effect of spinal loading on stimulating bone formation, inhibiting bone resorption, and promoting angiogenesis in OVX mice. It also suggests that Wnt3a might be a potential therapeutic target for osteoporosis treatment.-Li, X., Liu, D., Li, J., Yang, S., Xu, J., Yokota, H., Zhang, P. Wnt3a involved in the mechanical loading on improvement of bone remodeling and angiogenesis in a postmenopausal osteoporosis mouse model.

Mechanical loading mitigates osteoarthritis symptoms by regulating endoplasmic reticulum stress and autophagy.

Osteoarthritis (OA) is a disease characterized by cartilage damage and abnormal remodeling of subchondral bone. Our previous study showed that in the early stage of OA, knee loading exerts protective effects by suppressing osteoclastogenesis through Wnt signaling, but little is known about loading effects at the late OA stage. Endoplasmic reticulum (ER) stress and autophagy are known to be involved in the late OA stage. We determined the effects of mechanical loading on ER stress and autophagy in OA mice. One hundred seventy-four mice were used for a surgery-induced OA model. In the first set of experiments, 60 mice were devoted to evaluation of the role of ER stress and autophagy in the development of OA. In the second set, 114 mice were used to assess the effect of knee loading on OA. Histologic, cellular, microcomputed tomography, and electron microscopic analyses were performed to evaluate morphologic changes, ER stress, and autophagy. Mechanical loading increased phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and regulated expressions of autophagy markers LC3II/I and p62. Osteoarthritic mice also exhibited an elevated ratio of calcified cartilage to total articular cartilage (CC/TAC), and synovial hyperplasia with increased lining cells was found. At the early disease stage, subchondral bone plate thinning and reduced subchondral bone volume fraction (B.Ar/T.Ar) were observed. At the late disease stages, subchondral bone plate thickened concomitant with increased B.Ar/T.Ar. Mice subjected to mechanical loading exhibited resilience to cartilage destruction and a correspondingly reduced Osteoarthritis Research Society International score at 4 and 8 wk, as well as a decrease in synovitis and CC/TAC. While chondrocyte numbers in the OA group was notably decreased, mechanical loading restored chondrogenic differentiation. These results demonstrate that mechanical loading can retard the pathologic progression of OA at its early and late stages. The observed effects of loading are associated with the regulations of ER stress and autophagy.-Zheng, W., Li, X., Liu, D., Li, J., Yang, S., Gao, Z., Wang, Z., Yokota, H., Zhang, P. Mechanical loading mitigates osteoarthritis symptoms by regulating endoplasmic reticulum stress and autophagy.

Activation of protein kinase C-α/heme oxygenase-1 signaling pathway improves mitochondrial dynamics in lipopolysaccharide-activated NR8383 cells.

Mitochondrial function and morphology are dynamically regulated by fusion and fission. Heme oxygenase-1 (HO-1), which may be upregulated by protein kinase C-α (PKC-α), improves mitochondrial dynamics by controlling the balance between fusion and fission in vivo and in vitro. However, whether the PKC-α/HO-1 signaling pathway is one of the underlying mechanisms in adjusting mitochondrial dynamics in lipopolysaccharide (LPS)-activated macrophages has remained elusive. To explore this, NR8383 cells were pre-treated with PKC-α inhibitor Go6976 or PKC-α activator phorbol-12-myristate-13-acetate for 30 min and then stimulated with LPS for 24 h. Next, the expression of PKC-α, HO-1, mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2), optic atrophy 1 (OPA1), dynamin-related protein 1 (Drp1) and fission 1 (Fis1) was detected to evaluate the possible implication of the PKC-α/HO-1 signaling pathway in the LPS-induced NR8383 cells. The results indicated that activation of the PKC-α/HO-1 signaling pathway increased superoxide dismutase activities and the respiratory control ratio (RCR), decreased the levels of malondialdehyde, reactive oxygen species (ROS), Drp1 and Fis1, and simultaneously enhanced the levels of Mfn1, Mfn2 and OPA1. In contrast, the PKC-α inhibitor decreased the expression of RCR, Mfn1, Mfn2 and OPA1, and increased the expression of MDA and ROS in NR8383 cells. The results suggest that activation of the PKC-α/HO-1 signaling pathway is necessary for the balance of mitochondrial dynamics and oxidative stress in macrophages, which provides clues for probing novel strategies against the detrimental effects of sepsis and other disease states.

Effects of knee loading on obesity-related non-alcoholic fatty liver disease in an ovariectomized mouse model with high-fat diet.

AIM: Hormonal and nutritional disorders are the main causes of obesity and non-alcoholic fatty liver disease, especially in the elderly and in postmenopausal women. Although physical activity might alleviate these disorders, the elderly may often have difficulty in carrying out physical exercise. The purpose of this study was to investigate the therapeutic effect of knee loading, a new form of physical stimulation, on the symptoms of obesity and fatty liver. METHODS: Using ovariectomized mice fed a high-fat diet, we evaluated the effect of knee loading that applies gentle cyclic loads to the knee. Female C57BL/6 mice were divided into five groups: control (SCD), high-fat diet (HF), HF with loading (HF + L), HF with ovariectomy (HF + OVX), and HF + OVX with loading (HF + OVX + L). Except for SCD, mice underwent sham operation or ovariectomy and were maintained on HF diet. After 6 weeks, the mice in the HF + L and HF + OVX + L groups were treated with knee loading for 6 weeks. RESULTS: Compared to the obesity groups (HF and HF + OVX), knee loading significantly decreased a gain in body weight, liver weight, and white adipose tissue (all P < 0.01). It also reduced the lipid level in the serum (P < 0.01) and histological severity of hepatic steatosis (P < 0.01). Furthermore, knee loading downregulated biomarkers related to endoplasmic reticulum (ER) stress (GRP78, p-eIF2α, and ATF4) and altered biomarkers in autophagy (LC3 and p62). CONCLUSIONS: Knee loading suppressed obesity-associated metabolic alterations and hepatic steatosis. These effects with knee loading might be associated with suppression of ER stress and promotion of autophagy.

eIF2α signaling regulates ischemic osteonecrosis through endoplasmic reticulum stress.

Osteonecrosis of the femoral head (ONFH) primarily results from ischemia/hypoxia to the femoral head, and one of the cellular manifestations is the endoplasmic reticulum (ER) stress. To understand possible linkage of ischemic osteonecrosis to the ER stress, a surgery-induced animal model was employed and salubrinal was administered to evaluate the role of ER stress. Salubrinal is a synthetic chemical that inhibits de-phosphorylation of eIF2α, and it can suppress cell death from the ER stress at a proper dose. The results indicated that the ER stress was associated with ONFH and salubrinal significantly improved ONFH-induced symptoms such as osteonecrosis, bone loss, reduction in vessel perfusion, and excessive osteoclastogenesis in the femoral head. Salubrinal also protected osteoblast development by upregulating the levels of ATF4, ALP and RUNX2, and it stimulated angiogenesis of endothelial cells through elevating ATF4 and VEGF. Collectively, the results support the notion that the ER stress is an important pathological outcome in the surgery-induced ONFH model, and salubrinal improves ONFH symptoms by enhancing angiogenesis and bone healing via suppressing the ER stress.

Trauma to an inguinal hernia resulting in bowel rupture: A case report and literature review.

INTRODUCTION: We report on a rare case of a man with bowel rupture due to direct trauma to his diagnosed inguinal hernia, with reviewing the relevant literature, we have found some characteristics of our case different from the similar cases reported by other authors. PRESENTATION OF THE CASE: A 54-year-old man, with a dignosed right inguinal hernia without treatment for over six months, presented to our hospital with generalized peritonitis and possible sepsis, caused by minimal hit directly to his hernia. The patient underwent an immediate exploratory celiotomy with segmental intestine resection and anastomosis, without hernia repair at the same time because of the concomitant peritonitis. The patient recovered uneventfully and postoperative histology showed chronical inflammation of the perforated bowel. Later, he patient had his hernia repaired by elective operation. DISCUSSION: Different from other cases of the same kind, our patient only suffered a trivial blunt trauma, so we believe that the longlasting inflammation of the intestine is one of the major reasons for such a bowel perforation, which differs from the opinion that external force is the crucial factor. Besides, after the first non-herniorrhaphy procedure, our patient kept no recurrent hernia for about 10 months until it's recurrence and had the herniorrhaphy. CONCLUSION: Trauma directly to a known inguinal hernia is an uncommon, but a dangerous event, and the abnormal alterations of intestine in the hernial sac may be one of the major reasons for such event, so it is mandatory for the physician to explain the complication of the hernia to the patient, for the hernia being repaired as early as possible.