Risperidone ameliorated 1,2-Diacetylbenzene-induced cognitive impairments in mice via activating prolactin signaling pathways.

Cognitive impairment and organic solvent exposure have been becoming public health concerns due to an increasingly aging population, increased life expectancy, urbanization, and industrialization. Converging evidence indicates the link between 1,2-diacetylbenzene (DAB), prolactin (PRL), risperidone, and cognitive impairment. However, these relationships remain unclear. We investigated the therapeutic properties of risperidone in DAB-induced cognitive impairment using both in vivo and in silico methods. Risperidone alleviated DAB-induced cognitive impairment in hippocampal mice, possibly by inhibiting GSK-3ß, ß-amyloid, CDK5, BACE, and tau hyperphosphorylation. Risperidone also attenuated the activation of TREM-1/DAP12/NLRP3/caspase-1/IL-1ß, and TLR4/NF-κB pathways caused by DAB. Furthermore, risperidone inhibited DAB-induced oxidative stress, advanced glycation end products, and proinflammatory cytokines, as well as increased the expression of Nrf2, IL-10, Stat3, MDM2, and catalase activity. On the other hand, risperidone activated the expression of IRS1, PI3K, AKT, BDNF, Drd2, Scna5, and Trt as well as reduced the Bax/Bcl2 ratio and Caspase-3 levels. In silico analyses identified the prolactin signaling pathway, miR-155-5p, miR-34a-5p, and CEBPB as the main molecular mechanisms involved in the pathophysiology of DAB-induced cognitive impairment and targeted by risperidone. Our results suggest that risperidone could be used to treat cognitive impairment caused by organic solvents, especially DAB.

In silico identification of the potential molecular mechanisms involved in protective effects of prolactin on motor and memory deficits induced by 1,2-Diacetylbenzene in young and old rats.

We aimed to identify the molecular mechanisms through which prolactin protects against 1,2-Diacetylbenzene (DAB)-induced memory and motor impairments. The gene expression omnibus database (no. GSE119435), transcriptomic data, GeneMANIA, ToppGeneSuite, Metascape, STRING database, Cytoscape, and Autodock were used as the core tools in in-silico analyses. We observed that prolactin may improve memory and motor deficits caused by DAB via 13 genes (Scn5a, Lmntd1, LOC100360619, Rgs9, Srpk3, Syndig1l, Gpr88, Egr2, Ctxn3, Drd2, Ttr, Gpr6, and Ecel1) in young rats and 9 genes (Scn5a, Chat, RGD1560608, Ucma, Lrrc31, Gpr88, Col1a2, Cnbd1, and Ttr) in old rats. Almost all of these genes were downregulated in both young and old rats given DAB, but they were increased in both young and old rats given prolactin. Co-expression interactions were identified as the most important interactions (83.2 % for young rats and 100 % for old rats). The most important mechanisms associated with prolactin's ability to counteract DAB were identified, including "learning and memory," and "positive regulation of ion transport" in young rats, as well as "acetylcholine related pathways," "inflammatory response pathway," and "neurotransmitter release cycle" in old rats. We also identified several key miRNAs associated with memory and motor deficits, as well as prolactin and DAB exposure (rno-miR-141-3p, rno-miR-200a-3p, rno-miR-124-3p, rno-miR-26, and rno-let-7 families). The most significant transcription factors associated with differentially expressed gene regulation were Six3, Rxrg, Nkx26, and Tbx20. These findings will contribute to our understanding of the processes through which prolactin's beneficial effects counteract DAB-induced memory and motor deficits.

Curcumin-Attenuated TREM-1/DAP12/NLRP3/Caspase-1/IL1B, TLR4/NF-κB Pathways, and Tau Hyperphosphorylation Induced by 1,2-Diacetyl Benzene: An in Vitro and in Silico Study.

We aimed to evaluate the effects of 1,2-diacetylbenzene (DAB) and curcumin on neuroinflammation induced by DAB via triggering receptor expressed on myeloid cells 1 (TREM-1), Toll-like receptor 4 (TLR4), and NLR family pyrin domain containing 3 (NLP3)/calcium-dependent activator protein for secretion 1 (CAPS1)/interleukin 1 beta (IL1B) pathways; tau hyperphosphorylation; reactive oxygen species (ROS); and advanced glycation end-product (AGE) in microglia cells; and explore the molecular mechanisms involved in the key genes induced by DAB and targeted by curcumin in silico analysis. In this study, Western blot, quantitative polymerase chain reaction, and immunocytochemistry were used as the key methods in vitro. In silico analysis, GeneMANIA, ToppFun feature, Metascape, CHEA3, Cytoscape, Autodock, and MIENTURNET were the core approaches used. Curcumin inhibited both the DAB-induced TREM-1/DAP12/NLRP3/caspase-1/IL1B pathway and the TLR4/NF-κB pathway. In BV2 cells, curcumin inhibited ROS, AGE, hyperphosphorylation, glycogen synthase kinase-3ß (GSK-3ß), and ß-amyloid while activating nuclear factor erythroid 2-related factor 2 (Nrf2) expression. In silico studies showed that tumor necrosis factor (TNF), IL6, NFKB1, IL10, and IL1B, as well as MTF1 and ZNF267, were shown to be important genes and transcription factors in the pathogenesis of cognitive impairment produced by DAB and curcumin. Three significant miRNAs (hsa-miR-26a-5p, hsa-miR-203a-3p, and hsa-miR-155-5p) implicated in the etiology of DAB-induced cognitive impairment and targeted by curcumin were also identified. Inflammation and cytokine-associated pathways, Alzheimer's disease, and cognitive impairment were characterized as the most significant biological processes implicated in genes, miRNAs, and transcription factors induced by DAB and targeted by curcumin. Our findings provide new insight into fundamental molecular mechanisms implicated in the pathogenesis of cognitive impairment caused by DAB, particularly the effects of neuroinflammation. Furthermore, this study suggests that curcumin might be a promising therapeutic molecule for cognitive impairment treatment through modulating neuroinflammatory responses.

1,2-Diacetylbenzene impaired hippocampal memory by activating proinflammatory cytokines and upregulating the prolactin pathway: An in vivo and in vitro study.

Memory loss is the most common occurrence of dementia in the elderly population. Evidence shows 1,2-Diacetylbenzene (DAB) can exacerbate cerebral dysfunction. The molecular mechanisms involved in DAB actions in the hippocampus have not been well elucidated to date. qPCR, western blot, Morris water maze, and RNAseq analysis were used to identify the association between inflammation and hyperphosphorylated tau in male DAB-treated mice (1 or 5 mg/kg/day), rats (3 mg/kg/day), in vitro BV2 microglial cells (1 or 5 µM), and the hippocampal transcriptome of male DAB-treated rats. We found that DAB induces memory deficits by activating pro-inflammatory cytokines as well as down-regulating memory and learning genes. Several genes involved in learning, memory, and behavior induced by DAB (e.g., PRL, Pit-1, PRLR, Ttr, Notch2, Ntsr1, C5ar2, Cd74) were not changed or downregulated in young rats, but upregulated in old rats. Detoxification pathways were upregulated in young rats treated with DAB, whereas prolactin (PRL) signaling pathways were upregulated in old DAB-treated rats. Further work is needed to gain a better understanding of the roles of PRL during aging.

Associations among the TREM-1 Pathway, Tau Hyperphosphorylation, Prolactin Expression, and Metformin in Diabetes Mice.

INTRODUCTION: Diabetes mellitus (DM) is a risk factor for Alzheimer's disease (AD). Increasing evidence indicates that the triggering receptor expressed on myeloid cells (TREM)-1 amplifies chronic inflammation, as well as the roles of prolactin (PRL) and metformin (MET) in tau hyperphosphorylation. However, the associations among TREM-1, tau hyperphosphorylation, PRL expression, and MET in DM remain unclear. METHODS: Streptozotocin was used to induce experimental DM in C57BL/6N mice. MET was orally administered at a dose of 400 mg/kg body weight for 6 weeks prior to hippocampal collection in DM mice. Various parameters pertaining to the TREM-1 pathway, tau hyperphosphorylation, PRL, and related factors were analyzed. RESULTS: Quantitative polymerase chain reaction and Western blot analysis demonstrated that the expression levels of TREM-1, DAP12, casp1, interleukin-1ß, Cox2, inducible nitric oxide synthase, pituitary transcriptional factor-1 (Pit-1), and PRL were significantly increased in the hippocampus of DM mice; the expression levels of these pro-inflammatory mediators, PRL receptor (PRLR) short or long (PRLR-S and PRLR-L), and PRL regulatory element-binding (Preb) protein in DM mice treated with MET (DM + MET) were significantly decreased compared with those in control (CON) mice. The levels of p-Tau and glycogen synthase kinase-3 in the DM group were significantly higher than those in the CON group and significantly lower than those in the DM + MET group. CONCLUSION: We confirmed the therapeutic potential of MET for both DM and neurodegeneration. Our findings shed new light on the effects of DM on the pathophysiology of AD via the TREM-1 pathway and PRL expression. Thus, an improved understanding of the TREM-1 pathway in hyperglycemic conditions, as well as PRL, Preb, Pit-1, PRLR-L, and PRLR-S gene expression in the liver, brain, and other sites, may help unravel the pathogenesis of insulin resistance and neurodegeneration.

Mixtures modeling identifies heavy metals and pyrethroid insecticide metabolites associated with obesity.

We aim to examine the association between chemical mixtures and obesity. Blood and urinary levels of tween-six chemicals were measured in adults who participated in the KoNEHS. We identified the associations of chemicals with obesity using linear regression models. Weighted quantile sum (WQS) regression, quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR) were conducted as secondary analyses. Of the 3,692 participants included in the analysis, 18.0% had obesity. In the logistic regression model, mercury (Hg), lead (Pb), and 3PBA levels were associated with obesity, and significant trends were observed for these chemical tertiles (p < 0.001). Hg, Pb, and 3PBA levels were also associated with BMI. The WQS index was significantly associated with both obesity (OR = 2.15, 95% CI: 2.11-2.20) and BMI (ß = 0.39, 95% CI: 0.37-0.51). The qgcomp index also found a significant association between chemicals and both obesity (OR = 1.70, 95% CI: 1.56-1.85) and BMI (ß = 0.40, 95% CI: 0.39-0.41). Hg, Pb, and 3PBA were the most heavily weighed chemicals in these models. In BKMR analysis, the overall effect of the mixture was significantly associated with obesity. Hg, Pb, and 3PBA showed positive trends and were observed as the most important factors associated with obesity. Given increasing exposure to chemicals, there is a need to investigate the associations between chemical exposures, either separately or together, and incident obesity risk factors in well-characterized cohorts of different populations, and to identify potential approaches to chemical exposure prevention.

Association between Serum Prolactin Levels and Neurodegenerative Diseases: Systematic Review and Meta-Analysis.

INTRODUCTION: Prolactin (PRL) exerts inflammatory and anti-inflammatory properties and is also thought to play an important role in the pathogenesis of neurodegenerative diseases (NDs). However, serum PRL levels in patients with NDs were inconsistent in the research literature. OBJECTIVE: We aimed to assess the serum PRL levels in patients with NDs. METHODS: Electronic databases, including MEDLINE, Embase, Cochrane Library database, clinicaltrials.gov, Web of Science, and Google Scholar, and reference lists of articles were searched up to December 31, 2020. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by fixed-effect or random-effect model analysis. RESULTS: A total of 36 comparisons out of 29 studies (3 RCTs and 26 case controls) focusing on NDs (including Parkinson's disease, Alzheimer's disease, Huntington's disease [HD], multiple sclerosis [MS], and epilepsy) were reported. The meta-analysis showed that there was no statistically significant difference in serum PRL levels between patients with NDs and healthy controls (SMD = 0.40, 95% CI: -0.16 to 0.96, p = 0.16). Subgroup analysis showed that serum PRL levels in patients with HD and MS were higher than those of healthy controls. Furthermore, patients with NDs aged <45 years had higher serum PRL levels (SMD = 0.97, 95% CI: 0.16-1.78, p = 0.018) than healthy controls. High serum PRL levels were found in subgroups such as the microenzymatic method, Asia, and the Americas. CONCLUSIONS: Our meta-analysis showed serum PRL levels in patients with HD and MS were significantly higher than those in healthy controls. Serum PRL levels were associated with age, region, and detection method. Other larger sample studies using more uniform detection methods are necessary to confirm our results.

Environmental science and pollution research role of heavy metal concentrations and vitamin intake from food in depression: a national cross-sectional study (2009-2017).

Little is known about associations between depression and serum heavy metal levels, dietary vitamin intakes. Thus, we sought to determine the nature of these associations and to predict risks of depression using marginal effects. A data set of 16,371 individuals aged ≥10 years that participated in Korea National Health and Nutrition Examination Surveys (KNHANES) conducted from 2009 to 2017 (excluding 2014 and 2015) was used to obtain information on sociodemographics, family histories, lifestyles, serum heavy metal levels, food intakes, and depression. Serum cadmium (Cd) and lead (Pb) levels were analyzed by graphite furnace atomic absorption spectrometry and mercury (Hg) levels using a mercury analyzer. Daily vitamin intakes were calculated by 24-h dietary recall. The results obtained showed that females are at higher risk of depression than males. A doubling of serum Cd was associated with a 21% increase in depression (AOR 1.21, 95% CI: 1.07-1.37, p = 0.002), whereas twofold increases in daily vitamin B1, B3 and vitamin A intakes reduced the risk of depression by 17% (0.83, 95% CI: 0.73-0.95, p = 0.005), 20% (0.80, 95% CI: 0.70-0.91, p = 0.001), and 8% (0.92, 95% CI: 0.85-0.99, p = 0.020), respectively. Interactions between heavy metals, vitamin intakes, and sex did not influence the risk of depression. The result shows that increased daily dietary vitamin intake might protect the public against depression. Further studies are needed to reduce the risks posed by heavy metals and to determine more comprehensively the effects of daily dietary vitamin intake on depression.

Prolactin and Its Altered Action in Alzheimer's Disease and Parkinson's Disease.

BACKGROUND: Prolactin (PRL) is one of the most diverse pituitary hormones and is known to modulate normal neuronal function and neurodegenerative conditions. Many studies have described the influence that PRL has on the central nervous system and addressed its contribution to neurodegeneration, but little is known about the mechanisms responsible for the effects of PRL on neurodegenerative disorders, especially on Alzheimer's disease (AD) and Parkinson's disease (PD). SUMMARY: We review and summarize the existing literature and current understanding of the roles of PRL on various PRL aspects of AD and PD. KEY MESSAGES: In general, PRL is viewed as a promising molecule for the treatment of AD and PD. Modulation of PRL functions and targeting of immune mechanisms are needed to devise preventive or therapeutic strategies.

Associations between Prolactin, Diabetes, and Cognitive Impairment: A Literature Review.

BACKGROUND: Converging evidence indicates prolactin (PRL) and diabetes play an important role in the pathophysiology of cognitive impairment. However, little is known about the mechanisms responsible for the effects of PRL and diabetes on cognitive impairment. SUMMARY: We summarize and review the available literature and current knowledge of the association between PRL and diabetes on aspects of cognitive impairment. KEY MESSAGES: The phosphatidylinositol 3-kinase/protein kinase B pathway is central to the molecular mechanisms underlying how PRL and diabetes interact in cognitive impairment. Further work is needed to identify the interaction between PRL and diabetes, especially in the molecular aspects of cognitive impairment, which can suggest novel strategies for cognitive dysfunction treatment.