VHL suppresses UBE3B-mediated breast tumor growth and metastasis.

Protein homeostasis is predominantly governed through post-translational modification (PTM). UBE3B, identified as an oncoprotein, exhibits elevated protein levels in breast cancer. However, the impact of PTM on UBE3B remains unexplored. In this study, we show that VHL is a bona fide E3 ligase for UBE3B. Mechanistically, VHL directly binds to UBE3B, facilitating its lysine 48 (K48)-linked polyubiquitination at K286 and K427 in a prolyl hydroxylase (PHD)-independent manner. Consequently, this promotes the proteasomal degradation of UBE3B. The K286/427R mutation of UBE3B dramatically abolishes the inhibitory effect of VHL on breast tumor growth and lung metastasis. Additionally, the protein levels of UBE3B and VHL exhibit a negative correlation in breast cancer tissues. These findings delineate an important layer of UBE3B regulation by VHL.

LY333531 attenuates contraction of tumor necrosis factor-α-sensitized human airway smooth muscle cells.

OBJECTIVE: Protein kinase C (PKC) has been implicated in the increased contraction of human airway smooth muscle cells (HASMCs) in asthma. Using the three-dimensional collagen gel contraction system, the study aimed to determine the effects of LY333531, a specific inhibitor of the PKC-ß isoform, on the contraction of tumor necrosis factor (TNF)-α-sensitized HASMCs. METHODS: Cultured HASMCs were divided into five groups: the control group received no treatment, and the cells in the TNF-α group were sensitized with 10 ng/mL TNF-α for 48 h, while TNF-α was administered to sensitize HASMCs in the presence of 0.1, 0.2, and 0.5 µM LY333531 for 48 h in the 0.1LY, 0.2LY, and 0.5LY groups, respectively. Following this, HASMCs contraction was stimulated with 1 mM acetylcholine (ACh) for up to 24 h in each group and assessed using a three-dimensional collagen gel contraction assay. Furthermore, western blot and immunofluorescence analysis were performed. RESULTS: The collagen gel contraction assay revealed that TNF-α increased the protein expression of phosphorylated PKC-ß2, CPI-17, and MLC while exacerbating ACh-induced HASMCs contraction. LY333531 significantly attenuated HASMCs contraction and downregulated the protein expression of both p-CPI-17 and p-MLC. CONCLUSIONS: At least in part by regulating CPI-17 and MLC phosphorylation, LY333531 attenuates augmented contraction of TNF-α-sensitized HASMCs in a collagen gel contraction system.

Health inequality of rural-to-urban migrant workers in eastern China and its decomposition: a comparative cross-sectional study.

Objectives: As a specific group with high health inequality, it is crucial to improve the health status and health inequalities of rural-to-urban migrant workers. This study aimed to evaluate the health inequality of migrant and urban workers in China and decompose it. Methods: A cross-sectional study was carried out, using a standardized questionnaire to obtain basic information, self-rated health to evaluate health status, concentration index to measure health inequalities, and WDW decomposition to analyze the causes of health inequalities. Results: The concentration index of health for migrants was 0.021 and 0.009 for urban workers. The main factors contributing to health inequality among rural-to-urban migrant workers included income, exercise, and age. In contrast, the main factors of health inequality among urban workers included income, the number of chronic diseases, social support, and education. Conclusion: There were health inequalities in both rural-to-urban migrant and urban workers. The government and relevant authorities should formulate timely policies and take targeted measures to reduce income disparities among workers, thereby improving health inequality.

Transcriptome profile of reserpine-induced locomotor behavioral changes in zebrafish (Danio rerio).

Reserpine is a drug that is commonly used as an antihypertensive and antipsychotic drug in clinical practice. During our previous research, we found that reserpine treatment in zebrafish larvae can cause depression-like behaviors, but the corresponding mechanisms are still unclear. In this study, we aimed to investigate the molecular mechanism by which reserpine exposure affects locomotor behaviors in larval zebrafish through transcriptome analysis. The gene enrichment results showed that the differentially highly expressed genes of zebrafish are mainly enriched in voltage-gated ion channels, dopaminergic synapses and wnt signaling pathways. Selected genes (apc2, cacna1aa, drd2b, dvl1a, fzd1, wnt1, wnt3a, wnt9a and wnt10a) by transcriptomic results was validated by real-time PCR. Consistently, Wnt signaling pathway inhibitor XAV939 may induce reduced behavioral changes in zebrafish larvae, while the Wnt signaling pathway agonist SB415286 reversed the reserpine-induced depressive effects. Our study provides gene transcriptional profile data for future research on reserpine-induced locomotor behavioral changes.

Impact of Sapphire Step Height on the Growth of Monolayer Molybdenum Disulfide.

Although the synthesis of molybdenum disulfide (MoS2) on sapphire has made a lot of progress, how the substrate surface affects the growth still needs to be further studied. Herein, the impact of the sapphire step height on the growth of monolayer MoS2 through chemical vapor deposition (CVD) is studied. The results show that MoS2 exhibits a highly oriented triangular grain on a low-step (0.44-1.54 nm) substrate but nanoribbons with a consistent orientation on a high-step (1.98-3.30 nm) substrate. Triangular grains exhibit cross-step growth, with one edge parallel to the step edge, while nanoribbons do not cross steps and possess the same orientation as the step. Scanning electron microscopy (SEM) reveals that nanoribbons are formed by splicing multiple grains, and the consistency of the orientation of these grains is demonstrated with a transmission electron microscope (TEM) and second-harmonic generation (SHG). Furthermore, our CP2K calculations, conducted using the generalized gradient approximation and the Perdew-Burke-Ernzerhof (PBE) functional with D3 (BJ) correction, show that MoS2 domains prefer to nucleate at higher steps, while climbing across a higher step is more difficult. This work not only sheds light on the growth mechanism of monolayer MoS2 but also promotes its applications in electrical, optical, and energy-related devices.

Comparative study on the clinical efficacy of small plate assisted anatomic plate and traditional double plate in the treatment of Rüedi and Allgöwer II - III pilon fracture.

OBJECTIVE: The aim of this study was to investigate the clinical efficacy of small plate assisted anatomical plate and traditional double plate in the treatment of Rüedi and Allgöwer II - III pilon fracture. METHODS AND MATERIALS: The data of 68 patients with pilon fracture admitted to Hospital from June 2017 to June 2020 were retrospectively analyzed. Study group and control group were divided according to different operation methods, with 34 cases in each group. There were 28 cases of Rüedi and Allgöwer II type and 40 cases of Rüedi and Allgöwer III type. Perioperative period data, Ankle joint function score, visual analog scale (VAS) scores and the incidence of incision complications were analyzed between these two groups. RESULTS: There were no significant differences in full load time, fracture healing time between these two groups (P > 0.05). The operation time, intraoperative blood loss, length of hospital stay, Ankle joint function score and postoperative incision complication rate in observation group were lower than those in control group (P < 0.05). CONCLUSION: Small plate assisted anatomic plate is comparable to traditional double plate in the treatment of pilon fracture in terms of complete loading time, fracture healing time, but the former can shorten the operation time, reduce intraoperative blood loss and effectively reduce the incidence of postoperative complications.

Valbenazine promotes body growth via growth hormone signaling during zebrafish embryonic development.

Vesicular monoamine transporter 2 (VMAT-2) functions by uptake of cytoplasmic monoamines into vesicles for storage. Valbenazine (VBZ) is a newly FDA-approved oral VMAT-2 inhibitor used for the treatment of movement disorders such as tardive dyskinesia (TD), and Tourette syndrome (TS). Clinical data shows that VBZ is a relatively safe drug with no cardiotoxicity or hepatotoxicity. However, the effect of VBZ on embryonic development remains unknown. Here, we use zebrafish larvae as an animal model to demonstrate that VBZ exposure causes premature hatching and increased body size and hyperactivity-like behaviors in zebrafish larvae. In addition, VBZ exposure leads to increased dopamine (DA) and Glutamate (Glu) levels. Moreover, an increase of growth hormone (gh) and enriched PI3K/AKT signaling were found in VBZ-exposed zebrafish larvae, which may explain their accelerated development. In summary, VBZ exposure may be developmentally toxic in zebrafish larvae.

Evaluation of developmental toxicity of safinamide in zebrafish larvae (Danio rerio).

Monoamine oxidase-B (MAO-B), as a principal metabolizing enzyme, plays important roles in the metabolism of catecholamines and xenobiotics in the central nervous system and peripheral tissues. Safinamide, the third-generation reversible MAO-B inhibitor, has potential to alleviate many neurological diseases such as Parkinson's disease (PD) and depression. Exposure to clinical psychotropic drugs often has adverse effects on fetuses. Currently, a variety of studies of safinamide focus on its curative effect and pharmacological effect, while its side effect of embryonic development is barely studied. In this study, we used zebrafish as a model to evaluate the embryonic developmental toxicity of safinamide. Our results revealed that higher concentrations (30 µM) of safinamide treatment caused a decrease in hatching rate and an increase in malformation and mortality in zebrafish larvae. Meanwhile, we observed that lower safinamide exposure (10 µM) increased the body length of zebrafish larvae and resulted in hyperactivity-like behaviors. In addition, an increased trend in dopamine (DA) level was found in 3.3 µM and 10 µM safinamide-exposed groups. Transcriptome analysis identified that safinamide exposure may disturb a variety of physiological processes such as neuroactive ligand-receptor interaction signaling pathway. In summary, our study reveals that safinamide may cause developmental defects in zebrafish larvae and provides insights into its toxic reactions in early develoment.

Morphogenesis and functional organization of viral inclusion bodies.

Eukaryotic viruses are obligate intracellular parasites that rely on the host cell machinery to carry out their replication cycle. This complex process involves a series of steps, starting with virus entry, followed by genome replication, and ending with virion assembly and release. Negative strand RNA and some DNA viruses have evolved to alter the organization of the host cell interior to create a specialized environment for genome replication, known as IBs, which are precisely orchestrated to ensure efficient viral replication. The biogenesis of IBs requires the cooperation of both viral and host factors. These structures serve multiple functions during infection, including sequestering viral nucleic acids and proteins from innate immune responses, increasing the local concentration of viral and host factors, and spatially coordinating consecutive replication cycle steps. While ultrastructural and functional studies have improved our understanding of IBs, much remains to be learned about the precise mechanisms of IB formation and function. This review aims to summarize the current understanding of how IBs are formed, describe the morphology of these structures, and highlight the mechanism of their functions. Given that the formation of IBs involves complex interactions between the virus and the host cell, the role of both viral and cellular organelles in this process is also discussed.

Cost-effectiveness of palbociclib plus fulvestrant as second-line therapy of women with HR+/HER2- advanced breast cancer - A Chinese healthcare system perspective.

Aim: To evaluate the cost-effectiveness of palbociclib plus fulvestrant in the second-line treatment of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer based on the latest published follow-up data from the perspective of the Chinese healthcare system. Methods: In view of the PALOMA-3 trial, a Markov model was built for this purpose, which included three health states: progression-free survival (PFS), progressed disease (PD), and death. The cost and health utilities were mainly derived from the published literature. One-way sensitivity analysis and probabilistic sensitivity analysis were carried out to verify the robustness of the model. Results: In the base case analysis, compared with the placebo plus fulvestrant arm, the palbociclib plus fulvestrant arm yielded an additional 0.65 quality-adjusted life years (QALYs) (2.56 QALYs vs. 1.90 QALYs) with an incremental cost of $36,139.94 ($55,482.06 vs. $19,342.12), resulting an incremental cost-effectiveness ratio (ICER) of $55,224.90/QALY, which was deeply higher than a willingness-to-pay (WTP) threshold of $34,138.28 per QALY in China. The results of one-way sensitivity analysis indicated that the utility of PFS, cost of palbociclib, and cost of neutropenia had a great influence on the ICER. Conclusions: Palbociclib plus fulvestrant is unlikely to be cost-effective in comparison with placebo plus fulvestrant as second-line therapy of women with HR+/HER2- advanced breast cancer.

Melatonin promoted osteogenesis of human periodontal ligament cells by regulating mitochondrial functions through the translocase of the outer mitochondrial membrane 20.

BACKGROUND AND OBJECTIVE: Melatonin plays an important role in various beneficial functions, including promoting differentiation. However, effects on osteogenic differentiation, especially in human periodontal cells (hPDLCs), still remain inconclusive. Mitochondria are highly dynamic organelles that play an important role in various biological processes in cells, including energy metabolism and oxidative stress reaction. Furthermore, the translocase of the outer mitochondrial membrane 20 (TOM20) is responsible for recognizing and transporting precursor proteins. Thus, the objective of this study was to evaluate the functionality of melatonin on osteogenesis in human periodontal cells and to explore the involved mechanism of mitochondria. METHODS: The hPDLCs were extracted and identified by flow cytometry and multilineage differentiation. We divided hPDLCs into control group, osteogenic induction group, and osteogenesis with melatonin treatment group (100, 10, and 1 µM). Then we used a specific siRNA to achieve interference of TOM20. Alizarin red and Alkaline phosphatase staining and activity assays were performed to evaluate osteogenic differentiation. Osteogenesis-related genes and proteins were measured by qPCR and western blot. Mitochondrial functions were tested using ATP, NAD+/NADH, JC-1, and Seahorse Mito Stress Test kits. Finally, TOM20 and mitochondrial dynamics-related molecules expression were also assessed by qPCR and western blot. RESULTS: Our results showed that melatonin-treated hPDLCs had higher calcification and ALP activity as well as upregulated OCN and Runx2 expression at mRNA and protein levels, which was the most obvious in 1 µM melatonin-treated group. Meanwhile, melatonin supplement elevated intracellular ATP production and mitochondrial membrane potential by increasing mitochondrial oxidative metabolism, hence causing a lower NAD+ /NADH ratio. In addition, we also found that melatonin treatment raised TOM20 level and osteogenesis and mitochondrial functions were both suppressed after knocking down TOM20. CONCLUSION: We found that melatonin promoted osteogenesis of hPDLCs and 1 µM melatonin had the most remarkable effect. Melatonin treatment can reinforce mitochondrial functions by upregulating TOM20.

Developmental and behavioral toxicity assessment of opicapone in zebrafish embryos.

The use of clinical psychoactive drugs often poses unpredictable threats to fetal development. Catechol-O-methyltransferase (COMT) is a key enzyme that regulates dopamine metabolism and a promising target for modulation of cognitive functions. Opicapone, a newly effective third-generation peripheral COMT inhibitor, is used for the treatment of Parkinson's disease (PD) and possibly to improve other dopamine-related disorders such as alcohol use disorder (AUD) and obsessive-compulsive disorder (OCD). The widespread use of opicapone will inevitably lead to biological exposure and damage to the human body, such as affecting fetal development. However, the effect of opicapone on embryonic development remains unknown. Here, zebrafish larvae were used as an animal model and demonstrated that a high concentration (30 µM) of opicapone exposure was teratogenic and lethal, while a low concentration also caused developmental delay such as a shortened body size, a smaller head, and reduced locomotor behaviors in zebrafish larvae. Meanwhile, opicapone treatment specifically increased the level of dopamine (DA) in zebrafish larvae. The depletion response of the total glutathione level (including oxidized and reduced forms of glutathione) and changed antioxidant enzymes activities in zebrafish larvae suggest oxidative damage caused by opicapone. In addition, enhanced glutathione metabolism and cytokine-cytokine receptor interaction were found in zebrafish larvae treated with opicapone, indicating that opicapone treatment caused an oxidation process and immune responses. Our results provide a new insight into the significant developmental toxicity of opicapone in zebrafish larvae.

Dual peptide nanoparticle platform for enhanced antigen-specific immune tolerance for the treatment of experimental autoimmune encephalomyelitis.

Current therapeutic strategies for autoimmune diseases such as multiple sclerosis (MS) are directed towards nonspecific immunosuppression, which has severe side effects. The induction of antigen-specific tolerance has become an ideal therapy for autoimmune diseases. In this study, we have constructed a dual peptide nanoparticle platform, including the antigen peptide of the primary signal and inhibitory peptide of the co-stimulatory signal, for T-cell activation and to trigger antigen-specific immune tolerance to treat experimental autoimmune encephalomyelitis (EAE), a murine model for MS. The peptide LABL binding with ICAM-1 was encapsulated in PLGA nanoparticles and the antigenic peptide MOG35-55-KKK was then covalently bonded to the surface of the PLGA nanoparticles. In this way, peptide-loaded PLGA nanoparticles (NPsLABL+MOG) were developed. When the dual peptide nanoparticles were administered intravenously either prophylactically or therapeutically to MOG35-55-immunized mice, it completely prevented the occurrence of EAE in the prophylactic therapy trial and decreased inflammatory cell infiltration and the demyelination of the nerve myelin in the spinal cord in both prophylactic and therapeutic trials. In therapeutic experiments especially, the dual peptide nanoparticles a showed stronger inhibitory effect on EAE than the MOG peptide nanoparticles alone. Mechanistically, the dual peptide nanoparticles reduced MHC II and the co-stimulatory molecule CD86 expression of dendritic cells (DCs) on the surface and induced abortive T-cell activation, which eventually led to a decreased infiltration of Th1 and Th17 cells in the central nervous system and showed antigen-specific immune tolerance. The dual peptide nanoparticles have great potential for the treatment of autoimmune diseases by inducing immune tolerance.

Corrigendum: Case Report: Prenatal Diagnosis for a Rett Syndrome Family Caused by a Novel MECP2 Deletion With Heteroduplexes of PCR Product.

[This corrects the article DOI: 10.3389/fped.2021.748641.].

Cuprizone-induced dopaminergic hyperactivity and locomotor deficit in zebrafish larvae.

Cuprizone (CPZ) is a copper-chelator and toxic to mitochondria. Recent studies have shown oligodendrocyte (OL) loss and demyelination along with dopamine (DA) increase and behavioral abnormalities in CPZ-exposed mice, demonstrating its application in schizophrenia research. This study examined effects of CPZ exposure on autonomous behavior and dopaminergic neurotransmission in larval zebra fish. CPZ exposure was found to reduce the swimming velocity of zebra fish thus decreased swimming distance during day and night time. Moreover, the treatment induced a movement response of zebra fish larvae reacting to light-on/off switch featured by swimming velocity increase and decrease during the first and second half of the light-on/off phase, respectively. But, it abolished responses of zebra fish to sound-on/off seen in Control group. HPLC analysis showed elevated DA levels in the zebra fish, no change in NE and 5-HT levels. Transcriptome analysis reported changes in gene expression related to dopaminergic synapse and oxidative phosphorylation in CPZ-exposed larvae relative to Control group. Of the gene expression changes, up-regulation of drd2a, drd2b, drd4a and drd4rs was confirmed by RT-PCR, although no difference existed between Control and CPZ groups in dopaminergic neuron numbers. These results demonstrated dopaminergic hyperactivity and locomotor deficit in CPZ-exposed zebra fish larvae, encouraging further application of this model in exploring neurotoxic effects of CPZ on mitochondria and dopaminergic neurotransmission in zebra fish.

Case Report: Prenatal Diagnosis for a Rett Syndrome Family Caused by a Novel MECP2 Deletion With Heteroduplexes of PCR Product.

Rett syndrome is an X-linked dominant, postnatal neurological disorder. Approximately 80-90% of classic Rett syndrome patients harbor mutations in the coding region of MECP2. Somatic or germline MECP2 mosaicism is not rare, and paternal germline MECP2 mosaicism occurs in especially high proportions. Here, we report the case of a Chinese girl with Rett syndrome in whom a heterozygous deletion was found in exon 4 of MECP2 using multiplex ligation-dependent probe amplification. To obtain an accurate region of deletion, we narrowed down the deletion region using real-time quantitative PCR, and subsequent long-range PCR was performed to detect the deletion breakpoints. Surprisingly, three DNA bands from long-range PCR products were observed after gel electrophoresis. To exclude somatic mosaicism, we performed T-A cloning and DNA sequencing, the middle DNA band was proved to be a heteroduplex of the PCR product in vitro. Meanwhile, a prenatal diagnosis was performed for the pregnant mother of the patient. Our study showed that the patient was heterozygous for the deletion of 713-base pairs in exon 4 of MECP2 (MECP2: c.441_1153del713), resulting in a frameshift and premature termination of the 487 amino acid protein at the 154th codon. In summary, we reported a novel heterozygous deletion in the MECP2 gene with heteroduplexes of the PCR product in vitro, which can help in the genetic counseling and prenatal diagnosis of disorders of MECP2 defects.

Molecular characterization of the FCoV-like canine coronavirus HLJ-071 in China.

BACKGROUND: According to the differences of antigen and genetic composition, canine coronavirus (CCoV) consists of two genotypes, CCoV-I and CCoV-II. Since 2004, CCoVs with point mutations or deletions of NSPs are contributing to the changes in tropism and virulence in dogs. RESULTS: In this study, we isolated a CCoV, designated HLJ-071, from a dead 5-week-old female Welsh Corgi with severe diarrhea and vomit. Sequence analysis suggested that HLJ-071 bearing a complete ORF3abc compared with classic CCoV isolates (1-71, K378 and S378). In addition, a variable region was located between S gene and ORF 3a gene, in which a deletion with 104 nts for HLJ-071 when compared with classic CCoV strains 1-71, S378 and K378. Phylogenetic analysis based on the S gene and complete sequences showed that HLJ-071 was closely related to FCoV II. Recombination analysis suggested that HLJ-071 originated from the recombination of FCoV 79-1683, FCoV DF2 and CCoV A76. Finally, according to cell tropism experiments, it suggested that HLJ-071 could replicate in canine macrophages/monocytes cells. CONCLUSION: The present study involved the isolation and genetic characterization of a variant CCoV strain and spike protein and ORF3abc of CCoV might play a key role in viral tropism, which could affect the replication in monocyte/macrophage cells. It will provide essential information for further understanding the evolution in China.

Risk factors and predictive model of adrenocortical insufficiency in patients with traumatic brain injury.

BACKGROUND: Neuroendocrine dysfunction after traumatic brain injury (TBI) has received increased attention due to its impact on the recovery of neural function. The purpose of this study is to investigate the incidence and risk factors of adrenocortical insufficiency (AI) after TBI to reveal independent predictors and build a prediction model of AI after TBI. METHODS: Enrolled patients were grouped into the AI and non-AI groups. Fourteen preset impact factors were recorded. Patients were regrouped according to each impact factor as a categorical variable. Univariate and multiple logistic regression analyses were performed to screen the related independent risk factors of AI after TBI and develop the predictive model. RESULTS: A total of 108 patients were recruited, of whom 34 (31.5%) patients had AI. Nine factors (age, Glasgow Coma Scale [GCS] score on admission, mean arterial pressure [MAP], urinary volume, serum sodium level, cerebral hernia, frontal lobe contusion, diffuse axonal injury [DAI], and skull base fracture) were probably related to AI after TBI. Three factors (urinary volume [X 4], serum sodium level [X 5], and DAI [X 8]) were independent variables, based on which a prediction model was developed (logit P= -3.552+2.583X 4+2.235X 5+2.269X 8). CONCLUSIONS: The incidence of AI after TBI is high. Factors such as age, GCS score, MAP, urinary volume, serum sodium level, cerebral hernia, frontal lobe contusion, DAI, and skull base fracture are probably related to AI after TBI. Urinary volume, serum sodium level, and DAI are the independent predictors of AI after TBI.

Toxic effects of the dinoflagellate Karenia mikimotoi on zebrafish (Danio rerio) larval behavior.

Karenia mikimotoi is a toxic dinoflagellate that forms harmful blooms in coastal waters, threatening aquaculture worldwide. However, we do not know whether K. mikimotoi has a neurotoxic effect on aquatic animal behavior. Thus, this study investigated potential K. mikimotoi neurotoxicity in zebrafish larvae. Cells of K. mikimotoi were collected at the mid-exponential phase from a batch culture to prepare ruptured cell solutions (RCS). At 6 h post-fertilization (hpf), zebrafish embryos were exposed to different RCS concentrations (0, 102, 103, 104, and 2.5 × 104 cells mL-1). After 120 hpf, treated larvae were collected to analyze locomotor behavior; activities of acetylcholinesterase (AChE), superoxide dismutase (SOD), catalase (CAT); and expression of genes related to neurodevelopment. We found that RCS did not affect survival rate, but significantly decreased larval locomotion, as well as their AChE, SOD, and CAT activity. Additionally, the examination of the day-night behavioral experiment revealed RCS decreased locomotion only at night. Zebrafish larvae were also significantly hypoactive in response to light and sound stimulations. Of the neurodevelopment genes, three (th, neurog1, and neurod1) were downregulated, while two (bdnf and manf) were upregulated. Our study suggests that K. mikimotoi neurotoxicity occurs through causing oxidative damage, as well as disorders in the cholinergic system and nervous system development. The results provide new insight that K. mikimotoi in low abundance did not cause significant lethal effect but still exhibited significant neurotoxicity on aquatic animals.

Tumor-Targeted Delivery of Bufalin-Loaded Modified Albumin-Polymer Hybrid for Enhanced Antitumor Therapy and Attenuated Hemolysis Toxicity and Cardiotoxicity.

A novel albumin polymer hybrid with a core-shell structure was designed to target delivery of bufalin, which is an antineoplastic monomer with serious cardiotoxicity. The sheath layer was composed of ursodeoxycholic acid (UA)-modified bovine serum albumin (UA-BSA), while the stable core consisted of poly n-butyl cyanoacrylate (PBCA) nanoparticles. The UA-BSA was synthetized, and the substitution degree was characterized. The physical properties of bufalin-loaded UA-modified protein-PBCA nanocomplexes (BF-uPPNCs), such as morphology, particle size, and encapsulation efficiency, were evaluated. FTIR and DSC revealed the bufalin to be in an amorphous state. Furthermore, the in vitro release study indicated a sustained release profile of BF-uPPNCs. The MTT and cellular uptake study demonstrated that BF-uPPNCs significantly improved the inhibitory effect of the bufalin accompanied with an enhanced cell uptake capacity on HepG2 cells. In addition, in vivo research demonstrated that BF-uPPNCs had a better antitumor effect coupled with improved therapeutic effect, and reduced hemolysis, vascular irritation, and cardiotoxicity. This work therefore presented a novel albumin polymer hybrid with favorable stability, efficient tumor-targeted delivery potential, and side effect reduction ability, which can be a potential vehicle for an anticancer drug.