Lipid-based nanoparticles via nose-to-brain delivery: a mini review

Central nervous system disorders significantly affect the lives and health of millions of people worldwide. Despite many therapeutic drugs are available that could potentially target central nervous system disorders, their clinical utility is severely constrained by their inability to cross the blood-brain barrier (BBB). Fortunately, nanotechnology has been advanced to offers a solution to allow drugs reaching the targeted brain regions safely, efficiently, and precisely through nasal drug delivery system (NDDS), bypassing the BBB completely. This strategy can promote the drug accumulated in the targeted brain region, improve drug bioavailability, and minimal side effects and mucociliary clearance effectively. In this review, we elaborate recent advances in the use of lipid-based nanoparticles, involving liposomes, nanoemulsions, nanostructured lipid carriers, and solid lipid nanoparticles. Besides, we particularly introduced the nasal cavity physiological structure, and further summarized the nose-to-brain drug delivery pathways, including olfactory, trigeminal, and blood circulation pathway. Moreover, the mechanism and route of NDDS by various types of nanoparticles are also highlighted

Enhanced Delivery of Rituximab Into Brain and Lymph Nodes Using Timed-Release Nanocapsules in Non-Human Primates.

Tumor metastasis into the central nervous system (CNS) and lymph nodes (LNs) is a major obstacle for effective therapies. Therapeutic monoclonal antibodies (mAb) have revolutionized tumor treatment; however, their efficacy for treating metastatic tumors-particularly, CNS and LN metastases-is poor due to inefficient penetration into the CNS and LNs following intravenous injection. We recently reported an effective delivery of mAb to the CNS by encapsulating the anti-CD20 mAb rituximab (RTX) within a thin shell of polymer that contains the analogs of choline and acetylcholine receptors. This encapsulated RTX, denoted as n-RTX, eliminated lymphoma cells systemically in a xenografted humanized mouse model using an immunodeficient mouse as a recipient of human hematopoietic stem/progenitor cells and fetal thymus more effectively than native RTX; importantly, n-RTX showed notable anti-tumor effect on CNS metastases which is unable to show by native RTX. As an important step toward future clinical translation of this technology, we further analyzed the properties of n-RTX in immunocompetent animals, rats, and non-human primates (NHPs). Our results show that a single intravenous injection of n-RTX resulted in 10-fold greater levels in the CNS and 2-3-fold greater levels in the LNs of RTX, respectively, than the injection of native RTX in both rats and NHPs. In addition, we demonstrate the enhanced delivery and efficient B-cell depletion in lymphoid organs of NHPs with n-RTX. Moreover, detailed hematological analysis and liver enzyme activity tests indicate n-RTX treatment is safe in NHPs. As this nanocapsule platform can be universally applied to other therapeutic mAbs, it holds great promise for extending mAb therapy to poorly accessible body compartments

Posttraumatic stress disorder symptoms among healthcare workers during the Omicron era

BackgroundThe COVID-19 pandemic has caused significant psychological stress among healthcare workers. This study aimed to clarify the factors that influenced health workers’ posttraumatic stress disorder (PTSD) symptoms.MethodA total of 443 healthcare workers from eight Mental Health Centers in Shandong were recruited to attend an online survey. Participants completed self-evaluation measures of exposure to the COVID-19 environment and PTSD symptoms, as well as measures of potential protective factors such as euthymia and perceived social support.ResultsAbout 45.37% of healthcare workers had severe symptoms of PTSD symptoms. Healthcare workers with more serious PTSD symptoms were significantly related to higher exposure to COVID-19 (r = 0.177, p < 0.001), as well as lower levels of euthymia (r = −0.287, p < 0.001) and perceived social support (r = −0.236, p < 0.001). The structural equation model (SEM) further revealed that the impact of exposure to COVID-19 on PTSD symptoms was partially mediated by euthymia, and moderated by perceived social support, especially from others (e.g., friends, leaders, relatives and colleagues).ConclusionThese findings suggested that improving the state of euthymia, getting social support from others could alleviate PTSD symptoms among healthcare workers during the COVID-19

Molecular characterization of the viral structural protein genes in the first outbreak of dengue virus type 2 in Hunan Province, inland China in 2018

Abstract Background: An unexpected dengue outbreak occurred in the Hunan Province in 2018. This is the first dengue outbreak in this area of inland China, and 172 cases were reported. Methods: To verify the causative agent of this outbreak and investigate gene characterization, the structural protein C/prM/E genes of viruses isolated from local residents were sequenced followed by mutation and phylogenetic analysis. The recombination, selection pressure, potential secondary structure and three-dimensional structure analysis were also performed. Results: Phylogenetic analysis revealed that all epidemic strains were classified as the cosmopolitan DENV-2 genotype, closest to the Zhejiang strain (MH010629, 2017) and then Malaysia strain (KJ806803, 2013). Compared with the DENV-2SS, 151 base substitutions were found in 89 sequences of isolates, which resulted in 20 non-synonymous mutations, of which 17 mutations existed among all samples (two in capsid protein, six in prM/M, and nine in envelope proteins). Moreover, amino acid substitutions at 602th (E322:Q→H) and 670th (E390: N→S) may enhance virulence of the epidemic strains. One new DNA-binding site and five new protein binding sites were observed. Two polynucleotide-binding sites and seven protein binding sites were lost compared with DENV-2SS. Meanwhile, five changes were found in helix regions. Minor changes were observed in helical transmembrane and disordered regions. The 429th amino acid of E proteins was switch from histamine (positively charged) to asparagines (neutral) in all 89 isolate strains. No recombination events or positive selection pressure sites were observed. To our knowledge, this study is the first one to analyze the genetic characteristics of epidemic strain in the first dengue outbreak in Hunan Province, inland China. Conclusions: The causative agent is likely to come from Zhejiang Province, a neighbouring Province where dengue fever broke out in 2017. This study may help to understand the intrinsic geographical relatedness of DENV-2 and contributes to further research on pathogenicity and vaccine development.</jats:p

Molecular characterization of the viral structural gene of the first dengue virus type 2 outbreak in Hunan Province, inland China

Abstract Background: An unexpected dengue outbreak occurred in the Hunan Province in 2018. This is the first dengue outbreak in this area of inland China resulting 172 infected. Methods: To verify the causative agent of this outbreak and investigate gene characterization, the structural protein C/prM/E genes of viruses isolated from local residents were sequenced followed by mutation, phylogenetic analysis. The recombination, selection pressure, potential secondary structure and three-dimensional structure analysis were also performed. Results: Phylogenetic analysis revealed that all epidemic strains were classified as the cosmopolitan DENV-2 genotype, closest to the Zhejiang strain (MH010629, 2017) and then Malaysia strain (KJ806803, 2013). Compared with the DENV-2SS, 151 base substitutions were found in 89 sequences of isolates, resulting in 20 nonsynonymous mutations, of which 17 mutations existed among all samples (two in capsid protein, six in prM/M, and nine in envelope proteins). Moreover, amino acid substitutions at 602 th (E322:Q→H) and 670 th (E390: N→S) may result in heightened virulence of the epidemic strains. One new DNA-binding site and five new protein binding sites were observed. Two polynucleotide-binding sites and seven protein binding sites were lost compared with DENV-2SS. Meanwhile, five changes were found in helix regions. The helical transmembrane and disordered regions have minor changes. Protein tertiary structure prediction revealed the 429 th amino acid of E proteins was switch from histamine (positively charged) to asparagines (neutral) in 89 isolate strains. No recombination events or positive selection pressure sites were detected. To our knowledge, this study is the first gene analysis of epidemic strain in the first dengue outbreak in Hunan Province, inland China. Conclusions: The causative agent is likely to come from Zhejiang Province, a neighbouring Province where dengue fever broke out in 2017. This study may help understand the intrinsic geographical relatedness of DENV-2 and contributes further to research on pathogenicity and vaccine development.</jats:p

Molecular characterization of the viral structural protein genes in the first outbreak of dengue virus type 2 in Hunan Province, inland China in 2018

Abstract Background: An unexpected dengue outbreak occurred in Hunan Province in 2018. This was the first dengue outbreak in this area of inland China, and 172 cases were reported.Methods: To verify the causative agent of this outbreak and characterise the viral genes, the genes encoding the structural proteins C/prM/E of viruses isolated from local residents were sequenced followed by mutation and phylogenetic analysis. Recombination, selection pressure, potential secondary structure and three-dimensional structure analyses were also performed. Results: Phylogenetic analysis revealed that all epidemic strains were of the cosmopolitan DENV-2 genotype and were most closely related to the Zhejiang strain (MH010629, 2017) and then the Malaysia strain (KJ806803, 2013). Compared with the sequence of DENV-2SS, 151 base substitutions were found in the sequences of 89 isolates; these substitutions resulted in 20 non-synonymous mutations, of which 17 mutations existed in all samples (two in the capsid protein, six in the prM/M proteins, and nine in the envelope proteins). Moreover, amino acid substitutions at the 602nd (E322:Q→H) and 670th (E390: N→S) amino acids may have enhanced the virulence of the epidemic strains. One new DNA binding site and five new protein binding sites were observed. Two polynucleotide binding sites and seven protein binding sites were lost in the epidemic strains compared with DENV-2SS. Meanwhile, five changes were found in helical regions. Minor changes were observed in helical transmembrane and disordered regions. The 429th amino acid of the E protein switched from a histamine (positively charged) to an asparagine (neutral) in all 89 isolated strains. No recombination events or positive selection pressure sites were observed. To our knowledge, this study is the first to analyse the genetic characteristics of epidemic strains in the first dengue outbreak in Hunan Province in inland China.Conclusions: The causative agent is likely to come from Zhejiang Province, a neighbouring province where dengue fever broke out in 2017. This study may help clarify the intrinsic geographical relatedness of DENV-2 and contribute to further research on pathogenicity and vaccine development.</jats:p

Visualizing the spatial distribution of inflammation in the depressed brain with a targeted MRI nanoprobe in vivo

Abstract Depression is a prevalent mental illness that imposes a substantial public health burden. However, the diverse clinical phenotypes observed in patients make it difficult to realize precise diagnosis. Recently, accumulating preclinical and clinical evidence has suggested that inflammation is involved in the pathophysiology of depression. Herein, a molecular imaging–based strategy was proposed as a means to diagnose depression precisely by specifically visualizing the inflammation status associated with depression. Inflammation-targeting MRI nanoprobes were constructed by attaching an intercellular cell adhesion molecule-1 (ICAM-1)-targeting peptide to biocompatible Fe3O4 nanoparticles. Systematic studies demonstrated that the nanoprobes could specifically target inflamed vascular endothelial cells and visualize the spatial distribution of inflammation in the depressed brain in vivo through susceptibility-weighted imaging (SWI), which was further confirmed by histological analysis. Additionally, these inflammatory brain regions identified by nanoprobe-based imaging are consistent with the focal regions closely associated with the symptoms of depression as reported in previous behavioral studies. Overall, this is the first study to directly visualize the distribution of inflammation in the depressed brain in vivo through a molecular imaging strategy, which may not only facilitate insight into the biological mechanism underlying depression but also provide a potential target within the depressed brain for the further development of anti-inflammatory therapies

Molecular characterization of the viral structural protein genes in the first outbreak of dengue virus type 2 in Hunan Province, inland China in 2018

Abstract Background An unexpected dengue outbreak occurred in Hunan Province in 2018. This was the first dengue outbreak in this area of inland China, and 172 cases were reported. Methods To verify the causative agent of this outbreak and characterise the viral genes, the genes encoding the structural proteins C/prM/E of viruses isolated from local residents were sequenced followed by mutation and phylogenetic analysis. Recombination, selection pressure, potential secondary structure and three-dimensional structure analyses were also performed. Results Phylogenetic analysis revealed that all epidemic strains were of the cosmopolitan DENV-2 genotype and were most closely related to the Zhejiang strain (MH010629, 2017) and then the Malaysia strain (KJ806803, 2013). Compared with the sequence of DENV-2SS, 151 base substitutions were found in the sequences of 89 isolates; these substitutions resulted in 20 non-synonymous mutations, of which 17 mutations existed in all samples (two in the capsid protein, six in the prM/M proteins, and nine in the envelope proteins). Moreover, amino acid substitutions at the 602nd (E322:Q → H) and 670th (E390: N → S) amino acids may have enhanced the virulence of the epidemic strains. One new DNA binding site and five new protein binding sites were observed. Two polynucleotide binding sites and seven protein binding sites were lost in the epidemic strains compared with DENV-2SS. Meanwhile, five changes were found in helical regions. Minor changes were observed in helical transmembrane and disordered regions. The 429th amino acid of the E protein switched from a histamine (positively charged) to an asparagine (neutral) in all 89 isolated strains. No recombination events or positive selection pressure sites were observed. To our knowledge, this study is the first to analyse the genetic characteristics of epidemic strains in the first dengue outbreak in Hunan Province in inland China. Conclusions The causative agent is likely to come from Zhejiang Province, a neighbouring province where dengue fever broke out in 2017. This study may help clarify the intrinsic geographical relatedness of DENV-2 and contribute to further research on pathogenicity and vaccine development. </jats:sec