Duhuo Jisheng decoction (DJD) is considered beneficial for controlling knee osteoarthritis (KOA)-related symptoms in some Asian countries. This review compiles the evidence from randomised clinical trials and quantifies the effects of DJD on KOA.

Pyruvate kinase M2 (PKM2) is expressed at high levels during embryonic development and tumour progression and is important for cell growth. However, it is not known whether it directly controls cell division. Here, we found that Aurora B phosphorylates PKM2, but not PKM1, at T45; this phosphorylation is required for PKM2's localization and interaction with myosin light chain 2 (MLC2) in the contractile ring region of mitotic cells during cytokinesis. PKM2 phosphorylates MLC2 at Y118, which primes the binding of ROCK2 to MLC2 and subsequent ROCK2-dependent MLC2 S15 phosphorylation. PKM2-regulated MLC2 phosphorylation, which is greatly enhanced by EGF stimulation or EGFRvIII, K-Ras G12V and B-Raf V600E mutant expression, plays a pivotal role in cytokinesis, cell proliferation and brain tumour development. These findings underscore the instrumental function of PKM2 in oncogenic EGFR-, K-Ras- and B-Raf-regulated cytokinesis and tumorigenesis.

The type VI secretion system (T6SS) of pathogenic bacteria plays important roles in both virulence and inter-bacterial competitions. The effectors of T6SS are presumed to be transported either by attaching to the tip protein or by interacting with HcpI (haemolysin corregulated protein 1). In Edwardsiella tarda PPD130/91, the T6SS secreted protein EvpP (E. tarda virulent protein P) is found to be essential for virulence and directly interacts with EvpC (Hcp-like), suggesting that it could be a potential effector. Using limited protease digestion, nuclear magnetic resonance heteronuclear Nuclear Overhauser Effects, and hydrogen-deuterium exchange mass spectrometry, we confirmed that the dimeric EvpP (40 kDa) contains a substantial proportion (40%) of disordered regions but still maintains an ordered and folded core domain. We show that an N-terminal, 10-kDa, protease-resistant fragment in EvpP connects to a shorter, 4-kDa protease-resistant fragment through a highly flexible region, which is followed by another disordered region at the C-terminus. Within this C-terminal disordered region, residues Pro143 to Ile168 are essential for its interaction with EvpC. Unlike the highly unfolded T3SS effector, which has a lower molecular weight and is maintained in an unfolded conformation with a dedicated chaperone, the T6SS effector seems to be relatively larger, folded but partially disordered and uses HcpI as a chaperone.

Radiation therapy leads to increased risk of late-onset fragility and bone fracture due to the loss of bone mass. On the other hand, iron overloading causes osteoporosis by enhancing bone resorption. It has been shown that total body irradiation increases iron level, but whether the systemic bone loss is related to the changes in iron level and hepcidin regulation following bone irradiation remains unknown. To investigate the potential link between them, we first created an animal model of radiation-induced systemic bone loss by targeting the mid-shaft femur with a single 2 Gy dose of X-rays. We found that mid-shaft femur focal irradiation led to structural deterioration in the distal region of the trabecular bone with increased osteoclasts surface and expressions of bone resorption markers in both irradiated and contralateral femurs relative to non-irradiated controls. Following irradiation, reduced hepcidin activity of the liver contributed to elevated iron levels in the serum and liver. By injecting hepcidin or deferoxamine (an iron chelator) to reduce iron level, deterioration of trabecular bone microarchitecture in irradiated mice was abrogated. The ability of iron chelation to inhibit radiation-induced osteoclast differentiation was observed in vitro as well. We further showed that ionizing radiation (IR) directly stimulated osteoclast differentiation and bone resorption in bone marrow cells isolated not from contralateral femurs but from directly irradiated femurs. These results suggest that increased iron levels after focal radiation is at least one of the main reasons for systemic bone loss. Furthermore, bone loss in directly irradiated bones is not only due to the elevated iron level, but also from increased osteoclast differentiation. In contrast, the bone loss in the contralateral femurs is mainly due to the elevated iron level induced by IR alone. These novel findings provide proof-of-principle evidence for the use of iron chelation or hepcidin as therapeutic treatments for IR-induced osteoporosis.

C-X-C motif chemokine receptor 3 (CXCR3) is a G protein-coupled receptor for three ligands which are C-X-C motif chemokine 9 (CXCL9), CXCL10, and CXCL11 [1]. Previously we have reported that CXCL10 promotes pro-inflammatory cytokine expression, and forms positive feedback loop [2], [3]. In the present study, we described mRNA expression of CXCL9 and CXCL11 under CXCL10 stimuli in the presence or absence of CXCR3 antagonist, JN-2 in bone marrow-derived macrophages (BMMs) and CD4+ T cells. In addition, we examined pro-inflammatory cytokine expression under CXCL9 or CXCL11 stimuli in BMMs and CD4+ T cells.

This study was conducted to examine the effects of ad libitum consumption of highly palatable food (HPF) during adolescence on the adverse behavioral outcome of neonatal maternal separation.

B cell translocation gene 1 (BTG1) has long been recognized as a tumor suppressor gene. Recent reports demonstrated that BTG1 plays an important role in progression of cell cycle and is involved in cellular response to stressors. However, the microRNAs mediated regulatory mechanism of BTG1 expression has not been reported so far. MicroRNAs can effectively influence tumor radiosensitivity by preventing cell cycle progression, resulting in enhancement of the cytotoxicity of radiotherapy efficacy. This study aimed to demonstrating the effects of microRNAs on the BTG1 expression and cellular radiosensitivity.

The hypoglossal nerve controls tongue movements, and damages of it result in difficulty in mastication and food intake. Mastication has been reported to maintain hippocampus-dependent cognitive function. This study was conducted to examine the effect of tongue motor loss on the hippocampus-dependent cognitive function and its underlying mechanism. Male Sprague Dawley rats were subjected to the initial training of Morris water maze task before or after the bilateral transection of hypoglossal nerves (Hx). When the initial training was given before the surgery, the target quadrant dwelling time during the probe test performed at a week after the surgery was significantly reduced in Hx rats relative to sham-operated controls. When the initial training was given after the surgery, Hx affected the initial and reversal trainings and probe tests. Brain-derived neurotrophic factor (BDNF) expression, cell numbers and long-term potentiation (LTP) were examined in the hippocampus on the 10th day, and BrdU and doublecortin staining on the 14th day, after the surgery. Hx decreased the hippocampal BDNF and cells in the CA1/CA3 regions and impaired LTP. BrdU and doublecortin staining was decreased in the dentate gyrus of Hx rats. Results suggest that tongue motor loss impairs hippocampus-dependent cognitive function, and decreased BDNF expression in the hippocampus may be implicated in its underlying molecular mechanism in relation with decreased neurogenesis/proliferation and impaired LTP.

Magnesium (Mg) has the advantage of being resorbed in vivo, but its resorption rate is difficult to control. With uncontrolled resorption, Magnesium as a bone fixation material has minimal clinical value. During resorption not only is the strength rapidly weakened, but rapid formation of metabolite also occurs. In order to overcome these disadvantages, hydroxyapatite (HA) surface coating of pure magnesium plate was attempted in this study. Magnesium plates were inserted above the frontal bone of Sprague-Dawley rats in both the control group (Bare-Mg group) and the experimental group (HA-Mg group). The presence of inflammation, infection, hydrogen gas formation, wound dehiscence, and/or plate exposure was observed, blood tests were performed, and the resorption rate and tensile strength of the retrieved metal plates were measured. The HA-Mg group showed no gas formation or plate exposure until week 12. However, the Bare-Mg group showed consistent gas formation and plate exposure beginning in week 2. WBC (White Blood Cell), BUN (Blood Urea Nitrogen), Creatinine, and serum magnesium concentration levels were within normal range in both groups. AST (Aspartate Aminotransferase) and ALT (Alanine Aminotransferase) values, however, were above normal range in some animals of both groups. The HA-Mg group showed statistically significant advantage in resistance to degradation compared to the Bare-Mg group in weeks 2, 4, 6, 8, and 12. Degradation of HA-Mg plates proceeded after week 12. Coating magnesium plates with hydroxyapatite may be a viable method to maintain their strength long enough to allow bony healing and to control the resorption rate during the initial period.

Histone deacetylase (HDAC) enzymes play important roles in physiological and pathological processes by catalyzing the deacetylation of lysine residues in histone and non-histone proteins. Inhibition of HDACs has emerged as an attractive therapeutic strategy for various diseases including cancer and inflammatory diseases. We recently found that MS-275, a class I-specific HDAC inhibitor, exhibits an anabolic effect on bone through promoting expression of alkaline phosphatase in osteoblasts. MS-275 has also been suggested to inhibit inflammatory bone destruction, but the underlying mechanisms are still poorly understood. In this study, we investigated the effects and mechanism of action of MS-275 on osteoclast differentiation and activation. We found that MS-275 inhibits osteoclast differentiation in coculture of osteoblasts and bone marrow cells without affecting expression of receptor activator of NF-κB ligand (RANKL), a key cytokine for osteoclast differentiation, in osteoblasts. MS-275 inhibited RANKL-mediated osteoclast differentiation from its precursors by suppressing RANKL-induced expression of c-Fos, a crucial transcription factor for osteoclastogenesis. The inhibitory effect of MS-275 on osteoclast differentiation was blunted by ectopic overexpression of c-Fos. In addition to osteoclast differentiation, MS-275 decreased bone resorbing activity of mature osteoclasts. Consistent with the in vitro effects, MS-275 decreased osteoclast number and bone destruction in IL-1-induced mouse calvarial bone destruction model. Taken together, our results demonstrate that MS-275 suppresses bone destruction by inhibiting osteoclast differentiation and activation, suggesting a potential therapeutic value of MS-275 for bone disorders associated with increased bone resorption.

This study was conducted to define molecular mechanisms by which food deprivation increases phosphorylated extracellular signal-regulated protein kinase (pERK1/2) in the hypothalamic paraventricular nucleus of rats. pERK1/2 immunoreactivity (-ir) is markedly increased in the paraventricular nucleus by 48h of food deprivation. Treatment with RU486, glucocorticoid antagonists, during food deprivation did not affect the fasting-induced increase of pERK1/2-ir in the paraventricular nucleus, but intracerebroventricular (icv) leptin blocked the increase of pERK1/2-ir by food deprivation. Fasting-induced increases of neuropeptide Y (NPY) expression both in the arcuate nucleus and the paraventricular nucleus were also blunted by icv leptin; however, the icv NPY to satiated rats did not increase pERK1/2 in the paraventricular nucleus. These results suggest that the fasting-induced increase of pERK1/2 in the paraventricular nucleus may not be mediated either by plasma corticosterone or the hypothalamic NPY, but require leptin dis-inhibition.

Neural tissue regeneration is a significant challenge, because severe nerve injury is quite difficult to regenerate spontaneously. Although, many studies have been devoted to promote nerve regeneration, there are still many technical challenges to achieve satisfactory results. In this study, we designed biomimetic matrices composed of aligned laminin core-polydioxanone/collagen shell (Lam-PDO/Col) fibers, which can provide both topographical and biochemical cues for promoting neuritogenesis. The aligned Lam-PDO/Col core-shell fiber matrices were fabricated by magnetic field-assisted electrospinning with the coaxial system, and their potential as biofunctional scaffolds for promoting neuritogenesis was explored. It was demonstrated that the aligned Lam-PDO/Col core-shell fibers were successfully fabricated, and the laminin in the core of fibers was steadily and continuously released from fibers. In addition, the cellular behaviors of hippocampal neuronal cells on the matrices were significantly enhanced. Moreover, the aligned Lam-PDO/Col fiber matrices effectively improved and guided neurite outgrowth as well as the neurogenic differentiation by providing both topographical and biochemical cues through aligned fiber structure and sustained release of laminin. Collectively, it is suggested that the aligned Lam-PDO/Col core-shell fiber matrices are one of the most promising approaches for promoting neuritogenesis and neural tissue regeneration.

Avian leukosis virus (ALV) is an oncogenic virus causing a variety of neoplasms in chickens. The group of avian leukosis virus in chickens contains six closely related subgroups, A to E and J. The prevalence of ALVs in hosts may have imposed strong selective pressure toward resistance to ALVs infection. The tvb gene encodes Tvb receptor and determines susceptibility or resistance to the subgroups B, D, and E ALV. In this study, we characterized a novel resistant allele of the tvb receptor gene, tvbr3, which carries a single-nucleotide substitution (c.298C>T) that constitutes a premature termination codon within the fourth exon and leads to the production of a truncated TvbR3 receptor protein. As a result, we observed decreased susceptibility to infection by ALV-B, ALV-D and ALV-E both in vitro and in vivo, and decreased the binding affinity of the TvbR3 receptor for the subgroups B, D, and E ALV envelope glycoproteins. Additionally, we found that the tvbr3 allele was prevalent in Chinese broiler lines. This study demonstrated that premature termination codon in the tvb receptor gene can confer genetic resistance to subgroups B, D, and E ALV in the host, and indicates that tvbr3 could potentially serve as a resistant target against ALV-B, ALV-D and ALV-E infection.

SMADs, a family of proteins that function as signal transducers and transcriptional regulators to regulate various signaling pathways, including the transforming growth factor-β signaling pathway, are similar to the mothers against decapentaplegic family of genes and the sma gene family in Caenorhabditis elegans. SMADs generate context-dependent modulation by interacting with various sequence-specific transcription factors, such as E2F4/5, c-Fos, GATA3, YY1 and SRF, which have been found to serve a key role in lung carcinoma oncogenesis and progression. However, the prognostic values of the eight SMADs in lung cancer have not been fully understood. In the present study, the expression levels and survival data of SMADs in patients with lung carcinoma from the Oncomine, Gene Expression Profiling Interactive Analysis, Kaplan-Meier plotter and cBioPortal databases were downloaded and analyzed. It was found that the mRNA expression levels of SMAD-6, -7 and -9 were decreased in lung adenocarcinoma and squamous cell carcinoma compared with that in adjacent normal tissues, while there was no significant difference in SMADs 1-5. Survival analysis revealed that not only were low transcriptional levels of SMAD-6, -7 and -9 associated with low overall survival but they also had prognostic role for progression-free survival and post-progression survival (P<0.05) in patients with lung carcinoma. In conclusion, the present study demonstrated that SMAD-6, -7 and -9 are potential biomarkers for the prognosis of patients with lung carcinoma.

A polyphenolic extract from melon (Cucumis melo L.), as a potential source of natural antioxidants, has been reported to have a positive effect on osteoblast activity. In this study, the protective effects of heat-treated melon extract (ECO-A) on bone strength, mineralization, and metabolism were examined in osteoporotic rat models. Osteoporosis was induced by ovariectomy (OVX) in female rats and then maintained for 8 weeks, along with the ingestion of phosphate-buffered saline (PBS, OVXP) or ECO-A (OVXE) for an additional 4 weeks. At a pre-determined timepoint, bone strengths, as well as bone mineral contents (BMC) and the density (BMD) of femurs and/or lumbar spines extracted from each animal, were measured by a mechanical test and dual-energy X-ray absorptiometry, respectively. Moreover, several biochemical markers for bone turnover were analyzed by respective colorimetric assay kits in addition to clinical analyses. The maximum load and stiffness of femurs from the OVXE group were found to be significantly higher than the other groups. Furthermore, the OVXE group showed significantly higher BMC, BMD, and bone volume than the OVX and OVXP groups, which were comparable to the non-OVX (sham) group. The levels of bone formation and resorption markers in the OVXE group were similar to the sham group, but significantly different from other groups. In conclusion, these results suggest that ECO-A can play potentially positive roles in the protection of bone loss in rats with OVX-induced osteoporosis.

This study aimed to investigate the in vitro osteoinductivity of the combination of bone morphogenetic protein-2 (BMP-2) and nanohydroxyapatite (nHAp) and the in vivo effects of implants coated with nHAp/BMP-2.

This study aimed to demonstrate the function and molecular mechanism of protein regulator of cytokinesis 1 (PRC1) in the carcinogenesis of non-small cell lung cancer (NSCLC).

In humans, risk attitude is highly context-dependent, varying with wealth levels or for different potential outcomes, such as gains or losses. These behavioral effects have been modelled using prospect theory, with the key assumption that humans represent the value of each available option asymmetrically as a gain or loss relative to a reference point. It remains unknown how these computations are implemented at the neuronal level. Here we show that macaques, like humans, change their risk attitude across wealth levels and gain/loss contexts using a token gambling task. Neurons in the anterior insular cortex (AIC) encode the 'reference point' (i.e., the current wealth level of the monkey) and reflect 'loss aversion' (i.e., option value signals are more sensitive to change in the loss than in the gain context) as postulated by prospect theory. In addition, changes in the activity of a subgroup of AIC neurons correlate with the inter-trial fluctuations in choice and risk attitude. Taken together, we show that the primate AIC in risky decision-making may be involved in monitoring contextual information used to guide the animal's willingness to accept risk.

Diabetes was commonly seen in chronic total occlusion (CTO) patients but data regarding the impact of successful percutaneous coronary intervention (PCI) on clinical outcome of CTO patients with diabetes was controversial. And importantly, no studies have compared quality of life (QOL) after CTO-PCI in patients with and without diabetes.

Echovirus 3 (E3), a serotype of human enterovirus B (HEV-B), causes severe diseases in infants. Here, we determined the structures of E3 with a monoclonal antibody (MAb) 6D10 by cryo-EM to comprehensively understand the specificities and the immunological characteristic of this serotype. The solved cryo-EM structures of the F-, A-, and E-particles of E3 bound with 6D10 revealed the structural features of the virus-antibody interface. Importantly, the structures of E-particles bound with 6D10 revealed for the first time the nature of the C-terminus of VP1 for HEV-Bs at the structural level. The highly immunogenic nature of this region in the E-particles provides new strategies for vaccine development for HEV-Bs.