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In the peripheral nervous system, the activation of Sirtuin 1 can improve insulin resistance; however, the role played by Sirtuin 1 in the central nervous system remains unknown. In this study, rat models of diabetes mellitus were generated by a single injection of streptozotocin. At 8 weeks after streptozotocin injection, the Morris water maze test and western blot assays confirmed that the diabetic model rats had learning and memory deficits, insulin resistance, and Sirtuin 1 expression could be detected in the hippocampus. Insulin and the insulin receptor inhibitor S961 were intranasally administered to investigate the regulatory effects of insulin signaling on Sirtuin 1. The results showed that insulin administration improved the impaired cognitive function of diabetic model rats and increased the expression levels of phosphorylated insulin receptor, phosphorylated insulin receptor substrate 1, and Sirtuin 1 in the hippocampus. Conversely, S961 administration resulted in more severe cognitive dysfunction and reduced the expression levels of phosphorylated insulin receptor, phosphorylated insulin receptor substrate 1, and Sirtuin 1. The Sirtuin 1 activator SRT2104 and the inhibitor Sirtinol were injected into the lateral ventricle, which revealed that the activation of Sirtuin 1 increased the expression levels of target of rapamycin complex 1, phosphorylated cAMP-response element-binding protein, and brain-derived neurotrophic factor. Hippocampal dendritic length and spine density also increased in response to Sirtuin 1 activation. In contrast, Sirtinol decreased the expression levels of target of rapamycin complex 1, phosphorylated cAMP-response element-binding protein, and brain-derived neurotrophic factor and damaged the dendritic structure. These findings suggest that the Sirtuin 1 signaling pathway plays an important role in the development of insulin resistance-related cognitive deficits in diabetic rats. This study was approved by the Animal Ethics Welfare Committee of the First Affiliated Hospital of Hunan University of Chinese Medicine (approval No. ZYFY201811207) in November 2018.

Aging-related health and functioning are difficult to quantify in humans and nonhuman primates. We constructed an observer-based scale for daily application in assessing the aging-related health and functioning of rhesus macaques. Ten items referring to an aging appearance, musculoskeletal aging and aging-related eating behavior were selected through a panel consensus. The Aging-related Health and Functioning Scale (AHFS) was constructed based on these scored items form 57 healthy rhesus macaques. High reliability of the AHFS was shown based on Cronbach’s alpha coefficient (0.877). The structure of the AHFS was validated by three exploratory factors. The largest factor, whose four components were dietary uptake, iliac muscle mass, hair condition and fragility, and sex, explained 50.5% of the variation in aging-related health and functioning scores. The second factor, involving age, tooth loss and tooth wear, explained 15.5% of the variation. The lowest-ranking factor comprised only facial redness and accounted for 10% of the variation. A hierarchical cluster analysis validated the good applicability of the scale in distinct samples. From these scale-scored results, complicated aging phenomena observed in humans, including the sex-survival paradox and the calorie-related health-survival paradox, were both demonstrated in rhesus macaques. Therefore, the AHFS provides a valuable approach for aging-related research.

Objectives. Diabetes mellitus is frequently accompanied by depression (diabetes−depression, DD), and DD patients are at higher risk of diabetes-related disability and mortality than diabetes patients without depression. Hippocampal degeneration is a major pathological feature of DD. Here, we investigated the contribution of the Glu−mGluR2/3−ERK signaling pathway to apoptosis of hippocampal neurons in DD model rats. Methods. The DD model was established by high-fat diet (HFD) feeding and streptozotocin (STZ) injection followed by chronic unpredictable mild stress (CUMS). Other groups were subjected to HFD + STZ only (diabetes alone) or CUMS only (depression alone). Deficits in hippocampus-dependent memory were assessed in the Morris water maze (MWM), motor activity in the open field test (OFT), and depression-like behavior in the forced swim test (FST). Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) was used to estimate the rate of hippocampal neuron apoptosis. Hippocampal glutamate (Glu) content was measured by high performance liquid chromatography. Hippocampal expression levels of mGluR2/3, ERK, and the apoptosis effector caspase-3 were estimated by immunohistochemistry and Western blotting. Results. DD model rats demonstrated more severe depression-like behavior in the FST, greater spatial learning and memory deficits in the MWM, and reduced horizontal and vertical activity in the OFT compared to control, depression alone, and diabetes alone groups. All of these abnormalities were reversed by treatment with the mGluR2/3 antagonist LY341495. The DD group also exhibited greater numbers of TUNEL-positive hippocampal neurons than all other groups, and this increased apoptosis rate was reversed by LY341495. In addition, hippocampal expression levels of caspase-3 and mGluR2/3 were significantly higher, ERK expression was lower, and Glu was elevated in the DD group. The mGluR2//3 antagonist significantly altered all these features of DD. Conclusions. Comorbid diabetes and depression are associated with enhanced hippocampal neuronal apoptosis and concomitantly greater hippocampal dysfunction. These pathogenic effects are regulated by the Glu−mGluR2/3−ERK signaling pathway.

BACKGROUND Cardiogenic shock (CS) secondary to acute myocardial infarction (AMI) complicates management of the condition, and often leads to poor prognosis. Prompt and accurate monitoring of cardiovascular and accompanying hemodynamic changes is crucial in achieving adequate management of the condition. Advances in technology has availed procedures such as pulse index continuous cardiac output (PiCCO), which can offer precise monitoring of cardiovascular functions and hemodynamic parameters. In this study, PiCCO is evaluated for its potential utility in improving management and clinical outcomes among elderly patients with AMI complicated by CS. AIM To assess whether use of the PiCCO system can improve clinical outcomes in elderly patients with AMI complicated by CS. METHODS Patients from emergency intensive care units (EICU) or coronary care units (CCU) were randomized to receive PiCCO monitoring or not. The APACHE II score, SOFA score, hs-TnI, NT-proBNP, PaO2/FiO2 ratio and lactate levels on day 1, 3 and 7 after treatment were compared. The infusion and urine volume at 0-24 h, 24-48 h and 48-72 h were recorded, as were the cardiac index (CI), extravascular lung water index (EVLWI), intrathoracic blood volume index (ITBVI) and global end diastolic volume index (GEDVI) at similar time intervals. RESULTS Sixty patients with AMI complicated by CS were included in the study. The PiCCO group had a significantly lower APACHE II score, SOFA score, hs-TnI and NT-proBNP levels on day 1, 3 and 7 after treatment. The infusion and urine volume during 0-24 h in the PiCCO group were significantly greater, and this group also showed significantly higher ADL scores. Furthermore, the PiCCO group spent lesser days on vasoactive agents, mechanical ventilation, and had a reduced length of stay in EICU/CCU. Additionally, the CI was significantly higher at 48 h and 72 h in the PiCCO group compared with that at 24 h, and the EVLWI, ITBVI and GEDVI were significantly decreased at 48 h and 72 h. CONCLUSION Applying the PiCCO system could improve the clinical outcomes of elderly patients with AMI complicated by CS.

The characteristic accumulation of late-stage differentiated CD8+ T cells is enhanced by lifelong latent cytomegalovirus (CMV) persistence, which makes it challenging to screen for subclinical biomarkers of immune aging in the elderly. We systematically identified predominantly preformed, long, noncoding RNAs (lncRNAs) as integrative biomarkers of CD8+ T cell aging in 14 elderly CMV carriers over 80 years of age. After sorting the CD28nullCD8+ T cell subset and its CD28bearingCD8+ counterpart in five nonagenarians, we profiled the differential expression of lncRNAs and genes in CD28nullCD8+ T cells via array detection. We focused on 11 differentially expressed antisense lncRNAs and cross-referenced them with previously identified age-accumulated lncRNAs to create a set of candidates in CD28nullCD8+T cells. We performed intracellular validation on the age-accumulated candidate lncRNAs paired with their antisense target genes using quantitative polymerase chain reaction (qPCR). Simultaneously, we sorted the CMVpp65-specific CD8+ T cell subset and its counterpart from participant cells with the HLA-A-*0201 genotype. The validated age-accumulated lncRNAs in CD28nullCD8+ T cells were intracellularly cross-validated in CMVpp65CD8+ T cells. Finally, we identified the immunity-related gene(s) that acted as potential target(s) to the cross-validated age-accumulated lncRNA(s), using bioinformatics techniques. The potential regulation of the final identified lncRNA-gene pair(s) was simultaneously predicted in two pathway-integrated networks. We concluded that expression of an age-accumulated lncRNA (NRON) was decreased, whereas that of its immunity-related target gene (NFAT) was increased, in both CD28nullCD8+ T cells and CMVpp65CD8+ T cells of elderly individuals with persistent CMV infection. The identification of NRON as a potential biomarker suggests that NRON contributes to CMV-enhanced CD28nullCD8+ T cell aging by modulating phosphorylation and/or IL-4-dependent NFAT signaling.

Background. Zuogui Jiangtang Jieyu decoction (ZJJ) is mainly used for the treatment of diabetes-related depression in current clinical applications and research. This study aims to investigate whether the brain IR/IRS-1 signaling pathway is involved in the therapeutic effect of ZJJ on depression-like behavior in diabetic rats. Methods. Sprague–Dawley rats were fed with high-fat diet and subjected to streptozotocin injection to establish the diabetes animal model. After treatment with different doses of ZJJ (20.530 g/kg or 10.265 g/kg) for 4 weeks, the blood glucose level and peripheral insulin resistance were measured. The forced-swimming test (FST) and Morris water maze test (MWMT) were applied for the mood and cognitive function assessment. Then, the Western blot method was used to analyze the protein levels of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylonositol-3-kinase (PI3K), and protein kinase B (PKB, also as known as AKT) in the hippocampus of diabetic rats. Meanwhile, the immunofluorescence method was performed to analyze the above proteins’ expression in the neuron and astrocyte. At last, the levels of glycogen, lactate, and ATP were tested by the ELISA method. Additionally, the insulin-sensitive glucose transporter 4 (GLUT4) and the lactate transporter monocarboxylate transporter 4 (MCT4) were analyzed by the Western blot method. Results. ZJJ administration significantly decreased the level of blood glucose and improved the peripheral insulin resistance in diabetic rats. Besides, ZJJ attenuated the depression-like behavior and the cognitive dysfunction in rats with diabetes. Furthermore, we found the upregulation of protein expression of phospho-IR, phospho-IRS-1, phospho-PI3K, and phospho-AKT in the hippocampus of diabetic rats after being treated with ZJJ. Moreover, the above proteins are increased not only in the neuron but also in the astrocyte after ZJJ administration. In addition, ZJJ increased the content of ATP, glycogen, and lactate, as well as the expression of GLUT4 and MCT4 in the hippocampus of diabetic rats. Conclusions. These findings suggest that ZJJ improves the depression-like behavior of diabetic rats by activating the IR/IRS-1 signaling pathway in both hippocampal neuron and astrocyte. And the brain IR/IRS-1 signaling pathway plays an important role in astrocyte-neuron metabolic coupling, providing a potential mechanism by which the IR/IRS-1 signaling pathway may contribute to the treatment of ZJJ on diabetes-related depression.

Background Breast cancer is one of the most common cancer with high risk in females all over the world. It is usually complicated with depression, which can further accelerate the development and progression of breast tumors. We aim to identify a new drug and identify its functional mechanism in the regulation of hippocampal microglia (MG) in breast cancer complicated with depression (BCCD). Methods The activation model of MG was established by treatments from corticosterone (CORT) or lipopolysaccharides (LPS). The inhibitory effects of resatorvid on MG were investigated by CCK-8, ROS, immunofluorescence, TUNEL, scratch test, ELISA, RT-qPCR and Western blot. BCCD animal model was established using 4T1 inflammatory breast cancer cells and CORT treatment in vitro. Open field experiment (OFE), tail suspension test (TST), ELISA, RT-qPCR and Western blot experiments were utilized to examine the effects of resatorvid on the animal model in vivo. Results The cell viability and migration ability of the BCCD model group were suppressed. The expressions of inflammatory factors, ROS, and the apoptotic rate of the BCCD model group were up-regulated, in contrast to the control group. The expressions related to the TLR4/NF-κB/NLRP3 signaling in the BCCD model group were also elevated. Resatorvid reversed the above changes, which showed good therapeutic effects in depression-related behavioral changes, tumor treatment, and blood-brain barrier function. Conclusion In summary, resatorvid inhibited the activation of hippocampal MG in BCCD by regulating TLR4/NF-κB/NLRP3 signaling pathway.

Clinical studies have shown that diabetes can present with underlying depression, and a combination of the two can lead to emotional, memory and cognitive disorders, closely associated with hippocampal neuroinflammation. However, the mechanism underlying the development of hippocampal neuroinflammation under the above condition remains elusive. The aims of this study were to explore the pathogenesis of diabetes combined with depression, and the effect of dexamethasone (Dex), a glucocorticoid receptor (GR) agonist, on hippocampal neuroinflammation in diabetic rats with chronic unpredictable mild stress (CUMS). Therefore, rats were intragastrically fed on a high-fat diet (10% cholesterol 10 ml/kg) for 14 days and thereafter injected with 38 mg/kg of streptozotocin on the 15th day to induce diabetes. Dex treatment of the diabetic and CUMS rats ameliorated the depression-associated behavior in the respective rats. Apart from enhanced depressive behavior, diabetes-depressed condition also up-regulated the expression of hippocampus microglia chemokine Ⅰ receptor (CX3CR1) and secretion of several pro-inflammatory factors, in particular, interleukin 1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor - α (TNF-α). Hematoxylin-eosin staining revealed inflammatory damages in the hippocampus. Western blot analysis further revealed repression of GR proteins converse to the nuclear factor kappa-B (NF-κB) proteins, which were up-regulated. Intriguingly, Dex reversed the above events by inhibiting inflammatory reactions in the hippocampus. Consequently, played an antidepressant effect in diabetic and CUMS model rats. Overall, findings of this research suggest that the physiopathology of diabetes with stress cormobity are mediated by inflammatory reactions in the hippocampus. In particular, the responses are associated with regulation of GR/NF-κB signaling pathway.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. In coping with it, histopathology image analysis (HIA) provides key information for clinical diagnosis of CRC. Nowadays, the deep learning methods are widely used in improving cancer classification and localization of tumor-regions in HIA. However, these efforts are both time-consuming and labor-intensive due to the manual annotation of tumor-regions in the whole slide images (WSIs). Furthermore, classical deep learning methods to analyze thousands of patches extracted from WSIs may cause loss of integrated information of image. Herein, a novel method was developed, which used only global labels to achieve WSI classification and localization of carcinoma by combining features from different magnifications of WSIs. The model was trained and tested using 1346 colorectal cancer WSIs from the Cancer Genome Atlas (TCGA). Our method classified colorectal cancer with an accuracy of 94.6 %, which slightly outperforms most of the existing methods. Its cancerous-location probability maps were in good agreement with annotations from three individual expert pathologists. Independent tests on 50 newly-collected colorectal cancer WSIs from hospitals produced 92.0 % accuracy and cancerous-location probability maps were in good agreement with the three pathologists. The results thereby demonstrated that the method sufficiently achieved WSI classification and localization utilizing only global labels. This weakly supervised deep learning method is effective in time and cost, as it delivered a better performance in comparison with the state-of-the-art methods.

Accumulating studies have shown that high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) may improve cognitive dysfunction of the patients with schizophrenia (SCZ), but with inconsistent results. The present study aims to assess the efficacy of different frequencies of neuronavigated rTMS in ameliorating cognitive impairments and alleviating the psychotic symptoms. A total of 120 patients were randomly assigned to 3 groups: 20 Hz rTMS (n = 40), 10 Hz rTMS (n = 40), or sham stimulation (n = 40) for 8 weeks, and then followed up at week 32. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was performed to assess the cognitive functions of the patients at baseline, at the end of week 8, and week 32 follow-up. Psychotic symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS) at baseline and at the end of week 2, week 4, week 6, week 8, and week 32 follow-up. Our results demonstrated that 20 Hz rTMS treatment produced an effective therapeutic benefit on immediate memory of patients with chronic SCZ at week 8, but not in the 10 Hz group. Interestingly, both 10 Hz and 20 Hz rTMS treatments produced delayed effects on cognitive functions at the 6-month follow-up. Moreover, in both 10 Hz rTMS and 20 Hz rTMS, the improvements in RBANS total score were positively correlated with the reduction of PANSS positive subscore at the 6-month follow-up. Stepwise regression analysis identified that the visuospatial/constructional index, immediate memory index, and prolactin at baseline were predictors for the improvement of cognitive impairments in the patients. Our results suggest that add-on HF rTMS could be an effective treatment for cognitive impairments in patients with chronic SCZ, with a delayed effect. Trial registration: clinicaltrials.gov identifier—NCT03774927.

Because of the absence of data on the direct association between vitamin D and depression in patients with diabetes, we examined the association between vitamin D state (assessed by 25-hydroxyvitamin D [25(OH)D]) and the prevalence of depression in adult patients with type 2 diabetes mellitus(T2DM).Cross-sectional data were obtained from 2786 patients with T2DM recruited from a Chinese diabetes registry. Patients' records were reviewed to obtain data pertaining to age, sex, Body Mass Index (BMI), marital status, level of education, smoking status, duration of diabetes mellitus, use of insulin, and presence of additional illnesses. A multiple logistic regression analysis adjusted for potential confounders was used to assess independent associations between serum levels of 25 (OH)D and depression (defined by the Patient Health Questionnaire-9).Using the PHQ-9 cutoff value of ≥10, 5.71% (159/2786; 95% CI: 4.85-6.57%) were considered to have depression. The serum 25(OH)D levels were significantly lower in diabetic patients with depression than those patients without depression [10.2(IQR, 7.6-15.2)ng/ml vs. 14.6(IQR, 10.7-19.8)ng/ml, respectively; P0.0001]. Multivariate logistic regression analysis considering traditional risk factors and other biomarkers showed an inverse relationship between serum 25 (OH)D levels and depression when serum 25 (OH)D were used as a continuous variable (OR, 0.84; 95% CI, 0.77-0.90; P0.001). Compared with the first quartile of serum 25 (OH)D levels, the second quartile OR for depression was 0.83 (95% CI, 0.75-0.92, P=0.012). For the third and fourth quartiles, it was 0.40 (95% CI, 0.33-0.52, P0.001) and 0.15 (95% CI, 0.08-0.22; P0.001), respectively.We observed a significant negative association between serum levels of 25 (OH)D and depression in Chinese patients with T2DM.

Type 2 diabetes (T2DM) has been associated with learning and memory impairment; however, drugs for diabetes could not prevent the development of cognitive decline in T2DM patients. In the present study, compounds derived from thiazolidinediones (TZD), a PPAR-γ agonist, were synthesized by conjuncting the alkyl-substituted benzimidazole group to TZD group (ATZDs). Based on the in vitro evaluation, the neuroprotection of ATZD2 was further investigated using a streptozotocin-induced T2DM rat model. Pharmacokinetic study showed that ATZD2 could pass the blood-brain barrier (BBB) while the rosiglitazone (RSG, the precursor compound of ATZD2) not. Administration of ATZD2 significantly promoted the survival rate and attenuated fasting blood glucose (FBG) levels as compared to RSG treatment in T2DM rats. Furthermore, ATZD2 treatment ameliorated the impairment of learning and memory by Morris water maze test. The beneficial effects of ATZD2 were associated with the down-regulation of hypoxia induced factor-1α, aldose reductase, and Bax expression which are related to T2DM pathology. ATZD2 treatment also attenuated the expression of inflammatory cytokines and restored the balance of redox in the diabetic hippocampus. These effects were more potent as compared with that of RSG at the same dose. The data indicate that ATZD2 may be a potent agent for the treatment of cognitive dysfunction in T2DM.

Gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) is known to overexpress somatostatin receptors (SSTRs), most commonly SSTR2 and SSTR5. The expression of SSTRs on tumor cells forms the basis for somatostatin analog treatment of patients with NEN. The present study detected the expression of SSTR2 and SSTR5 in GEP-NEN and investigated the efficacy and safety of octreotide long-acting release (LAR) in the treatment of advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) in China. The present study reported that functionality of the pancreas, G1 and G2 grading, NET classification and Tumor-Node-Metastasis stages I and II were associated with higher SSTR2 positive expression. Similarly, SSTR5 was increased in pancreatic and well-differentiated tumors. SSTR2 and SSTR5 positive expression predicted improved survival in GEP-NEN patients. The median overall survival of patients treated with octreotide LAR was not reached. The median time to progression was 20.2 months, with the objective response rate being 5.6% and the stable disease rate being 79.6%. A total of 25.9% of the patients experienced adverse drug reactions. In conclusion, the present study demonstrated that SSTR2 and SSTR5 are heterogeneously expressed in GEP-NEN. Both markers may serve as potential prognostic factors. Octreotide LAR is effective and safe in the treatment of Chinese patients with advanced GEP-NET.

Adiponectin (ADPN) and fibroblast growth factor 9 (FGF9) has been reported as anti-depressive and pro-depressive factor, respectively. However, it is unknown whether there is directly interaction between ADPN and FGF9 in depression. The present study aims to investigate the correlation between ADPN and FGF9 in depression disorder. Firstly, the decreased level of ADPN and the increased level of FGF9 in plasma of depressive patients compared with non-depressive subjects were observed. Furthermore, these is a significant negative correlation between the ratio of ADPN to FGF9 and the total score of Hamilton Depression Scale in total investigated subjects. The similar changes of ADPN and FGF9 were also observed in elder adiponectin gene knockout (Adipo-/-) mice with an increasing trend to depressive-like behaviors. Secondly, the decreasing level of ADPN and increasing level of FGF9 in plasma and hippocampus tissues were observed in chronic unpredictable mild stress (CUMS)-induced depression in ICR mice with significant depressive-like behaviors and hippocampus damage, which attenuated by injection of recombinant ADPN or FGF9 antibody into lateral ventricle. In Adipo-/- mice, injection of FGF9 antibody into lateral ventricle also attenuated CUMS-induced depressivelike behaviors. The protein expression of FGF receptor 3 (FGFR3), the main receptor of FGF9, was significantly down-regulated in hippocampus tissues of CUMS-treated mice, which could be attenuated by treatment with either recombinant ADPN or anti-FGF9. In summary, the present results suggest that ADPN maybe a key negative regulator of FGF9/FGFR3 in depressive disorder and the dysfunction of ADPN-FGF9 pathway plays a key role in stress-induced depression.

Cognitive impairment is a central aspect of schizophrenia (SCZ) that occurs at the onset of the disease and is related to poor social function and outcome in patients with SCZ. Recent literatures have revealed repetitive transcranial magnetic stimulation (rTMS) to be one of the efficient medical interventions for cognitive impairments. However, no study has been conducted to investigate the treatment effectiveness of 20 Hz rTMS with neuronavigation system administered to the left dorsolateral prefrontal cortex (DLPFC) in patients with schizophrenia. In this randomized, double-blind and sham-controlled study, 56 patients were enrolled in 20 Hz rTMS (n = 28) or sham stimulation (n = 28) over left DLPFC for 8 weeks. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was performed to measure the cognitive function at baseline and after 8 weeks of rTMS treatment. The positive and negative syndrome scales (PANSS) was performed to assess the clinical symptoms at baseline, after 2-week treatment, 4-week treatment, 6-week treatment, and 8-week treatment. Totally, 15 subjects (seven in active group and eight in sham group) dropped out during the trial and the main findings were from completed 41 patients. At 2 weeks, 4 weeks, and 6 weeks, there were no significant differences in PANSS total score and subscores between the sham and treatment groups. At 8 weeks, the 20 Hz rTMS significantly increased the immediate memory score compared with the sham. Furthermore, the improvement in the immediate memory score was correlated with the decrease in the excitement factor score of the patients with SCZ. Our results suggest that 20 Hz rTMS appears to be an effective treatment for improving the cognitive performance and reducing the clinical symptoms of patients with SCZ.

Our previous studies have shown that glutamate and hippocampal neuron apoptosis are key signals and direct factors associated with diabetes-related depression, and structural and functional damage to the hippocampal neurovascular unit has been associated with diabetes-related depression. However, the underlying mechanism remains unclear. We hypothesized that diabetes-related depression might be associated with the glutamate (Glu)/metabotropic glutamate receptor2/3 (mGluR2/3)/phosphoinositide 3-kinase (PI3K) pathway, activated by glucocorticoid receptors in the hippocampal neurovascular unit. To test this hypothesis, rat hippocampal neurovascular unit models, containing hippocampal neurons, astrocytes, and brain microvascular endothelial cells, were treated with 150 mM glucose and 200 µM corticosterone, to induce diabetes-related depression. Our results showed that under conditions of diabetes complicated by depression, hippocampal neurovascular units were damaged, leading to decreased barrier function; elevated Glu levels; upregulated glucocorticoid receptor, vesicular glutamate transporter 3 (VGLUT-3), and metabotropic glutamate receptor 2/3 (mGluR2/3) expression; downregulated excitatory amino acid transporter 1 (EAAT-1) expression; and alteration of the balance of key proteins associated with the extracellular signal-regulated kinase (ERK)/glial cell-derived neurotrophic factor (GDNF)/PI3K signaling pathway. Moreover, the viability of neurons was dramatically reduced in the model of diabetes-related depression, and neuronal apoptosis, and caspase-3 and caspase-9 expression levels, were increased. Our results suggest that the Glu/mGluR2/3/PI3K pathway, induced by glucocorticoid receptor activation in the hippocampal neurovascular unit, may be associated with diabetes-related depression. This study was approved by the Laboratory Animal Ethics Committee of The First Hospital of Hunan University of Chinese Medicine, China (approval No. HN-ZYFY-2019-11-12) on November 12, 2019.

Aim To assess the outcomes of various interventions for malignant glaucoma (MG). Methods A retrospective, comparative analysis of case series were performed on 38 eyes of 35 MG patients treated in Aier Eye Hospital of Wuhan between Jan. 2009 and Dec. 2012. Numerous treatments were administered including medical therapy, neodymium: yttrium- aluminium-garnet (Nd:YAG) laser posterior capsulotomy and hyaloidotomy as well as 3 surgical options. The characteristic, treatment option and outcome of MG in every individual patient were reviewed and analyzed among all patients who were followed up for an average of 27.1±9.1mo. Results Four eyes of 3 patients achieved complete resolution with medical therapy. Nd:YAG laser posterior capsulotomy and hyaloidotomy were performed on 2 eyes, both of which achieved resolution after initial intervention. Thirty-two eyes were given surgical treatments with anterior vitrectomy- reformation of anterior chamber in 13 eyes, phacoemulsification- intraocular lens implantation in 10 eyes and phacoemulsification- intraocular lens implantation- anterior vitrectomy in 9 eyes. Resolution of MG was seen in almost all patients. The mean intraocular pressure decreased from 41.87±9.44 mm Hg at presentation to 15.84±3.73 mm Hg at the last visit. The mean anterior chamber depth improved from 0.28±0.27 mm to 2.28±0.19 mm. Twenty eyes with preoperative visual acuity better than counting figure/ 50 cm had various visual improvements. Complications occurred in 3 eyes of 3 patients including bleeding at the entry site of vitrectomy into vitreous cavity, corneal endothelial decompensation and allergic to atropine respectively. Conclusion MG occurs as a result of multiple mechanisms involved simultaneously or sequentially.Medical therapy is advocated as the initial treatment, laser therapy is beneficial in pseudophakic eyes, and different surgical regimen is recommended based on different pathogenesis of MG when non-response occurs to nonsurgical management. MG can be managed successfully by appropriate and timely interventions with good visual outcome.

MicroRNAs are reported as a vital important factor in cancer cell initiation and progression processes. MicroRNA-19-3p has drawn the attention of many researchers in recent years because of its wide expression and its key role in serious kinds of tumor cells. However, the detailed mechanism of microRNA-19a-3p in these tumors is still poorly understood. So, in the present study, we aimed to explore the biological function and potential molecular mechanism of microRNA-19a-3p in different cancer cells. We first detect the relative level of miR-19a-3p in cancer cell lines and tumor tissues compared to normal cells and tissues. Results indicated the messenger RNA expression of microRNA-19a-3p existing in an aberrant low level in cancer cells and tissues. The overexpression of microRNA-19a-3p significantly reduced the cell proliferation, migration, and invasion ability in HCT116 cells. In addition to this, increased microRNA-19a-3p could induce cell apoptosis via promoting reactive oxygen species (ROS) accumulation, whereas inhibition of microRNA-19a-3p exhibited an opposite effect. Moreover, we predicated the target genes and the binding sites of microRNA-19a-3p and confirmed FAS as the targeting of microRNA-19a-3p through luciferase activity assay. Taken together, these results indicated that microRNA-19a-3p overexpression inhibited HCT116 cell proliferation, migration and invasion, induced cell apoptosis, and ROS accumulation via FAS targeting effect. It was conceivable that microRNA-19a-3p might serve as a potential molecular target for breast and liver cancer treatment.

Background Rheumatoid arthritis (RA) is a chronic autoimmune diseased state, characterized by hyperplasia of the synovial membrane, degradation of cartilage, and bone erosion of diarthrodial joints. Kadsura heteroclita (Roxb) Craib (Schizandraceae), a traditional Tujia ethnomedicine called Xue Tong in China, has been long used for the prevention and treatment of rheumatic and arthritic diseases, especially in the southern China. This study aimed to evaluate anti-arthritic effects of the ethanol extract of Kadsura heteroclita stems (KHS) on complete Freund's adjuvant (CFA)-induced arthritis (AIA) in rats, as well as to explore the underlying mechanisms of anti-arthritis. Methods AIA was established in male Sprague-Dawley (SD) rats as described previously, and animals were daily treated by gavage with KHS ethanol extract (200, 400, or 800 mg/kg) or vehicle (0.3% CMC Na) throughout the 30-day experiment. The incidence and severity of arthritis were evaluated using clinical parameters. At the end of experiments, tissue swelling and bone destruction of the hind paws were assessed by computed tomography (CT) and histopathological analyses. Serum levels of tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-17A and IL-17F were measured by ELISA, and protein expression of matrix metalloproteinases-1 (MMP-1), MMP-3 and tissue inhibitor of MMP-1 (TIMP-1) were detected by Western blot. Results Treatment with KHS dose-dependently inhibited paw swelling and reduced arthritis scores of AIA rats. CT images displayed that KHS remarkably protected AIA rats from tissue swelling and bone erosion of joints. Histopathological analyses revealed that KHS markedly reduced inflammatory cell infiltration, synovial proliferation, and the formation of pannus in the ankle joints of AIA rats. KHS was found to significantly suppress the production of TNF-α, IL-1 β, IL-6, IL-17A and IL-17F, inhibited the protein expression of MMP-1 and MMP-3, and elevated the protein expressions of TIMP-1. Conclusion KHS demonstrates potential anti-arthritic effects via inhibiting pivotal mediators of inflammation and cartilage destruction. This study strongly support s identification and isolation of active fractions of KHS which would be a potential candidate for further investigation as a new anti-arthritic botanical drug.

Diabetes-induced brain insulin resistance is associated with many mental diseases, including depression. Epidemiological evidences demonstrate the pathophysiologic link between stress, depression, and diabetes. This study was designed to determine whether chronic unpredictable mild stress- (CUMS-) induced changes in brain insulin resistance could contribute to deterioration in mood and cognitive functions in diabetic rats. Male SD rats were randomly assigned to three groups, including standard control group, the diabetes group, and the diabetes with CUMS group. After 7 weeks, emotional behaviors and memory performances as well as metabolic phenotypes were measured. In addition, we examined the changes in protein expression related to brain insulin signaling. Our results show that rats in diabetes with CUMS group displayed a decreased locomotor behavior in open-field test, an increased immobility time in forced swim test, and tail suspension test, and an impaired learning and memory in the Morris water maze when compared to animals in diabetes group. Further, diabetes with CUMS exhibited a significant decrease in phosphorylation of insulin receptor and an increase phosphorylation of IRS-1 in brain. These results suggest that the depression-like behaviors and cognitive function impairments in diabetic rats with CUMS were related to the changes of brain insulin signaling.

Diagnosis with breast cancer is a major life event that elicits increases in depressive symptoms for up to 50% of women. Xiaoyao Kangai Jieyu Fang (XYKAJY) is derived from a canonical TCM formula, Xiaoyao San (XYS), which has a history of nearly 1000 years for treating depression. The aim of this study was to investigate whether XYKAJY alleviates depression-like behavior and breast tumor proliferation in breast cancer mice then explore the mechanisms underlying its action on HPA axis and hippocampal plasticity further. XYKAJY was treated at the high dose of 1.95 g/mL and 0.488 g/mL, after 21 days of administration. Different behaviors, monoamine neurotransmitters, tumor markers, and the index of HPA axis were detected to evaluate depressive-like symptoms of breast cancer mice. Also, the pathological changes of the tumor, hippocampus, and the expressions of GR, NR2A, NR2B, CAMKII, CREB, and BDNF were detected. In this study, XYKAJY formulation significantly improved the autonomic behavior, reduced the incubation period of feeding, and reversed the typical depressive-like symptoms in breast cancer mice. Also, it reduced the content of CORT, ACTH, CRH, and CA125, CA153, CEA in the blood, protected the pathological changes of the hippocampus and tumor, upregulated the expression of GR, CREB, and BDNF in the hippocampus, and significantly decreased the expression of NR2A, NR2B, and CaMKII. These results provide direct evidence that XYKAJY effectively alleviates depression-like behaviors and tumor proliferation in vehicle mice with ameliorates hippocampus synaptic plasticity dysfunctions.

In this study, we proposed a metabolomics strategy to distinguish different metabolic characters of healthy controls, breast benign (BE) patients, and breast malignant (BC) patients by using the GC-MS and random forest method (RF). In the current study, the serum samples from healthy controls, BE patients, and BC patients were characterized by using GC-MS. Then, random forest (RF) models were established to visually discriminate the differences among three groups' metabolites profiles, and further investigate the progress of breast cancer from benign to malignant in patients based on these GC-MS profiles. We successfully discovered the differences between the healthy and breast cancer patients. And the metabolic changes from benign to malignant cancer were obviously visualized. The results suggested that combining GC-MS profiling with random forest method is a useful approach to analyze metabolites and to screen the potential biomarkers for exploring the serum metabolic profiles of breast cancer.

Background The neuronal intermediate filament alpha-internexin (α-internexin) is a cytoskeleton protein which is involved in the tumor initiation and progression. In this study, we examined the expression and prognosis value of α-internexin in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Methods α-internexin was detected with immunohistochemical staining in 286 tumor specimens from patients with GEP-NENs. Methylation status of α-internexin was evaluated by bisulfite genomic sequencing. We assessed the prognostic value of α-internexin and its correlation with relevant clinicalpathological characteristics. Results The reduced/loss of expression rate of α-internexin in GEP-NEN was 73.4% (210/286), while the positive expression rate was 26.6% (76/286). The difference of α-internexin deficiency was not statistically significant between gastrointestinal NENs (GI-NENs) and pancreatic NENs (pNENs). However, we found significant difference of reduced/loss of α-internexin expression among different sites of GI-NENs (χ2 = 43.470, P

Acute hormone secretion triggered by G protein-coupled receptor (GPCR) activation underlies many fundamental physiological processes. GPCR signalling is negatively regulated by β-arrestins, adaptor molecules that also activate different intracellular signalling pathways. Here we reveal that TRV120027, a β-arrestin-1-biased agonist of the angiotensin II receptor type 1 (AT1R), stimulates acute catecholamine secretion through coupling with the transient receptor potential cation channel subfamily C 3 (TRPC3). We show that TRV120027 promotes the recruitment of TRPC3 or phosphoinositide-specific phospholipase C (PLCγ) to the AT1R-β-arrestin-1 signalling complex. Replacing the C-terminal region of β-arrestin-1 with its counterpart on β-arrestin-2 or using a specific TAT-P1 peptide to block the interaction between β-arrestin-1 and PLCγ abolishes TRV120027-induced TRPC3 activation. Taken together, our results show that the GPCR-arrestin complex initiates non-desensitized signalling at the plasma membrane by coupling with ion channels. This fast communication pathway might be a common mechanism of several cellular processes., Angiotensin II type 1 receptor (AT1R)-mediated acute catecholamine release is modulated by β-arrestin. Here the authors show that β-arrestin-1 recruits the Ca2+ channel TRPC3 and the PLCγ to the AT1R-β-arrestin complex, triggering G protein-independent calcium influx and catecholamine secretion.

This study aimed to investigate the hypoglycemic, lipid-lowering and antidepressant effects of Zuogui Jiangtang Jieyu formulation (ZGJTJY) in a model of unpredictable chronic mild stress (UCMS) in rats with diabetes mellitus (DM; the UCMS-DM model). Sixty rats were randomly divided into blank control, vehicle (model plus vehicle), positive control (model plus metformin and fluoxetine), and high, medium and low dose ZGJTJY (model plus high, medium and low doses of ZGJTJY, respectively) groups. Following establishment of DM by a high-fat diet with intraperitoneal injection of streptozotocin (38 mg/kg), the depression model was established by application of UCMS for 28 days. The behavioral scores of the rats were detected in an open field test and Morris water maze test. The levels of blood glucose, glycosylated hemoglobin (HbA1c) and blood lipids were assayed. The total scores of the open field test and the space exploration times (SETs) in the Morris water maze test were significantly lower and the escape latency (EL) times in the Morris water maze test were significantly longer in the vehicle group compared with those in the blank control group. In addition, in the vehicle group, the levels of blood glucose, HbA1c, total cholesterol (TC), triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-C) were significantly higher and the levels of high-density lipoprotein cholesterol (HDL-C) were significantly lower compared with those in the blank control group. The high dose of ZGJTJY decreased the locomotor activity levels in the open field test, the EL times of the model on day 4, the SETs in the Morris water maze test and the HDL-C levels, and reduced the blood glucose, HbA1c, TC, TG and LDL-C levels compared with those in the model group. Thus, ZGJTJY is a potential candidate for the prevention and treatment of the comorbidity of depression with DM.

Ethnopharmacological relevance Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by failure of spontaneous resolution of inflammation. The stem of Kadsura heteroclite (KHS) is a well-known anti-arthritic Tujia ethnomedicinal plant, which named Xuetong in folk, has long been used for the prevention and treatment of rheumatic and arthritic diseases. Aim of the study The analgesic and anti-inflammatory effects and the potential mechanisms behind such effects of KHS would be investigated by using different animal models. Materials and methods The abdominal writhing episodes of mice induced by intraperitoneal injection of acetic acid and the tail-flick response induced by radiant heat stimulation were used to evaluate the analgesic effect of KHS. The number of abdominal writhing episodes of mice and the latency of tail-flick in rats were measured and recorded. In acute inflammatory models, the ear edema of mice was induced by applying xylene on the ear surface, while the paw edema of male and female rats was induced by subcutaneous injection of carrageenan into the right hind paws of animals. The carrageenan-induced paw swelling in rats were selected as an anti-acute inflammatory mechanism of KHS. Serum levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α) were measured by ELISA, and protein expression of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were detected by Western blot. Results The maximal tolerated single dose of KHS was determined to be 26 g/kg in both sexes of mice. Pharmacological studies showed that KHS at the dose of 200 mg/kg significantly prolonged the reaction time of rats to radiant heat stimulation and suppressed abdominal writhing episodes of mice induced by intraperitoneal injection of acetic acid. KHS at the dose of 200, 400, and 800 mg/kg, showed dose-dependent inhibition of xylene-induced ear swelling in mice. KHS at the dose of 100, 200, 400, and 800 mg/kg demonstrated dose- and time-dependent suppression of paw edema induced by subcutaneous injection of carrageenan in both all rats. Mechanistic studies revealed that the anti-inflammatory effect of KHS was associated with inhibition of the production of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and effectively decreased the expression of COX and iNOS proteins in the carrageenan-injected rat serum, paw tissues and inflammatory exudates. The positive reference drug, rotundine at a dosage of 100 mg/kg and indomethacin at a dosage of 10 mg/kg were used in both mice and rat models. Conclusion These results suggested that KHS has significant effects on analgesia and anti-inflammation with decreasing the pro-inflammation cytokines of IL-1β, IL-6, and TNF-α and inhibiting the proteins expression of COX-2 and iNOS.

Previous studies have shown that models of depression exhibit structural and functional changes to the neurovascular unit. Thus, we hypothesized that diabetes-related depression might be associated with damage to the hippocampal neurovascular unit. To test this hypothesis, neurons, astrocytes and endothelial cells were isolated from the brain tissues of rat embryos and newborn rats. Hippocampal neurovascular unit co-cultures were produced using the Transwell chamber co-culture system. A model of diabetes-related depression was generated by adding 150 mM glucose and 200 μM corticosterone to the culture system and compared with the neuron + astrocyte and astrocyte + endothelial cell co-culture systems. Western blot assay was used to measure levels of structural proteins in the hippocampal neurovascular unit co-culture system. Levels of basic fibroblast growth factor, angiogenic factor 1, glial cell line–derived neurotrophic factor, transforming growth factor β1, leukemia inhibitory factor and 5-hydroxytryptamine in the hippocampal neurovascular unit co-culture system were measured by enzyme-linked immunosorbent assay. Flow cytometry and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling staining was used to assess neuronal apoptosis in the hippocampal neurovascular unit. The neurovascular unit triple cell co-culture system had better barrier function and higher levels of structural and secretory proteins than the double cell co-culture systems. In comparison, in the model of diabetes-related depression, the neurovascular unit was damaged with decreased barrier function, poor structural integrity and impaired secretory function. Moreover, neuronal apoptosis was markedly increased, and 5-hydroxytryptamine levels were reduced. These results suggest that diabetes-related depression is associated with structural and functional damage to the neurovascular unit. Our findings provide a foundation for further studies on the pathogenesis of diabetes-related depression.

Previous studies have reported that the expression of the opioid binding protein/cell adhesion molecule-like (OPCML) gene was frequently downregulated in various of types of cancer. However, little is known regarding the expression of the OPCML gene in gastric cancer. The present study identified that OPCML was downregulated in the gastric cancer SGC7901, KATO III, MKN45, MKN74, SNU1, AGS, N87 and a gastric mucosa cell line GES1, compared with normal gastric tissues by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). To investigate whether the downregulation of OPCML was due to promoter hypermethylation, the methylation of the OPCML promoter was assessed by methylation-specific polymerase chain reaction. Hypermethylation of the OPCML promoter was observed in the gastric cancer MKN45 cell lines, but was not as evident in normal gastric tissue. The methylation inhibitor 5-aza-2'-deoxycytidine was used to remove the methylation of the OPCML gene promoter, following which the expression of OPCML was restored. In addition, the function of the OPCML gene was studied in vitro, and it was found that the restoration expression of OPCML could lead to the suppression of cell growth. In conclusion, the present study has shown that OPCML, which acts as a tumor suppressor, was silenced in gastric cancer cell lines via aberrant hypermethylation of the promoter CpG islands, which may provide a novel molecular approach for the early diagnosis of gastric cancer.

Few studies have been performed on the individual-specific trajectory of left ventricular aging as assessed by echocardiography in an asymptomatic elderly cohort. In the present study, a representative cohort of elderly men, who were long-term asymptomatic for cardiovascular issues, were selected from an ongoing observational aging study. Annual echocardiographic data were used to establish an age-dependent hierarchical model. Based on two-level linear regression results, four echocardiographic indexes [left ventricular mass (LVmass; −1.872 g/yr), posterior ventricular wall thickness (−0.048 mm/yr), fraction shortening (0.097/yr), and transmitral peak A velocity (−0.006 m·s−1·yr−1)] changed significantly with increasing age and were age- and subject-dependent. The most characterized results of the study were the significant, age-related, within-individual variances in echocardiographic results, which were observed using the likelihood ratio test at an occasion-dependent level. Of these, fluctuated amplitudes of two systolic variables [i.e., LVmass (con/age = −0.012 ± 0.004; P = 0.0007) and fraction shortening (con/age = −0.001 ± 0.004; P = 0.05)] were significantly attenuated with increasing age within individuals. On the other hand, the age-related variability of four diastolic Doppler variables [i.e., peak A velocity (con/age = 0.003 ± 0.002; P = 0.0009), peak E velocity (con/age = 0.004 ± 0.003; P = 0.01), E/A ratio (con/age = 0.007 ± 0.003; P = 0.0002), and deceleration time of E wave (con/age = 0.025 ± 0.007; P < 0.0001)] significantly increased with increasing age within individuals. The age-related individual variability of left ventricular indexes observed in this continuous asymptomatic cohort may reflect the mechanism of preclinical, individualized heart aging. In conclusion, successfully fitted multilevel models were applied as a valuable tool to determine the mechanism of individual cardiac aging in the elderly.

Background Ageing brings about the gradual deterioration of the immune system, also known as immunosenescence. The role of non-coding circular RNA in immunosenescence is under studied. Using circular RNA microarray data, we assembled Comparison groups (C1, C2, C3 and C4) that allowed us to compare the circular RNA expression profiles between CD28(+)CD8(+) T cells and CD28(-)CD8(+) T cells isolated from healthy elderly or adult control subjects. Using a step-wise biomathematical strategy, the differentially-expressed circRNAs were identified in C1 (CD28(+)CD8(+) vs CD28(-)CD8(+)T cells in the elderly) and C4 (CD28(-)CD8(+)T cells in the elderly vs in the adult), and the commonly-expressed circRNA species from these profiles were optimized as immunosenescence biomarkers. Results Four overlapping upregulated circular RNAs (100550, 100783, 101328 and 102592) expressed in cross-comparison between C1 and C4 were validated using quantitative polymerase chain reaction. Of these, only circular RNA100783 exhibited significant validation. None of the down-regulated circular RNAs were expressed in the C1 and the C4 cross-comparisons. Therefore, we further predicted circular RNA100783-targeted miRNA-gene interactions using online DAVID annotation. The analysis revealed that a circular RNA100783-targeted miRNA-mRNA network may be involved in alternative splicing, the production of splice variants, and in the regulation of phosphoprotein expression. Considering the hypothesis of splicing-related biogenesis of circRNAs, we propose that circular RNA100783 may play a role in phosphoprotein-associated functions duringCD28-related CD8(+) T cell ageing. Conclusions This study is the first to employ circular RNA profiling to investigate circular RNA-micro RNA interactions in ageing human CD8(+)T cell populations and the accompanying loss of CD28 expression. The overlapping expression of circular RNA100783 may represent a novel biomarker for the longitudinal tracking ofCD28-related CD8(+) T cell ageing and global immunosenescence. Electronic supplementary material The online version of this article (doi:10.1186/s12979-015-0042-z) contains supplementary material, which is available to authorized users.

Background The serum (1 → 3)-β-D-glucan (BG) assay has been approved for diagnosing invasive fungal diseases (IFDs). However, the performance of (1 → 3)-β-D-glucan assay in bronchoalveolar lavage (BAL) fluid is various among studies. The present study aimed to assess the accuracy of (1 → 3)-β-D-glucan assay in bronchoalveolar lavage fluid for the diagnosis of invasive fungal diseases by means of meta-analysis and systematic review of relevant studies. Method The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (OR) and a summary receiver-operating characteristic curve of BAL-BG for diagnosing invasive fungal diseases were pooled using meta-analysis. We also performed meta-regression analysis. Results A total of 838 patients (138 with proven or probable invasive fungal diseases), included in 6 studies, were analyzed. The pooled sensitivity, specificity, PLR, NLR and diagnostic odds ratio were 0.52 (95%CI, 0.38–0.53), 0.58 (95%CI, 0.55–0.61), 1.34 (95%CI, 1.08–1.66), 0.82 (95% CI, 0.63–1.07) and 1.71 (95%CI, 1.01–2.92) respectively. The area under the summary receiver operating characteristic curve, with 95% confidence intervals was 0.61 (95%CI, 0.67–0.55). Conclusion The accuracy of (1 → 3)-β-D-glucan test in bronchoalveolar lavage fluid is marginal, so that the results should not be interpreted alone but can be used as a part of full assessment with clinical features, image findings and other laboratory results for the diagnosis of invasive fungal diseases.

Aim. To determine whether Zuogui Jiangtang Jieyu prescription (ZGJTJY) has hypoglycemic and antidepressant effects which are mediated by corticosterone through adjustment of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and glucocorticoid (GR) levels.Materials and Methods. The diabetes-related depression rats were randomly divided into four groups: the model group, metformin (1.8 mg/kg) combined with fluoxetine (10.8 mg/kg) group, and ZGJTJY high and low dose groups. Four weeks after modeling, blood glucose, behavior, and cognitive function of depression were detected. The expressions of 11β-HSD1 and GR in hippocampus were measured by western blotting and immunohistochemical experiments.Results. We found that (1) the treatment with ZGJTJY (10.26 g/kg) increases the motor activities and improves cognition ability. (2) ZGJTJY (10.26 g/kg) significantly relieves the disorder in blood and the relative indexes. (3) ZGJTJY (10.26 g/kg) can reduce hippocampal corticosterone expression levels and further improve hippocampus pathological changes. (4) ZGJTJY increased the expression of GR accompanied with decreasing 11β-HSD1 in hippocampus.Conclusions. ZGJTJY inhibits the expression of 11β-HSD1 and increases GR in hippocampus and subsequently modulates blood glucose levels, and therefore it is potential property that ZGJTJY could be of benefit for the treatment of behavior and cognitive function of diabetes-related depression.

Chromogranin A (CgA) not only plays an important role in pathologic diagnosis, but is also used as a circulating biomarker in patients with gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN). However, the relationship between immunohistochemistry (IHC) expression and serum levels of CgA has not been investigated. The value of CgA for evaluating treatment response and prognosis is still not well understood. We conducted this study to assess the significance of CgA in GEP-NEN in terms of diagnosis, curative effects evaluation and prognosis. One hundred forty-five patients comprising 88 patients with active disease and 57 disease-free patients were enrolled in this study from January 2011 to November 2013. The expression of CgA was assessed by IHC, and serial serum CgA levels were measured by enzyme linked immunosorbent assay. The overall expression rate of CgA was 69.0% (100/145). CgA expression was associated with tumor site and stage (P

Aim: To assess the efficacy and safety of indocyanine green (ICG) 0.5% and trypan blue 0.1% for anterior capsule staining in cases of white cataract. Methods: This prospective study comprised 55 eyes of 55 patients with white cataract that had phacoemulsification with foldable intraocular lens implantation. ICG in 30 eyes and trypan blue in 25 eyes were used under air to stain the anterior lens capsule. The staining patterns and the ease of creating a continuous curvilinear capsulorhexis (CCC) were assessed; the intraoperative and postoperative complications were noted. The mean follow-up was 17.68±1.65 months. Result: Either ICG or trypan blue stained the anterior capsule uniformly. However, the staining provided by trypan blue was slightly superior. A CCC was successfully achieved in 25 eyes (100%) with trypan blue, and 29 eyes (96.7%) with ICG, respectively. There was no significant postoperative reaction in any eye. Conclusion: The use of vital dyes such as ICG and trypan blue guarantees a complete CCC and makes it possible to deliver the benefits of phacoemulsification in the patients with white cataract.

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor associated with tumor initiation and progression. AhR expression is significantly increased in gastric cancer tissues and gastric cancer cell lines; however, the relationship between AhR and gastric cancer is still unclear. In the present study, we explored the effects of the inhibition of AhR expression by RNA interference on the biological behavior of gastric cancer cells (MKN45 and SGC7901), and elucidated the specific mechanisms of AhR action in the development of gastric cancer. Results showed that small interfering RNA (siRNA) against AhR effectively inhibited the expression of AhR, and decreased the expression of cytochrome P450 (CYP)1A1 and CYP1B1, which are classic target genes of the AhR pathway. Compared to the negative control group, AhR-siRNA-transfected cells showed decreased cellular growth, delayed G1-S cell cycle progression and increased apoptosis rate. Furthermore, inhibition of AhR expression by siRNA in SGC7901 cells led to decreased cell migratory and invasive ability, accompanied by downregulation of expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9. Our results, therefore, suggest that AhR promotes the growth and invasiveness of gastric cancer cells and AhR may serve as a promising therapeutic target for gastric cancer.

OBJECTIVE To compare the effect of three preparations of xiaoyao formula (xiaoyao capsule, xiaoyao pill and Xiaoyao decoction) on soothing liver and strengthening spleen. METHOD The liver depression and spleen deficiency rat model were established by forcing swimming, confining movement test and feeding on alternate days. The rats were randomly divided into eight groups, namely the blank group, the model group, the Cisapride group (2.7 mg x kg(-1)), the xiaoyao decoction group (1.62 g x kg(-1)), the xiaoyao pill group (1.62 g x kg(-1)) and the Xiaoyao capsule groups of high dose (3.24 g x kg(-1)), medium dose (1.62 g x kg(-1)) and low dose (0.81 g x kg(-1)), with intragastric administration for 3 weeks. The contents of NE, DA, 5-HT in serum were measured by HPLC-electrochemical detection method. The contents of motilin (MTL) and somatostation (SS) in plasma was determined by radioimmunassay. The expressions of MTL and SS in tissue were determined by immunohistochemical method. RESULT The contents of NE and MTL in the xiaoyao decoction group was significantly higher than that in the model group, while the content of 5-HT and SS was significantly lower than that in the model group (P < 0.01). The expression of MTL in the xiaoyao capsule group (1.62 g x kg(-1)) was significantly higher than that in the model group and the contents of 5-HT and SS was significantly lower than that in the model group (P < 0.05). The mean optical density of MTL in gastrointestinal tissue of rats in the xiaoyao decoction group and the xiaoyao capsule group (1.62 g x kg(-1)) was remarkably higher than that in the model group, while the expression of SS was notably lower than that in the model group (P < 0.05). CONCLUSION All of the three preparations of Xiaoyao formula have the effect on soothing liver and strengthening spleen. Xiaoyao decoction shows better effect than xiaoyao capsule with same dosage, while xiaoyao capsule shows better effect than xiaoyao pill with same dosage.

Purpose To describe the clinical features and the surgical management of primary iris stromal cyst with rapid growth. Methods A 14-year-old Chinese-Mongolian girl was referred to us with a 1-month history of obstructed vision and photophobia. On an examination, a semitransparent cyst with a densely pigmented posterior wall was revealed in the anterior chamber of the left eye. The information regarding the location and extent of the cyst was further analyzed by anterior segment optical coherence tomography and ultrasound biomicroscopy. It arose within the iris stroma, measuring 7.52 x 3.60 mm. Blood vessels on the surface of the lesion were revealed by iris angiography. There was no history of amniocentesis, birth trauma, antecedent ocular injury, or maternal illness during gestation. The diagnosis of primary iris stromal cyst was made. A combination of needle aspiration, piecemeal resection of cyst wall, cryotherapy, and argon laser photocoagulation with overlapped spots was used. Results Histopathology of the cyst wall revealed nonkeratinized, multilayered, stratified squamous epithelium with clusters of goblet cells. Complete resolution of the cyst was successfully achieved. The visual acuity improved to 20/25 from counting fingers. At 6 months of follow-up, there was no recurrence. Conclusions Complete eradication and devitalization of any remaining epithelial cells are the key factors for preventing recurrence and diffuse epithelialization of the anterior chamber.

We examined the effects of bilateral electric lesion of the habenula (Hb) on the acquisition and maintenance of heroin self-administration. The rats were trained to self-administer heroin (0.05 mg/kg/infusion) under FR1 schedule in daily 4h sessions. A progressive ratio schedule (PR3-4) was used to evaluate the relative motivational value of heroin reinforcement. Compared with the controls, neither pre-training nor post-training of Hb lesions had any effects on the total amount of infusions and motivational value of heroin reward. However, pre-training Hb lesion caused transient active and inactive nose-poke responding in the early phase of training, suggesting increased locomotor exploration. The results suggest that Hb might not play an important role in mediating the acute reinforcing effect of heroin.

We report a case of vitiligo with localized repigmentation induced by imatinib mesylate. An elderly Chinese man has been characterized with recurrent gastrointestinal stromal tumors originated from interstitial cells of Cajal with gain-of-function c-kit mutation. His recurrent tumors have responded to imatinib mesylate therapy. To our surprise, his decade-long vitiligo was dramatically ameliorated by localized repigmentation, which is considered to be the side effect of imatinib mesylate. Hypopigmentation induced by imatinib mesylate with possible molecular blockage to a melanin-dependent KIT signal has been well documented; however, our case with repigmentation suggested that KIT signal of melanin formation would be much more sophisticated than we have believed.

Background Pancreatic neuroendocrine tumors (PNETs) are a group of rare tumors. Chromogranin A (CgA) was considered as the most practical and useful serum tumor marker in PNET patients. But peripheral blood levels of CgA are not routinely tested in Chinese patients with PNETs. This study was to assess the diagnostic value of CgA in Chinese patients with PNETs especially in patients with insulinomas. Methods Eighty-nine patients with PNETs including 57 insulinomas and 32 non-insulinoma PNETs as well as 86 healthy participants were enrolled in this study between September 2003 and June 2013. Serum levels of CgA were measured by ELISA method. Expression of CgA protein was detected in 26 PNET tissues including 14 insulinomas by immunohistochemical staining. Results Serum levels of CgA in 89 PNET patients were significantly higher than that in healthy controls (P = 7.2 × 10−9). Serum levels of CgA in 57 patients with insulinomas (median 64.8 ng/ml, range 25–164) were slightly higher than the levels in healthy controls (median 53.4 ng/ml, range 39–94) but much lower than the levels in 32 patients with non-insulinoma PNETs (median 193 ng/ml, range 27–9021), P = 0.001. The serum CgA levels were reduced in 16 of 17 patients with insulinomas after tumor resection. ROC curve showed that CgA values at 60 ng/ml distinguished patients with insulinomas from healthy controls but its sensitivity and specificity were 66.7% and 73.3%, respectively. In contrast, CgA values at 74 ng/ml distinguished patients with non-insulinoma PNETs from healthy controls, and the sensitivity and specificity were 65.6% and 91.9%, respectively. Except for two insulinomas with negative staining of CgA, 12 insulinoma tissues showed positive staining of CgA. Conclusion CgA is a reliable serum diagnostic biomarker for PNETs but not for insulinomas.

OBJECTIVE This study was conducted was to detect vascular endothelial growth factor (VEGF) levels in peripheral blood of patients with pregnancy-induced hypertension (PIH) syndrome and to investigate VEGF correlation with PIH occurrence. METHODS Double-antibody enzyme-linked immunosorbent assay and fluorescent quantitative polymerase chain reaction were used to detect VEGF levels in the peripheral blood of non-pregnant women (normal group, 30 cases), normal pregnant women (pregnancy group, 30 cases) and PIH patients (PIH group, 30 cases). RESULTS VEGF level in the pregnancy group was significantly higher than in the normal group, and the difference between these two groups was significant (P < 0.001). In the pregnancy group, VEGF reached the maximum level at the metaphase stage of pregnancy and started to decrease at advanced pregnancy. VEGF level in the PIH group was significantly lower than in the pregnancy group at advanced pregnancy (P < 0.01), and VEGF level significantly and gradually decreased with PIH aggravation (P < 0.05). CONCLUSIONS The significant decrease of VEGF level after pregnancy was possibly an important factor of PIH pathogenesis.