Discovery of palmatine derivatives as potent neuroprotective agents.

Alzheimer's disease is a neurodegenerative disorder characterized by the presence of neurodegenerative lesions and cognitive impairment. In this study, a series of novel palmatine derivatives were designed and synthesized through the introduction of a heteroatom using carbodiimide-mediated condensation. The synthesized compounds were then screened for toxicity and potency, leading to the identification of compound 2q, which exhibited low toxicity and high potency. Our findings demonstrated that compound 2q displayed significant neuroprotective activity in vitro, emerging as a promising candidate for Alzheimer's disease treatment.

Chlorogenic Acid Inhibits Epithelial-Mesenchymal Transition and Invasion of Breast Cancer by Down-Regulating LRP6.

Epithelial-mesenchymal transition (EMT) is a crucial biologic process for breast cancer metastasis, and inhibition of EMT could be an effective approach to suppress metastatic potential of mammary cancer. High expression of low-density lipoprotein receptor-related protein 6 (LRP6) is usually observed in breast carcinoma and predicts poor prognosis. In the present study, we investigated whether chlorogenic acid (CA) can inhibit the EMT of breast cancer cells and underlying molecular mechanism. We found that CA treatment transformed MCF-7 cell morphology from spindle shape (mesenchymal phenotype) to spherical shape (epithelial phenotype). CA clearly increased epithelial biomarkers' expression (E-cadherin and ZO-1) but decreased mesenchymal proteins' expression (ZEB1, N-cadherin, vimentin, snail, and slug). In addition, CA attenuated MMP-2 and MMP-9 activities and inhibited cell migration and invasion. CA downregulated the expression of LRP6 in MCF-7 cells. Knockdown LRP6 with siRNA repressed cell mobility and invasion, wheras overexpression of LRP6 promoted EMT and antagonized the EMT inhibitory effect of CA on MCF-7 cells. Furthermore, CA directly interacted with Wnt/ß-catenin signaling coreceptor LRP6 and reduced LRP6, p-LRP6, and ß-catenin expression levels in MCF-7 cells. In vivo study revealed that CA notably reduced tumor volume and tumor weight. CA decreased the expression of LRP6, N-cadherin, ZEB1, vimentin, MMP2, MMP9, and increased the expression of E-cadherin and ZO-1. In conclusion, CA inhibited EMT and invasion of breast cancer by targeting LRP6. SIGNIFICANCE STATEMENT: CA, the familiar polyphenol compound in traditional Chinese medicine, repressed EMT and weakened cellular mobility and invasion in MCF-7 cells. The mechanism studies demonstrated that CA could inhibit EMT and invasion of MCF-7 cells via targeting LRP6. Additionally, CA restrained tumor growth and xenograft tumor EMT in vivo. The EMT inhibitory property of CA warrants further studies of CA as a drug candidate for the therapy of metastatic breast carcinoma.

Automated classification of protein expression levels in immunohistochemistry images to improve the detection of cancer biomarkers.

BACKGROUND: The expression changes of some proteins are associated with cancer progression, and can be used as biomarkers in cancer diagnosis. Automated systems have been frequently applied in the large-scale detection of protein biomarkers and have provided a valuable complement for wet-laboratory experiments. For example, our previous work used an immunohistochemical image-based machine learning classifier of protein subcellular locations to screen biomarker proteins that change locations in colon cancer tissues. The tool could recognize the location of biomarkers but did not consider the effect of protein expression level changes on the screening process. RESULTS: In this study, we built an automated classification model that recognizes protein expression levels in immunohistochemical images, and used the protein expression levels in combination with subcellular locations to screen cancer biomarkers. To minimize the effect of non-informative sections on the immunohistochemical images, we employed the representative image patches as input and applied a Wasserstein distance method to determine the number of patches. For the patches and the whole images, we compared the ability of color features, characteristic curve features, and deep convolutional neural network features to distinguish different levels of protein expression and employed deep learning and conventional classification models. Experimental results showed that the best classifier can achieve an accuracy of 73.72% and an F1-score of 0.6343. In the screening of protein biomarkers, the detection accuracy improved from 63.64 to 95.45% upon the incorporation of the protein expression changes. CONCLUSIONS: Machine learning can distinguish different protein expression levels and speed up their annotation in the future. Combining information on the expression patterns and subcellular locations of protein can improve the accuracy of automatic cancer biomarker screening. This work could be useful in discovering new cancer biomarkers for clinical diagnosis and research.

Factors affecting clinical pregnancy in controlled ovarian hyperstimulation with GnRH-a long protocol: a retrospective cross-sectional study.

This retrospective cross-sectional study was to investigate factors affecting clinical pregnancy in patients who received gonadotropin-releasing hormone agonist luteal phase long protocol (GnRH-a long protocol) and underwent fresh in-vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) embryo transfer cycle. One thousand five hundred and twenty-five patients who received GnRH-a long protocol and underwent fresh IVF/ICSI embryo transfer cycle were enrolled. The clinical pregnancy rate (63.1 vs. 22.4%, p < .05) and live birth rate (53.8 vs. 14.5%, p < .05) were significantly higher while the miscarriage rate (12.5 vs. 35.3%, p < .05) was significantly lower in the two embryo group than those in the one embryo group. The clinical pregnancy rate (48.5 vs. 64.1%, p < .05) and live birth rate (38.4 vs. 55.0%, p < .05) were significantly lower in patients older than 33.5 years than those in younger patients. The clinical pregnancy rate (52 and 60.6 vs. 79.7%, p < .05) and live birth rate (36 and 51.4 vs. 69.6%, p < .05) of the thin and mediate groups were significantly lower than those in the thick group, whereas the ectopic pregnancy rate (11.5 and 1.9 vs. 0%, p < .05) was significantly higher in the thin group than in the mediate and thick group. Multivariate logistic regression analysis showed that age (OR = 0.956, 95% CI [0.931, 0.982], p < .05), number of embryos transferred (OR = 2.491, 95% CI [1.670, 3.715], p < .05) and endometrial thickness on the transplantation day (OR = 1.124, 95% CI [1.067, 1.185], p < .05) were independent factors significantly associated with clinical pregnancy. In conclusion, endometrial thickness (>14.69 mm) on the day of transfer, two cleavage embryos transferred, and female age (≤33.5 years) are independent factors affecting clinical pregnancy outcomes in controlled ovarian hyperstimulation with GnRH-a long protocol for assisted conception. IMPACT STATEMENTWhat is already known on this subject? Fresh embryo transfer cycle with GnRH-a long protocol will result in a higher pregnancy rate in controlled ovarian hyperstimulation cycles.What do the results of this study add? Endometrial thickness on the day of transfer, number of embryos transferred, and female age were independent factors affecting clinical pregnancy outcomes.What are the implications of these findings for clinical practice and/or further research? When performing a fresh IVF/ICSI embryo transfer cycle with GnRH-a long protocol for ovulation induction, the independent affecting factors should be taken into consideration.

[Research progress of Gan-Yu-Hua-Huo syndrome based on emotional stress-induced latent herpes simplex virus-1 reactivation].

Gan-Yu-Hua-Huo syndrome(Live qi stagnation transforming into fire pattern) is one of the core contents of the theory of emotional diseases in traditional Chinese medicine(TCM). It is the key link of the pathogenesis change of emotion-related diseases and widely exists in the pathological process of various related diseases. However, due to the lack of animal models in line with the characteristics of TCM syndromes, the research on biomedical basis of Gan-Yu-Hua-Huo syndrome and study of Chinese medicines for soothing liver and purging fire have been restricted seriously. This study found that the pathological process of facial fire-heat symptoms of Gan-Yu-Hua-Huo syndrome was similar to the facial symptoms due to the emotional stress-induced latent herpes simplex virus-1(HSV-1) reactivation. Therefore, this study proposed that the emotional stress-induced latent HSV-1 activation be used to establish the animal model of Gan-Yu-Hua-Huo syndrome. In this study, the state-of-art literature in the field of Gan-Yu-Hua-Huo syndrome was summarized, and the experimental animal model of Gan-Yu-Hua-Huo syndrome was established from the perspective of emotional stress-induced latent HSV-1 reactivation to reveal the active substances, potential targets and pathways related to the pathological mechanism of the syndrome. This study was expected to provide reference and basis for the pharmacodynamic characterization of commonly used Chinese medicine for Gan-Yu-Hua-Huo syndrome in clinical practice.

New insights into the effects of caffeine on adult hippocampal neurogenesis in stressed mice: Inhibition of CORT-induced microglia activation.

Chronic stress-evoked depression has been implied to associate with the decline of adult hippocampal neurogenesis. Caffeine has been known to combat stress-evoked depression. Herein, we aim to investigate whether the protective effect of caffeine on depression is related with improving adult hippocampus neurogenesis and explore the mechanisms. Mouse chronic water immersion restraint stress (CWIRS) model, corticosterone (CORT)-established cell stress model, a coculture system containing CORT-treated BV-2 cells and hippocampal neural stem cells (NSCs) were utilized. Results showed that CWIRS caused obvious depressive-like disorders, abnormal 5-HT signaling, and elevated-plasma CORT levels. Notably, microglia activation-evoked brain inflammation and inhibited neurogenesis were also observed in the hippocampus of stressed mice. In comparison, intragastric administration of caffeine (10 and 20 mg/kg, 28 days) significantly reverted CWIRS-induced depressive behaviors, neurogenesis recession and microglia activation in the hippocampus. Further evidences from both in vivo and in vitro mechanistic experiments demonstrated that caffeine treatment significantly suppressed microglia activation via the A2AR/MEK/ERK/NF-κB signaling pathway. The results suggested that CORT-induced microglia activation contributes to stress-mediated neurogenesis recession. The antidepression effect of caffeine was associated with unlocking microglia activation-induced neurogenesis inhibition.

[Qingre Xiaoyanning Capsules alleviate HSV-1 susceptibility induced by emotional stress].

In this study, emotional stress-induced herpes simplex virus type 1(HSV-1) susceptibility model was employed to simu-late the pathological state of " depression-induced liver fire", and the protection effect of Qingre Xiaoyanning(QX) in clearing liver fire was investigated. BALB/c mice were randomly divided into a normal group, a HSV-1 group, a restraint stress + HSV-1 group,low-(0. 658 g·kg~(-1)) and high-dose(1. 316 g·kg~(-1)) QX groups, and an acyclovir group. Except for the normal group and the HSV-1 group, the mice in other groups received daily restraint stress for 6 h from day 3 of medication. On day 9 of medication, mice were anesthetized by isoflurane and infected intranasally with HSV-1. Survival rate, weight change, encephalitis symptoms, and eye injury of mice were recorded for 14 d after virus infection. Hematoxylin-eosin(HE) staining and immunohistochemical staining were used to detect pathological changes and HSV-1 antigen distribution. Plaque assay was performed to detect the titer of HSV-1. The protein ex-pression of ICP27 in the mouse brain was detected by Western blot. The experimental results showed that QX could increase the survival rate of HSV-1-infected mice loaded with emotional stress(P<0. 001), reduce the titer of HSV-1 in the mouse brain(P<0. 01), relieve brain inflammation(P<0. 05) and eye injury(P<0. 05), down-regulate the expression of ICP27 related to HSV-1(P<0. 05), and decrease the distribution of HSV-1 antigen in the mouse brain. The results demonstrated that QX significantly reduced the susceptibility to HSV-1 induced by emotional stress, which is expected to provide a theoretical basis for the treatment and preven-tion of HSV-1 infection and promote the clinical development and application of Chinese medicine effective in clearing liver fire.

The Immune Privilege of the Intervertebral Disc: Implications for Intervertebral Disc Degeneration Treatment.

The intervertebral disc (IVD) is the largest avascular organ of the body. It is composed of three parts: the nucleus pulposus (NP), the annulus fibrosus (AF) and the cartilaginous endplate (CEP). The central NP is surrounded by the AF and sandwiched by the two CEPs ever since its formation. This unique structure isolates the NP from the immune system of the host. Additionally, molecular factors expressed in IVD have been shown inhibitive effect on immune cells and cytokines infiltration. Therefore, the IVD has been identified as an immune privilege organ. The steady state of immune privilege is fundamental to the homeostasis of the IVD. The AF and the CEP, along with the immunosuppressive molecular factors are defined as the blood-NP barrier (BNB), which establishes a strong barrier to isolate the NP from the host immune system. When the BNB is damaged, the auto-immune response of the NP occurs with various downstream cascade reactions. This effect plays an important role in the whole process of IVD degeneration and related complications, such as herniation, sciatica and spontaneous herniated NP regression. Taken together, an enhanced understanding of the immune privilege of the IVD could provide new targets for the treatment of symptomatic IVD disease. However, the underlying mechanism above is still not fully clarified. Accordingly, the current study will extensively review and discuss studies regarding the immune privilege of the IVD.

Cajanolactone A from Cajanus cajan Promoted Osteoblast Differentiation in Human Bone Marrow Mesenchymal Stem Cells via Stimulating Wnt/LRP5/ß-Catenin Signaling.

Cajanolactone A (CLA) is a stilbenoid discovered by us from Cajanus cajan (L.) Millsp. In our study, CLA was found to promote osteoblast differentiation in human bone marrow mesenchymal stem cells (hBMSCs), as judged by increased cellular alkaline phosphatase activity and extracellular calcium deposits, and elevated protein expression of Runx2, collagen-1, bone morphogenetic protein-2, and osteopontin. Mechanistic studies revealed that hBMSCs undergoing osteoblast differentiation expressed upregulated mRNA levels of Wnt3a, Wnt10b, LRP5/6, Frizzled 4, ß-catenin, Runx2, and Osterix from the early stage of differentiation, indicating the role of activated Wnt/ß-catenin signaling pathway in osteoblast differentiation. Addition of CLA to the differentiation medium further increased the mRNA level of Wnt3a, Wnt10b, Frizzled 4, LRP5, and ß-catenin, inferring that CLA worked by stimulating Wnt/LRP5/ß-catenin signaling. Wnt inhibitor dickkopf-1 antagonized CLA-promoted osteoblastogenesis, indicating that CLA did not target the downstream of canonical Wnt signaling pathway. Treatment with CLA caused no changes in mRNA expression level, as well as protein secretion of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL), indicating that CLA did not affect the OPG/RANKL axis. Our results showed that CLA, which promoted osteoblast differentiation in hBMSCs, through activating Wnt/LRP5/ß-catenin signaling transduction, is a promising anti-osteoporotic drug candidate.

Facile Hydrothermal Synthesis of ZnWO4 for Enhanced Photocatalytic Performance.

ZnWO4 with controllable morphology was successfully synthesized via a facile hydrothermal method. The relationships between the structure, morphology, and catalytic activity were systemically studied by varying both the hydrothermal time and pH value. The optimal synthesis conditions for ZnWO4 with superior catalytic activity were a hydrothermal time of 12 h and a pH value of 10. Impressively, the highest photocatalytic activity for the degradation of RhB was 91% for 60 min under ultraviolet light. The increased photodegradation performance was mainly ascribed to the high crystallinity and enlarged surface area of the optimal ZnWO4.

Dysplastic spondylolysis is caused by mutations in the diastrophic dysplasia sulfate transporter gene.

Spondylolysis is a fracture in part of the vertebra with a reported prevalence of about 3-6% in the general population. Genetic etiology of this disorder remains unknown. The present study was aimed at identifying genomic mutations in patients with dysplastic spondylolysis as well as the potential pathogenesis of the abnormalities. Whole-exome sequencing and functional analysis were performed for patients with spondylolysis. We identified a novel heterozygous mutation (c.2286A > T; p.D673V) in the sulfate transporter gene SLC26A2 in five affected subjects of a Chinese family. Two additional mutations (e.g., c.1922A > G; p.H641R and g.18654T > C in the intron 1) in the gene were identified by screening a cohort of 30 unrelated patients with the disease. In situ hybridization analysis showed that SLC26A2 is abundantly expressed in the lumbosacral spine of the mouse embryo at day 14.5. Sulfate uptake activities in CHO cells transfected with mutant SLC26A2 were dramatically reduced compared with the wild type, confirming the pathogenicity of the two missense mutations. Further analysis of the gene-disease network revealed a convergent pathogenic network for the development of lumbosacral spine. To our knowledge, our findings provide the first identification of autosomal dominant SLC26A2 mutations in patients with dysplastic spondylolysis, suggesting a new clinical entity in the pathogenesis of chondrodysplasia involving lumbosacral spine. The analysis of the gene-disease network may shed new light on the study of patients with dysplastic spondylolysis and spondylolisthesis as well as high-risk individuals who are asymptomatic.

Traditional Chinese Medicine as a Potential Source for HSV-1 Therapy by Acting on Virus or the Susceptibility of Host.

Herpes simplex virus type 1 (HSV-1) is the most common virus, with an estimated infection rate of 60⁻95% among the adult population. Once infected, HSV-1 can remain latent in the host for a lifetime and be reactivated in patients with a compromised immune system. Reactivation of latent HSV-1 can also be achieved by other stimuli. Though acyclovir (ACV) is a classic drug for HSV-1 infection, ACV-resistant strains have been found in immune-compromised patients and drug toxicity has also been commonly reported. Therefore, there is an urge to search for new anti-HSV-1 agents. Natural products with potential anti-HSV-1 activity have the advantages of minimal side effects, reduced toxicity, and they exert their effect by various mechanisms. This paper will not only provide a reference for the safe dose of these agents if they are to be used in humans, referring to the interrelated data obtained from in vitro experiments, but also introduce the main pharmacodynamic mechanisms of traditional Chinese medicine (TCM) against HSV-1. Taken together, TCM functions as a potential source for HSV-1 therapy by direct (blocking viral attachment/absorption/penetration/replication) or indirect (reducing the susceptibility to HSV-1 or regulating autophagy) antiviral activities. The potential of these active components in the development of anti-HSV-1 drugs will also be described.

Effects of Ginkgo Biloba Extract EGb-761 on Neuropathic Pain in Mice: Involvement of Opioid System.

Neuropathic pain is considered as one of the most difficult types of pain to manage with conventional analgesics. EGb-761 is extracted from leaves of Ginkgo biloba and has analgesia and anti-inflammatory properties. This study aimed to examine the effect of EGb-761 on chronic constriction injury (CCI)-induced neuropathic pain behaviors, including thermal hyperalgesia and mechanical allodynia, and to explore the possible mechanisms underlying this action. To this end, CCI mice were intraperitoneally injected with EGb-761 (10, 20, 40, and 80 mg/kg), and thermal hyperalgesia, mechanical allodynia, cytokines, and mu-opioid receptor expression were measured. Results showed that EGb-761 attenuated thermal hyperalgesia and mechanical allodynia dose-dependently and the best delivery time window was from day 7 to day 14 after CCI. Additionally, EGb-761 treatment significantly decreased pro-inflammatory cytokines and enhanced mu opioid receptor (MOR) expression in the sciatic nerve. Moreover, the opioid antagonist naloxone prevented the effect of EGb-761 on thermal hyperalgesia and mechanical allodynia but did not influence the effect of EGb-761 on inflammatory cytokines. In conclusion, this study suggests that the potential of EGb-761 as a new analgesic for neuropathic pain treatment, and opioid system may be involved in the EGb-761-induced attenuation of thermal hyperalgesia and mechanical allodynia. Copyright © 2016 John Wiley & Sons, Ltd.

Inhibition of the spinal astrocytic JNK/MCP-1 pathway activation correlates with the analgesic effects of tanshinone IIA sulfonate in neuropathic pain.

BACKGROUND: Neuropathic pain (NP) continues to be challenging to treat due to lack of effective drugs. Accumulating evidence elucidated that glia-mediated inflammatory reactions play a pivotal role in the introduction and development of NP. Besides, activation of the c-Jun N-terminal kinase (JNK)/monocyte chemoattractant protein-1 (MCP-1) pathway in astrocytes has been reported to be critical for spinal astrocytic activation and neuropathic pain development after spinal nerve ligation (SNL). Tanshinone IIA, a major active component of a traditional Chinese drug, Danshen, possesses potent immuno-suppressive activities. The present study was undertaken to assess whether intraperitoneal administration of tanshinone IIA sulfonate (TIIAS) has analgesic effect on SNL-induced neuropathic pain and whether the inhibition of astrocytic activation and JNK/MCP-1 pathway is involved in the analgesic effect of TIIAS. METHODS: The effects of TIIAS on SNL-induced mechanical allodynia were assessed by behavioral testing. Immunofluorescence histochemical staining was used to detect changes of spinal astrocytes and spinal pJNK expression and localization. Immunofluorescence histochemistry and Western blot analysis were used to quantify the SNL-induced spinal pJNK expression after TIIAS administration. Enzyme-linked immunosorbent assay (ELISA) was used to detect the SNL-induced spinal expression of pro-inflammatory cytokines and MCP-1. RESULTS: Our results indicated that intraperitoneal TIIAS up-regulated the mechanical paw withdrawal threshold (PWT) of NP, while astrocytic activation was suppressed and accompanied by the down-regulation of IL-1ß and TNF-α expression, as well as JNK phosphorylation in the spinal dorsal horn. Additionally, the release of MCP-1 was dose dependently decreased. After co-treatment with TIIAS and JNK inhibitor (SP600125), no significant increases in mechanical PWT and MCP-1 expression were observed compared with the TIIAS-treated group. CONCLUSIONS: The present results suggest that the analgesic effects of TIIAS in neuropathic pain are mainly mediated by the down-regulation of SNL-induced astrocytic activation, which is via the inhibition of JNK/MCP-1 pathway.

CT Characterization of Duodenal Gastrointestinal Stromal Tumors.

OBJECTIVE: Diagnosis and staging of duodenal gastrointestinal stromal tumors (GISTs) by noninvasive imaging is critical for effective treatment, but the imaging features of duodenal GISTs remain largely undefined because of their rarity. The purpose of this article was to characterize duodenal GISTs using CT. MATERIALS AND METHODS: Thirty-four patients with duodenal GISTs were analyzed by clinical symptom evaluation, pathologic examination, and CT in this retrospective study. Unenhanced and contrast-enhanced examinations were performed in all patients. Imaging characteristics, including the lesion location, size, growth pattern, ulceration, internal components, arterial blood supply, intratumoral arterioportal shunting, intratumoral vessels, rim enhancement, and enhancement patterns were reviewed. RESULTS: The duodenal GISTs were solitary masses with well-defined margins. The average diameter was 7.1 cm. The second portion was the most common site (20/34). Ulceration was a common feature (15/34). Calcification was uncommon (3/34), and mixed growth pattern was more common (26/34). Rim enhancement (24/34) and mixed enhancement pattern (15/34) were common. Arterial blood supply, intratumoral vasculature, and draining veins were all detected and were obvious on the arterial phase. The portal venous trunk and superior mesenteric vein were the main veins into which early arterioportal shunting drained. CONCLUSION: Primary duodenal GISTs are generally large, well-defined, heterogeneously enhancing, and hypervascular masses with a prominent mixed growth pattern on CT images. Our findings suggest that CT can help depict the origin of the tumoral arteries and draining veins on the arterial phase and may be a key defining diagnostic feature for duodenal GISTs.

Timing of surgical decompression for traumatic cervical spinal cord injury.

PURPOSE: Although there have been numerous studies aimed at determining the effects and safety of early vs. late surgical decompression for traumatic cervical spinal cord injury, controversies still exist regarding the optimal timing of surgery for this serious spinal trauma. This study was conducted to evaluate the effectiveness and safety of early vs. late surgical decompression for lower cervical spine trauma associated with spinal cord injury. METHODS: A retrospective review of was performed on consecutive patients who underwent surgical decompression for lower cervical (C3-C7) spine trauma associated with spinal cord injury at six institutions across China from January 2007 to January 2012. These patients were analysed according to the timing of surgical intervention. The early group comprised patients who underwent surgery within the first 72 hours after being injured, whilst the late group comprised patients who underwent surgery after the first 72 hours. For analysis of neurologic improvement, patients who had completed a follow-up of at least six months were assessed. Other outcomes analysed were hospitalisation periods, complications and mortality. RESULTS: A total of 595 patients were identified (456 men and 139 women at an average age of 41.4 years), with 212 in the early group and 383 in the late group. Patients in both groups had made a significant neurologic improvement in the final follow-up, but no statistically significant difference was noted between groups. Patients in the early group had a significantly shorter hospital stay (15.4 vs. 18.3 days, p <0.001) but realised no benefits in terms of intensive care unit length of stay and ventilator days. No significant differences were identified between groups with regards complications (pneumonia, pulmonary embolism, wound infection, sepsis and urinary tract infection). Compared with the late group, the early group had a significantly higher incidence of postoperative neurological deterioration (6.6 vs. 0.7 %, p <0.001) and mortality (7.1 vs. 2.1 %, p = 0.003). CONCLUSION: The timing of surgery for patients sustaining traumatic lower cervical spine injury with neurological involvement did not affect neurological recovery. Early surgical intervention was associated with a higher incidence of mortality and neurological deterioration compared with late surgical intervention, indicating that surgery after the first 72 hours might be relatively safe.

17ß-Estradiol inhibits ER stress-induced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts.

Although many studies have suggested that estrogen prevents postmenopausal bone loss partially due to its anti-apoptosis effects in osteoblasts, the underlying mechanism has not been fully elucidated. In the present study, we found that 17ß-estradiol (17ß-E2), one of the primary estrogens, inhibited endoplasmic reticulum (ER) stress-induced apoptosis in MC3T3-E1 cells and primary osteoblasts. Interestingly, 17ß-E2-promoted Grp78 induction, but not CHOP induction in response to ER stress. We further confirmed that Grp78-specific siRNA reversed the inhibition of 17ß-E2 on ER stress-induced apoptosis by activating caspase-12 and caspase-3. Moreover, we found that 17ß-E2 markedly increased the phosphorylated TFII-I levels and nuclear localization of TFII-I in ER stress conditions. 17ß-E2 stimulated Grp78 promoter activity in a dose-dependent manner in the presence of TFII-I and enhanced the binding of TFII-I to the Grp78 promoter. In addition, 17ß-E2 notably increased phosphorylated ERK1/2 levels and Ras kinase activity in MC3T3-E1 cells. The ERK1/2 activity-specific inhibitor U0126 remarkably blocked 17ß-E2-induced TFII-I phosphorylation and Grp78 expression in response to ER stress. Together, 17ß-E2 protected MC3T3-E1 cells against ER stress-induced apoptosis by promoting Ras-ERK1/2-TFII-I signaling pathway-dependent Grp78 induction.

Protective effects of myricitrin against osteoporosis via reducing reactive oxygen species and bone-resorbing cytokines.

Oxidative stress is a crucial pathogenic factor in the development of osteoporosis. Myricitrin, isolated from Myrica cerifera, is a potent antioxidant. We hypothesized that myricitrin possessed protective effects against osteoporosis by partially reducing reactive oxygen species (ROS) and bone-resorbing cytokines in osteoblastic MC3T3-E1 cells and human bone marrow stromal cells (hBMSCs). We investigated myricitrin on osteogenic differentiation under oxidative stress. Hydrogen peroxide (H2O2) was used to establish an oxidative cell injury model. Our results revealed that myricitrin significantly improved some osteogenic markers in these cells. Myricitrin decreased lipid production and reduced peroxisome proliferator-activated receptor gamma-2 (PPARγ2) expression in hBMSCs. Moreover, myricitrin reduced the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and IL-6 and partially suppressed ROS production. In vivo, we established a murine ovariectomized (OVX) osteoporosis model. Our results demonstrated that myricitrin supplementation reduced serum malondialdehyde (MDA) activity and increased reduced glutathione (GSH) activity. Importantly, it ameliorated the micro-architecture of trabecular bones in the 4th lumbar vertebrae (L4) and distal femur. Taken together, these results indicated that the protective effects of myricitrin against osteoporosis are linked to a reduction in ROS and bone-resorbing cytokines, suggesting that myricitrin may be useful in bone metabolism diseases, particularly osteoporosis.

Estrogen improves the proliferation and differentiation of hBMSCs derived from postmenopausal osteoporosis through notch signaling pathway.

Estrogen deficiency is the main reason of bone loss, leading to postmenopausal osteoporosis, and estrogen replacement therapy (ERT) has been demonstrated to protect bone loss efficiently. Notch signaling controls proliferation and differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Moreover, imperfect estrogen-responsive elements (EREs) were found in the 5'-untranslated region of Notch1 and Jagged1. Thus, we examined the molecular and biological links between estrogen and the Notch signaling in postmenopausal osteoporosis in vitro. hBMSCs were obtained from healthy women and patients with postmenopausal osteoporosis. Notch signaling molecules were quantified using real-time polymerase chain reaction (real-time PCR) and Western Blot. Luciferase reporter constructs with putative EREs were transfected into hBMSCs and analyzed. hBMSCs were transduced with lentiviral vectors containing human Notch1 intracellular domain (NICD1). We also used N-[N-(3, 5-diflurophenylacetate)-l-alanyl]-(S)-phenylglycine t-butyl ester, a γ-secretase inhibitor, to suppress the Notch signaling. We found that estrogen enhanced the Notch signaling in hBMSCs by promoting the expression of Jagged1. hBMSCs cultured with estrogen resulted in the up-regulation of Notch signaling and increased proliferation and differentiation. Enhanced Notch signaling could enhance the proliferation and differentiation of hBMSCs from patients with postmenopausal osteoporosis (OP-hBMSCs). Our results demonstrated that estrogen preserved bone mass partly by activating the Notch signaling. Because long-term ERT has been associated with several side effects, the Notch signaling could be a potential target for treating postmenopausal osteoporosis.

Chinese organic rice transition spatial econometrics empirical analysis.

Based on the integrated model of Super-SBM model, spatial Durbin model (SDM) and Grey neural network model, this paper analyzes the panel data of various provinces in China from multiple angles and dimensions. It was found that there were significant differences in eco-efficiency between organic rice production and conventional rice production. The response of organic rice to climate change, the spatial distribution of ecological and economic benefits and the impact on carbon emission were analyzed. The results showed that organic rice planting not only had higher economic benefits, but also showed a rising trend of ecological benefits and a positive feedback effect. This finding highlights the importance of organic rice farming in reducing carbon emissions. Organic rice farming effectively reduces greenhouse gas emissions, especially carbon dioxide and methane, by improving soil management and reducing the use of fertilizers and pesticides. This has important implications for mitigating climate change and promoting soil health and biodiversity. With the acceleration of urbanization, the increase of organic rice planting area shows the trend of organic rice gradually replacing traditional rice cultivation, further highlighting the potential of organic agriculture in emission reduction, environmental protection and sustainable agricultural production. To this end, it is recommended that the Government implement a diversified support strategy to encourage technological innovation, provide guidance and training, and raise public awareness and demand for organic products. At the same time, private sector participation is stimulated to support the development of organic rice cultivation through a public-private partnership model. Through these measures, further promote organic rice cultivation, achieve the dual goals of economic benefits and environmental benefits, and effectively promote the realization of double carbon emission reduction targets.