What Can Inflammation Tell Us about Therapeutic Strategies for Parkinson's Disease?

Parkinson's disease (PD) is a common neurodegenerative disorder with a complicated etiology and pathogenesis. α-Synuclein aggregation, dopaminergic (DA) neuron loss, mitochondrial injury, oxidative stress, and inflammation are involved in the process of PD. Neuroinflammation has been recognized as a key element in the initiation and progression of PD. In this review, we summarize the inflammatory response and pathogenic mechanisms of PD. Additionally, we describe the potential anti-inflammatory therapies, including nod-like receptor pyrin domain containing protein 3 (NLRP3) inflammasome inhibition, nuclear factor κB (NF-κB) inhibition, microglia inhibition, astrocyte inhibition, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibition, the peroxisome proliferator-activated receptor γ (PPARγ) agonist, targeting the mitogen-activated protein kinase (MAPK) pathway, targeting the adenosine monophosphate-activated protein kinase (AMPK)-dependent pathway, targeting α-synuclein, targeting miRNA, acupuncture, and exercise. The review focuses on inflammation and will help in designing new prevention strategies for PD.

Toxic Effects and Mechanisms of Polybrominated Diphenyl Ethers.

Polybrominated diphenyl ethers (PBDEs) are a group of flame retardants used in plastics, textiles, polyurethane foam, and other materials. They contain two halogenated aromatic rings bonded by an ester bond and are classified according to the number and position of bromine atoms. Due to their widespread use, PBDEs have been detected in soil, air, water, dust, and animal tissues. Besides, PBDEs have been found in various tissues, including liver, kidney, adipose, brain, breast milk and plasma. The continued accumulation of PBDEs has raised concerns about their potential toxicity, including hepatotoxicity, kidney toxicity, gut toxicity, thyroid toxicity, embryotoxicity, reproductive toxicity, neurotoxicity, and immunotoxicity. Previous studies have suggested that there may be various mechanisms contributing to PBDEs toxicity. The present study aimed to outline PBDEs' toxic effects and mechanisms on different organ systems. Given PBDEs' bioaccumulation and adverse impacts on human health and other living organisms, we summarize PBDEs' effects and potential toxicity mechanisms and tend to broaden the horizons to facilitate the design of new prevention strategies for PBDEs-induced toxicity.

Drosophila ZIP13 over-expression or transferrin1 RNAi influences the muscle degeneration of Pink1 RNAi by elevating iron levels in mitochondria.

Disruption of iron homeostasis in the brain of Parkinson's disease (PD) patients has been reported for many years, but the underlying mechanisms remain unclear. To investigate iron metabolism genes related to PTEN-induced kinase 1 (Pink1) and parkin (E3 ubiquitin ligase), two PD-associated proteins that function to coordinate mitochondrial turnover via induction of selective mitophagy, we conducted a genetic screen in Drosophila and found that altered expression of genes involved in iron metabolism, such as Drosophila ZIP13 (dZIP13) or transferrin1 (Tsf1), significantly influences the disease progression related to Pink1 but not parkin. Several phenotypes of Pink1 mutant and Pink1 RNAi but not parkin mutant were significantly rescued by over-expression (OE) of dZIP13 (dZIP13 OE) or silencing of Tsf1 (Tsf1 RNAi) in the flight muscles. The rescue effects of dZIP13 OE or Tsf1 RNAi were not exerted through mitochondrial disruption or mitophagy; instead, the iron levels in mitochondira were significantly increased, resulting in enhanced activities of enzymes participating in respiration and increased ATP synthesis. Consistently, the rescue effects of dZIP13 OE or Tsf1 RNAi on Pink1 RNAi can be inhibited by decreasing the iron levels in mitochondria through mitoferrin (dmfrn) RNAi. This study suggests that dZIP13, Tsf1, and dmfrn might act independently of parkin in a parallel pathway downstream of Pink1 by modulating respiration and indicates that manipulation of iron levels in mitochondria may provide a novel therapeutic strategy for PD associated with Pink1.

EGCG ameliorates neuronal and behavioral defects by remodeling gut microbiota and TotM expression in Drosophila models of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Eigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, is known to exert a beneficial effect on PD patients. Although some mechanisms were suggested to underlie this intervention, it remains unknown if the EGCG-mediated protection was achieved by remodeling gut microbiota. In the present study, 0.1 mM or 0.5 mM EGCG was administered to the Drosophila melanogaster with PINK1 (PTEN induced putative kinase 1) mutations, a prototype PD model, and their behavioral performances, as well as neuronal/mitochondrial morphology (only for 0.5 mM EGCG treatment) were determined. According to the results, the mutant PINK1B9 flies exhibited dopaminergic, survival, and behavioral deficits, which were rescued by EGCG supplementation. Meanwhile, EGCG resulted in profound changes in gut microbial compositions in PINK1B9 flies, restoring the abundance of a set of bacteria. Notably, EGCG protection was blunted when gut microbiota was disrupted by antibiotics. We further isolated four bacterial strains from fly guts and the supplementation of individual Lactobacillus plantarum or Acetobacter pomorum strain exacerbated the neuronal and behavioral dysfunction of PD flies, which could not be rescued by EGCG. Transcriptomic analysis identified TotM as the central gene responding to EGCG or microbial manipulations. Genetic ablation of TotM blocked the recovery activity of EGCG, suggesting that EGCG-mediated protection warrants TotM. Apart from familial form, EGCG was also potent in improving sporadic PD symptoms induced by rotenone treatment, wherein gut microbiota shared regulatory roles. Together, our results suggest the relevance of the gut microbiota-TotM pathway in EGCG-mediated neuroprotection, providing insight into indirect mechanisms underlying nutritional intervention of Parkinson's disease.

Transferrin1 modulates rotenone-induced Parkinson's disease through affecting iron homeostasis in Drosophila melanogaster.

Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in Parkinson's disease (PD). In recent years, environmental toxins are employed to increase oxidative stress mediated neuropathology and sporadic PD. Disruption of iron homeostasis has been implicated in PD patients for many years, but the functional role of iron in sporadic PD pathogenesis is still not well clarified in vivo. To address this question, we set out to investigate the effect of iron on a Drosophila rotenone model of sporadic PD. Iron homeostasis is maintained by many transporters. We found that inhibition of transferrin1 (Tsf1) expression in the central nervous system (CNS) results in reduced iron levels in brains and significantly ameliorates the neurodegenerative phenotypes of rotenone exposure Drosophila; moreover, the rotenone induced reactive oxygen species (ROS) levels in the brain, the damaged complex I activity and the decreased ATP generation were dramatically rescued by Tsf1 knockdown. Further study indicated that all the rescue effects of Tsf1 knockdown on sporadic PD could be inhibited by malvolio (Mvl) overexpression, an iron transporter responsible for iron uptake. These results imply that Tsf1 knockdown in the CNS could attenuate rotenone toxicity by decreasing the ROS levels in brains through reducing iron levels, and manipulation of iron transporters in brains may provide a novel therapeutic strategy for sporadic PD.

Causal relationships between blood metabolites and diabetic retinopathy: a two-sample Mendelian randomization study.

Background: Diabetic retinopathy (DR) is a microvascular complication of diabetes, severely affecting patients' vision and even leading to blindness. The development of DR is influenced by metabolic disturbance and genetic factors, including gene polymorphisms. The research aimed to uncover the causal relationships between blood metabolites and DR. Methods: The two-sample mendelian randomization (MR) analysis was employed to estimate the causality of blood metabolites on DR. The genetic variables for exposure were obtained from the genome-wide association study (GWAS) dataset of 486 blood metabolites, while the genetic predictors for outcomes including all-stage DR (All DR), non-proliferative DR (NPDR) and proliferative DR (PDR) were derived from the FinnGen database. The primary analysis employed inverse variance weighted (IVW) method, and supplementary analyses were performed using MR-Egger, weighted median (WM), simple mode and weighted mode methods. Additionally, MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis were also conducted to guarantee the accuracy and robustness of the results. Subsequently, we replicated the MR analysis using three additional datasets from the FinnGen database and conducted a meta-analysis to determine blood metabolites associated with DR. Finally, reverse MR analysis and metabolic pathway analysis were performed. Results: The study identified 13 blood metabolites associated with All DR, 9 blood metabolites associated with NPDR and 12 blood metabolites associated with PDR. In summary, a total of 21 blood metabolites were identified as having potential causal relationships with DR. Additionally, we identified 4 metabolic pathways that are related to DR. Conclusion: The research revealed a number of blood metabolites and metabolic pathways that are causally associated with DR, which holds significant importance for screening and prevention of DR. However, it is noteworthy that these causal relationships should be validated in larger cohorts and experiments.

SIRT4 prevents hypoxia-induced apoptosis in H9c2 cardiomyoblast cells.

AIMS: Apoptosis plays a critical role in cardiomyocyte loss during ischaemic heart injury. A detailed understanding of the mechanism involved has a substantial impact on the optimization and development of treatment strategies. Here, we report that the expression of SIRT4, a mitochondrial sirtuin, is markedly down-regulated in hypoxia-induced apoptosis of H9c2 cardiomyoblast cells. METHODS AND RESULTS: SIRT4 interference significantly alters H9c2 cell viability, apoptotic cell number and caspase-3/7 activity. Furthermore, SIRT4 expression can affect the ratio of pro-caspase 9/caspase 9 or pro-caspase 3/caspase 3, an affect Bax translocation, which in turn alters the development of H9c2 cell apoptosis. CONCLUSION: These results suggest that SIRT4 is a key player in hypoxia-induced cardiomyocyte apoptosis, and that strategies based on its enhancement might be of benefit in the treatment of ischaemic heart disease.

The Potential of ANK1 to Predict Parkinson's Disease.

The main cause of Parkinson's disease (PD) remains unknown and the pathologic changes in the brain limit rapid diagnosis. Herein, differentially expressed genes (DEGs) in the Gene Expression Omnibus (GEO) database (GSE8397 and GSE22491) were assessed using linear models for microarray analysis (limma). Ankyrin 1 (ANK1) was the only common gene differentially down-regulated in lateral substantia nigra (LSN), medial substantia nigra (MSN) and blood. Additionally, DEGs between high ANK1 and low ANK1 in GSE99039 were picked out and then uploaded to the Database for Annotation, Visualization and Integrated Discovery (DAVID) for gene ontology (GO) functional annotation analysis. GO analysis displayed that these DEGs were mainly enriched in oxygen transport, myeloid cell development and gas transport (biological process (BP)); hemoglobin complex, haptoglobin-hemoglobin complex and cortical cytoskeleton (cellular component (CC)); and oxygen transporter activity, haptoglobin binding and oxygen binding (molecular function (MF)). Receiver operating characteristic (ROC) curve analysis showed ANK1 had good diagnostic accuracy and increased the area under the curve (AUC) value when combined with other biomarkers. Consistently, intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropy-ridi-ne (MPTP) in C57BL/6J mice reduced ANK1 mRNA expression in both substantia nigra and blood compared to the control group. Thus, ANK1 may serve as a candidate biomarker for PD diagnosis.

3% diquafosol sodium eye drops in Chinese patients with dry eye: a phase IV study.

Introduction: The efficacy and safety of 3% diquafosol sodium eye drops in Chinese patients with dry eye in the real-world setting remains unclear. Methods: 3099 patients with dry eye symptoms were screened according to Asia Dry Eye Society latest recommendation. Among them, 3000 patients were enrolled for a phase IV study. We followed up with multiple clinical characteristics including corneal fluorescein staining, tear break up time, Schirmer's tests, visual acuity, intraocular pressure, and others. The follow ups were performed at baseline, 2 weeks and 4 weeks after treatment. Results: Based on the results of corneal fluorescein staining and tear break up time, all age and gender subgroups exhibited obvious alleviation of the symptoms among the patients with dry eye, and the data in elderly group showed the most significant alleviation. All the adverse drug reactions (ADRs, 6.17%) were recorded, among which 6% local ocular ADRs were included. Meanwhile, mild ADRs (91.8%) accounted for the most. Most of the ADRs (89.75%) got a quick and full recovery, with an average time at 15.6 days. 1.37% of patients dropped out of the study due to ADRs. Discussion: The use of 3% diquafosol sodium eye drop is effective and safe in the treatment of dry eye, with a low incidence of ADRs showing mild symptoms. This trial was registered at Chinese Clinical Trial Registry ID: ChiCTR1900021999 (Registration Date: 19/03/2019).

Comparison of deep anterior lamellar keratoplasty and corneal cross-linking in patients with advanced keratoconus.

PURPOSE: To compare outcomes of deep anterior lamellar keratoplasty (DALK) and corneal cross-linking (CXL) in patients with advanced keratoconus, with the primary aim of assessing CXL as a potential therapeutic alternative. STUDY DESIGN: Retrospective, multi-center, comparative study. METHODS: Patients with advanced keratoconus (maximum keratometry reading (K-max) > 58D, best spectacle-corrected visual acuity worse than 0.52logMAR), undergoing either DALK or CXL treatment at four tertiary ophthalmic centers in Wenzhou, Hangzhou, Nanjing and Wuhan were included. Visual acuity, refractive error, corneal topography and complications were evaluated at baseline and at least 2 year postoperatively. RESULTS: 75 eyes of 72 patients were included, of which 37 eyes underwent DALK and 38 eyes, CXL. A larger reduction in Kmax was observed in the DALK group (-18.18 ± 9.44 D versus -1.10 ± 2.70D, p < 0.001). Seven eyes (18%) in the CXL group showed progression of keratoconus. No disease progression was observed in the DALK group. Greater improvements in best spectacle-corrected visual acuity (logMAR) were observed in the DALK group (-0.59 ± 0.25 versus -0.24 ± 0.44, p < 0.001). CONCLUSIONS: Compared to CXL, DALK leads to larger reductions in Kmax and better improvement in visual acuity in advanced keratoconus.

The requirement of phosphoenolpyruvate carboxykinase 1 for angiogenesis in vitro and in vivo.

We here examined the potential biological function of phosphoenolpyruvate carboxykinase 1 (PCK1) in angiogenesis. shRNA- or CRISPR-Cas9-induced PCK1 depletion potently inhibited endothelial cell proliferation, migration, sprouting, and tube formation, whereas ectopic PCK1 overexpression exerted opposite activity. In HUVECs, Gαi3 expression and Akt activation were decreased following PCK1 depletion, but were augmented by ectopic PCK1 overexpression. In vivo, retinal expression of PCK1 gradually increased from postnatal day 1 (P1) to P5. The intravitreous injection of endothelial-specific PCK1 shRNA adenovirus at P1 potently inhibited the radial extension of vascular plexus at P5. Conditional endothelial knockdown of PCK1 in adult mouse retina increased vascular leakage and the number of acellular capillaries while decreasing the number of RGCs in murine retinas. In diabetic retinopathy patients, PCK1 mRNA and protein levels were up-regulated in retinal tissues. Together, PCK1 is essential for angiogenesis possibly by mediating Gαi3 expression and Akt activation.

Cyanidin-3-O-glucoside represses tumor growth and invasion in vivo by suppressing autophagy via inhibition of the JNK signaling pathways.

Black bean seed coat extract (BBSCE) contains a high amount of bioactive compounds which can reduce the risk of cancers, but the underlying mechanism remains poorly understood in vivo. Here using a Drosophila model of a malignant tumor, wherein the activated oncogene Raf (RafGOF) cooperates with loss-of-function mutations in the conserved tumor suppressor scribble (scrib-/-), we investigated the antitumor mechanism of BBSCE and its main active component cyanidin-3-O-glucoside (C3G) in vivo. The results showed that supplementation of either BBSCE or C3G inhibited the tumor growth and invasion of RafGOFscrib-/- and extended their survival in a dose dependent manner. Strikingly, the activation of both autonomous and non-autonomous autophagy in tumor flies was significantly reduced by C3G treatment. A further study indicated that C3G exhibited an antitumor effect in vivo by blocking autophagy both in tumor cells and in its microenvironment by inhibiting the JNK pathway. Interestingly, the efficacy of chloroquine (CQ, an autophagy inhibitor used as an antitumor agent) combined with C3G is much better than either C3G or CQ treatment alone. C3G may be combined with CQ to treat cancers and to provide a theoretical basis for functional food or natural medicine development.

Investigation of expression and influence of CTGF and HO-1 in rats with diabetic retinopathy.

The expression and influence mechanism of CTGF and HO-1 in rats with diabetic retinopathy (DR) was investigated. One hundred and thirty male Sprague-Dawley (SD) rats were selected and randomly divided into the control group and DR group, with 65 rats in each group. DR was caused by intraperitoneal injection of streptozotocin in rats in the DR group. There were 55 successful models and 10 failed in the modelling. The successful models were sacrificed at the 2nd, 4th and 6th month, respectively. RT-qPCR technology was used for detection of the expression of CTGF and HO-1 in rat retina in each group, H&E staining for observation of the gradation structure in rat retina and TUNEL method for detection of apoptosis of retinal cells. In the DR group, the retina layers were disordered and a few blood vessels dilated at the 2nd month. In the DR group, the inner membrane of the retina swelled, and the ganglion cells were irregularly arranged at the 4th month. In the DR group, dilatation of the blood vessels was more obvious, the inner membrane edema was more severe, and the arrangement was more irregular at the 6th month. The retinal apoptosis rate of DR rats gradually increased at the 2nd, 4th and 6th month, after which, the CTGF expression gradually increased, but the HO-1 expression gradually decreased in retina in the DR group. However, the mRNA expression of CTGF and HO-1 in the rats at the 2nd, 4th and 6th month in the DR group was higher than that in the control group at the same period. Therefore, CTGF and HO-1 are associated with the occurrence and development of DR in rats and can be considered as targets for the treatment of DR.

The protective effect of polysaccharide extracted from Portulaca oleracea L. against Pb-induced learning and memory impairments in rats.

This paper studied the extraction of polysaccharide from Portulaca oleracea L. (POP) by hot water extraction and ethanol precipitation. Structural properties of the extracted polymers were determined. POP was composed of rhamnose, arabinose and galactose in ratios of 1: 2.34: 3.07 with a molecular weight of 1.55 × 107 Da. The neuroprotective effect of POP on Pb-induced neuronal toxicity was then evaluated in vitro and in vivo test. Treatment with POP markedly increased the survival of PC12 cells and repressed the generation of reactive oxygen species following Pb exposure. In Morris water maze analysis, Pb exposure led to an increase in escape latency and a decrease in platform crossing times of rats in the probe test, which could be attenuated by POP treatment. Additionally, the Pb-induced loss of dendritic spine was recovered after feeding rats with POP at 600 mg/kg/day. These results indicated that Pb-induced cognitive impairments could be inhibited by POP.

L-Menthone confers antidepressant-like effects in an unpredictable chronic mild stress mouse model via NLRP3 inflammasome-mediated inflammatory cytokines and central neurotransmitters.

L-Menthone (MTN) is a Chinese old remedy extracted from the genus Mentha. It has been widely used as a cooling agent and a counterirritant for pain relief, although its antidepressant-like effects have not yet been reported. The present study was designed to investigate whether MTN confers an antidepressant-like effect in mice exposed to unpredictable chronic mild stress (UCMS) and to explore its potential mechanisms. The effects of MTN on mouse behavioral changes were investigated in our study. We determined the levels of the nucleotide binding, oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, inflammatory cytokines and neurotransmitters in the hippocampus of mice. Behavioral tests, including the sucrose preference test (SPT), open field test (OFT), forced swimming test (FST) and tail suspension test (TST) revealed that MTN (15 and 30mg/kg) treatments for 3weeks alleviated the depression symptoms of UCMS in mice. Mice receiving MTN treatments exhibited reduced levels of NLRP3 and caspase-1. Moreover, MTN treatments reversed the UCMS-induced alterations in the concentrations of neurotransmitter norepinephrine (NE) and serotonin (5-HT) and inhibited the expression of pro-inflammatory cytokines (PIC) interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α in the hippocampus of mice. Taken together, our findings suggested that MTN may play a potential antidepressant-like role in the UCMS mouse model by regulating the NLRP3 inflammasome and mediating inflammatory cytokines and central neurotransmitters, which together provide insight towards the development of novel therapeutic treatments for depression.

Geraniol produces antidepressant-like effects in a chronic unpredictable mild stress mice model.

Geraniol (GE), which has neuroprotection and anti-inflammation activities, is mostly abundant in the essential oils of rose, ginger, lemon, orange, lavender etc. However, its antidepressant-like effect has not been reported before. The present study was designed to investigate whether GE confers an antidepressant effect in mice exposed to a chronic unpredictable mild stress (CUMS) model of depression and to explore its possible mechanisms. The results showed that GE treatments for 3 weeks significantly alleviated the depression-related behaviors of CUMS-exposed mice, as indicated by restored decreased sucrose preference and shortened immobile time in both the forced swimming tests (FST) and tail suspension tests (TST). And these ameliorative effects of GE treatment were involved with regulating CUMS-induced pro-inflammatory cytokine interleukin-1 beta (IL-1ß) related neuro-inflammation. We further found that GE treatment reversed CUMS-induced IL-1ß elevation, possibly by inhibiting nuclear factor kappa B (NF-κB) pathway activation and regulating nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome expression. Taken together, our findings suggested that GE exerted a potential antidepressant-like effect in CUMS mice model of depression, which may provide an insight into the potential of GE in therapeutic implications for depression.

Emodin opposes chronic unpredictable mild stress induced depressive-like behavior in mice by upregulating the levels of hippocampal glucocorticoid receptor and brain-derived neurotrophic factor.

Emodin, the major active component of Rhubarb, has shown neuroprotective activity. This study is attempted to investigate whether emodin possesses beneficial effects on chronic unpredictable mild stress (CUMS)-induced behavioral deficits (depression-like behaviors) and explore the possible mechanisms. ICR mice were subjected to chronic unpredictable mild stress for 42 consecutive days. Then, emodin and fluoxetine (positive control drug) were administered for 21 consecutive days at the last three weeks of CUMS procedure. The classical behavioral tests: open field test (OFT), sucrose preference test (SPT), tail suspension test (TST) and forced swimming test (FST) were applied to evaluate the antidepressant effects of emodin. Then plasma corticosterone concentration, hippocampal glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF) levels were tested to probe the mechanisms. Our results indicated that 6 weeks of CUMS exposure induced significant depression-like behavior, with high, plasma corticosterone concentration and low hippocampal GR and BDNF expression levels. Whereas, chronic emodin (20, 40 and 80 mg/kg) treatments reversed the behavioral deficiency induced by CUMS exposure. Treatment with emodin normalized the change of plasma corticosterone level, which demonstrated that emodin could partially restore CUMS-induced HPA axis impairments. Besides, hippocampal GR (mRNA and protein) and BDNF (mRNA) expressions were also up-regulated after emodin treatments. In conclusion, emodin remarkably improved depression-like behavior in CUMS mice and its antidepressant activity is mediated, at least in part, by the up-regulating GR and BDNF levels in hippocampus.

Effects of perillaldehyde on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration.

Perillaldehyde (PAH), a major component of essential oil of Perilla Frutescens, has antidepressant-like effects and anti-inflammatory effects. The present study was designed to determine whether PAH is effective in treating lipopolysaccharide (LPS)-induced depression-like behavior in mice and to explore the possible mechanism between its antidepressant-like effect and anti-inflammatory activity. PAH (60 and 120 mg/kg) and fluoxetine (20mg/kg) were administered intragastrically once daily for 7 consecutive days. In the 7th day, LPS (0.5mg/kg) was injected intraperitoneally 30 min after drug administration. Blood samples were collected 90 min after LPS injection to evaluate serum interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels by enzyme-linked immunosorbent assay (ELISA). Behavioral tests were measured 24h after LPS injection. After the behavioral tests the prefrontal cortex was rapidly dissected from the brain of the sacrificed mice, then the 5-hydroxytryptamine (5-HT) and norepinephrine (NE) levels in prefrontal cortex were determined by HPLC-MS, and IL-6 and TNF-α mRNA expression was measured using quantitative real-time PCR. Our results showed that a single administration of LPS significantly increased the levels of TNF-α and IL-6 in both the serum and the prefrontal cortex and decreased 5-HT and NE levels in the prefrontal cortex in mice. Pretreatment with fluoxetine (20mg/kg) or PAH (60 and 120 mg/kg) could effectively reverse the alterations in the concentrations of 5-HT and NE, and attenuate LPS-induced increases in TNF-α and IL-6 levels. Besides, LPS administration increased the immobility time in tail suspension test (TST) and forced swimming test (FST) without affecting spontaneous locomotor activity. Fluoxetine (20mg/kg) or PAH (60 and 120 mg/kg) significantly shortened LPS-induced increases of immobility time in both TST and FST. In conclusion, PAH exhibited significant antidepressant-like effects in mice with LPS-induced depression. The antidepressant activity of PAH might be related to the alteration of monoaminergic responses and the anti-inflammatory effects.

Tumor necrosis factor-alpha (TNF-α)-mediated in vitro human retinal pigment epithelial (RPE) cell migration mainly requires Akt/mTOR complex 1 (mTORC1), but not mTOR complex 2 (mTORC2) signaling.

When rhegmatogenous retinal detachment occurs, tumor necrosis factor-alpha (TNF-α) among other cytokines leaks into the subretinal space, induces resident retinal pigment epithelial (RPE) cells to migrate, which is the initial step of proliferative vitreoretinopathy (PVR). In the current study, we aim to understand how this is regulated by focusing the cellular mechanisms involved. Here we identified an Akt/Tuberous sclerosis protein 2 (TSC2)/mTOR complex1 (mTORC1) signaling pathway after TNF-α treatment to mediate RPE cell migration. Suppression of mTORC1 activation, either by its inhibitor rapamycin, or by activation of its suppressor AMP activated protein kinase (AMPK), inhibited TNF-α-mediated RPE cell migration, while RNA interference (RNAi)-mediated knocking-down of SIN1 or Rictor, two key components of mTOR complex 2 (mTORC2), had no significant effect on TNF-α-induced RPE cell migration. Our data provide initial evidence that TNF-α-mediated in vitro RPE cell migration mainly requires Akt/mTORC1, but not mTORC2 signaling. The results of this study may lead to indentify novel signaling targets against PVR.