Efficacy and mechanism of energy metabolism dual-regulated nanoparticles (atovaquone-albendazole nanoparticles) against cystic echinococcosis.

BACKGROUND: Albendazole (ABZ) and atovaquone (ATO) achieve killing efficacy on Echinococcus granulosus (Egs) by inhibiting energy metabolism, but their utilization rate is low. This study aims to analyze the killing efficacy of ABZ-ATO loading nanoparticles (ABZ-ATO NPs) on Egs. METHODS: Physicochemical properties of NPs were evaluated by ultraviolet spectroscopy and nanoparticle size potentiometer. In vitro experiments exmianed the efficacy of ATO, ABZ, or ATO-ABZ NPs on protoscolex activity, drug toxicity on liver cell LO2, ROS production, and energy metabolism indexes (lactic dehydrogenase, lactic acid, pyruvic acid, and ATP). In vivo of Egs-infected mouse model exmianed the efficacy of ATO, ABZ, or ATO-ABZ NPs on vesicle growth and organ toxicity. RESULTS: Drug NPs are characterized by uniform particle size, stability, high drug loading, and - 21.6mV of zeta potential. ABZ or ATO NPs are more potent than free drugs in inhibiting protoscolex activity. The protoscolex-killing effect of ATO-ABZ NPs was stronger than that of free drugs. In vivo Egs-infected mice experiment showed that ATO-ABZ NPs reduced vesicle size and could protect various organs. The results of energy metabolism showed that ATO-ABZ NPs significantly increased the ROS level and pyruvic acid content, and decreased lactate dehydrogenase, lactic acid content, and ATP production in the larvae. In addition, ATO-ABZ NPs promoted a decrease in DHODH protein expression in protoscolexes. CONCLUSION: ATO-ABZ NPs exhibits anti-CE in vitro and in vivo, possibly by inhibiting energy production and promoting pyruvic acid aggregation.

Prophylactic nicotinamide mononucleotide (NMN) mitigates CSDS-induced depressive-like behaviors in mice via preserving of ATP level in the mPFC.

Depression is a prevalent psychiatric disorder with accumulating evidence implicating dysregulation of extracellular adenosine triphosphate (ATP) levels in the medial prefrontal cortex (mPFC). It remains unclear whether facilitating endogenous ATP production and subsequently increasing extracellular ATP level in the mPFC can exert a prophylactic effect against chronic social defeat stress (CSDS)-induced depressive-like behaviors and enhance stress resilience. Here, we found that nicotinamide mononucleotide (NMN) treatment effectively elevated nicotinamide adenine dinucleotide (NAD+) biosynthesis and extracellular ATP levels in the mPFC. Moreover, both the 2-week intraperitoneal (i.p.) injection and 3-week oral gavage of NMN prior to exposure to CSDS effectively prevented the development of depressive-like behavior in mice. These protective effects were accompanied with the preservation of both NAD+ biosynthesis and extracellular ATP level in the mPFC. Furthermore, catalyzing ATP hydrolysis by mPFC injection of the ATPase apyrase negated the prophylactic effects of NMN on CSDS-induced depressive-like behaviors. Prophylactic NMN treatment also prevented the reduction in GABAergic inhibition and the increase in excitability in mPFC neurons projecting to the lateral habenula (LHb). Collectively, these findings demonstrate that the prophylactic effects of NMN on depressive-like behaviors are mediated by preventing extracellular ATP loss in the mPFC, which highlights the potential of NMN supplementation as a novel approach for protecting and preventing stress-induced depression in susceptible individuals.

Burst firing in Output-Defined Parallel Habenula Circuit Underlies the Antidepressant Effects of Bright Light Treatment.

Research highlights the significance of increased bursting in lateral habenula (LHb) neurons in depression and as a focal point for bright light treatment (BLT). However, the precise spike patterns of LHb neurons projecting to different brain regions during depression, their roles in depression development, and BLT's therapeutic action remain elusive. Here, LHb neurons are found projecting to the dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and median raphe nucleus (MnR) exhibit increased bursting following aversive stimuli exposure, correlating with distinct depressive symptoms. Enhanced bursting in DRN-projecting LHb neurons is pivotal for anhedonia and anxiety, while concurrent bursting in LHb neurons projecting to the DRN, VTA, and MnR is essential for despair. Remarkably, reducing bursting in distinct LHb neuron subpopulations underlies the therapeutic effects of BLT on specific depressive behaviors. These findings provide valuable insights into the mechanisms of depression and the antidepressant action of BLT.

Feruloylated oligosaccharides ameliorate MPTP-induced neurotoxicity in mice by activating ERK/CREB/BDNF/TrkB signalling pathway.

BACKGROUND: Feruloylated oligosaccharides (FOs) are natural esterification products of ferulic acid and oligosaccharides. STUDY DESIGN: In this study, we examined whether FOs contribute to the ensured survival of nigrostriatal dopamine neurons and inhibition of neuroinflammation in Parkinson's disease (PD). METHODS: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg) was injected intraperitoneally into mice to establish a Parkinson's disease (PD) mouse model. FOs (15 and 30 mg/kg) were orally administered daily to the MPTP-treated mice. The rotarod test, balance beam test, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR), and western blot analyses were performed to examine the neuroprotective effects of FOs on MPTP-treated mice. RESULTS: Our study indicated that FOs increased the survival of dopamine neurons in the substantia nigra pars compacta (SNc) of the MPTP-treated mice. The neuroprotective effects of FOs were accompanied by inhibited glial activation and reduced inflammatory cytokine production. The mechanistic experiments revealed that the neuroprotective effects of FOs might be mediated through the activation of the ERK/CREB/BDNF/TrkB signalling pathway. CONCLUSION: This study provides new insights into the mechanism underlying the anti-neuroinflammatory effect of phytochemicals and may facilitate the development of dietary supplements for PD patients. Our results indicate that FOs can be used as potential modulators for the prevention and treatment of PD.

The role of MeCP2 and the BDNF/TrkB signaling pathway in the stress resilience of mice subjected to CSDS.

RATIONALE: There is accumulating evidence to support the idea that brain-derived neurotrophic factor (BDNF) is involved in stress resilience. However, the precise molecular mechanisms underlying resilience in major depressive disorder (MDD) remain unknown. OBJECTIVE: The objective of this study was to explore the role of methyl CpG binding protein 2 (MeCP2) and the BDNF/tropomyosin-receptor-kinase B (TrkB) signaling pathway in the stress resilience to chronic social defeat stress (CSDS) in mice. RESULTS: We found that the overexpression of MeCP2 inhibited BDNF transcription, resulting in BDNF mRNA and protein downregulation in neuro-2a cells. The overexpression of MeCP2 increased S80-MeCP2 and decreased S421-MeCP2, BDNF, the ratio of S133-cyclic AMP response element binding protein (CREB)/CREB and p-TrkB/TrkB expression in neuro-2a cells. In addition, using the CSDS mouse model, we found that MeCP2 mRNA levels were decreased in the medial prefrontal cortex (mPFC) of resilient mice and increased in the hippocampus of susceptible mice. BDNF exon IV promoter and BDNF mRNA levels were decreased in the mPFC and hippocampus of susceptible mice. Finally, MeCP2 and S80-MeCP2 protein levels were increased in the mPFC and hippocampus of susceptible mice, whereas the protein expression of S421-MeCP2 and BDNF, the ratio of S133-CREB/CREB, and the levels of p-TrkB/TrkB were decreased in susceptible mice. CONCLUSIONS: These data suggest that the overexpression of MeCP2 inhibits BDNF transcription in neuro-2a cells. The inhibition of MeCP2 expression and activation of the BDNF/TrkB signaling pathway may confer stress resilience in CSDS mice.

The ATP Level in the Medial Prefrontal Cortex Regulates Depressive-like Behavior via the Medial Prefrontal Cortex-Lateral Habenula Pathway.

BACKGROUND: Depression is the most common mental illness. Mounting evidence suggests that dysregulation of extracellular ATP (adenosine triphosphate) is involved in the pathophysiology of depression. However, the cellular and neural circuit mechanisms through which ATP modulates depressive-like behavior remain elusive. METHODS: By use of ex vivo slice electrophysiology, chemogenetic manipulations, RNA interference, gene knockout, behavioral testing, and two depression mouse models, one induced by chronic social defeat stress and one caused by a IP3R2-null mutation, we systematically investigated the cellular and neural circuit mechanisms underlying ATP deficiency-induced depressive-like behavior. RESULTS: Deficiency of extracellular ATP in both defeated susceptible mice and IP3R2-null mutation mice led to reduced GABAergic (gamma-aminobutyric acidergic) inhibition and elevated excitability in lateral habenula-projecting, but not dorsal raphe-projecting, medial prefrontal cortex (mPFC) neurons. Furthermore, the P2X2 receptor in GABAergic interneurons mediated ATP modulation of lateral habenula-projecting mPFC neurons and depressive-like behavior. Remarkably, chemogenetic activation of the mPFC-lateral habenula pathway induced depressive-like behavior in C57BL/6J mice, while inhibition of this pathway was sufficient to alleviate the behavioral impairment in both defeated susceptible and IP3R2-null mutant mice. CONCLUSIONS: Overall, our study provides compelling evidence that ATP level in the mPFC is critically involved in regulating depressive-like behavior in a pathway-specific manner. These results shed new light on the mechanisms underlying depression and the antidepressant effect of ATP.

Super-hydrophobic Cellulose Nanofiber Air Filter with Highly Efficient Filtration and Humidity Resistance.

High-air humidity, especially condensation into droplets under the influence of temperature, can pose a serious threat to air purification filters. This report introduces the use of methyltrimethoxysilane (MTMS) for the silanization hydrophobic modification of cellulose nanofibers (CNFs) and obtains an air filter with super-hydrophobicity (CA = 152.4°) and high-efficiency filtration of particulate matter (PM) through the freeze-drying technology. The antihumidity performance of CNFs filters that undergo hydrophobic modification in high-humidity air is improved. Especially in the case of high-humidity air forming condensed water droplets, the increase in the rate of filtration resistance of the hydrophobically modified CNFs filter is much lower than that of the unmodified filter. In addition, the water-vapor-transmission rate of the hydrophobically modified filter is improved. More importantly, adding MTMS can regulate the porous structure of CNFs filters and improve the filtration performance. The specific surface area and the porosity of the filter are 26.54 m2/g and 99.21%, respectively, and the filtering effects of PM1.0 and PM2.5 reach 99.31 and 99.75%, respectively, while a low-filtration resistance (42 Pa) and a quality factor of up to 0.122 Pa-1 are achieved. This work has improved the application potential of high-performance air-purification devices to remove particulate pollution and may provide useful insights to design next-generation air filters suitable for application in high-air humidity.

Application of diatomite for gallic acid removal from molasses wastewater.

In this study, diatomite was refined by a simple purification method consisting of calcination combined with acid washing. Optimal purification conditions were the focus, including the influence of conditions on diatomite morphology, structure, and specific surface area. The results showed that the optimal conditions were a 550 °C carbonization temperature and 25 wt% HCl. This purified diatomite was then employed to adsorb gallic acid (GA) from molasses wastewater in a series of adsorption experiments, which illustrated that (i) GA adsorption fitted a pseudo-second-order model and the Freundlich equation better with GA adsorption by purified diatomite; (ii) the adsorption process was physical, nonspontaneous, and endothermic; (iii) the maximum GA adsorption capacity by purified diatomite was 19.852 mg g-1. This study reported the examination of a promising material for sugar mill wastewater pretreatment.

Effect of Harmine and Its Derivatives Against Echinococcus granulosus and Comparison of DNA Damage Targets.

Cystic echinococcosis (CE) is a worldwide zoonotic disease. At present, the treatment options of CE are limited. The main drugs used in clinical chemotherapy of echinococcosis are albendazole and mebendazole, but they mainly exert longterm antiparasitic effects based on high doses. Therefore, there is an urgent need for effective and safe anti-CE drugs. Previous studies have identified harmine (HM) as a new anti-CE drug. In this study, the efficacy of harmine derivatives was evaluated in vitro and in vivo. The harmine derivatives were tested against E. granulosus protoscoleces (PSC) in vitro. The effect of harmine derivatives was time and concentration dependent at different concentrations, and the anti-CE effect was better than that of harmine. The mortality rate of PSC reached 100% on the 5th day after exposure to harmine derivatives at a concentration of 100 µmol · L -1. Compared with the untreated model control mice, the weight of the cyst was significantly reduced in infected mice treated with harmine derivatives. The effect of harmine derivatives was better than that of harmine, and there was significant difference between harmine derivatives and albendazole (P <0.001). Histopathological examination of experimental mice organs (liver, spleen, lung, brain and small intestine) showed that there was no change in the tissues except for mild inflammation in the liver. The neurotoxicity test in Caenorhabditis elegans showed that the derivative inhibited the movement, feeding, perceptual behavior and acetylcholinesterase activity of C. elegans , and its effect was lower than that of harmine. In addition, intervention with HM derivatives was preliminarily proved to cause DNA damage. This study reveals the potential of HM derivatives as a new class of anti-CE agents and indicates that Topo2a may be a promising target for the development of anti-CE drugs.

Preparation and antimicrobial activity of thyme essential oil microcapsules prepared with gum arabic.

Thyme essential oils (TEO) exhibit antimicrobial activities against a wide range of pathogenic microorganisms. Microcapsulation technology can be used to improve the stability, water solubility and antibacterial performance of TEO. In this paper, TEO was selected as the core material, and ß-cyclodextrin (ß-CD) was the wall material for microcapsulation; gum arabic (GA) was used as an emulsifier to prepare microcapsules by coprecipitation. The effects of gum arabic on the encapsulation rate, particle size and release rate of microcapsules were investigated. The optimal condition was found to be TEO : GA by 1 : 3 (w/w) ratio. In this condition, the embedding rate, release rate, and average size of the microcapsules were 87.61%, 53.00%, and 8.20 µm, respectively. Scanning electron microscopy (SEM) revealed that, under the action of gum arabic, the surface of microcapsules was more complete, and the size apparently decreased. Fourier-transform infrared spectroscopy (FTIR) indicated that there was no significant chemical interaction between gum arabic and ß-CD. Gum arabic acted only as an emulsifier and remained in the mixed solution. For microcapsules with gum arabic as an emulsifier, the cumulative release rate of essential oils were slower at the initial time compared to microcapsules without added gum arabic. Antimicrobial activity assay exhibited TEO, which showed an inhibitory effect against Botryodiplodia theobromae Pat., and the inhibitory effect was especially strong against Colletotrichum gloeosporioides Penz. Finally, the obtained microcapsules showed the same antibacterial effect.