Homocysteine-potentiated Kelch-like ECH-associated protein 1 promotes senescence of neuroblastoma 2a cells via inhibiting ubiquitination of ß-catenin.

Elevated serum homocysteine (Hcy) level is a risk factor for Alzheimer's disease (AD) and accelerates cell aging. However, the mechanism by which Hcy induces neuronal senescence remains largely unknown. In this study, we observed that Hcy significantly promoted senescence in neuroblastoma 2a (N2a) cells with elevated ß-catenin and Kelch-like ECH-associated protein 1 (KEAP1) levels. Intriguingly, Hcy promoted the interaction between KEAP1 and the Wilms tumor gene on the X chromosome (WTX) while hampering the ß-catenin-WTX interaction. Mechanistically, Hcy attenuated the methylation level of the KEAP1 promoter CpG island and activated KEAP1 transcription. However, a slow degradation rate rather than transcriptional activation contributed to the high level of ß-catenin. Hcy-upregulated KEAP1 competed with ß-catenin to bind to WTX. Knockdown of both ß-catenin and KEAP1 attenuated Hcy-induced senescence in N2a cells. Our data highlight a crucial role of the KEAP1-ß-catenin pathway in Hcy-induced neuronal-like senescence and uncover a promising target for AD treatment.

TL1A induces apoptosis via DR3 in grass carp (Ctenopharyngodon idella).

Tumor necrosis factor like ligand 1A (TL1A), a member of TNF superfamily, regulates inflammatory response and immune defense. TL1A homologues have recently been discovered in fish, but their functions have not been studied. In this study, a TL1A homologue was identified in grass carp (Ctenopharyngodon idella) and its bioactivities were investigated. The grass carp tl1a (Citl1a) gene was constitutively expressed in tissues, with the highest expression detected in the liver. It was upregulated in response to infection with Aeromonas hydrophila. The recombinant CiTL1A was produced in bacteria and was shown to stimulate the expression of il1ß, tnfα, caspase 8 and ifnγ in the primary head kidney leucocytes. In addition, co-immunoprecipitation assay revealed that CiTL1A interacted with DR3 and induced apoptosis via activation of DR3. The results demonstrate that TL1A regulates inflammation and apoptosis and is involved in the immune defense against bacterial infection in fish.

Effectiveness and Accuracy of a Patient-Specific Instrumentation System for Total Hip Arthroplasty.

OBJECTIVE: Traditional total hip arthroplasty (THA) is often performed by visual inspection due to the lack of reliable reference, which results in inappropriate position of prosthesis and poor outcomes. This study attempts to introduce a novel patient-specific instrumentation (PSI) system and assess its effectiveness and accuracy compared with freehand operation and robot system through bone model experiments. METHODS: Equally divide 30 sawbone models into the freehand group, PSI group, and robot group. Ten sets of prosthesis parameters were randomly generated as planning, and the three groups underwent simulated THA depending on these parameters. After the placement of the femoral prosthesis, the acetabular anteversion plan was adjusted in the PSI and robot groups so that the combined anteversion was maintained before and after adjustment. After the surgery, the actual prosthesis parameters of all bone models were measured and analyzed statistically. RESULTS: No statistically significant difference was found in femoral anteversion error among the three groups (p = 0.951). The errors of acetabular cup anteversion, acetabular cup abduction, and combined anteversion in PSI group were 3.92° (2.94°, 4.62°), 5.65° (4.63°, 6.70°), and 3.93° (2.94°, 4.62°), respectively, which were significantly smaller than those in the freehand group [11.84° (9.92°, 13.87°), 13.54° (9.81°, 15.21°), 16.04° (8.18°, 19.25°), respectively, p < 0.05], but significantly larger than those in the robot group [1.34° (0.98°, 1.70°), 1.80° (1°, 2.02°), 1.34° (0.98°, 1.70°), respectively, p < 0.05]. CONCLUSION: Compared with the traditional freehand operation, the patient-specific instrumentation system is feasible in total hip arthroplasty because it improves the accuracy of prosthesis placement. In addition, the rapid measurement of intraoperative femoral prosthesis parameters can help surgeons optimize preoperative planning.

IL-27 suppresses spring viremia of carp virus replication in zebrafish.

Interleukin (IL) 27 is a member of the IL-12 family and is a heterodimeric cytokine composed of IL-27A and Epstein-Barr virus-induced 3 (EBI3). It plays an important role in regulating inflammation and cancer progression. IL-27A not only functions by dimerizing with EBI3 but also acts alone. Here, we report that IL-27A and EBI3 suppress spring viremia of carp virus (SVCV) replication in zebrafish. Expression analysis reveals that il-27a and ebi3 were significantly upregulated in the ZF4 cells by SVCV and poly(I:C), and in the zebrafish caudal fin (ZFIN) cells overexpressed with SVCV genes. Interestingly, il-27a and ebi3 were not modulated by IFNφ1, indicating that they are not IFN stimulated genes (ISGs). Furthermore, overexpression of IL-27A and EBI3 alone inhibited SVCV replication in the EPC cells, but less potent than co-expression of IL-27A and EBI3. Intriguingly, IL-27A could not induce the expression of irf3, ifn, isg15 and mx1. Taken together, our results demonstrate that IL-27A and EBI3 activate innate antiviral response in an IFN independent manner in zebrafish.

Expression and functional characterization of three ß-defensins in grass carp (Ctenopharyngodon idella).

ß-defensins (BDs) are a group of cysteine-rich cationic antimicrobial peptides and play important roles in the first line of defense against infection. In this study, the expression and antibacterial activities of three grass carp (Ctenopharyngodon idella) (Ci) ß-defensin (BD) peptides were comparatively investigated. Expression analysis reveals that CiBD1-3 were constitutively expressed in tissues, with the highest expression detected in the skin. The CiBD-1 transcripts were more abundant than CiBD-2 and CiBD-3. In the primary head kidney leukocytes, CiBDs were induced by PHA, LPS, poly(I:C) and cytokines such as IL-1ß and IFN-γ. In vivo challenge of fish with Aeromonas hydrophila resulted in the up-regulation of CiBDs in the head kidney and hindgut. To determine the biological activities, recombinant CiBD proteins were produced in the HEK293-F cells and purified for the minimum inhibitory concentration assay. It was found that all three recombinant CiBD proteins were effective to inhibit the growth of Gram-negative fish bacterial pathogens including Aeromonas hydrophila, Edwardsiella tarda, Flavobacterium columnare and Klebsiella pneumoniae and Gram-positive Staphylococcus aureus. CiBD-2 and CiBD-3 were more effective than CiBD-1. Our results demonstrate that all the three CiBDs have broad antibacterial activity against fish bacterial pathogens.

Severe tinnitus and migraine headache in a 37-year-old woman treated with trastuzumab for breast cancer: A case report.

BACKGROUND: Trastuzumab is a generally safe agent prescribed in the systemic treatment of breast cancer. Tinnitus is not a currently known adverse event related to trastuzumab. Here, we describe a rare case of severe tinnitus and a migraine headache induced by trastuzumab used for adjuvant therapy. CASE SUMMARY: A 37-year-old woman was diagnosed with hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancer. After surgery, she was treated with four cycles of epirubicin and cyclophosphamide; she then received docetaxel and a loading dose of trastuzumab plus pertuzumab. Less than half an hour after trastuzumab infusion, the patient complained of severe tinnitus and left-sided migraine headache. Trastuzumab monotherapy was discontinued immediately, and symptoms disappeared after 10 min. Trastuzumab was readministered, and severe tinnitus and migraine headache recurred. Trastuzumab was stopped, and severe tinnitus diminished after 10 min. Pertuzumab and docetaxel therapy was then administered, and no adverse events were observed. Subsequent infusions of trastuzumab every three weeks did not show the same symptoms. CONCLUSION: Although trastuzumab is well-tolerated in most patients, we should pay attention to the risk of severe tinnitus and migraine.

Comparison of cognitive impairments with lipid profiles and inflammatory biomarkers in unipolar and bipolar depression.

Cognitive impairments is one of important accompanied symptom in Unipolar depressive disorder (UD) and bipolar disorder (BD) that was hard to distinguish, as their diagnosis is based on behavioural observations and subjective symptoms. In this study, we could highlight the difference of cognitive ability in UD and BD by testing lipid profiles and inflammatory biomarkers in major depressive episodes (MDE). 207 subjects (96 unipolar and 111 bipolar depressed patients) were included in this study. We applied Montreal Cognitive Assessment (MoCA) to test cognitive ability. The 24-item Hamilton Depression Rating Scale was used for assessment at the beginning of treatment. A series of clinical variables and lipid profiles were collected from clinic record. We detected pro-inflammatory biomarkers Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6), C-reaction protein (CRP) levels and brain-derived neurotrophic factor (BDNF) by enzyme linked immunosorbent assay. From the results, cognitive impairments were more popular in BD than UD, most obviously in severe cognitive impairments (MoCA score<23). And UD showed better cognitive ability than BD in MoCA, particularly in language domain. Compared lipid profiles like total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), Apolipoprotein B (ApoB) and lipoprotein α (Lpα), we found that ApoB was higher in BD than UD that maybe a risk factor in cognition. There was no obviously difference in TC, TG, HDL-C, LDL-C, ApoA1, or Lpα. Also, we found CRP level in BD was higher than UD, and showed no significant difference in IL-1ß and IL-6 levels. Furthermore, BDNF level which was neurotrophic biomarker for cognition and mood was significantly declined in BD compared with UD. Correlation analysis showed that ApoB and CRP was negative closed associated with MoCA scores. And BDNF level was positive related with cognitive ability in MDE patients. From our results mentioned that quantitative lipid profiles and inflammatory biomarkers analysis might help to objectively identify between these disorders and up our understanding of their pathophysiology. And ApoB, CRP and BDNF could be as potential peripheral candidates in cognitive evaluation to distinguish UD and BD.

Structural and Functional Analyses of Type I IFNa Shed Light Into Its Interaction With Multiple Receptors in Fish.

Teleost type I interferons (IFNs) are categorized into group I and II subgroups that bind to distinct receptors to activate antiviral responses. However, the interaction between ifn ligands and receptors has not fully been understood. In this study, the crystal structure of grass carp [Ctenopharyngodon idella (Ci)] IFNa has been solved at 1.58Å and consists of six helices. The CiIFNa displays a typical structure of type I IFNs with a straight helix F and lacks a helix element in the AB loop. Superposition modeling identified several key residues involved in the interaction with receptors. It was found that CiIFNa bound to cytokine receptor family B (CRFB) 1, CRFB2, and CRFB5, and the three receptors could form heterodimeric receptor complexes. Furthermore, mutation of Leu27, Glu103, Lys117, and His165 markedly decreased the phosphorylation of signal transducer and activator of transcription (STAT) 1a induced by CiIFNa in the Epithelioma papulosum cyprini (EPC) cells, and Glu103 was shown to be required for the CiIFNa-activated antiviral activity. Interestingly, wild-type and mutant CiIFNa proteins did not alter the phosphorylation levels of STAT1b. Our results demonstrate that fish type I IFNs, although structurally conserved, interact with the receptors in a manner that may differ from mammalian homologs.

Forsythiaside A alleviates methotrexate-induced intestinal mucositis in rats by modulating the NLRP3 signaling pathways.

Most chemotherapeutic drugs can kill the tumor cells, but also cause a vast damage to body, such as intestinal mucositis (IM). The present study was design to find out the effect of Forsythiaside A (FTA) on chemotherapeutic-induced IM in rats. Briefly, for 3 consecutive days, male Sprague-Dawley rats were treated with 7 mg / kg methotrexate (MTX) to establish IM and simultaneously administered with 40 or 80 mg / kg FTA for 7 days. Our results showed that the final body weight and daily food intake were increased, and the disease activity index was reduced in the MTX group after FTA treatment. The MTX group showed the pathological alterations like the inflammatory cells infiltration, the mucosal layer destruction, glands expansion, intestinal villi structure disorder and goblet cells reduction, while we found that 80 mg / kg FTA treatment displayed evident reversal effects. ELISA further suggested that TNF-α, IL-1ß and IL-18 levels in serum in MTX-induced rats were reduced after 80 mg / kg FTA treatment. Moreover, FTA decreased the number of leukocytes, neutrophils and lymphocytes in peripheral blood. Western blot and immunofluorescence results indicated that the expression levels of NLRP3, cleaved caspase 1, cleaved IL-1ß and CD68 positive rate were down-regulated in MTX-induced rats after 80 mg / kg FTA intervention. The findings of the current study suggested that FTA effectively inhibited MTX-induced IM in rats by attenuating the activation of the NLRP3 signaling pathways.

CCL19 variants mediate chemotactic response via CCR7 in grass carp Ctenopharyngodon idella.

CC chemokine ligand 19 (CCL19) plays a key role in the regulation of immune responses including homeostasis, inflammation, and immune tolerance. In this study, two variants of CCL19 homologues (CCL19a2 and CCL19b) and CCR7 were investigated in grass carp Ctenopharyngodon idella. The three genes were widely expressed in immune tissues and could be modulated by stimulation with LPS, PHA and poly(I:C), and infection with Flavobacterium columnare and grass carp reovirus. In an in vitro chemotaxis assay, the recombinant CCL19a2 and CCL19b were active to promote the migration of HEK293 T cells expressing CCR7 and leucocytes isolated from the gills, head kidney and spleen. Moreover, their chemotactive effects were validated in vivo. We found that the cells recruited by CCL19a2 and CCl19b are mainly monocytes/macrophages expressing high levels of IL-1ß, IFN-γ, colony stimulating factor 1 receptor (CSF1R) and MHC II. Our work suggests that CCL19a2 and CCl19b are involved in recruitment of antigen presenting cells in fish.

Identification and expression analysis of group II C-type lectin domain containing receptors in grass carp Ctenopharyngodon idella.

Group II C-type lectin domain (CTLD) containing receptors belong to a large family of pattern recognition receptors which mainly act on the innate immunity. They are structurally related and consist of a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM) and a single extracellular CTLD. Although they have been described in teleost fish, their involvement in immune responses is not well understood. In this study, four immune-related lectin-like receptors (termed CiILLR1 and CiILLR5-7), belonging to the group II CTLD receptors, were identified in grass carp (Ctenopharyngodon idella). They contain a short cytoplasmic tail and a single CTLD in the extracellular region. The CiILLR1 has a WxHxxxxxY motif similar to the WxHxxxxY motif which is required for the recognition of ß-glucans by some of the group II CTLD containing lectins in mammals. Further, a modified QPD motif (EPD) known to be involved in binding to carbohydrate ligands is present in the CiILLR1, 5 and 6. However, CiILLR7 lacks these motifs. Expression analysis revealed that they were constitutively expressed in the head kidney and spleen. Moreover, CiILLR1, 5 and 6 could be up-regulated in the head kidney and spleen of fish after infection with Flavobacterium columnare and in the primary head kidney leukocytes by LPS and PHA. Expression of CiILLR1, CiILLR5 and CiILLR6 were mainly detected in the enriched lymphocytes whilst CiILLR7 was expressed in the enriched monocytes/macrophages. The results expand existing knowledge on the immune responses of the C-type lectin receptors in teleost fish.

The evolution and functional characterization of CXC chemokines and receptors in lamprey.

Chemokines are a large family of soluble peptides guiding cell migration in development and immune defense. They interact with chemokine receptors and are essential for the coordination of cell migration in diverse physiological processes. The CXC subfamily is one of the largest groups in the chemokine family and consists of multiple members. In this study, we identified homologues of three chemokine ligands (CXCL8, CXCL_F5 and CXCL12) and two CXC receptor like molecules (CXCR_L1 and CXCR_L2) in lamprey. Sequence analysis revealed that they share the same genomic organization with their counterparts in jawed vertebrates but synteny was not conserved. Lamprey CXCL8 and CXCL12 have four conserved cysteine residues whilst the CXCL_F5 has two additional cysteine residues. In addition, CXCL_F5 is evolutionarily related to the fish specific CXC chemokine groups previously identified and contains multiple cationic aa residues in the extended C- terminal region. The two CXCRs possess seven transmembrane domains and conserved structural elements for receptor activation and signaling, including the DRYXXI(V)Y motif in TM2, the disulphide bond connecting ECL2 and TM3, the WXP motif in TM6 and NPXXY motif in TM7. The identified CXC chemokines and receptors were constitutively expressed in tissues including the liver, kidney, intestine, heart, gills, supraneural body and primary leukocytes, but exhibited distinct expression patterns. Relatively high expression was detected in the gills for CXCL8, CXCL_F5 and CXCR_L1 and in the supraneural body for CXCL12 and CXCR_L2. All the genes except CXCL12 were upregulated by stimulation with LPS, pokeweed and bacterial infection, and the CXCL8 and CXCL_F5 was induced by poly (I:C). Functional analysis showed that the CXCL8 and CXCL_F5 specifically interacted with CXCR_L1 and CXCR_L2, respectively. Our results demonstrate that the CXC chemokine system had diversified in jawless fish.

Disruption of microRNA-214 during general anaesthesia prevents brain injury and maintains mitochondrial fusion by promoting Mfn2 interaction with Pkm2.

Duration of surgical general anaesthesia is associated with severe brain injury and neurological deficits. The specific mechanisms underlying post-general anaesthesia brain injury, however, still remain to be elucidated. Herein, we explore the role of microRNA-214 (miR-214) in the occurrence of brain injury after general anaesthesia and its underlying mechanism. Hippocampal tissues and neurons were isolated from rats exposed to 2% sevoflurane. TUNEL stains reflect hippocampal neuron apoptosis. Cultured hippocampal neurons stained with JC-1 and MitoTracker dyes were imaged by fluorescence microscope to visualize changes of mitochondrial membrane potential and mitochondrial fusion. Mitochondrial function was evaluated. Mitofusin 2 (Mfn2) binding to miR-214 or pyruvate kinase M2 (Pkm2) was confirmed by co-immunoprecipitation, immunofluorescence, dual luciferase reporter gene and RNA immunoprecipitation assays. After exposure to 2% sevoflurane, up-regulated miR-214 expression and impaired interaction between Mfn2 and Pkm2 were found in rat hippocampal tissues. Rats exposed to 2% sevoflurane also experienced neuronal injury, mitochondrial defects and deficits in the brain-derived neurotrophic factor (Bdnf) signalling. miR-214 was shown to target Mfn2 by impairing its binding with Pkm2. Inhibiting miR-214 expression using its specific inhibitor improved mitochondrial membrane potential, enhanced mitochondrial fusion, maintained mitochondrial function, restored interaction between Mfn2 and Pkm2, and activated the Bdnf signalling in cultured hippocampal neurons. Adenovirus infection of miR-214 inhibitor reduced neuron apoptosis and maintained mitochondrial function in the hippocampus of rats exposed to 2% sevoflurane. Taken together, the study demonstrates inhibition of miR-214 is cerebral protective against brain injury following general anaesthesia.

Exploring the Risk Factors for the Misdiagnosis of Osteonecrosis of Femoral Head: A Case-Control Study.

OBJECTIVE: The purpose of the present study was to evaluate the present situation and risk factors for the misdiagnosis of osteonecrosis of femoral head (ONFH), providing the basis for accurate diagnosis of ONFH. METHODS: For this retrospective study, 1471 patients with ONFH were selected from the China Osteonecrosis of Femoral Head Database (CONFHD). These patients had been recruited between July 2016 and December 2018. According to whether or not they were misdiagnosed, the patients were divided into two groups, with 1168 cases (22-84 years old) included in the diagnosis group and 303 cases (21-80 years old) in the misdiagnosis group. Misdiagnosis was measured using the following criteria: (i) the patient had the same symptoms and signs, and the second diagnosis was not consistent with the initial diagnosis within 6 months; and (ii) the patient was admitted to a hospital participating in CONFHD and the previous diagnosis was inconsistent with the diagnosis given by the expert group. Comparisons of age, visual analogue scale for pain, and body mass index between the two groups were performed using a t-test. Gender, causes of ONFH, primary diseases requiring corticosteroids, methods of corticosteroid use, corticosteroid species, type of trauma, onset side of the disease, pain side, whether symptoms are hidden, and type of imaging examination at the initial visit were compared using the χ2 -test. Years of alcohol consumption, weekly alcohol consumption, and physician title at the initial visit were compared using a Mann-Whitney U-test. Furthermore, the statistically significant factors were evaluated using multiple regression analysis to investigate the risk factors of misdiagnosis. RESULTS: A total of 303 patients (20.6%) were misdiagnosed: 118 cases were misdiagnosed as lumbar disc herniation, 86 cases as hip synovitis, 48 cases as hip osteoarthritis, 32 cases as rheumatoid arthritis, 11 cases as piriformis syndrome, 5 cases as sciatica, and 3 cases as soft-tissue injury. Whether symptoms are hidden (P = 0.038, odds ratio [OR] = 1.546, 95% confidence interval [CI] = 1.025-2.332), physician title at the initial visit (P < 0.001, OR = 3.324, 95% CI = 1.850-5.972), X-ray examination (P < 0.001, OR = 4.742, 95% CI = 3.159-7.118), corticosteroids (P < 0.001, OR = 0.295, 95% CI = 0.163-0.534), alcohol (P < 0.001, OR = 0.305, 95% CI = 0.171-0.546), and magnetic resonance imaging (MRI) examination (P = 0.042, OR = 0.649, 95% CI = 0.427-0.985) were each found to be associated with misdiagnosis. CONCLUSION: Osteonecrosis of the femoral head is easily misdiagnosed as lumbar disc herniation, hip synovitis, hip osteoarthritis, and rheumatoid arthritis. Patient history of corticosteroid use or alcohol abuse and MRI examination at the initial diagnosis may be protective factors for misdiagnosis. Hidden symptoms, physician title at the initial visit (as attending doctor or resident doctor), and only X-ray examination at the initial diagnosis may be risk factors for misdiagnosis.

Erratum to: Protein Phosphatase 2A as a Drug Target in the Treatment of Cancer and Alzheimer's Disease.

The article "Protein Phosphatase 2A as a Drug Target in the Treatment of Cancer and Alzheimer's Disease", written by Hui WEI, Hui-liang ZHANG, Jia-zhao XIE, Dong-li MENG, Xiao-chuan WANG, Dan KE, Ji ZENG, Rong LIU, was originally published electronically on the publisher's internet portal on 13 March 2020 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed to © The Author(s) 2020 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The original article has been corrected.Corresponding authors: Dan KE, E-mail: kedan@hust.edu.cn; Ji ZENG, E-mail: whzjmicro@163.com.

Protein Phosphatase 2A as a Drug Target in the Treatment of Cancer and Alzheimer's Disease.

Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase which participates in the regulation of multiple cellular processes. As a confirmed tumor suppressor, PP2A activity is downregulated in tumors and its re-activation can induce apoptosis of cancer cells. In the brains of Alzheimer's disease (AD) patients, decreased PP2A activity also plays a key role in promoting tau hyperphosphorylation and Aß generation. In this review, we discussed compounds aiming at modulating PP2A activity in the treatment of cancer or AD. The upstream factors that inactivate PP2A in diseases have not been fully elucidated and further studies are needed. It will help for the refinement and development of novel and clinically tractable PP2A-targeted compounds or therapies for the treatment of tumor and AD.

[Discordance of Estrogen Receptor,Progesterone Receptor,Cerb-B2,Ki-67 Index and P53 Expressions between Primary and Recurrent or Metastatic Sites in Breast Cancer Patients].

Objective To approach the discordance of estrogen receptor(ER),progesterone receptor(PR),Cerb-B2,Ki-67 index and P53 expressions between primary and regional or distant recurrent lesions in recurrent or metastatic breast cancer patients.Methods Clinical and pathological data of 56 recurrent or metastatic breast cancer patients who were treated in Peking Union Medical College Hospital from January 2001 to February 2015 were retrospectively analyzed.The changes in the expressions of ER,PR,Cerb-B2,Ki-67 index,and P53 status were analyzed.Results The hormone receptor positive rate between primary tumor and recurrent or metastatic sites decreased from 60.7% to 57.1% for ER and from 55.4% to 44.6% for PR,respectively.Changes in hormone receptor status were seen at the rate of 12.5%(7/56)and 16.1%(9/56)for ER and PR,respectively.Cerb-B2 receptor positive rate increased from 19.1% to 29.5% and the discordance rate was 9.1%(4/44).The discordance rate of Ki-67 index was 24.5%(12/49).The P53 receptor positive rate increased from 37.5% to 55.6% and the discordance rate was 13.3%(6/45).Conclusion Although the relevant rules of above changes are still controversial,these findings still have great clinical significance for making effective treatment decisions of recurrent or metastatic breast cancer.

Sex difference in IL-6 modulation of cognition among Chinese individuals with major depressive disorder.

Cognitive dysfunction and pro-inflammatory effect has been associated with major depressive disorder (MDD), but sex differences have seldom been studied. The study was to determine the sex difference of cognitive dysfunction and pro-inflammatory biomarkers among patients with MDD in Chinese Han population. 104 MDD patients (male n = 37, female n = 67) were included in the study. Their sociodemographic and clinical features, including age, body mass index (BMI), education, smoking, alcohol use, illness characteristics and medicine use were recorded. Montreal Cognitive Assessment (MoCA) was used to assess cognition. And we detected pro-inflammatory biomarkers Interleakin-1ß (IL-1ß), Interleakin-6 (IL-6) and C-reaction protein (CRP) levels by enzyme linked immunosorbent assay. We found that male patients showed higher scores than female in MoCA, and performed better than female patients particularly in visuaspatial, naming, attention, orientation subscale. CRP and IL-1ß levels showed no significant difference between male and female patients in MDD. However, Male's IL-6 level was significantly declined than female, negative closed associated with cognition in MOCA score. These results suggested that the difference in IL-6 could reflect a cognitive difference between male and female in MDD, and IL-6 elevation could represent a state indicator for cognitive ability particular in female MDD patients. And it maybe a biological treatment target in cognition dysfunction of female patients in MDD.

Exploring the protective effect of ShengMai-Yin and Ganmaidazao decoction combination against type 2 diabetes mellitus with nonalcoholic fatty liver disease by network pharmacology and validation in KKAy mice.

ETHNOPHARMACOLOGICAL RELEVANCE: ShengMai-Yin and Ganmaidazao decoction are classic formulas in traditional Chinese medicine. Individually, Shengmai-Yin is used to treat cardiovascular diseases, and Ganmaidazao decoction for therapy of mental disorders. The combination of Shengmai-Yin and Ganmaidazao decoction (SGD) is normally used as adjuvant therapy for type 2 diabetes mellitus (T2DM). AIM OF THE STUDY: The central aim is to elucidate the pharmacological efficacy of SGD and its mechanism in the treatment of T2DM with non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: Active ingredients in SGD and their drug targets were identified using network analysis followed by experimental validation. First, existing databases were mined for information relevant to SGD, including pharmacological actions, chemical components, physicochemical characteristics, potential targets, and implicated diseases. Candidate patterns obtained with the network analysis were then tested in a KKAy mouse model of T2DM with NAFLD. Various doses of SGD were administered, followed by measurements of fasting blood glucose, oral glucose tolerance tests, insulin tolerance tests, markers of lipid metabolism - including free fatty acids (FFA), triglycerides (TG), and total cholesterol (TC) - liver histology, and expression levels of implicated molecules including PI3K/AKT and PPARα. RESULTS: Over 300 potential active compounds with their physicochemical characteristics and 562 candidate targets were collected, and then the network of them was constructed. Follow-up pathway and functional enrichment analyses indicated that SGD influences metabolism-related signaling pathways including PI3K-Akt, AMPK, and PPAR. In validation experiments, treatment of KKAy mice with SGD reduced serum levels of glucose, TC, TG, and FFA, decreased numbers of crown-like structures in visceral adipose tissue, reduced adipocyte size, and lowered liver lipid deposits. Further, SGD improved liver metabolism by increasing the expressions of PPARα, HSL, and PI3K/Akt, and decreasing expressions of SREBP-1 and FASN, inhibiting lipid biosynthesis, and increasing insulin sensitivity. CONCLUSION: Experimental validation of network analysis revealed anti-diabetic effects of the plant product SGD, manifested most notably by improved serum profiles and diminished insulin resistance. These experimental results may have clinical implications.