An Interleukin-25-Mediated Autoregulatory Circuit in Keratinocytes Plays a Pivotal Role in Psoriatic Skin Inflammation.

Psoriasis is a chronic autoinflammatory skin disease. Although interleukin-17, derived from lymphocytes, has been shown to be critical in psoriasis, the initiation and maintenance of chronic skin inflammation has not been well understood. IL-25 (also called IL-17E), another IL-17 family cytokine, is well known to regulate allergic responses and type 2 immunity. Here we have shown that IL-25, also highly expressed in the lesional skin of psoriasis patients, was regulated by IL-17 in murine skin of a imiquimod (IMQ)-induced psoriasis model. IL-25 injection induced skin inflammation, whereas germline or keratinocyte-specific deletion of IL-25 caused resistance to IMQ-induced psoriasis. Via IL-17RB expression in keratinocytes, IL-25 stimulated the proliferation of keratinocytes and induced the production of inflammatory cytokines and chemokines, via activation of the STAT3 transcription factor. Thus, our data demonstrate that an IL-17-induced autoregulatory circuit in keratinocytes is mediated by IL-25 and suggest that this circuit could be targeted in the treatment of psoriasis patients.

Co-inhibitory Molecule B7 Superfamily Member 1 Expressed by Tumor-Infiltrating Myeloid Cells Induces Dysfunction of Anti-tumor CD8+ T Cells.

The molecular mechanisms whereby CD8+ T cells become "exhausted" in the tumor microenvironment remain unclear. Programmed death ligand-1 (PD-L1) is upregulated on tumor cells and PD-1-PD-L1 blockade has significant efficacy in human tumors; however, most patients do not respond, suggesting additional mechanisms underlying T cell exhaustion. B7 superfamily member 1 (B7S1), also called B7-H4, B7x, or VTCN1, negatively regulates T cell activation. Here we show increased B7S1 expression on myeloid cells from human hepatocellular carcinoma correlated with CD8+ T cell dysfunction. B7S1 inhibition suppressed development of murine tumors. Putative B7S1 receptor was co-expressed with PD-1 but not T cell immunoglobulin and mucin-domain containing-3 (Tim-3) at an activated state of early tumor-infiltrating CD8+ T cells, and B7S1 promoted T cell exhaustion, possibly through Eomes overexpression. Combinatorial blockade of B7S1 and PD-1 synergistically enhanced anti-tumor immune responses. Collectively, B7S1 initiates dysfunction of tumor-infiltrating CD8+ T cells and may be targeted for cancer immunotherapy.

Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction.

T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment1. The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction2. However, the molecular mechanisms that underlie this dysfunction remain unclear. Here, using an in vitro T cell tolerance induction system in mice, we characterize genome-wide epigenetic and gene expression features in tolerant T cells, and show that they are distinct from effector and regulatory T cells. Notably, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of NR4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumour and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector-gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes. This study thus identifies NR4A1 as a key general regulator in the induction of T cell dysfunction, and a potential target for tumour immunotherapy.

Effects of the thiol methyltransferase inhibitor DCMB on the pharmacokinetics and metabolism of vicagrel in rats.

P2Y12 receptor inhibitors are commonly used in clinical antiplatelet therapy, typically alongside other medications. Vicagrel, a promising P2Y12 receptor inhibitor, has submitted a new drug marketing application to the U.S. FDA. Its primary metabolites and some metabolic pathways are identical to those of clopidogrel. The aim of this study was to investigate the effects of the thiol methyltransferase inhibitor ({plus minus})-2,3-dichloro-α-methylbenzylamine (DCMB) on the metabolism and pharmacokinetics of vicagrel. In vitro incubation with human and rat liver microsomes revealed that DCMB significantly inhibited the methylation of vicagrel's thiol metabolite M15-1. Rats were orally administered 6 mg/kg [14C]vicagrel (100 µCi/kg) 1 h after peritoneal injection with or without DCMB (80 mg/kg). Compared to the control group, the plasma of DCMB-pretreated rats exhibited C max decrease and T max delay for all vicagrel-related substances, the methylation product of the thiol metabolite (M9-2) and the derivatization product of the active thiol metabolite (MP-M15-2). However, no significant changes in AUC or t 1/2 were observed. DCMB had negligible effect on the total radiological recovery of vicagrel within 72 h, although the rate of vicagrel excretion slowed down within 48 h. DCMB had a negligible impact on the metabolic pathway of vicagrel. Overall, the present study found that DCMB did not significantly affect the total exposure, metabolic pathways, metabolite profiles, or total excretion rates of vicagrel-related metabolites in rats, but led to C max decrease, T max delay, and slower excretion rate within 48 h. Significance Statement This study used LC-MS/MS combined with radiolabeling technology to investigate the effects of the TMT inhibitor DCMB on the absorption, metabolism and excretion of vicagrel in rats. This work helps to better understand the in vivo metabolism of active thiol metabolites of P2Y12 inhibitors such as clopidogrel and vicagrel, etc.

Duodenal-Jejunal bypass improves metabolism and re-models extra cellular matrix through modulating ceRNA network.

BACKGROUND: Bariatric surgery (BS) is an effective approach in treating obesity and ameliorating T2DM with obesity. Our previous studies demonstrated that duodenal-jejunal bypass (DJB) altered long non-coding RNAs (lncRNAs) in the gastrointestinal system, which is associated with modulation of lipid metabolism, and glycemic control through entero-pancreatic axis and gut-brain axis. The adipose non-coding RNA expression profile and the underlying competing endogenous RNA (ceRNA) regulatory network pattern post DJB needs further research and investigation. RESULTS: In this study, we compared the lncRNAs, circular RNAs (circRNAs) and messenger RNAs (mRNAs) expression in adipose tissues between the sham group and the DJB group. 2219 differentially expressed mRNAs (DEmRNAs), 722 differential expression of lncRNAs (DElncRNAs) and 425 differential expression of circRNAs (DEcircRNAs) were identified. GO terms and KEGG pathways analysis of the DEmRNAs implied that the dysregulated adipose mRNAs were associated with lipid, amino acid metabolism, insulin resistance, and extra cellular matrix (ECM)-related pathways. Moreover, via analyzing ceRNA regulatory networks of DElncRNAs and DEcircRNAs, 31 hub DE mRNAs, especially Mpp7, 9330159F19Rik, Trhde. Trdn, Sorbs2, were found on these pathways. CONCLUSIONS: The role of DJB in adipose tends to remodel ECM and improve the energy metabolism through the ceRNA regulatory network.

A high-throughput screening campaign against PFKFB3 identified potential inhibitors with novel scaffolds.

The growth of solid tumors depends on tumor vascularization and the endothelial cells (ECs) that line the lumen of blood vessels. ECs generate a large fraction of ATP through glycolysis, and elevation of their glycolytic activity is associated with angiogenic behavior in solid tumors. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) positively regulates glycolysis via fructose-2/6-bisphosphate, the product of its kinase activity. Partial inhibition of glycolysis in tumor ECs by targeting PFKFB3 normalizes the otherwise abnormal tumor vessels, thereby reducing metastasis and improving the outcome of chemotherapy. Although a limited number of tool compounds exist, orally available PFKFB3 inhibitors are unavailable. In this study we conducted a high-throughput screening campaign against the kinase activity of PFKFB3, involving 250,240 chemical compounds. A total of 507 initial hits showing >50% inhibition at 20 µM were identified, 66 of them plus 1 analog from a similarity search consistently displayed low IC50 values (<10 µM). In vitro experiments yielded 22 nontoxic hits that suppressed the tube formation of primary human umbilical vein ECs at 10 µM. Of them, 15 exhibited binding affinity to PFKFB3 in surface plasmon resonance assays, including 3 (WNN0403-E003, WNN1352-H007 and WNN1542-F004) that passed the pan-assay interference compounds screening without warning flags. This study provides potential leads to the development of new PFKFB3 inhibitors.

Efficient and risk-reduced genome editing using double nicks enhanced by bacterial recombination factors in multiple species.

Site-specific DNA double-strand breaks have been used to generate knock-in through the homology-dependent or -independent pathway. However, low efficiency and accompanying negative impacts such as undesirable indels or tumorigenic potential remain problematic. In this study, we present an enhanced reduced-risk genome editing strategy we named as NEO, which used either site-specific trans or cis double-nicking facilitated by four bacterial recombination factors (RecOFAR). In comparison to currently available approaches, NEO achieved higher knock-in (KI) germline transmission frequency (improving from zero to up to 10% efficiency with an average of 5-fold improvement for 8 loci) and 'cleaner' knock-in of long DNA fragments (up to 5.5 kb) into a variety of genome regions in zebrafish, mice and rats. Furthermore, NEO yielded up to 50% knock-in in monkey embryos and 20% relative integration efficiency in non-dividing primary human peripheral blood lymphocytes (hPBLCs). Remarkably, both on-target and off-target indels were effectively suppressed by NEO. NEO may also be used to introduce low-risk unrestricted point mutations effectively and precisely. Therefore, by balancing efficiency with safety and quality, the NEO method reported here shows substantial potential and improves the in vivo gene-editing strategies that have recently been developed.

Downregulation of zinc finger protein 71 in laryngeal squamous cell carcinoma tissues and its potential molecular mechanism and clinical significance: a study based on immunohistochemistry staining and data mining.

BACKGROUND: The molecular mechanism of laryngeal squamous cell carcinoma (LSCC) is not completely clear, which leads to poor prognosis and treatment difficulties for LSCC patients. To date, no study has reported the exact expression level of zinc finger protein 71 (ZNF71) and its molecular mechanism in LSCC. METHODS: In-house immunohistochemistry (IHC) staining (33 LSCC samples and 29 non-LSCC samples) was utilized in analyzing the protein expression level of ZNF71 in LSCC. Gene chips and high-throughput sequencing data collected from multiple public resources (313 LSCC samples and 192 non-LSCC samples) were utilized in analyzing the exact mRNA expression level of ZNF71 in LSCC. Single-cell RNA sequencing (scRNA-seq) data was used to explore the expression status of ZNF71 in different LSCC subpopulations. Enrichment analysis of ZNF71, its positively and differentially co-expressed genes (PDCEGs), and its downstream target genes was employed to detect the potential molecular mechanism of ZNF71 in LSCC. Moreover, we conducted correlation analysis between ZNF71 expression and immune infiltration. RESULTS: ZNF71 was downregulated at the protein level (area under the curve [AUC] = 0.93, p < 0.0001) and the mRNA level (AUC = 0.71, p = 0.023) in LSCC tissues. Patients with nodal metastasis had lower protein expression level of ZNF71 than patients without nodal metastasis (p < 0.05), and male LSCC patients had lower mRNA expression level of ZNF71 than female LSCC patients (p < 0.01). ZNF71 was absent in different LSCC subpopulations, including cancer cells, plasma cells, and tumor-infiltrated immune cells, based on scRNA-seq analysis. Enrichment analysis showed that ZNF71 and its PDCEGs may influence the progression of LSCC by regulating downstream target genes of ZNF71. These downstream target genes of ZNF71 were mainly enriched in tight junctions. Moreover, downregulation of ZNF71 may influence the development and even therapy of LSCC by reducing immune infiltration. CONCLUSION: Downregulation of ZNF71 may promote the progression of LSCC by reducing tight junctions and immune infiltration; this requires further study.

Expression of Cell Division Cycle Protein 45 in Tissue Microarrays and the CDC45 Gene by Bioinformatics Analysis in Human Hepatocellular Carcinoma and Patient Outcomes.

BACKGROUND Hepatocellular carcinoma (HCC) causes a heavy disease burden worldwide. Cell division cycle 45 (Cdc45) and its encoding gene (CDC45) have been studied for a long time, but their expression patterns and roles in liver carcinogenesis and advanced HCC deterioration are still incompletely understood. This study integrated tissue microarray and bioinformatics analyses to explore the expression and clinical value of CDC45 and Cdc45 in HCC. MATERIAL AND METHODS In HCC, the expression and relationships with clinic-pathological parameters of CDC45 and Cdc45 were investigated by integrating the RNA-sequencing data, downloaded from The Cancer Genome Atlas and Oncomine databases, and tissue microarray with immunohistochemistry staining. Co-expressed genes and genetic alterations of CDC45 separately obtained from Oncomine and cBioPortal databases were identified to shed light on the potential mechanisms of CDC45 in HCC. RESULTS CDC45 and Cdc45 were both overexpressed in HCC tissues, and the CDC45 level progressively increased from stage I to III. The survival outcomes of the group with high CDC45 expression were significantly worse compared with the group with low expression. Amplification and deep deletion were 2 major significant alteration types in HCC patients, and the outcomes were worse in patients with altered versus unaltered CDC45. NUDT1, E2F1, CCNE2, MCM5, and CENPM were identified as the most significantly co-expressed genes. CONCLUSIONS CDC45 and Cdc45 were both upregulated in HCC, and increased expression levels and genetic alternations of CDC45 were correlated with worse prognosis in HCC patients. CDC45 may promote HCC by co-expressing with NUDT1, E2F1, CCNE2, MCM5, and CENPM.

RNA-Sequencing, Connectivity Mapping, and Molecular Docking to Investigate Ligand-Protein Binding for Potential Drug Candidates for the Treatment of Wilms Tumor.

BACKGROUND Wilms tumor, or nephroblastoma, is a malignant pediatric embryonal renal tumor that has a poor prognosis. This study aimed to use bioinformatics data, RNA-sequencing, connectivity mapping, molecular docking, and ligand-protein binding to identify potential targets for drug therapy in Wilms tumor. MATERIAL AND METHODS Wilms tumor and non-tumor samples were obtained from high throughput gene expression databases, and differentially expressed genes (DEGs) were analyzed using the voom method in the limma package. The overlapping DEGs were obtained from the intersecting drug target genes using the Connectivity Map (CMap) database, and systemsDock was used for molecular docking. Gene databases were searched for gene expression profiles for complementary analysis, analysis of clinical significance, and prognosis analysis to refine the study. RESULTS From 177 cases of Wilms tumor, there were 648 upregulated genes and 342 down-regulated genes. Gene Ontology (GO) enrichment analysis showed that the identified DEGs that affected the cell cycle. After obtaining 21 candidate drugs, there were seven overlapping genes with 75 drug target genes and DEGs. Molecular docking results showed that relatively high scores were obtained when retinoic acid and the cyclin-dependent kinase inhibitor, alsterpaullone, were docked to the overlapping genes. There were significant standardized mean differences for three overlapping genes, CDK2, MAP4K4, and CRABP2. However, four upregulated overlapping genes, CDK2, MAP4K4, CRABP2, and SIRT1 had no prognostic significance. CONCLUSIONS RNA-sequencing, connectivity mapping, and molecular docking to investigate ligand-protein binding identified retinoic acid and alsterpaullone as potential drug candidates for the treatment of Wilms tumor.

Metformin and Docosahexaenoic Acid Hybrid Micelles for Premetastatic Niche Modulation and Tumor Metastasis Suppression.

Metastasis is the major cause of high mortality in cancer patients; thus, blocking the metastatic process is of critical importance for cancer treatments. The premetastatic niche, a specialized microenvironment with aberrant changes related to inflammation, allows the colonization of circulating tumor cells (CTCs) and serves as a potential target for metastasis prevention. However, little effort has been dedicated to developing nanomedicine to amend the premetastatic niche. Here this study reports a premetastatic niche-targeting micelle for the modulation of premetastatic microenvironments and suppression of tumor metastasis. The micelles are self-assembled with the oleate carbon chain derivative of metformin and docosahexaenoic acid, two anti-inflammatory agents with low toxicity, and coated with fucoidan for premetastatic niche-targeting. The obtained functionalized micelles (FucOMDs) exhibit an excellent blood circulation profile and premetastatic site-targeting efficiency, inhibit CTC adhesion to activated endothelial cells, alleviate lung vascular permeability, and reverse the aberrant expression of key marker proteins in premetastatic niches. As a result, FucOMDs prevent metastasis formation and efficiently suppress both primary-tumor growth and metastasis formation when combined with targeted chemotherapy. Collectively, the findings here provide proof of concept that the modulation of the premetastatic niche with targeted anti-inflammatory agents provides a potent platform and a safe and clinical translational option for the suppression of tumor metastasis.

Artemisinin inhibits breast cancer-induced osteolysis by inhibiting osteoclast formation and breast cancer cell proliferation.

In addition to being used to treat malaria, artemisinin (Art) can be used as an anti-inflammatory and antitumor agent. In this study, we evaluated the effects of Art on osteoclast formation and activation and on the development of breast cancer cells in bone. To evaluate the effect of Art on osteoclast differentiation in vitro, we treated bone marrow-derived macrophages (BMMs) with various concentrations of Art and evaluated the expression of genes and proteins involved in osteoclast formation. We also performed cell counting kit-8 assays to evaluate the toxicity of Art in BMMs and MDA-MB-231 cells. We also performed Transwell assays, wound-healing assays, colony formation assays, and cell apoptosis assays to evaluate the effect of Art in MDA-MB-231 cells. We also evaluated the effect of Art in an in vivo osteoclast bone resorption assay using a nude mouse model. We demonstrated that Art inhibits the differentiation and establishment of osteoclasts even though Art is not toxic to osteoclasts. In addition, Art reduced expression of genes involved in osteoclast formation and inhibited osteoclast bone resorption in a concentration-dependent manner. Based on our data, we believe that Art can inhibit proliferation of breast cancer cells by activating apoptosis pathways, and inhibit osteoclast formation and differentiation by inhibiting activation of cathepsin K, ATPase H+ transporting V0 subunit D2, nuclear factor of activated T cells 1, calcitonin receptor, and tartrate-resistant acid phosphatase and by inhibiting nuclear factor-κB activation.

GABARAP promotes bone marrow mesenchymal stem cells-based the osteoarthritis cartilage regeneration through the inhibition of PI3K/AKT/mTOR signaling pathway.

Osteoarthritis (OA) is a degenerative disease of the cartilage prevalent in the middle-aged and elderly demographic. Direct transplantation of bone marrow mesenchymal stem cells (BMSCs) or stem cell-derived chondrocytes into the damaged cartilage is a promising therapeutic strategy for OA, but is limited by the poor survival and in situ stability of the chondrocytes. Autophagy is a unique catabolic pathway conserved across eukaryotes that maintains cellular homeostasis, recycles damaged proteins and organelles, and promotes survival. The aim of this study was to determine the role of the proautophagic γ-aminobutyric acid receptor-associated protein (GABARAP) on the therapeutic effects of BMSCs-derived chondrocytes in a rat model of OA, and elucidate the underlying mechanisms. Anterior cruciate ligament transection (ACLT) was performed in Sprague-Dawley rats to simulate OA, and the animals were injected weekly with recombinant human His6-GABARAP protein, BMSCs-derived differentiated chondrocytes (DCs) or their combination directly into the knee cartilage. The regenerative effects of GABARAP and/or DCs were determined in term of International Cartilage Repair Society scores and cartilage thickness. The combination treatment of DCs and GABARAP significantly increased the levels of the ECM proteins Col II and SOX9, indicating formation of hyaline-like cartilage, and decreased chondrocyte apoptosis and inflammation. DCs + GABARAP treatment also upregulated the mediators of the autophagy pathway and suppressed the PI3K/AKT/mTOR pathway, indicating a mechanistic basis of its therapeutic action.

Artemisinin Ameliorates Osteoarthritis by Inhibiting the Wnt/ß-Catenin Signaling Pathway.

BACKGROUND/AIMS: Current drug therapies for osteoarthritis (OA) are not practical because of the cytotoxicity and severe side-effects associated with most of them. Artemisinin (ART), an antimalarial agent, is well known for its safety and selectivity to kill injured cells. Based on its anti-inflammatory activity and role in the inhibition of OA-associated Wnt/ß-catenin signaling pathway, which is crucial in the pathogenesis of OA, we hypothesized that ART might have an effect on OA. METHODS: The chondro-protective and antiarthritic effects of ART on interleukin-1-beta (IL-1ß)-induced and OA patient-derived chondrocytes were investigated in vitro using cell viability assay, glycosaminoglycan secretion, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blotting. We also used OA model rats constructed by anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) in the joints to investigate the effects of ART on OA by gross observation, morphological staining, immunohistochemistry, and enzyme-linked immunosorbent assay. RESULTS: ART exhibited potent anti-inflammatory effects by inhibiting the expression of proinflammatory chemokines and cytokines, including interleukin (IL)-1ß, IL-6, tumor necrosis factor alpha, and matrix metallopeptidase-13. It also showed favorable chondro-protective effect as evidenced by enhanced cell proliferation and viability, increased glycosaminoglycan deposition, prevention of chondrocyte apoptosis, and degeneration of cartilage. Further, ART inhibited OA progression and cartilage degradation via the Wnt/ß-catenin signaling pathway, suggesting that it might serve as a Wnt/ß-catenin antagonist to reduce inflammation and prevent cartilage degradation. CONCLUSION: In conclusion, ART alleviates IL-1ß-mediated inflammatory response and OA progression by regulating the Wnt/ß-catenin signaling pathway. Thereby, it might be developed as a potential therapeutic agent for OA.

What is the optimal sequence of decompression for multilevel noncontinuous spinal cord compression injuries in rabbits?

BACKGROUND: In recent years, multilevel spinal cord injuries (SCIs) have gained a substantial amount of attention from clinicians and researchers. Multilevel noncontinuous SCI patients cannot undergo the multiple steps of a one-stage operation because of a poor general condition or a lack of proper surgical approaches. The surgeon subsequently faces the decision of whether to initially relieve the rostral or caudal compression. In this study, we established a spinal cord compression model involving two noncontinuous segments in rabbits to evaluate the effects of differences in decompression order on the functional recovery of the spinal cord. METHODS: A Fogarty catheter was inserted into the epidural space through a hole in T6-7 and advanced 3 cm rostrally or caudally. Following successful model establishment, which was demonstrated by an evaluation of evoked potentials, balloons of different volumes (40 µl or 50 µl) were inflated in the experimental groups, whereas no balloons were inflated in the control group. The experimental groups underwent the first decompression in the rostral or caudal area at 1 week post-injury; the second decompression was performed at 2 weeks post-injury. For 6 weeks post-injury, the animals were tested to determine behavioral scores, somatosensory evoked potentials (SEPs) and radiographic imaging changes; histological and apoptosis assay results were subsequently analyzed. RESULTS: The behavioral test results and onset latency of the SEPs indicated that there were significant differences between priority rostral decompression (PRD) and priority caudal decompression (PCD) in the 50-µl compression group at 6 weeks post-injury; however, there were no significant differences between the two procedures in the 40-µl group at the same time point. Moreover, there were no significant peak-to-peak amplitude differences between the two procedures in the 50-µl compression group. CONCLUSIONS: The findings of this study suggested that preferential rostral decompression was more beneficial than priority caudal decompression with respect to facilitating spinal cord functional recovery in rabbits with severe paraplegia and may provide clinicians with a reference for the clinical treatment of multiple-segment spinal cord compression injuries.

Oral targeted drug delivery to post-gastrointestinal sites.

As an essential branch of targeted drug delivery, oral targeted delivery is attracting growing attention in recent years. In addition to site-specific delivery for the treatment of locoregional diseases in the gastrointestinal tract (GIT), oral targeted delivery to remote sites beyond the GIT emerges as a cutting-edge research topic. This review aims to provide an overview of the fundamental concepts and most recent advances in this field. Owing to the physiological barriers existing in the GIT, carrier systems should be transported across the enteric epithelia to target remote sites. Recently, pioneer investigations have validated the transport of intact micro- or nanocarriers across gastrointestinal barriers and subsequently to various distal organs and tissues. The microfold (M) cell pathway is the leading mechanism underlying the oral absorption of particulates, but the contribution of the transcellular and paracellular pathways should not be neglected either. In addition to well-acknowledged physicochemical and biological factors, the formation of a protein corona may also influence the biological fate of carrier systems. Although in an early stage of conceptualization, oral targeted delivery to remote diseases has demonstrated promising potential for the treatment of inflammation, tumors, and diseases inflicting the lymphatic and mononuclear phagocytosis systems.

Brain-targeted drug delivery by in vivo functionalized liposome with stable D-peptide ligand.

Brain-targeted drug delivery poses a great challenge due to the blood-brain barrier (BBB). In a previous study, we have developed a peptide-modified stealth liposome (SP-sLip) to enhance BBB penetration via the adsorption of apolipoproteins in plasma. SP is an 11-amino acid peptide derived from 25 to 35 of the Amyloid ß peptide (Aß1-42), which is a nature ligand of apolipoproteins. Although freshly prepared SP-sLip exhibited efficient brain targeting performance, it occured self-aggregation and instability in storage. In this study, we developed a D-peptide ligand according to the reverse sequence of SP with D-amino acids, known as DSP, to improve the stability in storage. Notably, DSP exhibited a reduced tendency for self-aggregation and improved stability in comparison to the SP peptide. Furthermore, compared to SP-sLip, DSP-modified sLip (DSP-sLip) demonstrated enhanced stability (>2 weeks), prolonged blood circulation (AUC increased 44.4%), reduced liver and spleen accumulation (reduced by 2.23 times and 1.86 times) with comparable brain-targeting efficiency. Similar to SP-sLip, DSP-sLip selectively adsorbed apolipoprotein A1, E, and J in the blood to form functionalized protein corona, thus crossing BBB via apolipoprotein receptor-mediated transcytosis. These findings underscored the importance of ligand stability in the in vitro and in vivo performance of brain-targeted liposomes, therefore paving the way for the design and optimization of efficient and stable nanocarriers.

What enlightenment has the development of lung cancer bone metastasis brought in the last 22 years.

BACKGROUND: Lung cancer bone metastasis (LCBM) is a disease with a poor prognosis, high risk and large patient population. Although considerable scientific output has accumulated on LCBM, problems have emerged, such as confusing research structures. AIM: To organize the research frontiers and body of knowledge of the studies on LCBM from the last 22 years according to their basic research and translation, clinical treatment, and clinical diagnosis to provide a reference for the development of new LCBM clinical and basic research. METHODS: We used tools, including R, VOSviewer and CiteSpace software, to measure and visualize the keywords and other metrics of 1903 articles from the Web of Science Core Collection. We also performed enrichment and protein-protein interaction analyses of gene expression datasets from LCBM cases worldwide. RESULTS: Research on LCBM has received extensive attention from scholars worldwide over the last 20 years. Targeted therapies and immunotherapies have evolved into the mainstream basic and clinical research directions. The basic aspects of drug resistance mechanisms and parathyroid hormone-related protein may provide new ideas for mechanistic study and improvements in LCBM prognosis. The produced molecular map showed that ribosomes and focal adhesion are possible pathways that promote LCBM occurrence. CONCLUSION: Novel therapies for LCBM face animal testing and drug resistance issues. Future focus should centre on advancing clinical therapies and researching drug resistance mechanisms and ribosome-related pathways.

Clinical significance and prospective mechanism of increased CDKN2A expression in small cell lung cancer.

BACKGROUND: Although it has been shown that cyclin dependent kinase inhibitor 2A (CDKN2A) plays a significant role in a number of malignancies, its clinicopathological value and function in small cell lung cancer (SCLC) is unclear and warrants additional research. METHODS: The clinical significance of CDKN2A expression in SCLC was examined by multiple methods, including comprehensive integration of mRNA level by high throughput data, Kaplan-Meier survival analysis for prognostic value, and validation of its protein expression using in-house immunohistochemistry. RESULTS: The expression of CDKN2A mRNA in 357 cases of SCLC was evidently higher than that in the control group (n = 525) combing the data from 20 research centers worldwide. The standardized mean difference (SMD) was 3.07, and the area under the curve (AUC) of summary receiver operating characteristic curve (sROC) was 0.97 for the overexpression of CDKN2A. ACC, COAD, KICH, KIRC, PCPG, PRAD, UCEC, UVM patients with higher CDKN2A expression had considerably worse overall survival rates than those with lower CDKN2A expression with the hazard ratio (HR) > 1. CONCLUSION: CDKN2A upregulation extensively enhances the carcinogenesis and progression of SCLC.