Relationship of the Neutrophil-Lymphocyte Ratio with All-Cause and Cardiovascular Mortality in Patients with Diabetic Kidney Disease: A Prospective Cohort Study of NHANES Study.

Background: To investigate the association between the NLR and the risk of all-cause and cardiovascular mortality in US adults with diabetic kidney disease (DKD). Methods: The data utilized for this analysis were sourced from ten National Health and Nutrition Examination Survey cycles (1999-2018) with mortality data (up to 31 December 2019) via linkage to the National Death Index. The optimum NLR threshold for predicting survival outcomes was determined through the maximally selected rank statistics. Restricted cubic spline (RCS), weighted Cox proportional hazard regression, stratified analyses, and time-dependent receiver-operating characteristic curve (ROC) were employed to delineate the prospective correlations of the NLR with both all-cause and cardiovascular mortality. Results: In this investigation, a cohort comprising 2581 patients diagnosed with DKD was examined, encompassing 624 individuals with a higher NLR (≥3.07) and 1957 subjects with a lower NLR (<3.07). Over a median follow-up of 79 months (interquartile range, 44-128 months), 1103 deaths occurred, including 397 from cardiovascular causes and 706 from non-cardiovascular causes. The RCS analysis elucidated the positive linear correlation (both nonlinear P > 0.05). In the multivariable analyses, each one-unit increase in the NLR value was correlated with a 51% increased risk of all-cause mortality (1.51(1.28, 1.77)) and a 71% increased risk of cardiovascular mortality (1.71(1.32, 2.21)). The results were largely consistent across stratified analyses encompassing variables such as age, sex, race/ethnicity, marital status, family income, education levels, BMI, drinking status, smoking status, hypertension, CVD, and anti-infective drugs (P for interaction >0.05 for all). Time-dependent ROC analyses underscored the NLR's credible predictive efficacy for both short-term and extended durations in forecasting both all-cause and cardiovascular mortality. Conclusion: The findings emphasize the promising use of the NLR in stratifying and prognosticating the risk of mortality in DKD in clinical practice.

Association of cardiovascular health using Life's Essential 8 with depression: Findings from NHANES 2007-2018.

OBJECTIVE: Few studies have explored the correlation between cardiovascular health (CVH) and depression. We aimed to investigate the relationship between CVH using Life's Essential 8 (LE8) and depression among US adults. METHODS: 16,362 individuals from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018 were included. The patient Health Questionnaire (PHQ-9) was utilized to recognized depression (PHQ-9 ≥ 10). LE8 was scored by four health behaviors (sleep, tobacco/nicotine exposure, physical activity and diet) and four health factors (body mass index, non-high-density lipoprotein cholesterol, blood glucose and blood pressure) and classified into low, moderate and high CVH groups. Weighted logistic regressions, restricted cubic splines and sensitivity analyses were utilized to investigate the correlation between LE8 and depression. RESULTS: 1306 subjects had depression (7.98% of the participants), of which 860 (7.42%), 305 (17.24%) and 141 (3.01%) had low, moderate and high CVH, separately. In the fully adjusted model, LE8 was negatively correlated with depression (OR: 5.50, 95% CI 3.92-7.71, P < 0.001). Furthermore, there were inversely dose-response relationships between LE8 and depression (overall P < 0.001). CONCLUSIONS: Adhering to a high CVH, estimated by the LE8 score, was correlated with lower odds of depression.

Current status and development trends in CKD with frailty research from 2000 to 2021: a bibliometric analysis.

INTRODUCTION: The prevalence of chronic kidney disease (CKD) is gradually increasing in the elderly population. At the same time, frailty has become one of the research hotspots in the field of geriatrics. Bibliometric analyses help to understand the direction of a field. Therefore, this study aimed to analyze the status and emerging trends of frailty in CKD patients. DATA AND METHODS: The Web of Science Core Collection (WoSCC) database was screened for relevant literature published between 1 January 2000 and 31 December 2021. Next, publications were analyzed for information including authors, journals, cited references, citing journals, institutions, countries and regions, high-frequency keywords and co-citations using VOSviewer, Microsoft Excel, and R software. RESULTS: A total of 2223 articles were obtained, from which 613 relevant articles were selected based on title and abstract screening. There was an upward trend in the number of annual publications and Johansen KL was considered the most contributing author in the field. The Clinical Journal of the American Society of Nephrology was the most productive research journal. Johns Hopkins University is the most published organization. The United States is the global leader in the field and contributes the most to research. Research hotspots focus on epidemiological studies of frailty and frailty intervention. CONCLUSIONS: This study presents a comprehensive bibliometric analysis of CKD and frailty research. Key findings highlight the current focus on early screening and assessment of frailty in CKD patients, as well as physical function interventions in frail patients.

Development and Validation of Prediction Models for All-Cause Mortality and Cardiovascular Mortality in Patients on Hemodialysis: A Retrospective Cohort Study in China.

Purpose: This study aimed to develop two predictive nomograms for the assessment of long-term survival status in hemodialysis (HD) patients by examining the prognostic factors for all-cause mortality and cardiovascular (CVD) event mortality. Patients and methods: A total of 551 HD patients with an average age of over 60 were included in this study. The patients' medical records were collected from our hospital and randomly allocated to two cohorts: the training cohort (n=385) and the validation cohort (n=166). We employed multivariate Cox assessments and fine-gray proportional hazards models to explore the predictive factors for both all-cause mortality and cardiovascular event mortality risk in HD patients. Two nomograms were established based on predictive factors to forecast patients' likelihood of survival for 3, 5, and 8 years. The performance of both models was evaluated using the area under the curve (AUC), calibration plots, and decision curve analysis. Results: The nomogram for all-cause mortality prediction included seven factors: age ≥ 60, sex (male), history of diabetes and coronary artery disease, diastolic blood pressure, total triglycerides (TG), and total cholesterol (TC). The nomogram for cardiovascular event mortality prediction included three factors: history of diabetes and coronary artery disease, and total cholesterol (TC). Both models demonstrated good discrimination, with AUC values of 0.716, 0.722 and 0.725 for all-cause mortality at 3, 5, and 8 years, respectively, and 0.702, 0.695, and 0.677 for cardiovascular event mortality, respectively. The calibration plots indicated a good agreement between the predictions and the decision curve analysis demonstrated a favorable clinical utility of the nomograms. Conclusion: Our nomograms were well-calibrated and exhibited significant estimation efficiency, providing a valuable predictive tool to forecast prognosis in HD patients.

n-3 PUFA poor seafood consumption is associated with higher risk of gout, whereas n-3 PUFA rich seafood is not: NHANES 2007-2016.

Background and aims: Gout, the most prevalent inflammatory arthritis, has undesirable effects on the quality of life. Omega-3 polyunsaturated fatty acids (n-3 PUFA) has a strong link with anti-inflammatory impacts. However, whether the harmful effects of seafood in relation to gout may vary owing to different levels of n-3 PUFA in seafood is still unclear. It was the goal of this study to examine the relationship between n-3 PUFA poor/rich seafood consumption and gout. Methods: Between 2007 and 2016, five NHANES cycles were performed, with 12,505 subjects having complete data for gout and two 24-h dietary intake interviews. The 24-h dietary recalls were utilized to evaluate dietary habits. Gout was defined based on questionnaires. Weighted logistic regression models were conducted to investigate the association between n-3 PUFA poor/rich seafood consumption and gout. Moreover, subgroup analysis was utilized to estimate the stability of results. Covariates including age, gender, race/ethnicity, income, education, body mass index, chronic kidney disease, diabetes mellitus, hypertension, smoking status, and drinking status were stratified in different models. Results: In the fully adjusted model, each unit of increase of n-3 PUFA poor seafood intake was associated with an 8.7% increased risk of gout (OR = 1.087, 95% CI: 1.039, 1.138, P < 0.001), whereas, no correlation was found between n-3 PUFA rich seafood consumption and gout. It also provided a proof-of-concept regarding the potential for n-3 PUFA rich seafood to counteract harmful effects of purines in relation to gout. A dose-response analysis showed that there was a non-linear relationship between n-3 PUFA rich seafood intake and the risk of gout in the female group. Conclusion: Findings suggest that n-3 PUFA poor seafood consumption is associated with higher risk of gout, whereas n-3 PUFA rich seafood is not.

Relationship between diet-related inflammation and bone health under different levels of body mass index.

BACKGROUND: Osteoporosis is a major public health problem. Dietary inflammatory preference and body mass index (BMI) are emerging factors that tends to affect bone health. There is limited evidence regarding the joint influence of BMI and dietary status on the bone health. This study aimed to investigate the relationship between dietary inflammatory index (DII) and bone health among adults under different levels of BMI utilizing the National Health and Nutrition Examination Survey (NHANES). METHODS: Data were collected from 2005-2010, 2013-2014 to 2017-2018 in NHANES. In total, 10,521 participants who aged ≥ 20 years and had complete data for dietary intake interview, bone mineral density (BMD) and bone mineral content (BMC) were included. DII was performed to evaluate the dietary inflammatory potential based on dietary intake interview. We evaluated bone health by femoral neck BMD and BMC measured by dual energy X-ray absorptiometry. Weighted multivariable linear regression and BMI-stratified subgroup analysis were performed. RESULTS: The average DII score for 10,521 participants was 1.24 ± 0.04, mean femoral neck BMD was 0.82 ± 0.00 g/cm2 and mean BMC was 4.37 ± 0.01 g. In the fully adjusted model, there was a negative correlation between DII with BMD (ß = - 0.016, P < 0.001) and BMC (ß = - 0.011, P < 0.001) in the most anti-inflammatory diet. Using BMI-stratified subgroup analysis, this correlation became more evident in both the overweight (BMD: ß = - 0.024, P < 0.001; BMC: ß = - 0.058, P = 0.042) and obese groups (BMD: ß = - 0.015, P = 0.049; BMC: ß = - 0.009, P = 0.042), while this correlation was opposite in DII tertile 2 (middle DII score) in the underweight group (BMD: ß = 0.047, P = 0.038; BMC: ß = 0.274, P = 0.010). CONCLUSION: Relationship between higher consumption of pro-inflammatory and increased risk of lower BMD and BMC was only existed in overweight and obese participants.

Esophageal chemical clearance and mucosa integrity values in refractory gastroesophageal reflux disease patients with different esophageal dynamics.

OBJECTIVES: Esophageal post-reflux swallow-induced peristaltic wave index (PSPWI) and mean nocturnal baseline impedance (MNBI), novel impedance-based markers of reflux burden, are associated with esophageal dynamics. We aim to investigate the characteristics of PSPWI and MNBI in Chinese refractory gastroesophageal reflux disease (RGERD) patients with different esophageal dynamic changes. MATERIALS AND METHODS: 201 RGERD and 76 functional heartburn patients, undergone off-PPI endoscopy, esophageal manometry and impedance-pH monitoring, were included. Comparisons of conventional and novel impedance-pH metrics were made among different esophageal dynamics groups. Receiver operating-characteristic analyses were utilized to evaluate the diagnostic efficacy of PSPWI and MNBI in differentiating abnormal esophageal dynamics. Correlations were used to investigate their associated factors. RESULTS: PSPWI and MNBI of RGERD with esophagogastric junction (EGJ) injury and esophageal dysmotility were lower than EGJ injury alone or normal dynamics (p < 0.05 for both comparisons). PSPWI with esophageal peristalsis abnormality was lower than EGJ injury (p = 0.049), while MNBI showed no statistical difference. PSPWI, MNBI and their combination have auxiliary diagnostic values for esophageal peristalsis [area under the curves (AUCs): 0.683, 0.656, 0.708)] while only their combination for EGJ injury (AUC: 0.610). And they positively correlated with esophageal motility while negatively correlated with ineffective swallows and acid reflux events. CONCLUSIONS: PSPWI and MNBI, indicating impairment of esophageal chemical clearance and mucosa integrity, were lower in RGERD patients with multiple esophageal dynamic injuries than single injuries or normal dynamics. Moreover, they provided useful contributing information for potential dynamic injuries if manometry has already been found normal or marginal.

The effects of vaccination on the disease severity and factors for viral clearance and hospitalization in Omicron-infected patients: A retrospective observational cohort study from recent regional outbreaks in China.

Object: This study attempted to explore the effects of vaccination on disease severity and the factors for viral clearance and hospitalization in omicron-infected patients. Methods: The clinical manifestations of 3,265 Omicron-infected patients (BA.2 lineage variant; the Omicron group) were compared with those of 226 Delta-infected patients (the Delta group). A Multi-class logistic regression model was employed to analyze the impacts of vaccination doses and intervals on disease severity; a logistic regression model to evaluate the risk factors for hospitalization; R 4.1.2 data analysis to investigate the factors for time for nucleic acid negativization (NAN). Results: Compared with the Delta group, the Omicron group reported a fast transmission, mild symptoms, and lower severity incidence, and a significant inverse correlation of vaccination dose with clinical severity (OR: 0.803, 95%CI: 0.742-0.868, p<0.001). Of the 7 or 5 categories of vaccination status, the risk of severity significantly decreased only at ≥21 days after three doses (OR: 0.618, 95% CI: 0.475-0.803, p<0.001; OR: 0.627, 95% CI: 0.482-0.815, p<0.001, respectively). The Omicron group also reported underlying illness as an independent factor for hospitalization, sore throat as a protective factor, and much shorter time for NAN [15 (12,19) vs. 16 (12,22), p<0.05]. NAN was associated positively with age, female gender, fever, cough, and disease severity, but negatively with vaccination doses. Conclusion: Booster vaccination should be advocated for COVID-19 pandemic-related control and prevention policies and adequate precautions should be taken for patients with underlying conditions.

Comprehensive functional genomic analyses link APC somatic mutation and mRNA-miRNA networks to the clinical outcome of stage-III colorectal cancer patients.

BACKGROUND: Colorectal cancer (CRC) is a major health concern globally, but exhibits regional and/or environmental distinctions in terms of outcome especially for patients with stage III CRC. METHODS: From 2014 to 2016, matched pairs of tumor and adjacent normal tissue samples from 60 patients with stage I-IV CRC from Chang Gung Memorial Hospital in Taiwan were analyzed using next-generation sequencing. The DNA, mRNA, and miRNA sequences of paired tumor tissues were profiled. An observational study with survival analysis was done. Online datasets of The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC) were also integrated and compared. RESULTS: The gene that exhibited the highest mutation rate was adenomatous polyposis coli (APC) (75.0%), followed by TP53 (70.0%), KRAS (56.6%), and TTN (48.3%). APC was also the most frequently mutated gene in TCGA and ICGC datasets. Surprisingly, for non-metastatic cases (stages I-III), CRC patients with mutated APC had better outcome in terms of overall survival (p = 0.041) and recurrence free survival (p = 0.0048). Particularly for stage III CRC, the overall survival rate was 94.4% and 67.7%, respectively (p = 0.018), and the recurrence free survival rate was 94.4% and 16.7%, respectively (p = 0.00044). Further clinical and gene expression analyses revealed that the APC wt specimens to a greater extent exhibit poor differentiation state as well as EGFR upregulation, providing molecular basis for the poor prognosis of these patients. Finally, based on integrated transcriptome analysis, we constructed the mRNA-miRNA networks underlying disease recurrence of the stage III CRC and uncovered potential therapeutic targets for this clinical condition. CONCLUSION: For stage III CRC, patients with mutated APC had better overall and recurrence free survival.

Diet-Related Inflammation is Associated with Malnutrition-Inflammation Markers in Maintenance Hemodialysis Patients: Results of a Cross-Sectional Study in China Using Dietary Inflammatory Index.

Purpose: This cross-sectional study aimed to explore the association between the inflammation potential of the diet and malnutrition-inflammation status in Chinese maintenance hemodialysis (MHD) patients. Methods: Dietary Inflammatory Index (DII) was computed based on a semi-quantitative food frequency questionnaire. Malnutrition-inflammation status was assessed by six indexes, including C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), hemoglobin (HB), albumin (ALB) and malnutrition-inflammation score (MIS). Multivariable linear regression and logistic regression were employed adjusting for covariables including age, gender, body mass index and dialysis vintage. Results: A total of 161 Chinese MHD patients with an average age of 60.0 ± 13.6 years were enrolled. The median (IQR) DII score among participants was 0.60 (-0.80, 2.32), revealing a generally pro-inflammatory diet. DII was positively associated with MIS score (ß= 0.61, 95% CI: 0.51, 0.69, p < 0.0001) and CRP (ß = 0.54, 95% CI: 0.46, 0.63, p < 0.0001). A negative relationship between DII and NLR (ß = -0.37, 95% CI: -0.61, -0.13, p = 0.008) was found in the most anti-inflammatory diet. Multivariable logistic regression showed that each unit increase in DII was linked with 3.06 (95% CI: 1.39, 6.69, p = 0.005) times increased odds of MIS. Conclusion: Diet with a higher DII score may act as a potential trigger contributing to the development of malnutrition-inflammation status. Further studies for verification and for developing strategies to decrease the dietary inflammation burden are warranted.

The mechanism of esophagus dysmotility in diabetes and research progress of relating treatments.

Introduction: Esophagus dysmotility is a crucial risk factor of gastroesophageal reflux disease (GERD), which is one of the most common diseases in digestive medicine globally. This review emphasizes the mechanisms of esophagus dysmotility in diabetes and summarizes more targeted treatments for these patients to avoid the overuse of proton pump inhibitors (PPIs).Areas covered: Diabetes mellitus (DM) is a clear factor that must not be neglected in the development of GERD. Previous studies have preliminarily researched the esophagus deterioration in diabetes. However, the multi-faceted mechanisms of esophagus dysmotility in diabetes need more studies. Besides, targeted treatments for these patients rather than conventional PPIs are urgently needed.Expert opinion: The treatments for GERD patients with diabetes should be further explored. Pharmacological approaches such as prokinetic agents, psychotherapy can be adopted. Meanwhile, it's feasible to explore non-drug treatments. For example, Electroacupuncture (EA) at Zusanli (ST-36) may be effective to protect the networks of intestinal cells of Cajal (ICCs) in diabetes. More effective approaches should be explored to achieve individualized treatment for these patients.

Scabronine G Methyl Ester Improves Memory-Related Behavior and Enhances Hippocampal Cell Proliferation and Long-Term Potentiation via the BDNF-CREB Pathway in Olfactory Bulbectomized Mice.

A previous study reported that scabronine G methyl ester (SG-ME) potentially enhances the in vitro secretion of neurotrophic factors such as nerve growth factor via the protein kinase C (PKC)-ζ pathway. However, it remains unknown whether SG-ME can improve cognitive dysfunctions in olfactory bulbectomized (OBX) mice. To address this question, we evaluated SG-ME-treated and untreated OBX mice in a passive avoidance test. We also investigated potential effects of SG-ME on several parameters: cell proliferation and cAMP response element-binding protein (CREB) phosphorylation in the hippocampal dentate gyrus by immunohistochemistry, brain-derived neurotrophic factor (BDNF) levels in the hippocampus by Western blotting, p-CREB levels in the hippocampus by MapAnalyzer, and long-term potentiation (LTP) by electrophysiology. On the 14th day after surgery OBX mice showed altered passive avoidance and decreases in both cell proliferation and long-term potentiation in the hippocampus, while these changes were reversed by SG-ME (20 µg/mouse) 24 h after the treatment. The improvement in memory deficits was prevented when SG-ME was co-administeredwith either zeta inhibitory peptide (PKC-ζ inhibitor), anti-BDNF antibody, ANA-12 (TrkB antagonist), U0126 (MEK inhibitor), H-89 (PKA inhibitor), LY294002 (PI3K inhibitor) or KN-93 (CaMKII inhibitor). We found that SG-ME enhanced brain-derived neurotrophic factor and p-CREB levels in the hippocampus while p-CREB was localized in neurons, but not in astrocytes nor microglial cells. These findings revealed the potential of SG-ME in improving memory impairments by enhancing cell proliferation and LTP via activation of the BDNF/CREB signaling pathway in neurons.

Comprehensive transcriptome profiling of Taiwanese colorectal cancer implicates an ethnic basis for pathogenesis.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. While both genetic and environmental factors have been linked to the incidence and mortality associated with CRC, an ethnic aspect of its etiology has also emerged. Since previous large-scale cancer genomics studies are mostly based on samples of European ancestry, the patterns of clinical events and associated mechanisms in other minority ethnic patients suffering from CRC are largely unexplored. We collected 104 paired and adjacent normal tissue and CRC tumor samples from Taiwanese patients and employed an integrated approach - paired expression profiles of mRNAs and microRNAs (miRNAs) combined with transcriptome-wide network analyses - to catalog the molecular signatures of this regional cohort. On the basis of this dataset, which is the largest ever reported for this type of systems analysis, we made the following key discoveries: (1) In comparison to the The Cancer Genome Atlas (TCGA) data, the Taiwanese CRC tumors show similar perturbations in expressed genes but a distinct enrichment in metastasis-associated pathways. (2) Recurrent as well as novel CRC-associated gene fusions were identified based on the sequencing data. (3) Cancer subtype classification using existing tools reveals a comparable distribution of tumor subtypes between Taiwanese cohort and TCGA datasets; however, this similarity in molecular attributes did not translate into the predicted subtype-related clinical outcomes (i.e., death event). (4) To further elucidate the molecular basis of CRC prognosis, we developed a new stratification strategy based on miRNA-mRNA-associated subtyping (MMAS) and consequently showed that repressed WNT signaling activity is associated with poor prognosis in Taiwanese CRC. In summary, our findings of distinct, hitherto unreported biosignatures underscore the heterogeneity of CRC tumorigenesis, support our hypothesis of an ethnic basis of disease, and provide prospects for translational medicine.

Liver hydrolysate improves depressive-like behavior in olfactory bulbectomized mice: Involvement of hippocampal neurogenesis through the AMPK/BDNF/CREB pathway.

Recently, we has reported that AMPK activator has antidepressant effect. Previous our study suggested that liver hydrolysate (LH) activated adenosine monophosphate-activated protein kinase (AMPK) in periphery. However, the effect of LH on depression is unclear. Therefore, we examines whether LH has antidepressant effect on olfactory bulbectomized (OBX) mice. OBX mice showed depressive-like behavior in tail-suspension test and reduction of hippocampal neurogenesis, while these changes were reversed by LH. LH enhanced hippocampal phosphate-AMPK, brain-derived neurotrophic factor (BDNF) and phosphate-cyclic adenosine monophosphate response element-binding protein (CREB) in OBX mice. These data indicate that LH may produce antidepressant effects via hippocampal AMPK/BDNF/CREB signaling.

Prenatal treatment with methylazoxymethanol acetate as a neurodevelopmental disruption model of schizophrenia in mice.

Methylazoxymethanol (MAM)-treated pregnant rat at gestation day (GD) 17 has been shown to be a valuable developmental animal model for schizophrenia. Yet, this model remains to be established in mice. In the present study, we examined behavioral, cytoarchitectural, and neurochemical changes in the offspring of MAM-treated mice and validated the model's face, construct and predictive validities. We found that in contrast to a single injection of MAM to dams at GD 15, 16 or 17, its daily administration from GD 15 to 17 led to deficits in prepulse inhibition (PPI) of startle in the post-pubertal offspring. In addition, we observed behavioral deficits in working memory and social interactions, as well as an increase in locomotor activity induced by the NMDA antagonist MK-801 in GD15-17 MAM offspring. These animals also showed a reduction in the volume of the prefrontal cortex (PFC) and hippocampus, neuroanatomical changes such as discontinuities and heterotopias in the hippocampus, and an increase of DA level and DOPAC/DA ratio in the medial PFC. Atypical antipsychotic drugs clozapine, risperidone, and aripiprazole, but not the typical drug haloperidol, reversed the deficit in PPI and social withdrawal in the offspring of MAM-treated dams. In contrast, MK-801-induced hyperactivity in MAM mice was reversed by both and typical or atypical antipsychotic drugs. Taken together, the treatment of pregnant mice with MAM during GD 15-17 offers a new approach to study neurobiological mechanisms involved in the pathogenesis of schizophrenia.

Mechanisms underpinning AMP-activated protein kinase-related effects on behavior and hippocampal neurogenesis in an animal model of depression.

Adenosine monophosphate-activated protein kinase (AMPK) is critical for whole-body energy metabolism regulation. Recent studies have suggested that physical exercise ameliorates depressive-like behaviors via AMPK activation; however, the underlying mechanism is unclear. Here, we examined the effects and underlying mechanisms of AMPK activation on depressive-like behavior in olfactory bulbectomized (OBX) mice. We treated OBX mice with the AMPK activator, 5-aminoimidazole-4-carboxamide-1-ß-d-ribonucleotide (AICAR) on the 7th or 14th day after bilateral bulbectomy and evaluated depressive-like behavior using the tail-suspension test (TST) and forced swimming test (FST) on the 21st day. The expression of phosphorylated AMPK, protein kinase C ζ (PKCζ), nuclear factor-kappa B (NF-κB), brain-derived neurotrophic factor (BDNF), and cAMP response element-binding protein (CREB) in the hippocampus was assessed by western blotting. Hippocampal neurogenesis and localization of AMPK and phosphorylated NF-κB were examined by immunohistochemistry. Chronic AICAR treatment suppressed the prolonged immobility of OBX mice in the TST and FST, and increased the levels of phosphorylated AMPK, PKCζ, NF-κB, CREB, and BDNF. Hippocampal neurogenesis in OBX mice was promoted by chronic AICAR treatment. Co-administration of AICAR with the PKCζ inhibitor or the neurotrophic tyrosine kinase receptor type 2 (TrkB) antagonist, ANA-12, inhibited these effects. Phosphorylated AMPK was detected in mature and immature hippocampal neurons and microglia, while phosphorylated NF-κB was detected only in neurons in AICAR-treated OBX mice. These data indicate that AMPK activation produces anti-depressant effects, which are mediated by elevated hippocampal neurogenesis potentially via PKCζ/NF-κB/BDNF/TrkB/CREB signaling in neurons.

BE360, a new selective estrogen receptor modulator, produces antidepressant and antidementia effects through the enhancement of hippocampal cell proliferation in olfactory bulbectomized mice.

We have reported that the carborane compound BE360 is a novel selective estrogen receptor modulator and new therapy option for osteoporosis. The aim of this study was to explore the effects and underlying mechanisms of BE360 on depressive-like behavior and memory impairment in the olfactory bulbectomized (OBX) mice, an experimental animal model of depression and dementia. BE360 was administered subcutaneously to mice using a mini-osmotic pump for 2 weeks. Depressive-like behavior was measured as the reduced intake of a sweet solution in the sucrose preference test. Short-term memory was assessed using the Y-maze test. Cell proliferation was assessed by the analysis of cells expressing 5-bromo-2'-deoxyuridine (BrdU) uptake. The expression of phosphorylated cyclic-AMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) were measured by immunoblot. The depressive-like behavior and memory impairment in OBX mice were improved by the chronic treatment with BE360. Immunohistochemical analysis showed that the number of BrdU-positive cells in the dentate gyrus of the hippocampus significantly decreased in OBX mice whereas they increased after the chronic treatment with BE360. Immunoblotting studies revealed that pCREB and BDNF were significantly increased in the hippocampus of OBX mice treated with BE360. The present study has shown that BE360 has antidepressant and antidementia effects characterized by hippocampal cell proliferation potentially activated via CREB/BDNF signaling pathways. These results indicate that BE360 may have valuable therapeutic potential against depression and neurodegenerative diseases.

The Mechanism of Safrole-Induced [Ca²âº]i Rises and Non-Ca²âº-Triggered Cell Death in SCM1 Human Gastric Cancer Cells.

Safrole is a carcinogen found in plants. The effect of safrole on cytosolic free Ca²âº concentrations ([Ca²âº](i)) and viability in SCM1 human gastric cancer cells was explored. The Ca²âº-sensitive fluorescent dye fura-2 was applied to measure [Ca²âº](i). Safrole at concentrations of 150-450 µM induced a [Ca²âº](i) rise in a concentration-dependent manner. The response was reduced by 60% by removing extracellular Ca²âº. Safrole-evoked Ca²âº entry was not altered by nifedipine, econazole, SKF96365, and protein kinase C activator or inhibitor. In Ca²âº-free medium, treatment with the endoplasmic reticulum Ca²âº pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) abolished safrole-evoked [Ca²âº](i) rises. Conversely, treatment with safrole abolished thapsigargin or BHQ-evoked [Ca²âº](i) rises. Inhibition of phospholipase C (PLC) with U73122 abolished safrole-induced [Ca²âº](i) rises. At 250-550 µM, safrole decreased cell viability concentration-dependently, which was not reversed by chelating cytosolic Ca²âº with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/acetoxy methyl (BAPTA/AM). Annexin V/propidium iodide staining data suggest that safrole (350-550 µM) induced apoptosis concentration-dependently. These studies suggest that in SCM1 human gastric cancer cells, safrole induced [Ca²âº](i) rises by inducing PLC-dependent Ca²âº release from the endoplasmic reticulum and Ca²âº influx via non-store-operated Ca²âº entry pathways. Safrole-induced cell death may involve apoptosis.

Effect of methoxychlor on Ca²âº homeostasis and apoptosis in HA59T human hepatoma cells.

Methoxychlor, an organochlorine pesticide, is thought to be an endocrine disrupter that affects Ca²âº homeostasis and cell viability in different cell models. This study explored the action of methoxychlor on cytosolic free Ca²âº concentrations ([Ca²âº]i) and apoptosis in HA59T human hepatoma cells. Fura-2, a Ca²âº-sensitive fluorescent dye, was applied to measure [Ca²âº]i. Methoxychlor at concentrations of 0.1-1 µM caused a [Ca²âº]i rise in a concentration-dependent manner. Removal of external Ca²âº abolished methoxychlor's effect. Methoxychlor-induced Ca²âº influx was confirmed by Mn²âº-induced quench of fura-2 fluorescence. Methoxychlor-induced Ca²âº entry was inhibited by nifedipine, econazole, SK&F96365, and protein kinase C modulators. Methoxychlor killed cells at concentrations of 10-130 µM in a concentration-dependent fashion. Chelation of cytosolic Ca²âº with 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid/AM (BAPTA/AM) did not prevent methoxychlor's cytotoxicity. Methoxychlor (10 and 50 µM) induced apoptosis concentration-dependently as determined by using Annexin V/propidium iodide staining. Together, in HA59T cells, methoxychlor induced a [Ca²âº]i rise by inducing Ca²âº entry via protein kinase C-sensitive Ca²âº-permeable channels, without causing Ca²âº release from stores. Methoxychlor also induced apoptosis that was independent of [Ca²âº]i rises.

Effect of deoxycholic acid on Ca2+ movement, cell viability and apoptosis in human gastric cancer cells.

Deoxycholic acid (DOA) is one of the secondary bile acids used as a mild detergent for the isolation of membrane associated proteins. This study examined whether the secondary bile acid, DOA, altered Ca(2+) movement, cell viability and apoptosis in SCM1 human gastric cancer cells. The Ca(2+)-sensitive fluorescent dye fura-2 was used to measure [Ca(2+)]i. DOA-evoked [Ca(2+)]i rises concentration dependently. The response was reduced by removing extracellular Ca(2+). DOA-evoked Ca(2+) entry was inhibited by store-operated Ca(2+) channel inhibitors (nifedipine, econazole and SKF96365), the protein kinase C (PKC) activator phorbol 12-myristate 13 acetate (PMA) and the PKC inhibitor GF109203X. In Ca(2+)-free medium, treatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (TG) abolished DOA-evoked [Ca(2+)]i rises. Conversely, treatment with DOA abolished TG-evoked [Ca(2+)]i rises. Inhibition of phospholipase C with U73122 abolished DOA-evoked [Ca(2+)]i rises. At 100-500 µM, DOA decreased cell viability, which was not changed by chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). DOA between 100 and 300 µM also induced apoptosis. Collectively, in SCM1 cells, DOA-induced [Ca(2+)]i rises by evoking phospholipase C-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via store-operated Ca(2+) channels. DOA also caused Ca(2+)-independent apoptosis.