D2 Receptors and Sodium Ion Channel Blockades of the Basolateral Amygdala Attenuate Lithium Chloride-Induced Conditioned Taste Aversion Applying to Cancer Chemotherapy Nausea and Vomiting.

Cancer patients regularly suffer from the behavioral symptoms of chemotherapy-induced nausea and vomiting. Particularly, it is involved in Pavlovian conditioning. Lithium chloride (LiCl) was used as the unconditioned stimulus (US) and contingent with the tastant, for example, a saccharin solution (i.e., the conditioned stimulus; CS), resulted in conditioned taste aversion (CTA) to the CS intake. The present study employed an animal model of LiCl-induced CTA to imitate chemotherapy-induced nausea and vomiting symptoms. Recently, the basolateral amygdala (BLA) was shown to mediate LiCl-induced CTA learning; however, which brain mechanisms of the BLA regulate CTA by LiCl remain unknown. The present study was designed to test this issue, and 4% lidocaine or D2 blocker haloperidol were microinjected into BLA between the 0.1% saccharin solution intake and 0.15M LiCl. The results showed lidocaine microinjections into the BLA could attenuate the LiCl-induced CTA. Microinjections of haloperidol blunted the CTA learning by LiCl. Altogether, BLA via the sodium chloride ion channel and D2 receptors control LiCl-induced conditioned saccharin solution intake suppression. The findings can provide some implications and contributions to cancer chemotherapy-induced nausea and vomiting side effects, and will help to develop novel strategies to prevent the side effects of cancer chemotherapy.

Methamphetamine and Modulation Functionality of the Prelimbic Cortex for Developing a Possible Treatment of Alzheimer's Disease in an Animal Model.

Alzheimer's disease (AD) is a progressive neurodegenerative condition that causes cognitive impairment and other neuropsychiatric symptoms. Previously, little research has thus far investigated whether methamphetamine (MAMPH) can enhance cognitive function or ameliorate AD symptoms. This study examined whether a low dose of MAMPH can induce conditioned taste aversion (CTA) learning, or can increase plasma corticosterone levels, neural activity, and neural plasticity in the medial prefrontal cortex (mPFC) (responsible for cognitive function), the nucleus accumbens (NAc) and the amygdala (related to rewarding and aversive emotion), and the hippocampus (responsible for spatial learning). Furthermore, the excitations or lesions of the prelimbic cortex (PrL) can affect MAMPH-induced CTA learning, plasma corticosterone levels, and neural activity or plasticity in the mPFC [i.e., PrL, infralimbic cortex (IL), cingulate cortex 1 (Cg1)], the NAc, the amygdala [i.e., basolateral amygdala (BLA) and central amygdala (CeA)], and the hippocampus [i.e., CA1, CA2, CA3, and dentate gyrus (DG)]. In the experimental procedure, the rats were administered either saline or NMDA solutions, which were injected into the PrL to excite or destroy PrL neurons. Additionally, rats received 0.1% saccharin solution for 15 min, followed by intraperitoneal injections of either normal saline or 1 mg/kg MAMPH to induce CTA. A one-way ANOVA was performed to analyze the effects of saccharin intake on CTA, plasma corticosterone levels, and the expression of c-Fos and p-ERK. The results showed that the MAMPH induced CTA learning and increased plasma corticosterone levels. The mPFC, and particularly the PrL and IL and the DG of the hippocampus, appeared to show increased neural activity in c-Fos expression or neural plasticity in p-ERK expression. The excitation of the PrL neurons upregulated neural activity in c-Fos expression and neural plasticity in p-ERK expression in the PrL and IL. In summary, MAMPH may be able to improve cognitive and executive function in the brain and reduce AD symptoms. Moreover, the excitatory modulation of the PrL with MAMPH administration can facilitate MAMPH-induced neural activity and plasticity in the PrL and IL of the mPFC. The present data provide clinical implications for developing a possible treatment for AD in an animal model.

LAIR-1 suppresses cell growth of ovarian cancer cell via the PI3K-AKT-mTOR pathway.

Recently, over-expression of LAIR-1 has been found in some solid cancers, including ovarian cancer. The role of LAIR-1 in cancer progression needs further investigation. In this study, we identified the LAIR-1 cDNA sequence of the ovarian cancer cells HO8910. Using SKOV3 cells, we confirmed the finding from our previous study that LAIR-1 could suppress in vitro cell proliferation and cell migration. We also found LAIR-1 overexpression can induce apoptosis of SKOV3 cells. We revealed LAIR-1 suppressed cell growth by inhibiting the PI3K-AKT-mTOR axis. Moreover, the LAIR-1 antitumor activity and its mechanism were also identified in vivo. We used Co-IP assay and mass spectrometry to identify potential LAIR-1-binding proteins in LAIR-1 overexpressing SKOV3 cells. MS analysis identified 167 potentially interacting proteins. GO analyses indicated a possible involvement of LAIR-1 in mRNA processing through its interaction with some eukaryotic translation initiation factors (eIF4E1B, eIF2S3, eIF3D, eIF4G2, eIF5B) and eukaryotic translation elongation factors (eEF1A2 and eEF1B2). Our findings suggest that LAIR-1 may suppress the growth of ovarian cancer cells by serving as a modulator that suppresses PI3K-AKT-mTOR directly or regulating protein synthesis at the translational level. Our results indicate that a LAIR-1-based strategy may prevent or suppress the progression of ovarian cancer.

Noninvasive and real-time pharmacokinetics imaging of polymeric nanoagents in the thoracoepigastric vein networks of living mice.

Noninvasive and real-time visualization of the thoracoepigastric veins (TVs) of living mice was demonstrated by using two-photon excitation (TPE) optical imaging with a Eu-luminescent polymeric nanoagent as the angiographic contrast. The spatiotemporal evolution of the polymeric nanoagent in TVs was monitored for up to 2 h by TPE time-resolved (TPE-TR) bioimaging, which is free from the interference of tissue autofluorescence. A wide field-of-view covering the thoracoabdominal region allowed the visualization of the entire TV network with an imaging depth of 1 to 2 mm and a lateral resolution of 80 µm at submillimeter. Detailed analysis of the uptake, transport, and clearance processes of the polymeric nanoagent revealed a clearance time constant of ∼30 min and an apparent clearance efficiency of 80% to 90% for the nanoagent in both axial and lateral TVs. TPE-TR imaging of the dissected internal organs proved that the liver is mainly responsible for the sequestration of the nanoagent, which is consistent with the apparent retention efficiency of liver, ∼32 % , as determined by the real-time in vivo TV imaging. We demonstrate the potency of TPE-TR modality in the pharmacokinetics imaging of the peripheral vascular systems of animal models, which can be beneficial for related nanotheranostics study.

Uptake and Translocation of Styrene Maleic Anhydride Nanoparticles in Murraya exotica Plants As Revealed by Noninvasive, Real-Time Optical Bioimaging.

This work reports the in vivo uptake and translocation of PNPs in the one-year grown terrestrial plant, Murraya exotica ( M. exotica), as investigated by two-photon excitation and time-resolved (TPE-TR) optical imaging with a large field of view (FOV, 32 × 32 mm2) in a noninvasive and real-time manner. The PNPs (⟨ Rh⟩ = 12 ± 4.5 nm) synthesized from poly(styrene- co-maleic anhydride) (SMA) were Eu-luminescence labeled (λL ≈ 617 nm). On exposing the roots of living M. exotica plants to the colloidal suspension of SMA PNPs at different concentrations, the spatiotemporal evolution of SMA PNPs along plant stems (60 mm in length) were monitored by TPE-TR imaging, which rendered rich information on the uptake and translocation of PNPs without any interference from the autofluorescence of the plant tissues. The TPE-TR imaging combined with the high-resolution anatomy revealed an intercell-wall route in the lignified epidermis of M. exotica plants for SMA PNP uptake and translocation, as well as the similar accumulation kinetics at different positions along the plant stems. We modeled the accumulation kinetics with Gaussian distribution to account for the trapping probability of a SMA PNP by the lignified cell walls, allowing the statistical parameters, the average trapping time ( tm) and its variance (σ), to be derived for the quantification of the PNP accumulation in individual plants. The TPE-TR imaging and the analysis protocols established herein will be helpful in exploring the mechanism of plant-PNP interaction under physiological condition.

Wide field of view, real time bioimaging apparatus for noninvasive analysis of nanocarrier pharmacokinetics in living model animals.

Understanding nanocarrier pharmacokinetics is crucial for the emerging nanopharmacy, which highly demands noninvasive and real-time visualization of the in vivo dynamics of nanocarriers. To this end, we have developed a 2-photon excitation and time-resolved (TPE-TR) bioimaging apparatus for the analysis of the spatial distribution and temporal evolution of nanocarriers in living model animals. The specific polymeric nanocarrier, Eu@pmma-maa doped with Eu-complexes luminescing in long persistence at ∼615 nm upon near-infrared 2-photon excitation, allows the complete rejection of tissue autofluorescence by selective luminescence detection. This together with a unique beam shaping scheme for homogeneous line excitation, a delicate timing strategy for single-shot line scanning, and an equal optical path design for in-plane scan endows the TPE-TR apparatus with the following prominent features: an imaging depth of ∼10 mm, a field of view (FOV) of 32 × 32 mm2 along with a horizontal resolution of ∼60 µm, a sub-10 s frame time, and negligible laser heating effect. In addition, a combination of the in-plane line scan with the 3D scan of a model animal offers the convenience for examining an interested FOV with a millimeter vertical resolution. Application of TPE-TR bioimaging to a living mouse reveals rich information on the dynamics of nanocarriers including the spatial distribution and temporal evolution and the kinetics of domains of interest. The noninvasive TPE-TR bioimaging instrumentation with a wide FOV and a large imaging depth will find applications in the pharmaceutical development of nanocarriers and relevant research fields.

Nanoprobes for two-photon excitation time-resolved imaging of living animals: In situ analysis of tumor-targeting dynamics of nanocarriers.

Great challenges remain in the noninvasive luminescence imaging analysis of tumor-targeting dynamics of nanocarriers in living animals which is of significance for the development of anti-cancer nanomedicine. In this work, luminescent nanoparticles Eu(tta)3bpt@SMA (dav = 15 nm), which exhibited good water dispersion stability and high yields of red Eu-luminescence under near-infrared two-photon excitation, were prepared by a modified microfluidic mixing method in the absence of surfactants. Tumor-targeting agents, Arg-Gly-Asp-D-Phe-Lys (cRGD) polypeptide or transferrin (Tf), were then anchored on the nanoparticle surfaces to form the desired nanocarriers Eu@SMA-RGD or Eu@SMA-Tf. The tumor-targeting processes of the prepared nanocarriers in intact living mice were analyzed on a home-built two-photon excitation time-resolved (TPE-TR) imaging apparatus having a wide view filed. The TPE-TR strategy could effectively suppress the interference from biological autofluorescence, which allowed the targeted domains to be visualized with a high signal-to-noise ratio. It was found that the tumor-tissue trapping efficacy of Eu@SMA-RGD was much higher than that of Eu@SMA-Tf, and the desorption process from the tumor tissues of Eu@SMA-RGD was slower than that of Eu@SMA-Tf. The methods developed in this work pave a way to investigate the in vivo tumor-targeting dynamics of nanocarriers by noninvasive luminescence imaging of living animals.