Stellettin B Induces Cell Death in Bladder Cancer Via Activating the Autophagy/DAPK2/Apoptosis Signaling Cascade.

Bladder cancer (BC) is one of the most prevalent cancers worldwide. However, the recurrence rate and five-year survival rate have not been significantly improved in advanced BC, and new therapeutic strategies are urgently needed. The anticancer activity of stellettin B (SP-2), a triterpene isolated from the marine sponge Rhabdastrella sp., was evaluated with the MTT assay as well as PI and Annexin V/7-AAD staining. Detailed mechanisms were elucidated through an NGS analysis, protein arrays, and Western blotting. SP-2 suppressed the viability of BC cells without severe toxicity towards normal uroepithelial cells, and it increased apoptosis with the activation of caspase 3/8/9, PARP, and γH2AX. The phosphorylation of FGFR3 and its downstream targets were downregulated by SP-2. Meanwhile, it induced autophagy in BC cells as evidenced by LC3-II formation and p62 downregulation. The inhibition of autophagy using pharmacological inhibitors or through an ATG5-knockout protected RT-112 cells from SP-2-induced cell viability suppression and apoptosis. In addition, the upregulation of DAPK2 mRNA and protein expression also contributed to SP-2-induced cytotoxicity and apoptosis. In RT-112 cells, an FGFR3-TACC3-knockout caused the downregulation of DAPK2, autophagy, and apoptosis. In conclusion, this is the first study demonstrating that SP-2 exhibits potent anti-BC activity by suppressing the FGFR3-TACC3/Akt/mTOR pathway, which further activates a novel autophagy/DAPK2/apoptosis signaling cascade.

Potential anti-Parkinsonian's effect of S-(+)-linalool from Cinnamomum osmophloeum ct. linalool leaves are associated with mitochondrial regulation via gas-1, nuo-1, and mev-1 in Caenorhabditis elegans.

Parkinson's disease (PD) is one of the prevalent neurodegenerative diseases, and developing new treatments from natural products is of particular interest. Essential oils from Cinnamomum osmophloeum ct. linalool leaves contain high levels (~95%) of S-(+)-linalool. The neuroprotective effects of linalool have been previously described, yet the underlying molecular mechanisms remain largely unknown. This study aimed to investigate the potential anti-Parkinsonian's effect of S-(+)-linalool on mitochondrial regulation and decipher the underlying molecular mechanisms in Caenorhabditis elegans PD model. Essential oils at 20 mg/L and 20 mg/L S-(+)-linalool each significantly attenuated the damaging effects of 6-hydroxydopamine (6-OHDA) on dopaminergic (DA) neurons and decreased the mitochondrial unfolded protein response (UPRmt ) to antimycin. RNAi knockdown of mitochondrial complex I (gas-1, nuo-1), and complex II (mev-1) genes prevented the improvement of mitochondrial activity by S-(+)-linalool. The protective effects of S-(+)-linalool on 6-OHDA-induced behavior changes were absent in a DA-specific strain of C. elegans produced by gas-1, nuo-1, and mev-1 RNAi knockdown. These results suggest the potential anti-Parkinsonian's effect of S-(+)-linalool is associated with mitochondrial activity and regulated by gas-1, nuo-1, and mev-1 in C. elegans. Our findings suggest that S-(+)-linalool might be a promising candidate for therapeutic application to inhibit the progression of PD.

Use of an inflatable mat to reduce body discomfort development when performing computer work at a standing desk.

This study aimed to determine the effects of inflatable mat design on body discomfort, task performance, and musculoskeletal exposures during standing computer work. Twenty-seven healthy adults completed three 2-hour standing trials on different mediums (concrete floor, foam mat, and inflatable mat) on different days in an experimental laboratory. Both mats were associated with reduced discomfort in all lower-body regions and increased typing performance compared to the concrete floor. Perceived discomfort in lower extremities (except thighs) was further alleviated while standing on the inflatable mat than on the foam mat. Use of the inflatable mat led to increased lower-body muscle activity, a flexed lower back, and a wide range of sagittal knee movements. As standing time increased, body discomfort increased, typing accuracy decreased, and there were increased variations in muscle activity and postural movements in the lower body. The inflatable mat shows potential to improve the ergonomic experience during prolonged standing. Practitioner summary: Incorporating standing postures in office-based workplaces can reduce sitting time and may mitigate the health hazards associated with sedentary behaviour. With adequate weight-shifting movements, using an inflatable mat for standing could be an effective way to lessen discomfort and accumulated musculoskeletal strain due to constrained standing, without jeopardising task productivity. Abbreviations: APDF: amplitude probability distribution function. AVR: average rectified value. CI: confidence interval. CMRR: common mode rejection ratio. COP: center of pressure. CV: coefficient of variation. EA: electrical activity. EMG: electromyography. FL: fibularis longus. GM: gluteus medius. LBP: lower back pain. LES: lumbar erector spinae. MVC: maximum voluntary contraction. PD: pain developer. rANOVA: repeated-measures analysis of variance. SOL: soleus. VAS: visual analog scale. WPM: words per minute.

Parental CuO nanoparticles exposure results in transgenerational toxicity in Caenorhabditis elegans associated with possible epigenetic regulation.

Environmental nanomaterials contamination is a great concern for organisms including human. Copper oxide nanoparticles (CuO NPs) are widely used in a huge range of applications which might pose potential risk to organisms. This study investigated the in vivo transgenerational toxicity on development and reproduction with parental CuO NPs exposure in the nematode Caenorhabditis elegans. The results showed that CuO NPs (150 mg/L) significantly reduced the body length of parental C. elegans (P0). Only about 1 mg/L Cu2+ (~0.73%) were detected from 150 mg/L CuO NPs in 0.5X K-medium after 48 h. In transgenerational assays, CuO NPs (150 mg/L) parental exposure significantly induced developmental and reproductive toxicity in non-exposed C. elegans progeny (CuO NPs free) on body length (F1) and brood size (F1 and F2), respectively. In contrast, parental exposure to Cu2+ (1 mg/L) did not cause transgenerational toxicity on growth and reproduction. This suggests that the transgenerational toxicity was mostly attributed to the particulate form of CuO NPs. Moreover, qRT-PCR results showed that the mRNA levels of met-2 and spr-5 genes were significantly decreased at P0 and F1 upon only maternal exposure to CuO NPs (150 mg/L), suggesting the observed transgenerational toxicity was associated with possible epigenetic regulation in C. elegans.

Significant association of high-grade inflammation and thick lining epithelium with the increased number of Langerhans cells in dentigerous cysts.

BACKGROUND/PURPOSE: Langerhans cells (LCs) are antigen-presenting cells. This study assessed the LC counts in 80 dentigerous cysts (DCs). METHODS: The CD1a-positive LC numbers in the lining epithelia and subepithelial connective tissues were counted at 80 DC sites without inflammation, 33 DC sites with mild/moderate inflammation, and 9 DC sites with severe inflammation from 80 DC specimens. RESULTS: The mean LC counts in the lining epithelia and subepithelial connective tissues increased significantly from no inflammation (0.5 ± 0.5 and 0.2 ± 0.3 cell/high-power field or HPF, respectively) through mild/moderate inflammation (6.8 ± 1.8 and 2.4 ± 2.0 cells/HPF, respectively) to severe inflammation DC sites (18.9 ± 7.0 and 6.7 ± 5.8 cells/HPF, respectively; all P-values < 0.001). DC sites with inflammation had thicker lining epithelia than those without inflammation. Moreover, the mean LC counts in the lining epithelia and subepithelial connective tissues of DCs were significantly higher in the thicker lining epithelium (>50 µm) group (7.4 ± 6.5 and 2.6 ± 3.4 cells/HPF, respectively) than in the thinner lining epithelium (≦ 50 µm) group (0.5 ± 0.5 and 0.2 ± 0.3 cells/HPF, respectively; both P-values < 0.001). CONCLUSION: A significant association of high-grade inflammation and thick lining epithelium with the increased LC number in DCs is found. The finding of few LCs in the lining epithelia of DCs without inflammation indicates the reduced immunosurveillance ability against DC lining epithelial cells in DC patients. It needs further studies to confirm the role of reduced immunosurveillance in the enlargement of the DC.

Significant association of inflammation grade with the number of Langerhans cells in odontogenic keratocysts.

BACKGROUND/PURPOSE: Langerhans cells (LCs) are antigen-presenting cells. This study assessed the LC counts in odontogenic keratocysts (OKCs). METHODS: The LC numbers in the lining epithelia and subepithelial connective tissues were counted at 60 OKC sites without inflammation, 39 OKC sites with mild/moderate inflammation, and 13 OKC sites with severe inflammation from 60 OKC specimens immunostained with anti-S100 antibodies. RESULTS: The mean LC counts in the lining epithelia and subepithelial connective tissues increased significantly from no inflammation (0.5 ± 0.4 and 0.7 ± 0.6 cell/high-power field or HPF, respectively) through mild/moderate inflammation (5.9 ± 2.7 and 5.0 ± 3.5 cells/HPF, respectively) to severe inflammation OKC sites (14.7 ± 5.3 and 13.3 ± 6.8 cells/HPF, respectively; all P-values < 0.001). OKC sites with inflammation had thicker lining epithelia than those without inflammation. Moreover, the mean LC counts in the lining epithelia and subepithelial connective tissues of OKCs were significantly higher in the thicker lining epithelium (>100 µm) group (7.7 ± 5.6 and 6.5 ± 5.8 cells/HPF, respectively) than in the thinner lining epithelium (≦ 100 µm) group (1.0 ± 2.0 and 1.4 ± 2.6 cells/HPF, respectively; both P-values < 0.001). CONCLUSION: A significant association of inflammation grade with the number of LCs in OKCs is found. The paucity of finding LCs in the lining epithelia of OKCs without inflammation indicates the loss of immunosurveillance ability against the OKC lining epithelial cells; this can explain why OKCs have aggressive clinical behavior, a great growth potential, and a high recurrence rate.

High Gamma-Aminobutyric Acid (GABA) Oolong Tea Alleviates High-Fat Diet-Induced Metabolic Disorders in Mice.

Obesity and overweight are associated with an increasing risk of developing health conditions and chronic non-communicable diseases, including cardiovascular diseases, cancer, musculoskeletal problems, respiratory problems, and mental health, and its prevalence is rising. Diet is one of three primary lifestyle interventions. Many bioactive components in tea especially oolong tea, including flavonoids, gamma-aminobutyric acid (GABA), and caffeine were reported to show related effects in reducing the risk of obesity. However, the effects of GABA oolong tea extracts (OTEs) on high-fat diet (HFD)-induced obesity are still unclear. Therefore, this study aims to explore whether the intervention of GABA OTEs can prevent HFD-induced obesity and decipher its underlying mechanisms using male C57BL/6 J mice. The result indicated that GABA OTEs reduced leptin expression in epididymal adipose tissue and showed a protective effect on nonalcoholic fatty liver disease. It promoted thermogenesis-related protein of uncoupling protein-1 and peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), boosted lipid metabolism, and promoted fatty acid oxidation. It also reduced lipogenesis-related protein levels of sterol regulatory element binding protein, acetyl-CoA carboxylase, and fatty acid synthase and inhibited hepatic triglyceride (TG) levels. These data suggest that regular drinking of GABA oolong tea has the potential to reduce the risk of being overweight, preventing obesity development through thermogenesis, lipogenesis, and lipolysis.

Co-contaminants of ethinylestradiol and sulfamethoxazole in groundwater exacerbate ecotoxicity and ecological risk and compromise the energy budget of C. elegans.

Ethinylestradiol (EE2) and sulfamethoxazole (SMX) are among pharmaceuticals and personal care products (PPCPs) and regarded as emerging contaminants in groundwater worldwide. However, the ecotoxicity and potential risk of these co-contaminants remain unknown. We investigated the effects of early-life long-term co-exposure to EE2 and SMX in groundwater on life-history traits of Caenorhabditis elegans and determined potential ecological risks in groundwater. L1 larvae of wild-type N2 C. elegans were exposed to measured concentrations of EE2 (0.001, 0.75, 5.1, 11.8 mg/L) or SMX (0.001, 1, 10, 100 mg/L) or co-exposed to EE2 (0.75 mg/L, no observed adverse effect level derived from its reproductive toxicity) and SMX (0.001, 1, 10, 100 mg/L) in groundwater. Growth and reproduction were monitored on days 0 - 6 of the exposure period. Toxicological data were analyzed using DEBtox modeling to determine the physiological modes of action (pMoAs) and the predicted no-effect concentrations (PNECs) to estimate ecological risks posed by EE2 and SMX in global groundwater. Early-life EE2 exposure significantly inhibited the growth and reproduction of C. elegans, with lowest observed adverse effect levels (LOAELs) of 11.8 and 5.1 mg/L, respectively. SMX exposure impaired the reproductive capacity of C. elegans (LOAEL = 0.001 mg/L). Co-exposure to EE2 and SMX exacerbated ecotoxicity (LOAELs of 1 mg/L SMX for growth, and 0.001 mg/L SMX for reproduction). DEBtox modeling showed that the pMoAs were increased growth and reproduction costs for EE2 and increased reproduction costs for SMX. The derived PNEC falls within the range of detected environmental levels of EE2 and SMX in groundwater worldwide. The pMoAs for EE2 and SMX combined were increased growth and reproduction costs, resulting in lower energy threshold values than single exposure. Based on global groundwater contamination data and energy threshold values, we calculated risk quotients for EE2 (0.1 - 123.0), SMX (0.2 - 91.3), and combination of EE2 and SMX (0.4 - 341.1). Our findings found that co-contamination by EE2 and SMX exacerbates toxicity and ecological risk to non-target organisms, suggesting that the ecotoxicity and ecological risk of co-contaminants of pharmaceuticals should be considered to sustainably manage groundwater and aquatic ecosystems.

Protective Effects of Piceatannol on DNA Damage in Benzo[a]pyrene-Induced Human Colon Epithelial Cells.

Evidence shows that the dietary intake of polycyclic aromatic hydrocarbons (PAHs) from food processing induces the cellular DNA damage response and leads to the development of colorectal cancer (CRC). Therefore, protecting from cellular DNA damage might be an effective strategy in preventing CRC. Benzo[a]pyrene (B[a]P) was used as a CRC initiator in the present study. Compared with other stilbenoids, piceatannol (PIC) showed the most effective inhibition of B[a]P-induced cytochrome P450 1B1 (CYP1B1) protein expression in NCM460 normal human colon epithelial cells. PIC treatment alleviated DNA migration and enhanced the expression of DNA-repair-related proteins, including histone 2AX (H2AX), checkpoint kinase 1 (Chk1), and p53, in B[a]P-induced NCM460 cells. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, flow cytometry, and enzyme-linked immunosorbent assay (ELISA) revealed that PIC exerted antioxidative effects on NCM460 cells by increasing the glutathione (GSH) content and scavenging the excess intracellular reactive oxygen species (ROS) induced by B[a]P. Furthermore, PIC suppressed B[a]P-induced CYP1B1 protein expression and stimulated miR-27b-3p expression. The upregulation of phase II detoxification enzymes, such as nicotinamide adenine dinucleotide phosphate (NADPH) and quinone oxidoreductase 1 (NQO1), and the antioxidative enzyme, heme oxygenase 1 (HO-1), via the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was observed in the PIC-treated group. Our results suggest that PIC is a potential CRC-blocking agent due to its ability to alleviate DNA damage, decrease intracellular ROS production, modulate the metabolism and detoxification of B[a]P, and activate the Nrf2 signaling pathway in B[a]P-induced NCM460 cells.

Prevention of Glutamate-Induced Neurodegeneration by Piceatannol via Mitochondrial Rescue In Vitro and In Vivo.

SCOPE: Parkinson's disease is one of the neurodegenerative diseases that have no cure. Excitotoxicity induced by excess glutamate is known to be a hallmark of these diseases. Therefore, this study aims to evaluate the preventive effect of piceatannol on glutamate-induced neurodegeneration via mitochondrial rescue. METHODS AND RESULTS: The PC12 cell line and three Caenorhabditis elegans (C. elegans) strains are employed to achieve the aim. In the in vitro study, the results show that piceatannol can prevent glutamate-induced apoptosis. Piceatannol also reduces mitochondrial reactive oxygen species (ROS) accumulation by activating the antioxidant system. Moreover, piceatannol can also promote mitochondrial biogenesis and induced mitochondrial fusion-related genes to preserve mitochondrial functionality. In the C. elegans model, piceatannol can prevent mitochondrial fragmentation induced by glutamate. More importantly, piceatannol effectively protects dopaminergic neurons from degradation and preserves the responses controlled by these neurons. CONCLUSION: The findings suggest that piceatannol can be a more effective and potent candidate for the treatment of neurodegenerative diseases, such as Parkinson's disease, compared to resveratrol. It is capable of preventing neurodegeneration induced by excess glutamate, possibly via mitochondrial rescue. It is recommended that piceatannol be developed into a neuroprotective agent.

Chronic di(2-ethylhexyl) phthalate exposure leads to dopaminergic neuron degeneration through mitochondrial dysfunction in C. elegans.

The plasticizer di(2-ethylhexyl) phthalate (DEHP) is frequently detected in the environment due to the abundance of its use. These levels might be hazardous to human health and ecosystems. Phthalates have been associated with neurological disorders, yet whether chronic DEHP exposure plays a role in Parkinson's disease (PD) or its underlying mechanisms is unknown. We investigated the effects of chronic DEHP exposure less than an environmentally-relevant dose on PD hallmarks, using Caenorhabditis elegans as a model. We show that developmental stage and exposure timing influence DEHP-induced dopaminergic neuron degeneration. In addition, in response to chronic DEHP exposure at 5 mg/L, mitochondrial fragmentation became significantly elevated, reactive oxygen species (ROS) levels increased, and ATP levels decreased, suggesting that mitochondrial dysfunction occurs. Furthermore, the data show that mitochondrial complex I (nuo-1 and gas-1) and complex II (mev-1) are involved in DEHP-induced dopaminergic neuron toxicity. These results suggest that chronic exposure to DEHP at levels less than an environmentally-relevant dose causes dopaminergic neuron degeneration through mitochondrial dysfunction involving mitochondrial complex I and II. Considering the high level of genetic conservation between C. elegans and mammals, chronic DEHP exposure might elevate the risk of developing PD in humans.

Nanoplastic exposure in soil compromises the energy budget of the soil nematode C. elegans and decreases reproductive fitness.

Environmental nanoplastics (NPs) can accumulate in soils, posing a potential risk to soil ecosystems. However, the ecotoxicity of NPs for soil organisms has received little research attention. This study investigated whether NP exposure in soil leads to reproductive decline in the soil nematode Caenorhabditis elegans and sought to determine the mechanisms by which it may occur. Wild-type N2 C. elegans L1 larvae were exposed to various concentrations of nano-sized polystyrene (100 nm) in soil (0, 1, 10, 100, and 1000 mg/kg dry weight) for 96 h. We show that nano-sized polystyrene (100 nm) labeled with red fluorescence significantly accumulated in the intestine of C. elegans in a dose-dependent fashion via soil exposure (8%-47% increase). In addition, NP soil exposure led to 7%-33% decline in the number of eggs in utero and 2.6%-4.4% decline in the egg hatching percentage. We also find that the number of germ cell corpses (31%-55% increase) and the mRNA levels of germline apoptosis marker gene ced-3 (14%-31% increase) were significantly higher with greater NP soil exposure (10, 100, and 1000 mg/kg), while intracellular ATP levels were significantly reduced. Finally, the DEBtox model, which is based on the dynamic energy budget theory, was applied to show that the increased reproductive costs for C. elegans caused by NPs in soil are associated with energy depletion and reproductive decline. The threshold value (4.18 × 10-6 mg/kg) for the energy budget also highlighted the potential high reproductive risk posed by NPs in terrestrial ecosystems. Our study provides new insights into how soil organisms interact with NPs in soil ecosystems.

S-Allylcysteine Ameliorates Aging Features via Regulating Mitochondrial Dynamics in Naturally Aged C57BL/6J Mice.

SCOPE: S-Allylcysteine (SAC) is the most abundant organosulfur molecule derived from aged garlic. The effects ofSAC on improving Aging in naturally aged C57BL/6J male mice and mitochondrial dynamics in Caenorhabditis elegans and its underlying mechanisms is evaluated. METHODS AND RESULTS: When mice have attained reproductive senescence at 60 weeks of age, SAC is supplemented to 0.05% and 0.2% into their normal diet for 12 weeks. The results show that SAC could significantly improve the level of hepatic optic atrophy 1 (OPA1) mRNA, which is a key factor for mitochondrial fusion, and consequently elevated the mitochondrial biogenesis-related proteins sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), thus ameliorating oxidative stress, such as malondialdehyde (MDA) in the liver and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine. Among the biochemical markers of aging, SAC significantly reduces liver galactosidase ß1 (GLB1) and senescence-associated ß-galactosidase (SA-ßgal), which are induced by replicative senescence. The mitochondria with green fluorescent protein (GFP)-tagged transgenic strain SJ4103 C. elegans is incubated with 5 or 50 µM SAC, and SAC treated groups maintain the linear morphology of mitochondria. CONCLUSION: SAC regulates mitochondrial dynamics and ameliorated aging to a significant degree. This study also confirms that mitochondrial dynamics are a promising target for screening materials to combat aging and as a direction for anti-aging product development.

N-γ-(L-glutamyl)-L-selenomethionine shows neuroprotective effects against Parkinson's disease associated with SKN-1/Nrf2 and TRXR-1 in Caenorhabditis elegans.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disease, yet fundamental treatments for the disease remain sparse. Thus, the search for potentially efficacious compounds from medicinal plants that can be used in the treatment of PD has gained significant interest. PURPOSE: In many medicinal plants, selenium is primarily found in an organic form. We investigated the neuroprotective potential of an organic form of selenium, N-γ-(L-glutamyl)-L-selenomethionine (Glu-SeMet) in a Caenorhabditis elegans PD model and its possible molecular mechanisms. METHODS: We used a C. elegans pharmacological PD strain (BZ555) that specifically expresses green fluorescent protein (GFP) in dopaminergic neurons and a transgenic PD strain (NL5901) that expresses human α-synuclein (α-syn) in muscle cells to investigate the neuroprotective potential of Glu-SeMet against PD. RESULTS: We found that Glu-SeMet significantly ameliorated 6-hydroxydopamine (6-OHDA)-induced dopaminergic neuron damage in the transgenic BZ555 strain, with corresponding improvements in slowing behavior and intracellular ROS levels. In addition, compared with clinical PD drugs (L-DOPA and selegiline), Glu-SeMet demonstrated stronger ameliorated effects on 6-OHDA-induced toxicity. Glu-SeMet also triggered the nuclear translocation of SKN-1/Nrf2 and significantly increased SKN-1, GST-4, and GCS-1 mRNA levels in the BZ555 strain. However, Glu-SeMet did not increase mRNA levels or ameliorate the damage to dopaminergic neurons when the BZ555 strain was subjected to skn-1 RNA interference (RNAi). Glu-SeMet also upregulated the mRNA levels of the selenoprotein TRXR-1 in both the BZ555 and BZ555; skn-1 RNAi strains and significantly decreased α-syn accumulation in the NL5901 strain, although this was not observed in the NL5901; trxr-1 strain. CONCLUSION: We found that Glu-SeMet has a neuroprotective effect against PD in a C. elegans PD model and that the anti-PD effects of Glu-SeMet were associated with SKN-1/Nrf2 and TRXR-1. Glu-SeMet may thus have the potential for use in therapeutic applications or supplements to slow the progression of PD.

The bioavailability and potential ecological risk of copper and zinc in river sediment are affected by seasonal variation and spatial distribution.

River sediment is the ultimate sink for heavy metal pollution. Copper (Cu) and zinc (Zn) are consistently found at environmentally significant levels in sediments worldwide. We hypothesized that the bioavailability and potential ecological risk of Cu and Zn in river sediments may be affected by seasonal variations and spatial distribution. In this study, we tested our hypothesis using highly industrialized river sediments (Laojie River) as an example. The concentration of heavy metals, pollution indexes, and risk indexes were evaluated and multivariate statistical analyses were performed. We found that seasonal variations affect heavy metal contamination, pollution indexes, and potential ecological risk in sediments and this effect was more severe in the dry season. In addition, higher levels of metal contamination, pollution indexes, and potential ecological risk were observed midstream and downstream of the Laojie River. We found that Cu and Zn were the primary contaminants in Laojie River sediments and may originate from common anthropogenic sources. Analysis of the chemical fractions further revealed that Cu and Zn exhibited high mobility and potential bioavailability risk. In addition, a high percentage and amount of Cu and Zn were found in exchangeable fractions, suggesting they pose a great risk to aquatic organisms. Our results indicate that seasonal variations and spatial distribution affect the bioavailability and potential ecological risk of Cu and Zn in river sediments. These findings suggest that seasonal variations and spatial distribution are important parameters to consider for environmental monitoring and environmental management in aquatic environments.

The anti-TH17 polarization effect of Indigo naturalis and tryptanthrin by differentially inhibiting cytokine expression.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal medicine Qing-Dai (also known as Indigo naturalis) extracted from indigo-bearing plants including Baphicacanthus cusia (Ness) Bremek was previously reported to exhibit anti-psoriatic effects in topical treatment. TH17 was later established as a key player in the pathogenesis of psoriasis. We investigated the anti-TH17 effect of Indigo naturalis and its active compounds. The aim of this study is to evaluate the toxicity of Indigo naturalis (IN) and its derivatives on five cell types involved in psoriasis, and to study the anti-inflammatory mechanism for the toxicity. MATERIALS AND METHODS: Following the fingerprint and quantity analysis of indirubin, indigo, and tryptanthrin in IN extract, we used MTS kits to measure the anti-proliferative effect of IN and three active compounds on five different cell types identified in psoriatic lesions. Quantitative RT-PCR analysis was used to measure the expression of various genes identified in the activated keratinocytes and TH17 polarized gene expression in RORγt-expressing T cells. RESULTS: We showed that IN differentially inhibited the proliferation of keratinocytes and endothelial cells but not monocytes, fibroblasts nor Jurkat T cells. Among three active compounds identified in IN, tryptanthrin was the most potent compound to reduce their proliferation. In addition to differentially reducing IL6 and IL8 expression, both IN and tryptanthrin also potently decreased the expression of anti-microbial S100A9 peptide, CCL20 chemokine, IL1B and TNFA cytokines, independent of NF-κB-p65-activation. Their attenuating effect was also detected on the expression of signature cytokines or chemokines induced during RORγT-induced TH17 polarization. CONCLUSIONS: We were the first to confirm a direct anti-TH17 effect of both IN herbal extract and tryptanthrin.

N-ϒ-(l-Glutamyl)-l-Selenomethionine Inhibits Fat Storage via the Stearoyl-CoA Desaturases FAT-6 and FAT-7 and the Selenoprotein TRXR-1 in Caenorhabditis elegans.

SCOPE: Selenium is an important nutrient for human health. The influence of dietary selenium on lipid metabolism remains largely unknown. N-γ-(l-glutamyl)-l-selenomethionine (Glu-SeMet) on inhibition of fat accumulation and its underlying mechanisms in the nematode Caenorhabditis elegans are investigated. METHODS AND RESULTS: Triacylglyceride quantification and post-fixed Nile red staining methods are conducted to evaluate fat accumulation in wild-type N2 worms in normal or high-glucose diet. Glu-SeMet (0.01 µm) treatment effectively reduces fat storage in wild-type N2 C. elegans in both a normal and high-glucose diet. Further evidence shows that Glu-SeMet (0.01 µm) decreases the ratio of oleic acid/stearic acid (C18:1Δ9/C18:0) using gas chromatography-mass spectrometry analysis. The mRNA levels of fatty acid stearoyl-CoA desaturases, FAT-6 and FAT-7, and the mediator-15 (MDT-15) are downregulated while the wild-type N2 worms are co-treated with high glucose and Glu-SeMet (0.01 µm). The effect of reduced fat accumulation is absent in fat-6, fat-7, and trxr-1 mutant worms under high glucose and Glu-SeMet (0.01 µm) co-treatment. CONCLUSIONS: This study demonstrates that Glu-SeMet inhibiting fat accumulation may be associated with FAT-6 and FAT-7 and the selenoprotein TRXR-1 in C. elegans. This study implies a potential for Glu-SeMet as a new treatment for obesity or its complications.

Anti-Parkinsonian effects of ß-amyrin are regulated via LGG-1 involved autophagy pathway in Caenorhabditis elegans.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease that is associated with aging and is characterized as a movement disorder. Currently, there is still no complete therapy for PD. In recent years, the identification and characterization of medicinal plants to cure or treat PD has gained increasing scientific interest. PURPOSE: In this study, we investigated a pentacyclic triterpenoid compound, ß-amyrin, which is found in many medicinal plants for its anti-Parkinsonian effects, using Caenorhabditis elegans (C. elegans) disease models and their underlying mechanisms. METHODS: C. elegans treated or untreated with ß-amyrin were investigated for oxidative stress resistance, neurodegeneration, and α-synuclein aggregation assays. The C. elegans ortholog of Atg8/LC3, LGG-1 that is involved in the autophagy pathway was also evaluated by quantitative RT-PCR and transgenic strain experiments. RESULTS: ß-Amyrin exerted excellent antioxidant activity and reduced intracellular oxygen species in C. elegans. Using the transgenic strain BZ555, ß-amyrin showed a protective effect on dopaminergic neurons reducing cell damage induced by 6-hydroxydopamine (6-OHDA). In addition, ß-amyrin significantly reduced the α-synuclein aggregation in the transgenic strain NL5901. Moreover, ß-amyrin up-regulated LGG-1 mRNA expression and increased the number of localized LGG-1 puncta in the transgenic strain DA2123. CONCLUSION: The results from this study suggest that the anti-Parkinsonian effects of ß-amyrin might be regulated via LGG-1 involved autophagy pathway in C. elegans. Therefore, ß-amyrin may be useful for therapeutic applications or supplements to treat or slow the progression of PD.

N-γ-(L-Glutamyl)-L-selenomethionine enhances stress resistance and ameliorates aging indicators via the selenoprotein TRXR-1 in Caenorhabditis elegans.

SCOPE: Selenium is an essential trace nutrient for human health. This study investigates the organic form of selenium, N-γ-(L-Glutamyl)-L-selenomethionine (Glu-SeMet), for its effects on aging indicators and stress resistance. The role of the selenoprotein TRXR-1 was also evaluated in Caenorhabditis elegans. METHODS AND RESULTS: Glu-SeMet-treated wild-type N2 worms showed increased survival upon oxidative and thermal stress challenges. However, Glu-SeMet treatment did not extend the lifespan of wild-type N2 C. elegans under normal conditions (p = 0.128 for 0.01 µM and p = 0.799 for 10 µM Glu-SeMet). Under stress conditions, Glu-SeMet significantly increased the survival of wild-type N2 C. elegans, but the phenomenon was absent from trxr-1 null mutant worms. Furthermore, Glu-SeMet treatments significantly ameliorated aging indicators, including body bends, pumping rate, defecation duration, and lipofuscin accumulation in wild-type N2 nematodes. Nevertheless, the ameliorative effects by Glu-SeMet were absent in the trxr-1 null mutant worms. CONCLUSION: The findings indicate that enhanced stress resistance and improved aging indicators by Glu-SeMet in C. elegans are mediated by the selenoprotein TRXR-1. Glu-SeMet has potential for improving health and also provides new insights into selenium's regulatory mechanisms in intact organisms.