Charge barriers in the kidney elimination of engineered nanoparticles.

The renal elimination pathway is increasingly harnessed to reduce nonspecific accumulation of engineered nanoparticles within the body and expedite their clinical applications. While the size of nanoparticles is recognized as crucial for their passive filtration through the glomerulus due to its limited pore size, the influence of nanoparticle charge on their transport and interactions within the kidneys remains largely elusive. Herein, we report that the proximal tubule and peritubular capillary, rather than the glomerulus, serve as primary charge barriers to the transport of charged nanoparticles within the kidney. Employing a series of ultrasmall, renal-clearable gold nanoparticles (AuNPs) with precisely engineered surface charge characteristics as multimodal imaging agents, we have tracked their distribution and retention across various kidney components following intravenous administration. Our results reveal that retention in the proximal tubules is governed not by the nanoparticle's zeta-potential, but by direct Coulombic interactions between the positively charged surface ligands of the AuNPs and the negatively charged microvilli of proximal tubules. However, further enhancing these interactions leads to increased binding of the positively charged AuNPs to the peritubular capillaries during the initial phase of elimination, subsequently facilitating their slow passage through the glomeruli and interaction with tubular components in a charge-selective manner. By identifying these two critical charge-dependent barriers in the renal transport of nanoparticles, our findings offer a fundamental insight for the design of renal nanomedicines tailored for selective targeting within the kidney, laying down a foundation for developing targeting renal nanomedicines for future kidney disease management in the clinics.

High fried food consumption impacts anxiety and depression due to lipid metabolism disturbance and neuroinflammation.

Western dietary patterns have been unfavorably linked with mental health. However, the long-term effects of habitual fried food consumption on anxiety and depression and underlying mechanisms remain unclear. Our population-based study with 140,728 people revealed that frequent fried food consumption, especially fried potato consumption, is strongly associated with 12% and 7% higher risk of anxiety and depression, respectively. The associations were more pronounced among male and younger consumers. Consistently, long-term exposure to acrylamide, a representative food processing contaminant in fried products, exacerbates scototaxis and thigmotaxis, and further impairs exploration ability and sociality of adult zebrafish, showing anxiety- and depressive-like behaviors. Moreover, treatment with acrylamide significantly down-regulates the gene expression of tjp2a related to the permeability of blood-brain barrier. Multiomics analysis showed that chronic exposure to acrylamide induces cerebral lipid metabolism disturbance and neuroinflammation. PPAR signaling pathway mediates acrylamide-induced lipid metabolism disorder in the brain of zebrafish. Especially, chronic exposure to acrylamide dysregulates sphingolipid and phospholipid metabolism, which plays important roles in the development of anxiety and depression symptoms. In addition, acrylamide promotes lipid peroxidation and oxidation stress, which participate in cerebral neuroinflammation. Acrylamide dramatically increases the markers of lipid peroxidation, including (±)5-HETE, 11(S)-HETE, 5-oxoETE, and up-regulates the expression of proinflammatory lipid mediators such as (±)12-HETE and 14(S)-HDHA, indicating elevated cerebral inflammatory status after chronic exposure to acrylamide. Together, these results both epidemiologically and mechanistically provide strong evidence to unravel the mechanism of acrylamide-triggered anxiety and depression, and highlight the significance of reducing fried food consumption for mental health.

Crosstalk between Hepatic Glutathione Efflux and Tumor Targeting Efficiency of Indocyanine Green-Conjugated Gold Nanoparticles.

The elevated glutathione (GSH) level in solid tumors has been used as a major hallmark for GSH-responsive nanoparticles to enhance targeting efficiency and specificity. Meanwhile, GSH is mainly synthesized inside the hepatocytes of the liver in the body and constantly released into the blood through hepatic GSH efflux to regulate redox potential of the entire body. However, it remains largely unknown how this hepatic GSH efflux affects the tumor targeting of GSH-responsive nanoparticles. Herein, we report that depletion of hepatic GSH enhanced the tumor targeting of GSH-responsive indocyanine green-conjugated Au25 nanoclusters coated with 18 GSH ligand (ICG-Au25 SG18 ). The dissociation of ICG from Au25 SG18 by the hepatic GSH through thiol-exchange reaction and the subsequent hepatobiliary clearance of the detached ICG were slowed down by GSH depletion, which in turn prolonged the blood circulation of intact ICG-Au25 SG18 and enhanced its tumor targeting. Our work highlights glutathione-mediated crosstalk between the liver and tumor, in addition to well-known Kupffer cell-mediated uptake, in the tumor targeting of engineered nanoparticles, which could be modulated to enhance targeting efficiency and specificity of cancer nanomedicines while reducing their nonspecific accumulation.

Drug-Drug Interactions With Cyclosporine in the Anti-Hepatitis C Viral PrOD Combination Regimen of Paritaprevir/Ritonavir-Ombitasvir and Dasabuvir in Organ Transplant Recipients With Severe Hepatic Fibrosis or Cirrhosis.

BACKGROUND: The clinical guidelines suggest that the dosing of cyclosporine (CsA), during combination therapy with paritaprevir/ritonavir-ombitasvir and dasabuvir (PrOD), would be only one-fifth of the pre-PrOD total daily dose to be administered once daily. However, this dosing may not be applicable to all patients depending on their clinical condition. This study focuses on the pharmacokinetic dynamics of PrOD with CsA in Asian organ transplant recipients with severe liver fibrosis or cirrhosis who undergo concurrent treatment with PrOD treatment and CsA. The efficacy and safety of PrOD treatment was also evaluated. METHODS: Data from 7 patients obtained between January 2017 and September 2017 were retrospectively analyzed. Determinations of the blood concentrations of CsA were made, whether used as a single treatment or in combination therapy with PrOD. RESULTS: The combination regimen compared with CsA administered alone resulted in a 4.53-fold and 5.52-fold increase in the area under the concentration-time curve from time 0-12 hours (AUC0-12 h) of CsA on days 1 and 15, respectively. In addition, the maximal concentration, time to maximum concentration, and terminal phase elimination half-life (t1/2) of CsA were increased during the combined treatment of PrOD and CsA. The authors proposed reducing the CsA dosage during PrOD treatment to one-seventh of that of the pre-PrOD treatment of the total daily dose to maintain target CsA levels. All patients achieved sustained virologic responses at week 12. There were no episodes of serious adverse events or graft rejections observed. CONCLUSIONS: Although the combination with PrOD significantly affects the pharmacokinetics of CsA, it is effective and safe with regular monitoring of the CsA blood concentrations and appropriate CsA dose adjustment.

Sustained visual attention improves visuomotor timing.

Relative to audition, vision is considered much less trustworthy in sensorimotor timing such as synchronizing finger movements with a temporally regular sequence. Visuomotor timing requires maintaining attention over time, whereas the sustained visual attention may not be well held in conventional visuomotor timing task settings where flashing visual stimuli consisted of a briefly presented flash and a long blank period. In the present study, the potential attentional lapses in time due to the disappearance of the flash were carefully controlled in Experiment 1 by changing the color of the flash instead of its disappearance, or in Experiment 2 by adding an additional continuously presented fixation point serving as an external attentional cue when the flash disappeared. Improvement of visuomotor timing performance was found in both experiments. The finding suggests a role of enhanced sustained visual attention in improving visuomotor timing, by which vision could also be a trustworthy modality for processing temporal information in sensorimotor interactions.

Cancer Photothermal Therapy with ICG-Conjugated Gold Nanoclusters.

The coming era of precision nanomedicine demands engineered nanoparticles that can be readily translated into the clinic, like that of molecular agents, without being hindered by intrinsic size heterogeneity and long-term body retention. Herein we report that conjugation of indocyanine green (ICG), an FDA-approved near-infrared (NIR) dye, onto an atomically precise glutathione-coated Au25 (GS-Au25) nanocluster led to a molecular-like photothermal nanoparticle (ICG4-GS-Au25) with significantly enhanced ICG photostability and tumor targeting. Under weak NIR light irradiation conditions, free ICG failed to suppress tumor growth but the original tumors were completely eradicated with ICG4-GS-Au25. In the meantime, "off-target" ICG4-GS-Au25 was effectively cleared out from the body like small-molecule drugs after glutathione-mediated biotransformation in the liver. These findings highlight the merits of molecular-like nanomedicines, offering a new pathway to meet FDA's criteria for the clinical translation of nanomedicines.

Tailoring Kidney Transport of Organic Dyes with Low-Molecular-Weight PEGylation.

Subtle changes in size can induce distinct responses of the body to hard nanomaterials; however, it is largely unknown whether just a few ethylene oxide unit differences in soft poly(ethylene glycol) (PEG) molecules could significantly alter the renal clearance of small molecules. By systematically investigating in vivo transport of the representative renal clearable organic dyes, IRDye800CW after being conjugated with a series of PEG molecules with molecular weight (MW) below 10 kDa, we found a MW-dependent scaling law: PEG45 (MW = 2100 Da) is an optimized MW to generate the most efficient renal clearance for IRDye800CW by expediting the glomerular filtration of organic dyes and reducing their nonspecific interactions with background tissue. Moreover, the uniqueness of PEG45 can be generalized to other organic dyes such as ZW800-1 and fluorescein. This finding highlights the importance of low-MW PEGylation in tailoring in vivo transport of organic fluorophores, which would broaden their biomedical applications.

Enhancing ZnO nanowire gas sensors using Au/Fe2O3 hybrid nanoparticle decoration.

Heterojunctions are an important strategy for designing high performance electrical sensor materials and related devices. Herein, a new type of metal-semiconductor hybrid nanoparticle has been successfully used to remarkably sensitize the surface of ZnO nanowires for detecting NO2 with high responses over a broad temperature window ranging from room temperature to 600 °C. These hybrid nanoparticles are comprised of iron oxide nanowires with well dispersed single crystalline Au nanoparticles. The hybrid nanoparticle decorated ZnO nanowires have achieved a giant response, as high as 74 500 toward NO2 gas, about 42 times that of Au decorated ZnO nanowire sensors. This dramatic enhancement may be attributed to the efficient charge transfer across the Au-Fe2O3 Schottky and Fe2O3-ZnO semiconductor heterojunction interfaces. Due to the incorporation of thermally-stable Fe2O3 nanoparticles as the support of Au nanoparticles, the working temperature of nanowire sensors was successfully extended to higher temperatures, with an increase of 200 °C, from 400 °C to 600 °C. Such a combination of semiconductor heterojunction and semiconductor-metal Schottky contact presents a new strategy for designing high performance electrical sensors with high sensitivity, stability, selectivity, and wide operation temperature window, which are potentially suitable for advanced energy systems such as automotive engines and power plants.

Advantage of audition over vision in a perceptual timing task but not in a sensorimotor timing task.

Timing is essential for various behaviors and relative to vision, audition is considered to be specialized for temporal processing. The present study conducted a sensorimotor timing task that required tapping in synchrony with a temporally regular sequence and a perceptual timing task that required detecting a timing deviation among a temporally regular sequence. The sequence was composed of auditory tones, visual flashes, or a visual bouncing ball. In the sensorimotor task, sensorimotor timing performance (synchronization stability) of the bouncing ball was much greater than that of flashes and was comparable to that of tones. In the perceptual task, where perceptual timing performance of the bouncing ball was greater than that of flashes, it was poorer than that of tones. These results suggest the facilitation of both perceptual and sensorimotor processing of temporal information by the bouncing ball. Given such facilitation of temporal processing, however, audition is still superior over vision in perceptual detection of timing.

Tapping ahead of time: its association with timing variability.

Researchers have puzzled over the phenomenon in sensorimotor timing that people tend to tap ahead of time. When synchronizing movements (e.g., finger taps) with an external sequence (e.g., a metronome), humans typically tap tens of milliseconds before event onsets, producing the elusive negative asynchrony. Here, we present 24 metronome-tapping data sets from 8 experiments with different experimental settings, showing that less negative asynchrony is associated with lower tapping variability. Further analyses reveal that this negative mean-SD correlation of asynchrony is likely to be observed for sequence types appropriate for synchronization, as indicated by the statistically negative lag 1 autocorrelation of inter-response intervals. The reported findings indicate an association between negative asynchrony and timing variability.

Salivary Excretion of Renal-Clearable Silver Nanoparticles.

Salivary elimination is an important pathway for the body to excrete small molecules with digestive enzymes. However, very few engineered nanoparticles can be excreted through salivary glands, which often host bacteria or viruses during infection and involve in disease transmission. Herein, we report that renal clearable glutathione coated AgNPs (GS-AgNPs) can selectively accumulate in the submandibular salivary gland, followed by being excreted in its excretory duct. By conducting head-to-head comparison on in vivo transport and interactions of both GS-AgNPs and glutathione coated gold nanoparticles (GS-AuNPs) with the same sizes, we found that low-density GS-AgNPs showed much higher vascular permeability than GS-AuNPs and can rapidly penetrate into submandibular salivary glands, be efficiently taken up by striated and excretory duct cells, and eventually secreted into saliva.

Tuning the In†Vivo Transport of Anticancer Drugs Using Renal-Clearable Gold Nanoparticles.

Precise control of in vivo transport of anticancer drugs in normal and cancerous tissues with engineered nanoparticles is key to the future success of cancer nanomedicines in clinics. This requires a fundamental understanding of how engineered nanoparticles impact the targeting-clearance and permeation-retention paradoxes in the anticancer-drug delivery. Herein, we systematically investigated how renal-clearable gold nanoparticles (AuNPs) affect the permeation, distribution, and retention of the anticancer drug doxorubicin in both cancerous and normal tissues. Renal-clearable AuNPs retain the advantages of the free drug, including rapid tumor targeting and high tumor vascular permeability. The renal-clearable AuNPs also accelerated body clearance of off-target drug via renal elimination. These results clearly indicate that diverse in vivo transport behaviors of engineered nanoparticles can be used to reconcile long-standing paradoxes in the anticancer drug delivery.

Generation and characterization of pathogenic Mab21l2(R51C) mouse model.

MAB21L2(R51C) is one of the five documented MAB21L2 mutations in human patients with bilateral eye malformations identified via whole exome sequencing. In addition to the eye abnormality, patients with MAB21L2 R51C/+ mutation also have skeletal dysplasia and intellectual disability. To evaluate the pathology of this mutant allele systematically in understanding the functional role of MAB21L2 in human development, we introduce the R51C mutation into the mouse genome by CRISPR/Cas9 system to generate a mouse model for detailed characterization. The Mab21l2 R51C/+ mice have eyeless phenotype and skeletal abnormalities. Micro-computed tomography (micro-CT) analysis showed the Mab21l2 R51C/+ mice have no eye balls but with two abnormal tissues underneath the brain. Histological analysis revealed that the early eye development in the mutant embryos is interrupted. In addition, Mab21l2 R51C/+ mice also have joint fusion phenotype; the humerus is fused with radius, whereas femur is fused with tibia. Limbs in the mutant animals are distinctly shorter than the wild type; and deltoid tuberosities in humeri are absent in these Mab21l2 R51C/+ mice. In summary, we showed that our Mab21l2 R51C/+ mutant mice have recapitulated the pathological features in eye and bone of human patients. Further analyses of the mutant phenotype with molecular markers will provide insight on how MAB21L2 guides the optic differentiation and skeletogenesis, revealing specific underlying pathogenic mechanism of the MAB21L2(R51C) mutation.

Effect of Hydrophobicity on Nano-Bio Interactions of Zwitterionic Luminescent Gold Nanoparticles at the Cellular Level.

Fundamental understanding of how the hydrophobicity impacts cellular interactions of engineered nanoparticles is critical to their future success in healthcare. Herein, we report that inserting hydrophobic octanethiol onto the surface of zwitterionic luminescent glutathione coated gold nanoparticles (GS-AuNPs) of 2 nm enhanced their affinity to the cellular membrane and increased cellular uptake kinetics by more than one order of magnitude, rather than inducing the accumulation of the AuNPs in the bilayer core or enhancing their passive diffusion. These studies highlight the diversity and heterogeneity in the hydrophobicity-induced nano-bio interactions at the cellular level and offer a new pathway to expediting cellular uptake of engineered nanoparticles. In addition, the amphiphilic luminescent AuNPs with high affinity to cell membrane and rapid endocytosis potentially serve as dual-modality imaging probes to correlate fluorescence and electron microscopies at the cellular level.

Neuroprotective Natural Products for the Treatment of Parkinson's Disease by Targeting the Autophagy-Lysosome Pathway: A Systematic Review.

The autophagy-lysosome pathway (ALP) is a primary means by which damaged organelles and long-lived proteins are removed from cells and their components recycled. Impairment of the ALP has been found to be linked to the pathogenesis of Parkinson's disease (PD), a chronic neurodegenerative disorder characterized by the accumulation of protein aggregates and loss of dopaminergic neurons in the midbrain. In recent years, some active compounds derived from plants have been found to regulate the ALP and to exert neuroprotective effects in experimental models of PD, raising the possibility that autophagy enhancement may be an effective therapeutic strategy in PD treatment. In this review, we summarize recent findings of natural products that enhance ALP and thereby protect against PD. Research articles were retrieved from PubMed using relevant keywords in combination. Papers related to the topic were identified, and then the reliability of the experiments was assessed in terms of methodology. The results suggest that targeting the ALP with natural products is a promising strategy for PD treatment. However, risk of bias exists in some studies due to the defective methodology. Rigorous experimental design following the guidelines of autophagy assays, molecular target identification and in vivo efficacy evaluation is critical for the development of ALP enhancers for PD treatment in future studies. Copyright © 2017 John Wiley & Sons, Ltd.

Neurogenic Traditional Chinese Medicine as a Promising Strategy for the Treatment of Alzheimer's Disease.

Hippocampal neurogenesis plays a critical role in the formation of new neurons during learning and memory development. Attenuation of neurogenesis in the brain is one of the primary causes of dementia in Alzheimer's disease (AD), and, conversely, modulating the process of hippocampal neurogenesis benefit patients with AD. Traditional Chinese medicine (TCM), particularly herbal medicine, has been in use for thousands of years in Asia and many regions of the world for the treatment of cancer, cardiovascular diseases and neurodegenerative diseases. In this review, we summarize the role of neurotrophic factors, signal transducing factors, epigenetic modulators and neurotransmitters in neurogenesis, and we also discuss the functions of several Chinese herbs and their active molecules in activating multiple pathways involved in neurogenesis. TCM herbs target pathways such as Notch, Wnt, Sonic Hedgehog and receptor tyrosine kinase pathway, leading to activation of a signaling cascade that ultimately enhances the transcription of several important genes necessary for neurogenesis. Given these pathway activating effects, the use of TCM herbs could be an effective therapeutic strategy for the treatment of AD.

Trends in the use of maintenance immunosuppressive drugs among liver transplant recipients in Taiwan: a nationwide population-based study.

PURPOSE: During the past two decades, many novel immunosuppressive drugs have been approved for transplant recipients. Trends in the use of maintenance immunosuppressants after liver transplantation in Asia are unclear. Thus, we aimed to analyze the prescription trends in maintenance immunosuppressive drugs among liver transplant recipients in Taiwan and compare the results with the trends reported from western countries. METHODS: We conducted a retrospective nationwide population-based study utilizing the National Health Insurance Research Database (NHIRD) to analyze the prescribing patterns of immunosuppressants used in Taiwanese liver transplant recipients from 2000 to 2009. RESULTS: A total of 1686 liver transplant patients and their prescriptions of immunosuppressants were analyzed. The 5-year survival rate of liver transplant recipients was 79.6%. In 2009, the major immunosuppressive therapy among liver transplant recipients was a dual-drug regimen with tacrolimus and mycophenolic acid (57.3%). Among the calcineurin inhibitors (CNI), the use of cyclosporine decreased from 58.9% to 12.5%, while the use of tacrolimus notably increased from 23.3% to 77.5%. The use of azathioprine decreased from 21.3% to 0.4%, while the use of mycophenolic acid increased from 56.1% to 76.5%. Among the mammalian target of rapamycin (mTOR) inhibitors, sirolimus was approved in 2002, and its use increased to 8.7% in 2009. In the first 3 months after liver transplantation, a total of 17 different regimens were used in 2009, compared with seven regimens in 2000. CONCLUSIONS: Although the CNI-based combination obviously remains the major regimen, our results reveal a trend toward individualized immunosuppressive regimens among Taiwanese liver transplant recipients. Copyright © 2016 John Wiley & Sons, Ltd.

Prescription trends of immunosuppressive drugs in post-heart transplant recipients in Taiwan, 2000-2009.

PURPOSE: Significantly increasing heart transplantations have been performed in Taiwan in the past decades, but the trends of maintenance immunosuppression for heart transplant recipients have not been well known. In this study, we aimed to explore the trends of maintenance immunosuppressive therapy and common complications for heart transplant recipients. METHODS: We retrospectively analyzed ambulatory prescriptions in 488 heart transplant recipients for the period 2000-2009. Patient complications after heart transplantation were also identified. RESULTS: The annual number of new heart transplant recipients ranged from 18 to 68. The 5-year survival rate was 77.9%. The total number of regimens was 10 in 2000, and increased to 28 in 2009. Most prescriptions were immunosuppressive combinations (95.5%-89.5%). The majority of immunosuppressive regimens were a triple regimen: cyclosporine, mycophenolic acid and corticosteroid in 2009. Cyclosporine was a predominant calcineurin inhibitor with a decreasing trend from 73.9% to 59.1%, whereas the use of tacrolimus significantly increased from 11.9% to 38.4%. Mycophenolic acid was the most frequently used antimetabolite (60.1%-80.3%), while the use of azathioprine was reduced (21.6%-2.3%). From 2008, the launch of everolimus initiated a new era in the utilization of mammalian target of rapamycin inhibitors for maintenance immunosuppression. CONCLUSIONS: Cyclosporine remained the most frequently used calcineurin inhibitors, and tacrolimus increased gradually. Mycophenolic acid was the most popular antimetabolite rather than azathioprine. The rapidly increased everolimus combined regimen may change the patterns of maintenance immunosuppression. The increasing number of combination therapies indicates an active role of everolimus and a tendency of complex tailored individual therapies.

Sintilimab combined with anlotinib as first-line treatment for advanced sarcomatoid carcinoma of head and neck: a case report and literature review.

Sarcomatoid carcinoma (SC) is a rare, complex, aggressive tumor that spreads rapidly, is highly malignant, and has metastasized. Surgical resection is the primary treatment, and it usually occurs in the lungs and kidneys but rarely in the neck. Patients with advanced sarcomatoid carcinoma (SC) of the head and neck (HN) have a poor progonsis. In recent years, immune checkpoint inhibitors (ICIs) have been established as treatments for many solid tumors; however, the effectiveness of ICIs in treating SC of HN is still little recognized. We report a case study of a middle-aged woman with primary sarcomatoid carcinoma of the neck. She developed sarcomatoid carcinoma of the contralateral neck 7 months after the first surgical treatment. Subsequently, disease recurrence and metastasis occurred 8 months after the second surgery. The patient did not receive any treatment after both surgeries. The tumor showed high programmed death-ligand 1 (PD-L1) expression, with a combined positive score (CPS): 95. The patient's response to treatment was assessed as partial remission (PR) after 2 cycles of anlotinib combined with sintilimab. The patient has survived for over 2 years and remains in PR status, despite experiencing grade 2 hypothyroidism as an adverse event during treatment. The case highlights the efficacy and safety of anlotinib and sintilimab as a first-line treatment.

Sustaining attention in visuomotor timing is associated with location-based binding.

Maintaining focus of attention over prolonged periods can be challenging, especially when the target stimulus is absent from the temporal sequence. Prior research has shown that a temporal attentional cue filling in the temporal blank can improve sustained attention: in a sustained visual attention task requiring synchronizing finger tapping with a temporally regular sequence composed of brief flash disks interleaved with blank periods, task performance was improved when a continuous fixation point that served as a temporal attentional cue was presented superimposed on the disk stimulus. To test the hypothesis that binding the temporal attentional cue with the target temporal sequence by spatial overlapping is crucial for enhancing sustained attention, the present study conducted a series of three experiments that deconstructed the bound connection between the cue and the sequence stimulus. In Experiment 1, the cue was placed above or below a flash disk. In Experiment 2, the cue was between two vertically arranged flash disks. In Experiment 3, the cue was in a flash ring. No significant effect of sustained attention improvement was found in any of the three experiments. Experiment 4 further replicated these null results and the previously observed effect of sustained attention improvement when the temporal cue was superimposed on the sequence stimulus. Our finding demonstrates that binding by spatial overlapping during the temporal blank when the sequence stimulus is absent is critical for enhancing sustained attention, which should be beneficial for improving performance across a broader range of tasks that require prolonged maintenance of attention.