TERT mediates the U-shape of glucocorticoids effects in modulation of hippocampal neural stem cells and associated brain function.

BACKGROUND: Glucocorticoids (GCs) are steroidal hormones produced by the adrenal cortex. A physiological-level GCs have a crucial function in maintaining many cognitive processes, like cognition, memory, and mood, however, both insufficient and excessive GCs impair these functions. Although this phenomenon could be explained by the U-shape of GC effects, the underlying mechanisms are still not clear. Therefore, understanding the underlying mechanisms of GCs may provide insight into the treatments for cognitive and mood-related disorders. METHODS: Consecutive administration of corticosterone (CORT, 10 mg/kg, i.g.) proceeded for 28 days to mimic excessive GCs condition. Adrenalectomy (ADX) surgery was performed to ablate endogenous GCs in mice. Microinjection of 1 µL of Ad-mTERT-GFP virus into mouse hippocampus dentate gyrus (DG) and behavioral alterations in mice were observed 4 weeks later. RESULTS: Different concentrations of GCs were shown to affect the cell growth and development of neural stem cells (NSCs) in a U-shaped manner. The physiological level of GCs (0.01 µM) promoted NSC proliferation in vitro, while the stress level of GCs (10 µM) inhibited it. The glucocorticoid synthesis blocker metyrapone (100 mg/kg, i.p.) and ADX surgery both decreased the quantity and morphological development of doublecortin (DCX)-positive immature cells in the DG. The physiological level of GCs activated mineralocorticoid receptor and then promoted the production of telomerase reverse transcriptase (TERT); in contrast, the stress level of GCs activated glucocorticoid receptor and then reduced the expression of TERT. Overexpression of TERT by AD-mTERT-GFP reversed both chronic stresses- and ADX-induced deficiency of TERT and the proliferation and development of NSCs, chronic stresses-associated depressive symptoms, and ADX-associated learning and memory impairment. CONCLUSION: The bidirectional regulation of TERT by different GCs concentrations is a key mechanism mediating the U-shape of GC effects in modulation of hippocampal NSCs and associated brain function. Replenishment of TERT could be a common treatment strategy for GC dysfunction-associated diseases.

Advances in Atherosclerosis Theranostics Harnessing Iron Oxide-Based Nanoparticles.

Atherosclerosis, a multifaceted chronic inflammatory disease, has a profound impact on cardiovascular health. However, the critical limitations of atherosclerosis management include the delayed detection of advanced stages, the intricate assessment of plaque stability, and the absence of efficacious therapeutic strategies. Nanotheranostic based on nanotechnology offers a novel paradigm for addressing these challenges by amalgamating advanced imaging capabilities with targeted therapeutic interventions. Meanwhile, iron oxide nanoparticles have emerged as compelling candidates for theranostic applications in atherosclerosis due to their magnetic resonance imaging capability and biosafety. This review delineates the current state and prospects of iron oxide nanoparticle-based nanotheranostics in the realm of atherosclerosis, including pivotal aspects of atherosclerosis development, the pertinent targeting strategies involved in disease pathogenesis, and the diagnostic and therapeutic roles of iron oxide nanoparticles. Furthermore, this review provides a comprehensive overview of theranostic nanomedicine approaches employing iron oxide nanoparticles, encompassing chemical therapy, physical stimulation therapy, and biological therapy. Finally, this review proposes and discusses the challenges and prospects associated with translating these innovative strategies into clinically viable anti-atherosclerosis interventions. In conclusion, this review offers new insights into the future of atherosclerosis theranostic, showcasing the remarkable potential of iron oxide-based nanoparticles as versatile tools in the battle against atherosclerosis.

Kyasanur Forest disease virus NS3 helicase: Insights into structure, activity, and inhibitors.

Kyasanur Forest disease virus (KFDV), a tick-borne flavivirus prevalent in India, presents a serious threat to human health. KFDV NS3 helicase (NS3hel) is considered a potential drug target due to its involvement in the viral replication complex. Here, we resolved the crystal structures of KFDV NS3hel apo and its complex with three phosphate molecules, which indicates a conformational switch during ATP hydrolysis. Our data revealed that KFDV NS3hel has a higher binding affinity for dsRNA, and its intrinsic ATPase activity was enhanced by dsRNA while being inhibited by DNA. Through mutagenesis analysis, several residues within motifs I, Ia, III, V, and VI were identified to be crucial for NS3hel ATPase activity. Notably, the M419A mutation drastically reduced NS3hel ATPase activity. We propose that the methionine-aromatic interaction between residues M419 and W294, located on the surface of the RNA-binding channel, could be a target for the design of efficient inhibitor probes. Moreover, epigallocatechin gallate (EGCG), a tea-derived polyphenol, strongly inhibited NS3hel ATPase activity with an IC50 value of 0.8 µM. Our computational docking data show that EGCG binds at the predicted druggable hotspots of NS3hel. Overall, these findings contribute to the development and design of more effective and specific inhibitors.

The Story of Ferumoxytol: Synthesis Production, Current Clinical Applications, and Therapeutic Potential.

Ferumoxytol, approved by the U.S. Food and Drug Administration in 2009, is one of the intravenous iron oxide nanoparticles authorized for the treatment of iron deficiency in chronic kidney disease and end-stage renal disease. With its exceptional magnetic properties, catalytic activity, and immune activity, as well as good biocompatibility and safety, ferumoxytol has gained significant recognition in various biomedical diagnoses and treatments. Unlike most existing reviews on this topic, this review primarily focuses on the recent clinical and preclinical advances of ferumoxytol in disease treatment, spanning anemia, cancer, infectious inflammatory diseases, regenerative medicine application, magnetic stimulation for neural modulation, etc. Additionally, the newly discovered mechanisms associated with the biological effects of ferumoxytol are discussed, including its magnetic, catalytic, and immunomodulatory properties. Finally, the summary and future prospects concerning the treatment and application of ferumoxytol-based nanotherapeutics are presented.

Navigating the landscape: Prospects and hurdles in targeting vascular smooth muscle cells for atherosclerosis diagnosis and therapy.

Vascular smooth muscle cells (VSMCs) have emerged as pivotal contributors throughout all phases of atherosclerotic plaque development, effectively dispelling prior underestimations of their prevalence and significance. Recent lineage tracing studies have unveiled the clonal nature and remarkable adaptability inherent to VSMCs, thereby illuminating their intricate and multifaceted roles in the context of atherosclerosis. This comprehensive review provides an in-depth exploration of the intricate mechanisms and distinctive characteristics that define VSMCs across various physiological processes, firmly underscoring their paramount importance in shaping the course of atherosclerosis. Furthermore, this review offers a thorough examination of the significant strides made over the past two decades in advancing imaging techniques and therapeutic strategies with a precise focus on targeting VSMCs within atherosclerotic plaques, notably spotlighting meticulously engineered nanoparticles as a promising avenue. We envision the potential of VSMC-targeted nanoparticles, thoughtfully loaded with medications or combination therapies, to effectively mitigate pro-atherogenic VSMC processes. These advancements are poised to contribute significantly to the pivotal objective of modulating VSMC phenotypes and enhancing plaque stability. Moreover, our paper also delves into recent breakthroughs in VSMC-targeted imaging technologies, showcasing their remarkable precision in locating microcalcifications, dynamically monitoring plaque fibrous cap integrity, and assessing the therapeutic efficacy of medical interventions. Lastly, we conscientiously explore the opportunities and challenges inherent in this innovative approach, providing a holistic perspective on the potential of VSMC-targeted strategies in the evolving landscape of atherosclerosis research and treatment.

Design of a Multifunctional Nanozyme for Resolving the Proinflammatory Plaque Microenvironment and Attenuating Atherosclerosis.

Persistent inflammation within atherosclerotic plaques is a crucial factor contributing to plaque vulnerability and rupture. It has become increasingly evident that the proinflammatory microenvironment of the plaque, characterized by heightened monocyte recruitment, oxidative stress, and impaired clearance of apoptotic cells, plays a significant role in perpetuating inflammation and impeding its resolution. Consequently, targeting and eliminating these proinflammatory features within the plaque microenvironment have emerged as a promising therapeutic approach to restore inflammation resolution and mitigate the progression of atherosclerosis. While recent advancements in nanotherapeutics have demonstrated promising results in targeting individual proinflammatory characteristics, the development of an effective therapeutic strategy capable of simultaneously addressing multiple proinflammatory features remains a challenge. In this study, we developed a multifunctional nanozyme based on Prussian blue, termed PBNZ@PP-Man, to simultaneously target and eliminate various proinflammatory factors within the plaque microenvironment. Through systematic investigations, we have elucidated the antiatherosclerotic mechanisms of PBNZ@PP-Man. Our results demonstrate that PBNZ@PP-Man possesses the ability to accumulate within atherosclerotic plaques and effectively eliminate multiple proinflammatory factors, leading to inflammation resolution. Specifically, PBNZ@PP-Man suppresses monocyte recruitment, scavenges reactive oxygen species, and enhances efferocytosis. Notably, PBNZ@PP-Man exhibits a much stronger efficacy to resolve the proinflammatory plaque microenvironment and attenuate atherosclerosis in comparison to the approach that merely eliminates one single risky factor in the plaque. It significantly enhances the inflammation resolution capabilities of macrophages and attenuates atherosclerosis. These results collectively underscore the importance of modulating the proinflammatory plaque microenvironment as a complementary strategy for resolving inflammation in atherosclerosis.

Preparation, Characterization and Multiple Biological Properties of Peptide-Modified Cerium Oxide Nanoparticles.

Although cerium oxide nanoparticles are attracting much attention in the biomedical field due to their unique physicochemical and biological functions, the cerium oxide nanoparticles greatly suffer from several unmet physicochemical challenges, including loss of enzymatic activity during the storage, non-specific cellular uptake, off-target toxicities, etc. Herein, in order to improve the targeting property of cerium oxide nanoparticles, we first modified cerium oxide nanoparticles (CeO2) with polyacrylic acid (PAA) and then conjugated with an endothelium-targeting peptide glycine-arginine-aspartic acid (cRGD) to construct CeO2@PAA@RGD. The physiochemical characterization results showed that the surface modifications did not impact the intrinsic enzymatic properties of CeO2, including catalase-like (CAT) and superoxide dismutase-like (SOD) activities. Moreover, the cellular assay data showed that CeO2@PAA@RGD exhibited a good biocompatibility and a higher cellular uptake due to the presence of RGD targeting peptide on its surface. CeO2@PAA@RGD effectively scavenged reactive oxygen species (ROS) to protect cells from oxidative-stress-induced damage. Additionally, it was found that the CeO2@PAA@RGD converted the phenotype of macrophages from proinflammatory (M1) to anti-inflammatory (M2) phenotype, inhibiting the occurrence of inflammation. Furthermore, the CeO2@PAA@RGD also promoted endothelial cell-mediated migration and angiogenesis. Collectively, our results successfully demonstrate the promising application of CeO2@PAA@RGD in the future biomedical field.

Identification of Novel Therapeutic Candidates Against SARS-CoV-2 Infections: An Application of RNA Sequencing Toward mRNA Based Nanotherapeutics.

Due to fast transmission and various circulating SARS-CoV-2 variants, a significant increase of coronavirus 2019 infection cases with acute respiratory symptoms has prompted worries about the efficiency of current vaccines. The possible evasion from vaccine immunity urged scientists to identify novel therapeutic targets for developing improved vaccines to manage worldwide COVID-19 infections. Our study sequenced pooled peripheral blood mononuclear cells transcriptomes of SARS-CoV-2 patients with moderate and critical clinical outcomes to identify novel potential host receptors and biomarkers that can assist in developing new translational nanomedicines and vaccine therapies. The dysregulated signatures were associated with humoral immune responses in moderate and critical patients, including B-cell activation, cell cycle perturbations, plasmablast antibody processing, adaptive immune responses, cytokinesis, and interleukin signaling pathway. The comparative and longitudinal analysis of moderate and critically infected groups elucidated diversity in regulatory pathways and biological processes. Several immunoglobin genes (IGLV9-49, IGHV7-4, IGHV3-64, IGHV1-24, IGKV1D-12, and IGKV2-29), ribosomal proteins (RPL29, RPL4P2, RPL5, and RPL14), inflammatory response related cytokines including Tumor Necrosis Factor (TNF, TNFRSF17, and TNFRSF13B), C-C motif chemokine ligands (CCL3, CCL25, CCL4L2, CCL22, and CCL4), C-X-C motif chemokine ligands (CXCL2, CXCL10, and CXCL11) and genes related to cell cycle process and DNA proliferation (MYBL2, CDC20, KIFC1, and UHCL1) were significantly upregulated among SARS-CoV-2 infected patients. 60S Ribosomal protein L29 (RPL29) was a highly expressed gene among all COVID-19 infected groups. Our study suggested that identifying differentially expressed genes (DEGs) based on disease severity and onset can be a powerful approach for identifying potential therapeutic targets to develop effective drug delivery systems against SARS-CoV-2 infections. As a result, potential therapeutic targets, such as the RPL29 protein, can be tested in vivo and in vitro to develop future mRNA-based translational nanomedicines and therapies to combat SARS-CoV-2 infections.

Anchoring ß-CD on simvastatin-loaded rHDL for selective cholesterol crystals dissolution and enhanced anti-inflammatory effects in macrophage/foam cells.

Macrophage/foam cells and cholesterol crystals (CCs) have been regarded as the central triggers of maladaptive inflammation in atherosclerotic plaque. Despite the tremendous progress of recombinant high-density lipoprotein (rHDL) serving for targeted drug delivery to alleviate inflammation in macrophage/foam cells, the active attempt to modulate/improve its CCs dissolution capacity remains poorly explored. The untreated CCs can seriously aggravate inflammation and threaten plaque stability. Based on the superb ability of ß-cyclodextrin (ß-CD) to bind CCs and promote cholesterol efflux, simvastatin-loaded discoidal-rHDL (ST-d-rHDL) anchored with ß-CD (ßCD-ST-d-rHDL) was constructed. We verified that ßCD-ST-d-rHDL specifically bound and dissolved CCs extracellularly and intracellularly. Furthermore, anchoring ß-CD onto the surface of ST-d-rHDL enhanced its cholesterol removal ability in RAW 264.7 cell-derived foam cells characterized by accelerated cholesterol efflux, reduced intracellular lipid deposition, and improved cell membrane fluidity/permeability. Finally, ßCD-ST-d-rHDL exerted efficient drug delivery and effective anti-inflammatory effects in macrophage/foam cells. Collectively, anchoring ß-CD onto the surface of ST-d-rHDL for selective CCs dissolution, accelerated cholesterol efflux, and improved drug delivery represents an effective strategy to enhance anti-inflammatory effects for the therapy of atherosclerosis.

A biomimetic nanocomposite with enzyme-like activities and CXCR4 antagonism efficiently enhances the therapeutic efficacy of acute myeloid leukemia.

Despite the progress made to improve therapeutic outcomes for acute myeloid leukemia (AML), many unmet clinical needs remain to be resolved. Unlike existing anti-AML strategies, here we developed a biomimetic nanocomposite to efficiently eliminate the leukemia cells in the bone marrow and prevent the homing of AML. To fulfill our design, the ultra-small nanozyme was conjugated onto the surface of an oxygen-carrying nanoparticle, which was further coated with bone marrow stromal cell membrane. After entering the blood, this biomimetic nanocomposite got actively internalized by the leukemia cells in the blood and released the loaded chemotherapeutics and nanozyme inside the leukemia cells to achieve a synergistic antitumor efficacy. Meanwhile, the adhesive properties of the stromal cell membrane enabled the nanocomposite to home to the bone marrow, where the nanocomposite effectively killed the retained leukemia cells. More importantly, the biomimetic cell membrane also acted as a CXCR4 antagonism to block the CXCR4/CXCL12-mediated homing of leukemia cells to the bone marrow and infiltration to other organs like the liver and spleen. In conclusion, this proof-of-concept study demonstrated that our designed platform effectively kills leukemia cells while preventing their infiltration, thus providing a promising prospect for resolving the clinical challenges in current AML treatment.

Neutrophil-to-Lymphocyte Ratios Are Closely Associated With the Severity and Course of Non-mild COVID-19.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide. Measuring the prevention and control of the disease has become a matter requiring urgent focus. Objective: Based on coronavirus disease 2019 (COVID-19) clinical data from Wuhan, we conducted an in-depth analysis to clarify some of the pathological mechanisms of the disease and identify simple measures to predict its severity early on. Methods: A total of 230 patients with non-mild COVID-19 were recruited, and information on their clinical characteristics, inflammatory cytokines, and T lymphocyte subsets was collected. Risk factors for severity were analyzed by binary logistic regression, and the associations of neutrophil-to-lymphocyte ratios (N/LRs) with illness severity, disease course, CT grading, inflammatory cytokines, and T lymphocyte subsets were evaluated. Results: Our results showed that the N/LRs were closely related to interleukin (IL)-6 and IL-10 (P < 0.001, P = 0.024) and to CD3+ and CD8+ T lymphocytes (P < 0.001, P = 0.046). In particular, the N/LRs were positively correlated with the severity and course of the disease (P = 0.021, P < 0.001). Compared to the values at the first test after admission, IL-6 and IL-10 were significantly decreased and increased, respectively, as of the last test before discharge (P = 0.006, P < 0.001). More importantly, through binary logistic regression, we found that male sex, underlying diseases (such as cardiovascular disease), pulse, and N/LRs were all closely related to the severity of the disease (P = 0.004, P = 0.012, P = 0.013, P = 0.028). Conclusions: As a quick and convenient marker of inflammation, N/LRs may predict the disease course and severity level of non-mild COVID-19; male sex, cardiovascular disease, and pulse are also risk factors for the severity of non-mild COVID-19.

Advances on Non-Genetic Cell Membrane Engineering for Biomedical Applications.

Cell-based therapeutics are very promising modalities to address many unmet medical needs, including genetic engineering, drug delivery, and regenerative medicine as well as bioimaging. To enhance the function and improve the efficacy of cell-based therapeutics, a variety of cell surface engineering strategies (genetic engineering and non-genetic engineering) are developed to modify the surface of cells or cell-based therapeutics with some therapeutic molecules, artificial receptors, and multifunctional nanomaterials. In comparison to complicated procedures and potential toxicities associated with genetic engineering, non-genetic engineering strategies have emerged as a powerful and compatible complement to traditional genetic engineering strategies for enhancing the function of cells or cell-based therapeutics. In this review, we will first briefly summarize key non-genetic methodologies including covalent chemical conjugation (surface reactive groups-direct conjugation, and enzymatically mediated and metabolically mediated indirect conjugation) and noncovalent physical bioconjugation (biotinylation, electrostatic interaction, and lipid membrane fusion as well as hydrophobic insertion), which have been developed to engineer the surface of cell-based therapeutics with various materials. Next, we will comprehensively highlight the latest advances in non-genetic cell membrane engineering surrounding different cells or cell-based therapeutics, including whole-cell-based therapeutics, cell membrane-derived therapeutics, and extracellular vesicles. Advances will be focused specifically on cells that are the most popular types in this field, including erythrocytes, platelets, cancer cells, leukocytes, stem cells, and bacteria. Finally, we will end with the challenges, future trends, and our perspectives of this relatively new and fast-developing research field.

Survey of Clinical Translation of Cancer Nanomedicines-Lessons Learned from Successes and Failures.

In 1995, the year the first cancer nanomedicine, Doxil, was approved by the Food and Drug Administration (FDA), only 23 manuscripts appeared in a PubMed search for "nanoparticles for cancer" keywords. Now, over 25 000 manuscripts can be found using those same keywords, yet only 15 nanoparticle-based cancer nanomedicines are approved globally. Based on the clinicaltrials.gov database, a total of 75 cancer nanomedicines are under clinical investigation involving 190 clinical trials summarized here. In this Account, we focus on cancer nanomedicines that have been approved or reached clinical trials to understand this high attrition rate. We classify the various nanomedicines, summarize their clinical outcomes, and discuss possible reasons for product failures and discontinuation of product development efforts. Among ongoing and completed clinical trials, 91 (48 completed) are phase 1, 78 (59 completed) phase 2, and 21 (11 completed) phase 3. The success rate of phase 1 trials has been high-roughly 94%. Of those phase 1 trials with identified outcomes, 45 showed positive safety and efficacy results, with only one negative result (low efficacy) and two terminated due to adverse reactions. In some cases, findings from these trials have not only shown improved pharmacokinetics, but also avid drug accumulation within tumor tissues among active-targeting nanoparticles, including BIND-014, CALAA-01, and SGT-94. However, the success rate drops to ∼48% among completed phase 2 trials with identified outcomes (31 positive, 15 negative, and 4 terminated for toxicity or poor efficacy). A majority of failures in phase 2 trials were due to poor efficacy (15 of 19), rather than toxicity (4 of 19). Unfortunately, the success rate for phase 3 trials slumps to a mere ∼14%, with failures stemming from lack of efficacy. Although the chance of success for cancer nanomedicines starting from the proof-of-concept idea in the laboratory to valuable marketed product may seem daunting, we should not be discouraged. Despite low success rates, funding from the government, foundations, and research organizations are still strong-an estimated > $130 M spent by the National Institutes of Health (NIH) on R01s focused on nanomedicine in 2018 alone. In addition, the NIH created several special initiatives/programs, such as the National Cancer Institute (NCI) Alliance, to facilitate clinical translation of nanomedicines. Companies developing cancer nanomedicines raised diverse ranges of funds from venture capital, capital markets, and industry partnerships. In some cases, the development efforts resulted in regulatory approvals of cancer nanomedicines. In other cases, clinical failures and market pressure from improving standard of care products resulted in product terminations and business liquidation. Yet, recent approvals of nanomedicine products for orphan cancers and continuing development of nanoparticle based drugs for immune-oncology applications fuel continuing industrial and academic interest in cancer nanomedicines.

Drug-Conjugated Dendrimer Hydrogel Enables Sustained Drug Release via a Self-Cleaving Mechanism.

In this study, the anticancer drug, camptothecin (CPT), was covalently grafted onto polyamidoamine (PAMAM) dendrimer surface and then reacted with polyethylene glycol diacrylate (PEG-DA) to form dendrimer hydrogel (DH-G3-CPT) with low cross-linking density. In this novel drug delivery system, CPT was cleaved from dendrimer via the ammonolysis of ester bonds and then diffused out of the hydrogel network, thus leading to significantly prolonged drug release. The self-cleaving release kinetics of camptothecin can be further tuned by pH. This DH-G3-CPT drug delivery system has both injectability and sustained drug release. It showed an excellent tumor inhibition effect following intratumoral injection in a head and neck cancer model of mouse.

Combination Treatments of Plasma Exchange and Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation for Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure: A Clinical Trial in China.

BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a common type of liver failure with a high mortality. This study aimed at investigating the safety and efficacy of the combination treatment of plasma exchange (PE) and umbilical cord-derived mesenchymal stem cell (UC-MSCs) transplantation for HBV-ACLF patients. METHODS: A total of 110 HBV-ACLF patients treated in our hospital from January 2012 to September 2017 were enrolled into this trial and divided into the control group (n = 30), UC-MSC group (n = 30), PE group (n = 30), and UC-MSC + PE group (n = 20) based on their treatments. The hepatic function, coagulation, and virological and immunological markers were assessed at baseline and 30, 60, 90, 180, and 360 days. The endpoint outcomes were death and unfavorable outcome (need for liver transplantation or death). RESULTS: The UC-MSC + PE group had the lowest rates of death and unfavorable outcome at 30 days, 60 days, and 90 days posttreatment among the four groups, but the difference did not reach significances. The multivariate logistic regression analysis demonstrated that hemoglobin, prothrombin activity, and MELD (model for end-stage liver disease) score were the independent factors associated with the unfavorable outcome (all P < 0.05). The levels of total bilirubin, alanine aminotransferase, aspartate transaminase, and MELD score were significantly decreased during treatments (all P < 0.05). CONCLUSION: UC-MSCs combined with PE treatment had good safety but cannot significantly improve the short-term prognosis of HBV-ACLF patients with as compared with the single treatment. The long-term efficacy should be further evaluated. This trial is registered with registration no. NCT01724398.

Leutusome: A Biomimetic Nanoplatform Integrating Plasma Membrane Components of Leukocytes and Tumor Cells for Remarkably Enhanced Solid Tumor Homing.

Cell membrane-camouflaged nanoparticles have appeared as a promising platform to develop active tumor targeting nanomedicines. To evade the immune surveillance, we designed a composite cell membrane-camouflaged biomimetic nanoplatform, namely, leutusome, which is made of liposomal nanoparticles incorporating plasma membrane components derived from both leukocytes (murine J774A.1 cells) and tumor cells (head and neck tumor cells HN12). Exogenous phospholipids were used as building blocks to fuse with two cell membranes to form liposomal nanoparticles. Liposomal nanoparticles made of exogenous phospholipids only or in combination with one type of cell membrane were fabricated and compared. The anticancer drug paclitaxel (PTX) was used to make drug-encapsulating liposomal nanoparticles. Leutusome resembling characteristic plasma membrane components of the two cell membranes were examined and confirmed in vitro. A xenograft mouse model of head and neck cancer was used to profile the blood clearance kinetics, biodistribution, and antitumor efficacy of the different liposomal nanoparticles. The results demonstrated that leutusome obtained prolonged blood circulation and was most efficient accumulating at the tumor site (79.1 ± 6.6% ID per gram of tumor). Similarly, leutusome composed of membrane fractions of B16 melanoma cells and leukocytes (J774A.1) showed prominent accumulation within the B16 tumor, suggesting the generalization of the approach. Furthermore, PTX-encapsulating leutusome was found to most potently inhibit tumor growth while not causing systemic adverse effects.

Curcumin-mediated regulation of intestinal barrier function: The mechanism underlying its beneficial effects.

Curcumin has anti-inflammatory, anti-oxidant and anti-proliferative properties established largely by in vitro studies. Accordingly, oral administration of curcumin beneficially modulates many diseases including diabetes, fatty-liver disease, atherosclerosis, arthritis, cancer and neurological disorders such as depression, Alzheimer's or Parkinson's disease. However, limited bioavailability and inability to detect curcumin in circulation or target tissues has hindered the validation of a causal role. We established curcumin-mediated decrease in the release of gut bacteria-derived lipopolysaccharide (LPS) into circulation by maintaining the integrity of the intestinal barrier function as the mechanism underlying the attenuation of metabolic diseases (diabetes, atherosclerosis, kidney disease) by curcumin supplementation precluding the need for curcumin absorption. In view of the causative role of circulating LPS and resulting chronic inflammation in the development of diseases listed above, this review summarizes the mechanism by which curcumin affects the several layers of the intestinal barrier and, despite negligible absorption, can beneficially modulate these diseases.

Sodium butyrate increases P-gp expression in lung cancer by upregulation of STAT3 and mRNA stabilization of ABCB1.

As a new type of anticancer drug, the effect of histone deacetylase inhibitors (HDACIs) in cancer clinical therapy is disappointing owing to drug resistance. P-glycoprotein (P-gp) is clearly recognized as a multidrug resistance protein. However, the relationship between P-gp and sodium butyrate (SB), a kind of HDACIs, has not been investigated. In this study, we found that SB increased mRNA and protein expression of P-gp in lung cancer cells and the underlying mechanisms were elucidated. We found that SB treatment enhanced the mRNA and protein expression of STAT3 rather than that of ß-catenin, Foxo3a, PXR, or CAR, which were reported to directly regulate the transcription of ABCB1, a P-gp-encoding gene. Interestingly, inhibition of STAT3 expression obviously attenuated SB-increased P-gp expression in lung cancer cells, indicating that STAT3 played an important role in SB-mediated P-gp upregulation. Furthermore, we found that SB increased the mRNA stability of ABCB1. In summary, this study showed that SB increased P-gp expression by facilitating transcriptional activation and improving ABCB1 mRNA stability. This study indicated that we should pay more attention to HDACIs during cancer clinical therapy.

Development of mannose functionalized dendrimeric nanoparticles for targeted delivery to macrophages: use of this platform to modulate atherosclerosis.

Dysfunctional macrophages underlie the development of several diseases including atherosclerosis where accumulation of cholesteryl esters and persistent inflammation are 2 of the critical macrophage processes that regulate the progression as well as stability of atherosclerotic plaques. Ligand-dependent activation of liver-x-receptor (LXR) not only enhances mobilization of stored cholesteryl ester but also exerts anti-inflammatory effects mediated via trans-repression of proinflammatory transcription factor nuclear factor kappa B. However, increased hepatic lipogenesis by systemic administration of LXR ligands (LXR-L) has precluded their therapeutic use. The objective of the present study was to devise a strategy to selectively deliver LXR-L to atherosclerotic plaque-associated macrophages while limiting hepatic uptake. Mannose-functionalized dendrimeric nanoparticles (mDNP) were synthesized to facilitate active uptake via the mannose receptor expressed exclusively by macrophages using polyamidoamine dendrimer. Terminal amine groups were used to conjugate mannose and LXR-L T091317 via polyethylene glycol spacers. mDNP-LXR-L was effectively taken up by macrophages (and not by hepatocytes), increased expression of LXR target genes (ABCA1/ABCG1), and enhanced cholesterol efflux. When administered intravenously to LDLR-/- mice with established plaques, significant accumulation of fluorescently labeled mDNP-LXR-L was seen in atherosclerotic plaque-associated macrophages. Four weekly injections of mDNP-LXR-L led to significant reduction in atherosclerotic plaque progression, plaque necrosis, and plaque inflammation as assessed by expression of nuclear factor kappa B target gene matrix metalloproteinase 9; no increase in hepatic lipogenic genes or plasma lipids was observed. These studies validate the development of a macrophage-specific delivery platform for the delivery of anti-atherosclerotic agents directly to the plaque-associated macrophages to attenuate plaque burden.

In Situ-Forming Polyamidoamine Dendrimer Hydrogels with Tunable Properties Prepared via Aza-Michael Addition Reaction.

In this work, we describe synthesis and characterization of novel in situ-forming polyamidoamine (PAMAM) dendrimer hydrogels (DHs) with tunable properties prepared via highly efficient aza-Michael addition reaction. PAMAM dendrimer G5 was chosen as the underlying core and functionalized with various degrees of acetylation using acetic anhydride. The nucleophilic amines on the dendrimer surface reacted with α, ß-unsaturated ester in acrylate groups of polyethylene glycol diacrylate (PEG-DA, Mn = 575 g/mol) via aza-Michael addition reaction to form dendrimer hydrogels without the use of any catalyst. The solidification time, rheological behavior, network structure, swelling, and degradation properties of the hydrogel were tuned by adjusting the dendrimer surface acetylation degree and dendrimer concentration. The DHs were shown to be highly cytocompatible and support cell adhesion and proliferation. We also prepared an injectable dendrimer hydrogel formulation to deliver the anticancer drug 5-fluorouracil (5-FU) and demonstrated that the injectable formulation efficiently inhibited tumor growth following intratumoral injection. Taken together, this new class of dendrimer hydrogel prepared by aza-Michael addition reaction can serve as a safe tunable platform for drug delivery and tissue engineering.