Activation of the TLR4-JNK but not the TLR4-ERK pathway induced by indole-3-acetic acid exerts anti-proliferative effects on Caco-2 cells.

We previously found that indole-3-acetic acid (IAA) produced from tryptophan by gut microbiota decreases the expression of tumor necrosis factor α (TNFα), which is implicated in the pathogenesis of colorectal cancer (CRC). The present study aimed to determine IAA involvement in the proliferation of CRC-derived Caco-2 cells. Cell proliferation was suppressed by IAA, whereas IAA-induced aryl hydrocarbon receptor activation had no impact. IAA activated extracellular signal-related (ERK) and c-Jun N-terminal (JNK) kinases, but not p38. Toll-like receptor 4 (TLR4) may be required to activate ERK and JNK, but only the TLR4-JNK pathway might elicit the anti-proliferative effects of IAA. Thus, IAA may be a ligand for TLR4 that contributes to inhibiting CRC cell proliferation by activating TLR4-mediated JNK. Because IAA did not induce cytotoxicity, inhibiting cell cycle progression might affect the anti-proliferative capacity of IAA. Therefore, colonic IAA accumulation might help to prevent CRC development and progression.

Skatole-induced p38 and JNK activation coordinately upregulates, whereas AhR activation partially attenuates TNFα expression in intestinal epithelial cells.

Increased tumor necrosis factor α (TNFα) expression in intestinal epithelial cells (IECs) plays a major role in the development and progression of inflammatory bowel disease (IBD) and colorectal cancer (CRC). The present study aimed to clarify the relationship between TNFα and skatole, a tryptophan-derived gut microbiota metabolite. The aryl hydrocarbon receptor (AhR) antagonist CH223191 promoted, whereas the p38 inhibitor SB203580 suppressed the increase in TNFα mRNA and protein expression induced by skatole in intestinal epithelial Caco-2 cells. The c-Jun N-terminal kinase (JNK) inhibitor SP600125 repressed only the increased TNFα protein expression, whereas the extracellular signal-regulated kinase (ERK) pathway inhibitor U0126 did not affect increased TNFα expression at any level. A neutralizing antibody against TNFα partially inhibited skatole-induced cell death. Overall, these results suggested that TNFα expression is increased by the concerted actions of skatole-activated p38 and JNK, and that TNFα exerts autocrine/paracrine actions on IECs despite partial suppression by activated AhR. Therefore, skatole might play an important role in the development and progression of IBD and CRC via increased TNFα expression.

Microcystin-LR incorporated into colonic cells through probenecid-sensitive transporters leads to upregulated MCP-1 expression induced by JNK activation.

Harmful algae that inhabit eutrophic lakes produce cyanotoxic microcystins. Therefore, the relationship between chronic exposure to microcystins via drinking water and organ disorders has been investigated. The present study aimed to determine whether representative microcystin-LR is involved in increased monocyte chemoattractant protein-1 (MCP-1) expression in rat colonic mucosa and enterocyte-like differentiated Caco-2 cells. The mRNA expression of MCP-1 was increased in the colons of rats administered with microcystin-LR, compared with controls. Furthermore, mRNA levels of MCP-1 expression significantly and positively correlated with those of Adhesion G Protein-Coupled Receptor E1 (ADGRE1; EMR1; F4/80), an indicator of macrophage infiltration, suggesting that increased MCP-1 expression induced by microcystin-LR promotes macrophage infiltration into the colon. Microcystin-LR increased MCP-1 expression in enterocyte-like differentiated Caco-2 cells, by activating c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase (ERK) or p38. The findings of transporter inhibitors indicated that microcystin-LR is incorporated into cells via ATP Binding Cassette (ABC) or solute carrier (SLC) transporters other than the organic anion transporting polypeptides (OATPs)1B1, 1B3, 2B1, and 1A2, which this leads to increased MCP-1 expression in the colon through activating JNK. Thus, increased MCP-1 expression induced by microcystin-LR might be a trigger for initiating tumorigenesis with inflammation in the colon because increased MCP-1 expression induces inflammation associated with macrophage infiltration into the colon, and chronic inflammation is associated with the initiation of tumorigenesis.

TLR4 may be a novel indole-3-acetic acid receptor that is implicated in the regulation of CYP1A1 and TNFα expression depending on the culture stage of Caco-2 cells.

Most studies of indole derivatives such as IAA produced by intestinal microbiota have been based on the premise that binding to AhR leads to biological responses. We previously revealed that IAA binds to more than one receptor, and thus the present study aimed to identify a new receptor for IAA and analyze its mechanism of action. We found that the TLR4 antagonist TAK-242 did not affect the IAA-induced increase in CYP1A1 expression at 3 h and decreased TNFα expression at 8 days. However, TAK-242 alleviated decreased TNFα expression induced by IAA at 2 days and promoted IAA-induced increased CYP1A1 expression by inhibiting JNK activation at 8 days. Taken together, TLR4 may be a novel IAA receptor with signaling pathways that regulate CYP1A1 and TNFα expression depending on the culture stage of Caco-2 cells. Furthermore, our findings offer important clues for elucidating the action mechanisms of indole derivatives that affect hosts.

Suppression of TNFα expression induced by indole-3-acetic acid is not mediated by AhR activation in Caco-2 cells.

Indole-3-acetic acid (IAA) produced by intestinal bacteria from tryptophan in dietary proteins is considered to suppress the inflammatory response through aryl hydrocarbon receptor (AhR) activation. However, AhR activation was not involved in the downregulation of tumor necrosis factor α (TNFα) expression induced by IAA in Caco-2 cells. The activation of unidentified IAA receptors might attenuate the inflammatory response to TNFα in colorectal cancer cells.

Thermal stability and bioavailability of inclusion complexes of perilla oil with γ-cyclodextrin.

Perilla oil is abundant in α-linolenic acid, which is metabolized to long-chain n-3 fatty acids. This study aimed to determine thermal stability and bioavailability of perilla oil that was powdered by inclusion complexation with γ-cyclodextrin. Fatty acid analysis revealed that the relative abundance of α-linolenic and linoleic acids in the complexes was not affected by heating at 40 °C for six days but decreased after heating at 60 °C for three days. No adverse events occurred in rats fed with an experimental diet containing the complexes for two weeks. Plasma α-linolenic and eicosapentaenoic acids in rats fed with diets containing complexes and liquid perilla oil were equally high, indicating the preserved bioavailability of perilla oil in the complexes. Plasma arachidonic acid decreased only in rats fed with a diet containing the complexes. Results suggest that the complexes have potential as a useful source of α-linolenic acid to increase plasma n-3 fatty acids.

Skatole regulates intestinal epithelial cellular functions through activating aryl hydrocarbon receptors and p38.

Intestinal bacteria produce skatole (3-methylindole) from tryptophan in dietary proteins and ingesting large quantities of animal protein is associated with increased fecal skatole concentrations. Although possibly associated with disrupted intestinal homeostasis, the influence of skatole on intestinal epithelial cellular function has not been characterized in detail. The present study aimed to determine whether skatole induces intestinal epithelial cell (IEC) dysfunction. We found that skatole dose-dependently caused IEC death and time-dependently induced IEC apoptosis. Since skatole directly interacts with aryl hydrocarbon receptors (AhR), we investigated whether these receptors influence the skatole-induced death of IEC. In addition to increased AhR transcriptional activity induced by skatole, the AhR antagonist CH223191 partially suppressed of skatole-induced IEC death. Extracellular signal-related kinase (ERK), p38 and c-Jun N-terminal kinase (JNK) are mitogen-activated protein kinases (MAPK) induced by skatole. None of them were repressed by CH223191, whereas the p38 inhibitor SB203580 promoted skatole-induced IEC death. These findings together indicated that skatole induces both AhR-dependent activation pathways and the AhR-independent activation of p38, consequently regulating the amount of IEC death. Accumulating evidence indicates that consuming large amounts of animal protein is associated with the pathogenesis and progression of inflammatory bowel diseases (IBD). Thus, intestinal skatole production induced by large amounts of dietary animal protein might be associated via IEC death with intestinal pathologies such as IBD.

Predictors of time to discharge in patients hospitalized for behavioral and psychological symptoms of dementia.

BACKGROUND/AIMS: In Japan, more than 50,000 patients with dementia are housed in psychiatric facilities, a trend precipitated by prolonged hospitalizations. This study aimed to determine predictors for the time to discharge in patients hospitalized for behavioral and psychological symptoms of dementia (BPSD). METHODS: Medical charts of patients admitted to an acute psychogeriatric ward for treatment of BPSD were reviewed. Cox's proportional hazards model was used to evaluate relationships between active behavioral problems and/or demographics at the time of admission, and the time until favorable discharge (FD), defined as discharge to the patient's own home or a care facility. RESULTS: For the 402 study patients included in this study, median time to FD was 101 days. In addition to family and residential factors, multivariate analysis identified higher Mini-Mental State Examination scores as independent clinical predictors for a shorter hospital stay, whereas male gender and combative behavior as the primary reason for hospital admission were predictors for a longer hospital stay. CONCLUSION: Clinical characteristics can be predictive of the time to discharge for patients with BPSD. Earlier interventions and enhanced care strategies may be needed for patients with a lower likelihood of FD.

Gender differences in clinical manifestations and outcomes among hospitalized patients with behavioral and psychological symptoms of dementia.

OBJECTIVE: To clarify whether hospitalized patients with behavioral and psychological symptoms of dementia (BPSD) show gender differences in manifested symptoms and outcomes. METHOD: A chart review study of patients hospitalized from April 2006 to March 2008 for the treatment of BPSD was conducted. We evaluated the prevalence of symptoms in each of 7 clusters constituting a subscale of the Behavioral Pathology in Alzheimer's Disease Rating Scale and the incidence of favorable discharge, defined as discharge to the patient's own home or care facility. Dementia was diagnosed according to DSM-IV. RESULTS: The study cohort comprised 122 men and 170 women. The men were more likely than the women to present with aggressiveness (78% vs 52%, P < .001) and diurnal rhythm disturbances (89% vs 79%, P < .05) and less likely to present with paranoid, delusional ideation (12% vs 41%, P < .001); hallucination (7% vs 29%, P < .001); affective disturbances (20% vs 40%, P < .001); and anxieties and phobias (15% vs 44%, P < .001). Incidence of favorable discharge was lower in the men (58% vs 77%, P = .001). Even after matching for age, sociodemographic factors, and physical and cognitive functions, the differences in these symptoms persisted, with the exception of diurnal rhythm disturbances. Incidence of favorable discharge was lower in the men (60% vs 77%, P = .0173). CONCLUSION: The data demonstrated gender differences in BPSD and outcomes among hospitalized patients. The findings should be considered when deciding on the optimal management plan for patients with BPSD.

'Time slip' phenomenon in adolescents and adults with autism spectrum disorders: case series.

In recent years, it has been noticed that adolescent and adult patients with autism spectrum disorder (ASD) sometimes visit psychiatric medical institutions. In some cases, these patients commit an act of violence and are dealt with by psychiatric emergency and forensic psychiatric services. In this report, we present two cases with ASD who visited a psychiatric emergency service because of the 'time slip' phenomenon, and discuss the clinical significance of this phenomenon.

Late-life bipolar depression due to the soft form of bipolar disorder compared to unipolar depression: an inpatient chart review study.

BACKGROUND: Several studies have been conducted regarding the clinical features of the manic state in elderly patients with bipolar disorder; however, little information is available about bipolar depression in these patients, especially depression related to bipolar II disorder (BP-II) and bipolar disorder not otherwise specified (BP-NOS). METHODS: A chart review study of 87 patients (age > or = 60 years) hospitalized due to a major depressive episode (MDE) was conducted. RESULTS: Thirty-two (36.8%) and 55 (63.2%) patients were diagnosed with bipolar disorder and major depressive disorder (MDD), respectively. BP-II/BP-NOS accounted for 81.3% of bipolar disorder and 29.9% of MDE. Of the 26 BP-II/BP-NOS patients, 73% had been initially diagnosed with MDD (61.0%) or others (12.0%). Compared to MDD patients, BP-II/BP-NOS patients showed a significantly younger age-at-onset of the first MDE (median, 52 vs. 66 years, p=0.000) and significantly more frequent MDEs (median, 3 vs. 1, p=0.000). The depressed mixed state (DMX) was observed in 61.5% of BP-II/BP-NOS patients in contrast to only 16.4% of MDD patients (p=0.000). The multiple logistic regression analysis revealed that younger age at onset of first MDE and DMX were independent markers of bipolarity. LIMITATIONS: Certain features were retrospectively specified by a single reviewer. CONCLUSION: Late-life depression due to BP-II/BP-NOS is generally misdiagnosed, but should never be neglected in elderly inpatients. Some features of the depression suggest bipolarity. In particular, DMX was found to be an independent marker of bipolarity, which supports the mixed nature of this disorder across generations.

Lactate production and neurotransmitters; evidence from microdialysis studies.

Recent studies have found that lactate metabolism plays a significant role in energy supply during acute neural activation in the brain. We will review evidence from microdialysis studies for a relationship between neurotransmitters and lactate production, as revealed in studies of the effects of psychotropic drugs on stress-induced enhancement of extracellular lactate concentrations. Glutamate enhances stress-induced lactate production via activation of N-methyl-D-asparate receptors, and is affected by uptake of glutamate through glutamate transporters. Findings from microdialysis studies suggest that major neurotransmitters, including norepinephrine, dopamine, serotonin, and GABA (via benzodiazepine-receptors) affect lactate production, depending on brain areas, especially during stress. Among these neurotransmitters, glutamate may principally contribute to the regulation of lactate production, with other neurotransmitter systems affecting the extracellular lactate levels in a glutamate-mediated manner. The role for anaerobic metabolism in the supply of energy, as represented by lactate dynamics, deserves further clarification. Monitoring with intracerebral microdialysis is a reliable method for this purpose. Research into this area is likely to provide a novel insight into the mode of action of psychotropic drugs, and the pathophysiology of some of the stress-related mental disorders as well.