Inhibiting MAPK14 showed anti-prolactinoma effect.

BACKGROUND: The specific underlying pathogenesis of prolactinoma has not been clarified yet, to the best of our knowledge. p38 mitogen-activated protein kinase (MAPK) signaling including p38α MAPK (MAPK14), p38ß (MAPK11), p38γ (MAPK12) and p38δ (MAPK13) is associated with the development and progression of several types of cancer. METHODS: Immunofluorescence analysis was performed on the prolactin (PRL) and MAPK14 expressions of pituitary gland in C57BL/6 mice and human prolactinoma specimen. In the present study, the role of MAPK14 in prolactinoma was determined using estradiol-induced mice and dopamine D2 receptor knockout (DRD2-/-) mice models in C57BL/6 wild-type (WT), MAPK14-/- and DRD2-/-MAPK14+/- mice. GH3 cells were transfected with different sets of MAPK14 small interfering RNA, which to study MAPK14 and PRL expression in GH3 cells. RESULTS: Immunofluorescence analysis showed that PRL and MAPK14 expression were colocalized and increased in the pituitary gland of mice and human prolactinoma specimen compared with the control specimen. It was shown that PRL and MAPK14 expression was colocalized and increased significantly in the pituitary gland of estradiol-injected prolactinoma mice compared with the control mice. Knockout of MAPK14 significantly inhibited tumor overgrowth, and PRL expression was decreased in estradiol-induced mice. Furthermore, MAPK14 knockout of DRD2-/-MAPK14+/- mice significantly reduced the overgrowth of pituitary gland and PRL production and secretion compared with DRD2-/- mice. MAPK14 knockout using siRNA inhibited PRL production in GH3 cells. CONCLUSION: These results suggest that MAPK14 serves a promoting role in the formation of prolactinoma, and highlights the potential of MAPK14 as a potential therapeutic target in the treatment of prolactinoma.

Enhanced Antitumor Efficacy of Curcumin-Loaded PLGA Nanoparticles Coated with Unique Fungal Hydrophobin.

Modifications to the surface chemistry, charge, and hydrophilicity/hydrophobicity of nanoparticles are applicable approaches to the alterations of the in vivo fate of intravenously administered nano-sized drug carriers. The objective of this study is to investigate the in vitro and in vivo antitumor efficacies of curcumin PLGA nanoparticles in relation to their surface structural modification via self-assembling coating with unique fungal hydrophobin. The hydophobin-coated curcumin PLGA nanoparticles (HPB PLGA NPs) were obtained by simply soaking curcumin-loaded PLGA nanoparticles (PLGA NPs) in aqueous fungal hydrophobin solution. The in vitro drug release behavior of the HPB PLGA NPS was also tested. The cytotoxicity and cellular uptake of these nanoparticles were determined in HepG2, A549, and Hela cell lines using MTT assay method and CLSM observation. The in vivo antitumor activity was evaluated in Hela tumor xenografted mice model. Compared with the PLGA NPs, the size and zeta potential of the nanoparticles were changed after hydrophobin coating, whereas similar in vitro release pattern was observed. The pharmacodynamics study showed prolonged blood retention of both nano-formulations than that of free curcumin, but no significant difference between the hydrophobin coated and uncoated nanoparticles. It was found that HPB PLGA NPs had increased cytotoxicities, higher cellular uptake, and improved antitumor efficacy. Surface modification of nanoparticles via self-assembling of hydrophobin is a convenient and promising method of changing particle surface physiochemical properties and antitumor performances. Further investigations, especially on tissue distribution, were needed to assess the potential application of the hydrophobin self-assembling coating in nano-drug delivery carriers.

Coexpression network analysis of platelet genes in sickle cell disease.

Platelets play important roles in vascular health. Activation of platelet may contribute to coagulation and inflammation. Evidence suggests circulating platelets are chronically activated in sickle cell disease (SCD) patients with steady state and further activated in vaso-occlusive crisis. However, the molecular basis of sickle platelet dysfunction remains obscure. Here, we used weighted gene coexpression network analysis combined with differentially expressed genes (DEGs) analysis to further investigate this basis. We found 57 DEGs were closely related to platelet dysfunction in SCD. Enrichment analysis showed that these 57 genes were mostly related to protein synthesis, adenosine triphosphate (ATP) synthase activity and inflammation, suggesting a hyperactivation status of platelets in SCD. We identified six hub genes from the 57 DEGs according to their Gene Significance value ranking, including CRYM, CCT6P1, SUCNR1, PRKAB2, GSTM3 and FCGR2C. Altogether, our results offered some new insight into platelet activation and identified novel potential targets for antiplatelet therapy in SCD.

Salvianolic acid A attenuates kidney injury and inflammation by inhibiting NF-κB and p38 MAPK signaling pathways in 5/6 nephrectomized rats.

Salvianolic acid A (SAA) is a minor phenolic carboxylic acid extracted from Salviae miltiorrhizae Bunge (Danshen). SAA exhibits a variety of pharmacological activities, such as antioxidative, anti-thrombotic, neuroprotective, and anti-fibrotic effects, as well as protection from myocardial ischemia and prevention of diabetes and other diseases. Furthermore, SAA has shown renal-protective effects in doxorubicin-induced nephropathy. However, there has been limited research regarding the effects of SAA and underlying mechanisms in chronic kidney disease (CKD). Here, we examined the effects and molecular mechanisms of SAA in an established animal model of 5/6 nephrectomized (5/6Nx) rats. The rats were injected with SAA (2.5, 5, and 10 mg/kg per day, intraperitoneally (ip)) for 28 days. SAA dose-dependently lowered the levels of urine protein, blood urea nitrogen, serum creatinine, plasma total cholesterol, and plasma triglycerides in 5/6Nx rats. Histological examination revealed that SAA dose-dependently attenuated renal pathological lesions, evidenced by reduced renal tubulointerstitial fibrosis by decreasing the expression levels of tumor growth factor-ß1 and α-smooth muscle actin in 5/6Nx rats. Moreover, SAA dose-dependently inhibited the activation of nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signaling pathways, subsequently attenuating the secretion of tumor necrosis factor-α and interleukin-1ß and inhibiting the expression of monocyte chemotactic protein-1, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in kidneys of 5/6Nx rats. The above results were consistent with those obtained in lipopolysaccharide-induced HK-2 cells in vitro (a recognized in vitro inflammatory model). In conclusion, our results demonstrated that SAA effectively attenuates kidney injury in 5/6Nx rats. The therapeutic effects of SAA on kidney injury can be attributed to its anti-inflammatory activities through inhibition of the activation of the NF-κB and p38 MAPK signaling pathways.

The Role of the Oxytocin/Arginine Vasopressin System in Animal Models of Autism Spectrum Disorder.

The nonapeptides oxytocin (OXT) and arginine vasopressin (AVP) are two key mediators in regulating various aspects of mammalian social behaviours. There are several lines of evidence that genetic variants of the OXT/AVP system exist in autism spectrum disorder (ASD) and that this system is dysfunctional at least in some ASD entities. These findings have stimulated the interest to perform studies testing the potential therapeutic application of OXT/AVP in ASD. In this respect animal models are critical for investigating the pathophysiology and for compound screening leading to new therapeutic approaches. Based on findings in animal models that show alterations of the OXT/AVP system, it has been hypothesised that single- or multiple-dose administration or the stimulation of endogenous release can improve several social deficits. Here we comprehensively review the role of the OXT/AVP system in social recognition, social interaction and maternal behaviour in the light of different ASD animal models and patient studies. We further discuss implications for OXT/AVP-related pharmacological interventions to alleviate social deficits in ASD in the future.

Epigenetically upregulated NSUN2 confers ferroptosis resistance in endometrial cancer via m5C modification of SLC7A11 mRNA.

Endometrial cancer (EC) is a prevalent gynecological malignancy worldwide, and 5-methylcytosine (m5C) modification of mRNA is a crucial epigenetic modification associated with the development and occurrence of several cancers. However, the precise function of m5C modification in EC remains elusive. This study aimed to investigate the expression and clinical significance of the primary m5C modification writer, NSUN2, in EC. Our findings indicated that NSUN2 exhibited a substantial up-regulation in EC as a result of an epigenetic augmentation in H3K4me3 levels within the promoter region, which was triggered by the down-regulation of KDM5A. Moreover, gain- and loss-of-function experiments revealed the role of NSUN2 in enhancing m5C modification of mRNA, thereby promoting EC cell proliferation. RNA bisulfite sequencing and transcriptomic sequencing were employed to elucidate the involvement of NSUN2 in the regulation of ferroptosis. Subsequent in vitro experiments confirmed that the knockdown of NSUN2 significantly up-regulated the levels of lipid peroxides and lipid ROS in EC cells, thereby augmenting the susceptibility of EC to ferroptosis. Mechanistically, NSUN2 stimulated the m5C modification of SLC7A11 mRNA, and the m5C reader YBX1 exhibited direct recognition and binding to the m5C sites on SLC7A11 mRNA via its internal cold shock domain (CSD), leading to an increase in SLC7A11 mRNA stability and elevated levels of SLC7A11. Additionally, rescue experiments showed that NSUN2 functioned as a suppressor of ferroptosis, which was dependent on SLC7A11. Overall, targeting the NSUN2/SLC7A11 axis inhibited tumor growth by increasing lipid peroxidation and ferroptosis of EC cells both in vitro and in vivo. Therefore, our study provides new insight into the role of NSUN2, suggesting that NSUN2 may serve as a prognostic biomarker and therapeutic target in patients with EC.

[Study on clinical efficacy of zhennaoning capsules in treatment of cerebral arteriosclerosis and analysis on its economic benefits].

To study clinical efficacy of Zhennaoning capsules in treating cases with cerebral arteriosclerosis, and analyze its economic benefits. Totally 254 cases with cerebral arteriosclerosis were randomly divided into two groups according to their doctor-consulting sequence: the test group (n = 128) that was administered with Zhennaoning capsules, and the control group (n = 126) that was administered with Yangxueqingnao granules. A double-blind parallel-controlled study was conducted for four weeks, in order to observe the clinical efficacy and adverse effects of the two groups, and evaluate their pharmacoeconomics. Additionally, the clinical efficacy and safety of Zhennaoning capsules in treating cerebral arteriosclerosis, as well as its pharmacoeconomics were also discussed. This study showed that Zhennaoning capsules had a better efficacy than its control drug Yangxueqingnao granules in relieving traditional Chinese medicinal syndromes (according to traditional Chinese medicinal syndrome coring, efficacy and cure rate), suggesting a statistical significance (P < 0.01). Despite statistical significance showed from the differences in the remaining indexes and the occurrence rate of adverse effects, the test group displayed a lower cost effectives than the control group (P < 0.01). Zhennaoning capsules have a better clinical efficacy in treating cases with cerebral arteriosclerosis than Yangxueqingnao granules, demonstrating safe clinical application and better economic advantages.

Combination of the Barthel Index at Discharge with GRACE Leads to Improved One-Year Mortality Prediction in Older Patients with Acute Myocardial Infarction.

Purpose: Many older patients with acute myocardial infarction (AMI) have impaired ability for activities of daily living (ADL). Impaired ADL leads to poor prognosis in elderly patients. The Global Registry of Acute Coronary Events (GRACE) score is widely used for risk stratification in AMI patients but does not consider physical performance, which is an important prognosis predictor for older adults. This study assessed whether the Barthel Index (BI) score combine the GRACE score would achieve improved one-year mortality prediction in older AMI patients. Patients and Methods: This single-center retrospective study included 688 AMI patients aged ≥65 years who were divided into an impaired ADL group (BI ≤60, n = 102) and a normal ADL group (BI >60, n = 586) based on BI scores at discharge. The participants were followed up for one year. Cox survival models were constructed for BI score, GRACE score, and BI score combined GRACE score for one-year mortality prediction. Results: Patients had a mean age of 76.29 ± 7.42 years, and 399 were men (58%). A lower BI score was associated with more years of hypertension and diabetes, less revascularization, longer hospital stays, and higher one-year mortality after discharge. Multivariable Cox regression analysis identified BI as a significant risk factor for one-year mortality in older AMI patients (HR 0.977, 95% CI, 0.963-0.992, P = 0.002). BI (0.774, 95% CI: 0.731-0.818) and GRACE (0.758, 95% CI: 0.704-0.812) scores had similar predictive power, but their combination outperformed either score alone (0.810, 95% CI: 0.770-0.851). Conclusion: BI at discharge is a significant risk factor for one-year mortality in older AMI patients, which can be better predicted by the combination of BI and GRACE scores.

Comprehensive Analyses and Experiments Confirmed IGFBP5 as a Prognostic Predictor Based on an Aging-genomic Landscape Analysis of Ovarian Cancer.

BACKGROUND: Ovarian cancer (OC) is one of the malignant diseases of the reproductive system in elderly women. Aging-related genes (ARGs) were involved in tumor malignancy and cellular senescence, but the specifics of these mechanisms in OC remain unknown. METHODS: ARGs expression and survival data of OC patients were collected from TCGA and CPTAC databases. Subtype classification was used to identify the roles of hub ARGs in OC progression, including function enrichment, immune infiltration, and drug sensitivity. LASSO regression was utilized to confirm the prognosis significance for these hub ARGs. MTT, EdU, Transwell, and wounding healing analysis confirmed the effect of IGFBP5 on the proliferation and migration ability of OC cells. RESULTS: ARGs were ectopically expressed in OC tissues compared to normal ovary tissues. Three molecular subtypes were divided by ARGs for OC patients. There were significant differences in ferroptosis, m6A methylation, prognosis, immune infiltration, angiogenesis, differentiation level, and drug sensitivity among the three groups. LASSO regression indicated that 4 signatures, FOXO4, IGFBP5, OGG1 and TYMS, had important prognosis significance. Moreover, IGFBP5 was significantly correlated with immune infiltration. The hub ARG, IGFBP5, expression was significantly decreased in OC patients compared to normal women. IGFBP5 could also reduce the migration and proliferation ability of OC cells compared to vector and NC groups. CONCLUSION: IGFBP5 was correlated with OC prognosis and associated with OC migration and proliferation. This gene may serve as potential prognostic biomarkers and therapeutic targets for OC patients.

Regulation of the activity and expression of aryl hydrocarbon receptor by ethanol in mouse hepatic stellate cells.

BACKGROUND: During the course of alcohol-induced liver damage, hepatic stellate cells are transformed into proliferative, fibrogenic, and contractile myofibroblasts. Aryl hydrocarbon receptor (AhR) is a transcription factor that controls the expression of genes involved in the metabolism of xenobiotics, inflammation, cell proliferation, and death. METHODS: Immortal mouse hepatic stellate cells (MHSCs) were isolated from transgenic mice that expressed a thermolabile SV40 tumor antigen. Quantitative real-time reverse transcription polymerase chain reaction assays, Western blot analysis, promoter activity assays, and chromatin immunoprecipitation analyses were performed for studying the effect of ethanol (EtOH) on AhR expression and transcriptional activity. RESULTS: Treatment of MHSCs with 50 to 200 mM EtOH for 6 hours induced AhR nuclear translocation, enhanced the promoter activity of cytochrome P450 (CYP) 1A1, increased the amount of AhR bound to the promoter of CYP1A1 and 1B1, and up-regulated the mRNA expression of these AhR target genes in a dose-dependent manner. In contrast, EtOH exposure down-regulated AhR mRNA and protein expression. Similarly, benzo(a)pyrene (BaP) at 10 nM reduced AhR and increased CYP1A1 and 1B1 mRNAs. Pretreatment of MHSCs with 50 mM EtOH for 7 days diminished the capacity of MHSCs to express CYP1A1 and 1B1 induced by a 200 mM EtOH challenge, or by 10 nM BaP. However, the up-regulatory effect of EtOH on solute carrier family 16, member 6 (SLC16a6) was unaffected by EtOH pretreatment. Similar to EtOH, dimethyl sulfoxide (DMSO) at concentrations of 50 to 100 mM down-regulated AhR and up-regulated CYP1A1 mRNA expression in a dose-dependent manner. CONCLUSIONS: These data, for the first time, demonstrate that EtOH activates MHSC AhR and down-regulates its expression. Chronic EtOH pretreatment lowers the availability of AhR, and specifically diminishes the inducibility of CYP genes. The effect on AhR appears to not be an EtOH-specific response, as DMSO alone (and possibly other organic solvents) was also able to activate AhR.

[NADPH oxidase inhibitor apocynin attenuates ischemia/reperfusion induced myocardial injury in rats].

OBJECTIVE: To explore the role of NADPH oxidase inhibitor apocynin on ischemia/reperfusion (I/R)-induced myocardial injury. METHODS: Male SD rat hearts were divided into the normal control group; sham group; I/R group (1 h ischemia followed by 3 h reperfusion); I/R + apocynin group (50 mg/kg, administrated at 30 min before reperfusion) and I/R + vehicle group (same volume vehicle administrated at 30 min before reperfusion). At the end of reperfusion, myocardial infarct size, apoptosis, plasma CK activity, myocardial NOX activity, myocardial caspase-3 expression and activity, myocardial mRNA and protein expressions of vascular peroxidase 1 (VPO1) and NOX2 were measured. RESULTS: Infarct size, ratio of cardiomyocyte apoptosis, mRNA and protein expression of VOP1 and NOX2, serum CK, myocardial NOX and caspase-3 activities in the I/R group were all significantly increased compared to those in the sham group (P < 0.01). Above parameters were similar between I/R + vehicle group and I/R group (all P > 0.05). Infarct size, ratio of cardiomyocyte apoptosis, myocardial mRNA and protein expression of VOP1 and NOX2, serum CK, myocardial NOX and caspase-3 activities were significantly lower in I/R + apocynin group compared to those in I/R group (all P < 0.01). CONCLUSIONS: NOX/VPO pathway plays an important role in mediating I/R-induced myocardial oxidative injury. NOX inhibition could reduce I/R-induced myocardial oxidative injury by attenuating myocardial apoptosis in this model.

[Advance of studies on interaction between active components of natural medicines and lysozymes].

Lysozyme (LYSO), as an alkalescent protein micromolecule in living organisms, exhibits important pharmacological actions such as antibiosis, anti-inflammatory, antivirus and enhancing immunity. LYSO can combine with many exogenous and endogenous substances and carry many drugs. This essay summarizes interaction between different kinds of active components of natural medicines and lysozymes, which is significant to comprehensively understand pharmacological mechanism of natural drugs and their transfer and metabolic process in organisms, optimize molecule structures of drugs and increase bioavailability and biological effects of natural drugs.

LncRNA UCA1 mediates Cetuximab resistance in Colorectal Cancer via the MiR-495 and HGF/c-MET Pathways.

Background: Cetuximab is one of the most widely used monoclonal antibodies to treat patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC). Unfortunately, cetuximab resistance often occurs during targeted therapy. However, the underlying epigenetic mechanisms remain unclear. Our previous study demonstrated that the exosomal transfer of urothelial carcinoma-associated 1 (UCA1) confers cetuximab resistance to CRC cells. The goal of this study was to elucidate the detailed role of UCA1 in cetuximab resistance in CRC and the underlying molecular mechanism. Methods: In vitro and in vivo functional studies were performed to assess the role of UCA1 in cetuximab resistance in CRC cell lines and xenograft models. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to examine UCA1 localization and expression. Bioinformatics analysis was performed to predict the potential mechanism of UCA1, which was further validated by the dual-luciferase reporter assay and the RNA immunoprecipitation (RIP) assay. Cells treated with indicators were subjected to Cell Counting Kit-8 (CCK-8) and western blotting to investigate the role of hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition (c-MET) signalling in UCA1-mediated cetuximab resistance. Results: We showed that UCA1 decreased CRC cell sensitivity to cetuximab by suppressing apoptosis. Mechanistic studies revealed that UCA1 promoted cetuximab resistance by competitively binding miR-495 to facilitate HGF and c-MET expression in CRC cells. Moreover, HGF was shown to attenuate the cetuximab-induced inhibition of cell proliferation by activating the HGF/c-MET pathway in CRC cells. Conclusion: We provide the first evidence of a UCA1-miR-495-HGF/c-MET regulatory network involved in cetuximab resistance in CRC. Therefore, UCA1 has potential as a predictor and therapeutic target for cetuximab resistance.

Antiproliferative and apoptotic sesquiterpene lactones from Carpesium faberi.

Four new (1-4) and 13 known (5-17) sesquiterpene lactones along with two known diterpenes (18, 19) were isolated from the whole plant of Carpesium faberi. The new structures were elucidated by means of spectroscopic techniques and some chemical transformations to be pseudoguaian-1α(H)-8α,12-olide-4ß-O-ß-d-glucopyranoside (1), 4ß,10α-dihydroxy-5α(H)-1,11(13)-guaidien-8α,12-olide (2), 4ß,10ß-dihydroxy-5α(H)-1, 11(13)-guaidien-8ß,12-olide (3), and (4S)-acetyloxyl-11(13)-carabren-8ß,12-olide (4). All isolates were tested against MCF-7 human breast cancer cells using the MTT assay. Among them, the sesquiterpene lactones (except tomentosin 17) possessing an α-methylene-γ-lactone moiety were found to have in vitro antiproliferative activities, with IC(50) values of 3.0-38.8µg/mL. The effects of four selected sesquiterpene lactones (guaianolide 2, carabranolide 4, pseudoguaianolide 9, eudesmanolide 13) on the cell cycle were examined using flow cytometry (FCM).

[Clinical study of total glucosides of paeony in patients with systemic lupus erythematosus].

OBJECTIVE: To study the therapeutic efficacy and adverse reaction of total glucosides of paeony (TGP, extracted from Paeonia lactiflora Pall.) in patients with systemic lupus erythematosus (SLE). METHODS: Clinical data of patients with SLE were analyzed. Those who orally took TGP continuously for five years or more were taken as TGP1 group (29 cases). Those who orally took TGP continuously or intermittently for more than one year but less than five years were taken as TGP2 group (47 cases). Twenty patients matched with the TGP1 group and the TGP2 group in age, affected duration, urine protein, and SLE disease activity index (SLEDAI) were selected as the control group. The average daily dose of prednisone, total cyclophosphamide (CTX) dose, urine protein, SLEDAI score, recurrent case, and episodes of infection were compared among the three groups after five-year treatment. RESULTS: The average daily dose of prednisone, total CTX dose, and SLEDAI score were obviously lower in the TGP1 group than in the control group (P<0.01). The average daily dose of prednisone, total CTX dose, and SLEDAI score were obviously lower in the TGP1 group than in the TGP2 group, Significant difference was shown (P <0. 05). The average daily dose of prednisone and total CTX dose were lower in the TGP2 group than in the control group (P<0.05, P<0.01). There was no statistical difference in the urine protein among the three groups. As for the recurrence, one case occurred in the TGP1 group, nine in the TGP2 group, and seven in the control group. As for episodes of infection, there were three cases in the TGP1 group, seventeen in the TGP2 group, and eighteen in the control group during the five years. No adverse reaction correlated to TGP was found in the three groups. CONCLUSIONS: TGP had definite therapeutic efficacy in treatment of patients with SLE. It could reduce the average daily dose of prednisone and the total CTX dose, lower the recurrent cases and episodes of infection, especially for the medication of more than five years.

Genomic analysis of host gene responses to cerebral Plasmodium falciparum malaria.

INTRODUCTION: A vaccine for malaria is urgently required but no vaccine has yet shown satisfactory protective efficacy especially for Plasmodium falciparum. P. falciparum infection can progress to cerebral malaria (CM), a neurological syndrome with exceedingly high mortality. Designing effective P. falciparum vaccines require more understanding of the protective immune response while the host immune response to CM and the mechanisms are still elusive. Here, we aim to identify host gene responses to CM and host gene networks associated with CM pathogenesis. METHODS: An innovative genomic analysis strategy, the weighted gene coexpression network analysis (WGCNA) combined with differential gene expression analysis, was used in this study. Data for analysis contain 93 whole blood samples, derived from two previous public transcriptome datasets. RESULTS: This approach led to the identification of numerous differentially expressed human transcripts and dozens of coexpression gene modules. We further identified nine key genes, including MBP, SAMSN1, PSMF1, SLC39A8, EIF3B, SMPDL3A, FABP5, SPSB3, and SHARPIN, of which the last four genes were first identified to be related to CM in the present study. CONCLUSION: The results provided a comprehensive characterization of host gene expression profiles in CM and offered some new insight into malaria vaccine design. These identified key genes could be potential targets or immune modulators for novel therapeutic interventions of CM.

Microglial NLRP3 inflammasome activation-mediated inflammation promotes prolactinoma development.

Prolactinomas have harmful effects on human health, and the pathogenesis is still unknown. Furthermore, 25% of prolactinoma patients do not respond to the therapy of dopamine receptor agonist in the clinic. Thus, it is important to reveal the pathogenesis and develop new therapeutic methods for prolactinomas. Herein, two animal models of prolactinomas, namely oestrogen-treated rats and transgenic D2 dopamine receptor-deficient mice, were used. PET/CT imaging detection showed that translocator protein-mediated microglia activation and inflammation significantly increased in the pituitary glands of prolactinomas rats. Messenger RNA microarrays were used to analyze and compare the differential gene and signal pathways of the pituitary glands between control and prolactinomas rats. Statistical results pertaining to gene enrichment showed that the innate immune response genes were upregulated in the pituitary glands of prolactinoma rats. This suggested that the innate immune response was activated. We analyzed the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome that is one of the most important members of the innate immune system in mammals and found that the expressions of NLRP3, Caspase-1, apoptosis-associated speck-like, interleukin 1B (IL1B) and IL18 proteins of pituitary glands in prolactinomas rats were increased considerably compared with those in control rats. This suggested the activation of the NLRP3 inflammasome during the emergence and evolution of prolactinomas. Immunohistochemistry results also confirmed that the NLRP3 expression was elevated in human prolactinoma tissues, and the microglia marker-ionised calcium binding adaptor molecule-1 was co-located with the NLRP3 protein in prolactinomas by immunofluorescence assay. Finally, compared with the WT mice, NLRP3-/- mice had smaller pituitary glands (weight/body weight) and diminished prolactin (PRL) expressions and secretions. These findings were associated with a reduction in the caspase-1 activation and maturation of IL1B. Furthermore, MCC950 decreased the PRL expression and secretion following the inhibition of NLRP3 inflammasome activation in GH3 cells stimulated with lipopolysaccharide and nigericin. And MCC950 inhibited the pituitary tumor overgrowth and PRL expression and secretion in prolactinoma rats. These data confirm that the microglial NLRP3 inflammasome activation upregulates the inflammatory cytokines IL1/IL18 in the pituitary glands and induces prolactinomas. Our findings showed that microglial NLRP3 inflammasome activation-mediated IL1B-related inflammation promoted the development of prolactinomas and identified the inflammasome as a new therapeutic target for prolactinomas.

Postnatal AVP treatments prevent social deficit in adolescence of valproic acid-induced rat autism model.

Studies have shown that arginine-vasopressin (AVP) is an important neuropeptide regulating social behaviors. The present work aimed to detect changes in the AVP numbers and level in a valproic acid (VPA)-induced rat model of autism and the underlying mechanism of its pathogenesis. Our results indicated that infants exposed to VPA showed obviously impaired communication and repetitive behaviors with reduced number of AVP-ir cells in paraventricular nucleus (PVN) and cerebrospinal fluid (CSF). The postnatal subcutaneous injection of AVP can alleviate social preference deficits and stereotyped behaviors, accompanied with the increase of the AVP concentrations in the CSF. We concluded that AVP system was involved in etiology of VPA-induced autism-like symptoms and postnatal AVP treatment rescued the behavioral deficits,which could be a promising treatment for autism.

Clinicopathologic characteristics and prognosis of mucinous gastric carcinoma.

BACKGROUND AND OBJECTIVES: Reports of clinicopathological features and prognosis in patients with mucinous gastric carcinoma (MGC) are conflicting. The aim was to describe the clinicopathological features and prognosis of patients with MGC in comparison with nonmucinous gastric carcinoma (NMGC). METHODS: We reviewed the records of 1,278 consecutive patients diagnosed with gastric carcinoma who were resected surgically from 1993 to 2003. Among them, 48 patients (3.8%) with MGC were compared to 1,230 patients with NMGC. RESULTS: There were significant differences in tumor location, stage of disease, lymphatic invasion, and vascular invasion between the patients with MGC and NMGC. The overall 5-year survival of patients with MGC was 27.2% as compared with 42.8% for patients with NMGC (P = 0.031). For the patients with the same stage, there was no significant difference between MGC and NMGC. With respect to patients with MGC, multivariate analysis showed that lymph node metastasis and curative resection were significant factors affecting survival. CONCLUSIONS: MGC is rare and detected mostly in an advanced stage. Mucinous histology type itself is not an independent prognostic factor.

Antiproliferative and apoptotic activities of linear furocoumarins from Notopterygium incisum on cancer cell lines.

Bioassay-guided fractionation of the antiproliferative chloroform extract of the traditional Chinese medicine Qiang-Huo (Notopterygium incisum) led to the isolation of nine linear furocoumarins (1- 9). All the isolates were tested against two human cancer cell lines (HepG-2 and MCF-7) and a rat cancer cell line (C6) using the MTT assay method. Among them, notopol (1), notopterol (2), 5-[(2 E,5 Z)-7-hydroxy-3,7-dimethyl-2,5-octadienoxy]psoralene (3), and 5-[(2,5)-epoxy-3-hydroxy-3,7-dimethyl-6-octenoxy]psoralene (4) showed significant antiproliferative activity against the HepG-2 and C6 cancer cell lines, with IC(50) values of 7.7-24.8 microg/mL (5-FU: ca. 5 microg/mL). Compounds 1- 3 also showed moderate cytotoxicity against the MCF-7 cancer cell line, with IC(50) values of 39.4-61.3 microg/mL (5-FU: 17.3 microg/mL). The cell cycle-specific inhibition and apoptosis induced by compounds 1 and 2 were determined using flow cytometry. The structure-activity relationship (SAR) is briefly discussed herein. It was found that the presence of a free hydroxy at the lipophilic side chain linked to C-5 of the linear furocoumarins was essential for their in vitro antiproliferative activity.