Microencapsulation is a fundamental concept behind a wide range of daily applications ranging from paints, adhesives, and pesticides to targeted drug delivery, transport of vaccines, and self-healing ...concretes. The beauty of microfluidics to generate microcapsules arises from the capability of fabricating monodisperse and micrometer-scale droplets, which can lead to microcapsules/particles with fine-tuned control over size, shape, and hierarchical structure, as well as high reproducibility, efficient material usage, and high-throughput manipulation. The introduction of supramolecular chemistry, such as host–guest interactions, endows the resultant microcapsules with stimuli-responsiveness and self-adjusting capabilities, and facilitates hierarchical microstructures with tunable stability and porosity, leading to the maturity of current microencapsulation industry. Supramolecular architectures and materials have attracted immense attention over the past decade, as they open the possibility to obtain a large variety of aesthetically pleasing structures, with myriad applications in biomedicine, energy, sensing, catalysis, and biomimicry, on account of the inherent reversible and adaptive nature of supramolecular interactions. As a subset of supramolecular interactions, host–guest molecular recognition involves the formation of inclusion complexes between two or more moieties, with specific three-dimensional structures and spatial arrangements, in a highly controllable and cooperative manner. Such highly selective, strong yet dynamic interactions could be exploited as an alternative methodology for programmable and controllable engineering of supramolecular architectures and materials, exploiting reversible interactions between complementary components. Through the engineering of molecular structures, assemblies can be readily functionalized based on host–guest interactions, with desirable physicochemical characteristics. In this Account, we summarize the current state of development in the field of monodisperse supramolecular microcapsules, fabricated through the integration of traditional microfluidic techniques and interfacial host–guest chemistry, specifically cucurbitnuril (CBn)-mediated host–guest interactions. Three different strategies, colloidal particle-driven assembly, interfacial condensation-driven assembly and electrostatic interaction-driven assembly, are classified and discussed in detail, presenting the methodology involved in each microcapsule formation process. We highlight the state-of-the-art in design and control over structural complexity with desirable functionality, as well as promising applications, such as cargo delivery stemming from the assembled microcapsules. On account of its dynamic nature, the CBn-mediated host–guest complexation has demonstrated efficient response toward various external stimuli such as UV light, pH change, redox chemistry, and competitive guests. Herein, we also demonstrate different microcapsule modalities, which are engineered with CBn host–guest chemistry and also can be disrupted with the aid of external stimuli, for triggered release of payloads. In addition to the overview of recent achievements and current limitations of these microcapsules, we finally summarize several perspectives on tunable cargo loading and triggered release, directions, and challenges for this technology, as well as possible strategies for further improvement, which will lead to substainitial progress of host–guest chemistry in supramolecular architectures and materials.
BackgroundRecent studies have demonstrated that T cells can induce vasodilation in a choline-acetyltransferase dependent manner, leading to an increase in T cell migration to infected tissues in ...response to viral infection, but its role in cancer is unclear. Choline acetyltransferase catalyzes the production of acetylcholine from choline and acetyl-CoA, however, acetylcholine is challenging to quantify due to its extremely short half-life while choline is stable. This study aims to correlate serum choline levels in patients with advanced solid tumors receiving pembrolizumab with treatment outcomes.MethodsBlood samples were collected at baseline and at week 7 (pre-cycle 3) in patients treated with pembrolizumab in the INvestigator-initiated Phase 2 Study of Pembrolizumab Immunological Response Evaluation phase II trial (NCT02644369). Samples were analyzed for choline and circulating tumor DNA (ctDNA). Multivariable Cox models were used to assess the association between choline and overall survival (OS) and progression-free survival (PFS) when including ΔctDNAC3 (the change in ctDNA from baseline to cycle 3), cohort, PD-L1 expression and tumor mutation burden (TMB). An independent validation cohort from the LIBERATE study (NCT03702309) included patients on early phase trials treated with a PD-1 inhibitor.ResultsA total of 106 pts were included in the analysis. With a median follow-up of 12.6 months, median PFS and OS were 1.9 and 13.7 months, respectively. An increase in serum choline level at week 7 compared with baseline (ΔcholineC3) in 81 pts was significantly associated with a better PFS (aHR 0.48, 95% CI 0.28 to 0.83, p=0.009), and a trend toward a better OS (aHR 0.64, 95% CI 0.37 to 1.12, p=0.119). A combination of ΔctDNAC3 and ΔcholineC3 was prognostic for both OS and PFS. Multivariable analyses show ΔcholineC3 was a prognostic factor for PFS independent of ΔctDNAC3, cohort, PD-L1 and TMB. In the independent validation cohort (n=51), an increase in serum choline at cycle 2 was associated with a trend to improved PFS.ConclusionsThis is the first exploratory report of serum choline levels in pan-cancer patients receiving pembrolizumab. The association between improved PFS and ΔcholineC3 suggests a possible role for the cholinergic system in the regulation of antitumor immunity. Further pre-clinical and clinical studies are required to validate this finding.Trial registration numberNCT03702309.
The cancer research community continues to search for additional biomarkers of response and resistance to immune checkpoint treatment (ICT). The ultimate goal is to direct the use of ICT in patients ...whose tumors are most likely to benefit to achieve a refinement that is equivalent to that of a genotype-matched targeted treatment. Dissecting the mechanisms of ICT resistance can help us characterize ICT nonresponders more efficiently. In this opinion, we argue that there may be additional knowledge gained about immune evasion in cancer by analyzing the loss of the human 9p21.3 locus; as an example, we highlight findings of 9p21.3 loss from the investigator-initiated, pan-cancer INSPIRE study, in which patients were treated with pembrolizumab (anti-PD-1 antibody) ICT.
Human chromosomal 9p21.3 loss is emerging as a biomarker of a ‘cold’ tumor immune microenvironment and poor response to cancer immunotherapy with ICT.9p21.3 loss might exert its effect on immune evasion through cell cycle, metabolic, and/or type I interferon (IFN) response pathways. It might also be implicated in long-distance transcriptional regulation through the presence of an abundance of DNA regulatory elements.We posit that, by including 9p21.3 copy number loss into response score tools, alongside PD-L1 expression and tumor mutational burden, it may be possible to better define those patients who would not derive benefit from ICT.Defining ‘9p21-ness’ with further mechanistic research might help us identify strategies for ICT enhancement and novel pharmacological vulnerabilities.
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disorder that causes permanent disability and mortality to approximately 1 to 100 people in the world. Patients with RA not ...only suffer from pain, stiffness, swelling, and loss of function in their joints, but also have a higher risk of cardiovascular disease and lymphoma. Typically prescribed medications, including pain-relieving drugs, nonsteroidal anti-inflammatory drugs (NSAID), and disease-modifying antirheumatic drugs, can help to relieve pain, reduce inflammation and slow the course of disease progression in RA patients. However, the general effectiveness of the drugs has been far from satisfactory. Other therapeutic modalities like TNF-alpha (TNF-α) inhibitors and interleukin-1 receptor antagonists targeting precise pathways within the immune system are expensive and may be associated with serious side effects. Recently, botanical medicines have become popular as alternative remedies as they are believed to be efficacious, safe and have over a thousand years experience in treating patients. In this review, we will summarize recent evidence for pharmacological effects of herbs including Black cohosh,
Angelica sinensi
s, Licorice,
Tripterygium wilfordii
,
Centella asiatica
, and
Urtica dioica
. Scientific research has demonstrated that these herbs have strong anti-inflammatory and anti-arthritic effects. A wide range of phytochemicals including phenolic acids, phenylpropanoid ester, triterpene glycosides, phthalide, flavonoids, triterpenoid saponin, diterpene and triterpene have been isolated and demonstrated to be responsible for the biological effects of the herbs. Understanding the mechanisms of action of the herbs may provide new treatment opportunities for RA patients.
Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved ...by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization
. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
Stroke is the third most common cause of death worldwide. Recent findings showed that the severity of cerebrovascular diseases including ischemic stroke correlates with inflammation mediated ...responses in the neural cells. During ischemia, inflammatory mediators including tumor necrosis factor-alpha (TNF-α) and nitric oxide are produced by microglia, which play a central role in the pathogenesis of the disease.
Ligusticum chuanxiong (LCX) is a commonly used traditional Chinese medicine (TCM) for empiric treatment of cerebrovascular and cardiovascular diseases for many centuries. By applying a bioactivity-guided fractionation scheme, two compounds with inhibition on neuroinflammation were isolated from LCX. Using chromatographic and spectrometric methods, they were identified to be senkyunolide A and Z-ligustilide. They could inhibit the production of proinflammatory mediators in lipopolysaccharide (LPS)-stimulated murine BV-2 microglial cells and human peripheral blood monocyte derived macrophages. In addition, both compounds protected Neuro-2a cells from neuroinflammatory toxicity induced by the conditioned culture media produced by LPS-stimulated BV-2 cells. The underlying mechanisms of action of senkyunolide A were further delineated. Its inhibitory effects were shown to be independent of the phosphorylation of mitogen-activated protein kinases (MAPK) and translocation of nuclear factor kappa B (NF-κB). However, senkyunolide A could increase the degradation of TNF-α mRNA and reduce its half life by 43%. In conclusion, bioactivity-guided fractionation is an effective way of isolating bioactive compounds from medicinal herbs. In addition, senkyunolide A and Z-ligustilide isolated from LCX may be considered as potential complementary drug candidates for treating inflammatory processes associated with cerebrovascular diseases.
► Senkyunolide A and Z-ligustilide are isolated from
Ligusticum chuanxiong. ► They inhibit TNF-α and nitrite productions in activated microglia. ► Their mechanisms of action are independent of MAP kinases and NF-κB activation. ► Inhibition of TNF-α is mainly through increasing degradation of mRNA transcripts. ► These two compounds can be potential drug candidates for cerebrovascular diseases.
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in China. It is usually asymptomatic and transabdominal ultrasound (USS) is the usual means for diagnosis, but it ...may not be feasible to have USS screening of the whole population.
To develop a risk scoring model for predicting the presence of NAFLD using parameters that can be easily obtain in clinical settings.
A retrospective study on the data of 672 adults who had general health check including a transabdominal ultrasound. Fractional polynomial and multivariable logistic regressions of sociodemographic and biochemical variables on NAFLD were used to identify the predictors. A risk score was assigned to each predictor using the scaled standardized β-coefficient to create a risk prediction algorithm. The accuracy for NAFLD detection by each cut-off score in the risk algorithm was evaluated.
The prevalence of NAFLD in our study population was 33.0% (222/672). Six significant factors were selected in the final prediction model. The areas under the curve (AUC) was 0.82 (95% CI: 0.78-0.85). The optimal cut-off score, based on the ROC was 35, with a sensitivity of 76.58% (95% CI: 70.44-81.98%) and specificity of 74.89% (95% CI: 70.62-78.83%).
A NAFLD risk scoring model can be used to identify asymptomatic Chinese people who are at risk of NAFLD for further USS investigation.
Neurodegenerative diseases refer to the selective loss of neuronal systems in patients. The diseases cause high morbidity and mortality to approximately 22 million people worldwide and the number is ...expected to be tripled by 2050. Up to now, there is no effective prevention and treatment for the neurodegenerative diseases. Although some of the clinical therapies target at slowing down the progression of symptoms of the diseases, the general effectiveness of the drugs has been far from satisfactory. Traditional Chinese medicine becomes popular alternative remedies as it has been practiced clinically for more than thousands of years in China. As neurodegenerative diseases are mediated through different pathways, herbal decoction with multiple herbs is used as an effective therapeutic approach to work on multiple targets. Gastrodia and Uncaria Decoction, a popular TCM decoction, has been used to treat stroke in China. The decoction contains compounds including alkaloids, flavonoids, iridoids, carotenoids, and natural phenols, which have been found to possess anti-inflammatory, antioxidative, and antiapoptotic effects. In this review, we will summarize the recent publications of the pharmacological effects of these five groups of compounds. Understanding the mechanisms of action of these compounds may provide new treatment opportunities for the patients with neurodegenerative diseases.
Targeting myeloid cells, especially microglia, for the treatment of neuroinflammatory diseases such as multiple sclerosis (MS), is underappreciated. Our in silico drug screening reveals topoisomerase ...1 (TOP1) inhibitors as promising drug candidates for microglial modulation. We show that TOP1 is highly expressed in neuroinflammatory conditions, and TOP1 inhibition using camptothecin (CPT) and its FDA‐approved analog topotecan (TPT) reduces inflammatory responses in microglia/macrophages and ameliorates neuroinflammation in vivo. Transcriptomic analyses of sorted microglia from LPS‐challenged mice reveal an altered transcriptional phenotype following TPT treatment. To target myeloid cells, we design a nanosystem using β‐glucan‐coated DNA origami (MyloGami) loaded with TPT (TopoGami). MyloGami shows enhanced specificity to myeloid cells while preventing the degradation of the DNA origami scaffold. Myeloid‐specific TOP1 inhibition using TopoGami significantly suppresses the inflammatory response in microglia and mitigates MS‐like disease progression. Our findings suggest that TOP1 inhibition in myeloid cells represents a therapeutic strategy for neuroinflammatory diseases and that the myeloid‐specific nanosystems we designed may also benefit the treatment of other diseases with dysfunctional myeloid cells.
Synopsis
Topoisomerase 1 is upregulated in activated microglia, suggesting a potential therapeutic target in neuroinflammation. Myeloid‐specific delivery of the TOP1 inhibitor topotecan using a novel nanosystem reduces neuroinflammation and ameliorates multiple sclerosis‐like disease progression.
Connectivity map‐based drug screening reveals potential microglia modulating drugs including TOP1 inhibitors.
TOP1 is involved in microglia activation and neuroinflammation and represents a therapeutic target.
A DNA origami‐based drug delivery system (MyloGami) is developed for targeting myeloid cells.
Myeloid cell‐specific TOP1 inhibition (TopoGami) mitigates experimental autoimmune encephalomyelitis.
Topoisomerase 1 is upregulated in activated microglia, suggesting a potential therapeutic target in neuroinflammation. Myeloid‐specific delivery of the TOP1 inhibitor topotecan using a novel nanosystem reduces neuroinflammation and ameliorates multiple sclerosis‐like disease progression.
![Cucurbit[n]uril-Based Micro...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0001-4842_1520-4898/small "Cucurbit[n]uril-Based Microcapsules Self-Assembled within Microfluidic Droplets: A Versatile Approach for Supramolecular Architectures and Materials")
PDF
