Potential therapeutic targets for COVID-19 complicated with pulmonary hypertension: a bioinformatics and early validation study.

Coronavirus disease (COVID-19) and pulmonary hypertension (PH) are closely correlated. However, the mechanism is still poorly understood. In this article, we analyzed the molecular action network driving the emergence of this event. Two datasets (GSE113439 and GSE147507) from the GEO database were used for the identification of differentially expressed genes (DEGs).Common DEGs were selected by VennDiagram and their enrichment in biological pathways was analyzed. Candidate gene biomarkers were selected using three different machine-learning algorithms (SVM-RFE, LASSO, RF).The diagnostic efficacy of these foundational genes was validated using independent datasets. Eventually, we validated molecular docking and medication prediction. We found 62 common DEGs, including several ones that could be enriched for Immune Response and Inflammation. Two DEGs (SELE and CCL20) could be identified by machine-learning algorithms. They performed well in diagnostic tests on independent datasets. In particular, we observed an upregulation of functions associated with the adaptive immune response, the leukocyte-lymphocyte-driven immunological response, and the proinflammatory response. Moreover, by ssGSEA, natural killer T cells, activated dendritic cells, activated CD4 T cells, neutrophils, and plasmacytoid dendritic cells were correlated with COVID-19 and PH, with SELE and CCL20 showing the strongest correlation with dendritic cells. Potential therapeutic compounds like FENRETI-NIDE, AFLATOXIN B1 and 1-nitropyrene were predicted. Further molecular docking and molecular dynamics simulations showed that 1-nitropyrene had the most stable binding with SELE and CCL20.The findings indicated that SELE and CCL20 were identified as novel diagnostic biomarkers for COVID-19 complicated with PH, and the target of these two key genes, FENRETI-NIDE and 1-nitropyrene, was predicted to be a potential therapeutic target, thus providing new insights into the prediction and treatment of COVID-19 complicated with PH in clinical practice.

Exploring Memory Function Beyond Immune Cells: ANGPTL4-Mediated Memory Functions in Tissue Resident Stem Cells.

Adapted immune cells are known to develop memory functions that increase resistance to subsequent infections after initial pathogen exposure, however, it is unclear whether non-immune cells, like tissue-resident stem cells, have similar memory functions. Here, it is found that tissue-resident stem cells crucial for tissue regeneration show diminished adverse effects on diverse stem cell functions against successive exposure to foreign antigen (ß-glucan) to maintain tissue homeostasis and stability both in vitro and in vivo. These data suggest that endometrial stem cells may possess a robust memory function, in contrast, fully differentiated cells like fibroblasts and vesicular cells do not show these memory mechanisms upon consecutive antigen exposure. Moreover, the pivotal role of Angiopoietin-like 4 (ANGPTL4) in regulating the memory functions of endometrial stem cells is identified through specific shRNA knockdown in vitro and knockout mice in vivo experiments. ANGPTL4 is associated with the alteration of diverse stem cell functions and epigenetic modifications, notably through histone H3 methylation changes and two pathways (i.e., PI3K/Akt and FAK/ERK1/2 signaling) upon consecutive antigen exposure. These findings imply the existence of inherent self-defense mechanisms through which local stem cells can adapt and protect themselves from recurrent antigenic challenges, ultimately mitigating adverse consequences.

Repeated photodynamic therapy using a chlorin e6-embedded device to prolong the therapeutic effects on obesity.

OBJECTIVE: This study aimed to investigate the efficacy and safety of repeated photodynamic therapy (PDT) with a chlorin e6 (Ce6)-embedded intragastric satiety-inducing device (ISD) to maintain therapeutic effects of obesity in a juvenile pig. METHODS: The Ce6-embedded ISD was fabricated with a dipping method. Twelve pigs were divided into four groups of three and were administered control, single, biweekly, or weekly PDT, respectively. The therapeutic effects were assessed by comparing the results of phototoxicity, endoscopy, fluoroscopy, hormone and weight changes, and histological examination. RESULTS: The percentage of total body weight gain was significantly suppressed in PDT-treated pigs compared with control pigs (all p < 0.001). This suppression persisted in the repeated PDT groups, but percentage of total body weight gain gradually increased when PDT was stopped. Ghrelin levels in the PDT-treated groups were significantly lower and leptin levels were significantly higher than those in the control group (all p < 0.05). Inflammatory cell infiltration, collagen, TUNEL, and anti-ghrelin-positive deposition in the weekly group were significantly higher than those in the control, single, and biweekly groups (all p < 0.01). CONCLUSIONS: Repeated and periodic PDT was technically feasible and safe and successfully maintained the therapeutic effects against obesity while eliminating the indwelling time and reducing ISD-related complications in pigs.

Identification of memory mechanism in tissue-resident stem cells via ANGPTL4 beyond immune cells upon viral antigen exposure.

Although memory functions of immune cells characterized by increased resistance to subsequent infections after initial pathogen exposure are well-established, it remains unclear whether non-immune cells, especially tissue-resident stem cells, exhibit similar memory mechanisms. The present study revealed that detrimental effects of initial viral antigen exposure (human papillomavirus [HPV]) on diverse stem cell functions were significantly exacerbated upon subsequent secondary exposure both in vitro and in vivo. Importantly, endometrial stem cells exhibited robust memory functions following consecutive HPV antigen exposures, whereas fully differentiated cells such as fibroblasts and vesicular cells did not show corresponding changes in response to the same antigen exposures. Deficiency of angiopoietin-like 4 (ANGPTL4) achieved through small hairpin RNA knockdown in vitro and knockout (KO) mice in vivo highlighted the critical role of ANGPTL4 in governing memory functions associated with various stem cell processes. This regulation occurred through histone H3 methylation alterations and PI3K/Akt signaling pathways in response to successive HPV antigen exposures. Furthermore, memory functions associated with various stem cell functions that were evident in wild-type mice following consecutive exposures to HPV antigen were not observed in ANGPTL4 KO mice. In summary, our findings strongly support the presence of memory mechanism in non-immune cells, particularly tissue-resident stem cells.

Overcoming antibiotic resistance caused by genetic mutations of Helicobacter pylori with mucin adhesive polymer-based therapeutics.

Herein, we describe the 3'-sialyllactose-polyethyleneimine-chlorine e6 conjugate (3PC), meticulously engineered to effectively target Helicobacter bacteria (H. pylori) within the gastric environment. The composition of 3PC comprises polyethyleneimine, a cationic polymer, 3'-sialyllactose, which exhibits a specific binding affinity for H. pylori surface proteins, and a photosensitizer capable of generating oxygen radicals in response to specific wavelengths. The distinctive feature of 3PC lies in its capacity to enhance interaction with the anionic mucus layer facilitated by electrostatic forces. This interaction results in prolonged residence within the intestinal environment. The extended vacation in the intestinal milieu overcomes inherent limitations that have historically impeded conventional antibiotics from efficiently reaching and targeting H. pylori. 3PC can be harnessed as a potent tool for antibacterial photodynamic therapy, and its versatility extends to addressing the challenges posed by various antibiotic-resistant strains. The exceptional efficacy of 3PC in enhancing intestinal residence time and eradicating H. pylori has been robustly substantiated in animal models, particularly in mice. In summary, 3PC is a formidable agent capable of eradicating H. pylori, irrespective of its antibiotic resistance status, by efficiently penetrating and selectively targeting the mucus layer within the gastric environment.

Localized Photodynamic Therapy Using a Chlorin e6-Embedded Silicone-Covered Self-Expandable Metallic Stent as a Palliative Treatment for Malignant Esophageal Strictures.

Localized photodynamic therapy (PDT) uses a polymeric-photosensitizer (PS)-embedded, covered self-expandable metallic stent (SEMS). PDT is minimally invasive and a noteworthy potential alternative for treating esophageal strictures, where surgery is not a viable option. However, preclinical evidence is insufficient, and optimized irradiation energy dose ranges for localized PDT are unclear. Herein, we validated the irradiation energy doses of the SEMS (embedded in a PS using chlorin e6 [Ce6] and covered in silicone) and PDT-induced tissue changes in a rat esophagus. Cytotoxicity and phototoxicity in the Ce6-embedded SEMS piece with laser irradiation were significantly higher than that of the silicone-covered SEMS with or without laser and the Ce6-embedded silicone-covered SEMS without laser groups (all p < 0.001). Moreover, surface morphology, atomic changes, and homogeneous coverage of the Ce6-embedded silicone-covered membrane were confirmed. The ablation range of the porcine liver was proportionally increased with the irradiation dose (all p < 0.001). The ablation region was identified at different irradiation energy doses of 50, 100, 200, and 400 J/cm2. The in vivo study in the rat esophagus comprised a control group and 100, 200, and 400 J/cm2 energy-dose groups. Finally, histology and immunohistochemistry (TUNEL and Ki67) confirmed that the optimized Ce6-embedded silicone-covered SEMS with selected irradiation energy doses (200 and 400 J/cm2) effectively damaged the esophageal tissue without ductal perforation. The polymeric PS-embedded silicone-covered SEMS can be easily placed via a minimally invasive approach and represents a promising new approach for the palliative treatment of malignant esophageal strictures.

Intranasal mRNA Delivery via Customized RNA-Polyplex Nanoparticles Enhancing Gene Expression through Photochemical Mechanisms.

Achieving effective mRNA expression in vivo requires careful selection of an appropriate delivery vehicle and route of administration. Among the various routes of administration, intranasal administration has received considerable attention due to its ability to induce potent immune responses. In this context, we designed a specialized cationic polymer tailored for delivery of mRNA into the nasal cavity. These polymers are designed with varying degrees of substitution in different amine groups to allow for identification of the most suitable amine moiety for effective mRNA delivery. We also incorporated a photosensitizer within the polymer structure that can trigger the generation of reactive oxygen species when exposed to light. The synthesized cationic polymer is complexed with anionic mRNA to form a polyplex. Illuminating these polyplexes with laser light enhances their escape from intracellular endosomes, stimulating mRNA translocation into the cytoplasm, followed by increased mRNA expression at the cellular level. Through intranasal administration to C57BL/6 mice, it was confirmed that these photoactive polyplexes effectively induce mRNA expression and activate immune responses in vivo using photochemical effects. This innovative design of a photoactivated cationic polymer presents a promising and reliable strategy to achieve efficient intranasal mRNA delivery. This approach has potential applications in the development of mRNA-based vaccines for both prophylactic and therapeutic purposes.

Bioinformatics analyses of potentially common pathogenic networks for primary Sjögren's syndrome complicated with acute myocardial infarction.

Both primary Sjögren's syndrome (pSS) and acute myocardial infarction (AMI) are intricately linked. However, their common mechanism is not fully understood. Herein, we examined the underlying network of molecular action associated with developing this complication. Datasets were downloaded from the GEO database. We performed enrichment and protein-protein interaction analyses and screened key genes. We used external datasets to confirm the diagnostic performance for these hub genes. Transcription factor and microRNA regulatory networks were constructed for the validated hub genes. Finally, drug prediction and molecular docking validation were performed. We identified 62 common DEGs, many of which were enriched regarding inflammation and immune response. 5 DEGs were found as key hub genes (IGSF6, MMP9, S100A8, MNDA, and NCF2). They had high diagnostic performance in external datasets. Functional enrichment of these five hub genes showed that they were associated with the adaptive immune response. The Type 1T helper cell showed the most association among all cell types related to AMI and pSS. We identified 36 common TFs and 49 identical TF-miRNAs. The drugs, including Benzo, dexamethasone, and NADP, were predicted as potential therapeutic agents. Herein, we revealed common networks involving pSS and AMI etiologies. Knowledge of these networks and hub genes can enhance research into their associated mechanism and the development of future robust therapy.

Surfactant-like photosensitizer for endoscopic duodenal ablation: Modulating meal-stimulated incretin hormones in obese and type 2 diabetes.

Duodenal ablation improves glycaemic control and weight loss, so it has been applied using hydrothermal catheters in obese and type 2 diabetes patients, indicating similar mechanisms and therapeutic effects as bariatric surgeries. Endoscopic photodynamic therapy is an innovative procedure that easily accessible to endocrine or gastrointestinal organs, so it is critical for the sprayed photosensitizer (PS) to long-term interact with target tissues for enhancing its effects. Surfactant-like PS was more stable in a wide range of pH and 2.8-fold more retained in the duodenum at 1 h than hydrophilic PS due to its amphiphilic property. Endoscopic duodenal ablation using surfactant-like PS was performed in high fat diet induced rat models, demonstrating body weight loss, enhanced insulin sensitivity, and modulation of incretin hormones. Locoregional ablation of duodenum could affect the profiles of overall intestinal cells secreting meal-stimulated hormones and further the systemic glucose and lipid metabolism, regarding gut-brain axis. Our strategy suggests a potential for a treatment of minimally invasive bariatric and metabolic therapy if accompanied by detailed clinical trials.

Stem Cell-Derived Extracellular Vesicles for Cancer Therapy and Tissue Engineering Applications.

Recently, stem cells and their secretomes have attracted great attention in biomedical applications, particularly extracellular vesicles (EVs). EVs are secretomes of cells for cell-to-cell communication. They play a role as intercellular messengers as they carry proteins, nucleic acids, lipids, and therapeutic agents. They have also been utilized as drug-delivery vehicles due to their biocompatibility, low immunogenicity, stability, targetability, and engineerable properties. The therapeutic potential of EVs can be further enhanced by surface engineering and modification using functional molecules such as aptamers, peptides, and antibodies. As a consequence, EVs hold great promise as effective delivery vehicles for enhancing treatment efficacy while avoiding side effects. Among various cell types that secrete EVs, stem cells are ideal sources of EVs because stem cells have unique properties such as self-renewal and regenerative potential for transplantation into damaged tissues that can facilitate their regeneration. However, challenges such as immune rejection and ethical considerations remain significant hurdles. Stem cell-derived EVs have been extensively explored as a cell-free approach that bypasses many challenges associated with cell-based therapy in cancer therapy and tissue regeneration. In this review, we summarize and discuss the current knowledge of various types of stem cells as a source of EVs, their engineering, and applications of EVs, focusing on cancer therapy and tissue engineering.

Stem cell-derived paracrine factors by modulated reactive oxygen species to enhance cancer immunotherapy.

Herein, we present an approach for manipulating paracrine factors and signaling pathways in adipose-derived stem cells (ADSCs) to achieve highly effective tumor immunotherapy. Our method involves precise control of reactive oxygen species concentration using the CD90-maleimide-pluronic F68-chlorin e6 conjugate (CPFC) to create ACPFC, which is then attached to ADSCs through the CD90 receptor-specific interaction. By regulating the irradiated laser power, ACPFC promotes signaling pathways such as cascade-3, VEGFR2, α2ß1, C3AR1, CR1-4, and C5AR1, leading to the secretion of various inflammatory cytokines such as IFN-γ, TGF-ß, and IL-6, while inhibiting AKT, ERK, NFkB, PAR1, and PAR3/4 signaling pathways to reduce the secretion of cell growth factors like TIMP-1, TIMP-2, VEGF, Ang-2, FGF-2, and HGF. When ACPFC is injected intravenously into a tumor animal model, it autonomously targets and accumulates at the tumor site, and upon laser irradiation, it generates various anti-inflammatory factors while reducing angiogenesis growth factors. The resulting antitumor response recruits CD3+CD8+ cytotoxic T cells and CD3+CD4+ helper T cells into the tumor and spleen, leading to highly effective melanoma and pancreatic tumor treatment in mice. Our technology for regulating stem cell paracrine factors holds significant promise for the treatment of various diseases.

Effect of dual antiplatelet therapy prolongation in acute coronary syndrome patients with both high ischemic and bleeding risk: insight from the OPT-CAD study.

Background: In current clinical practice, controversy remains regarding the clinical benefits of prolonged dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) patients facing high risks of both ischemia and bleeding ("bi-risk") following percutaneous coronary intervention (PCI). This study aimed to investigate the feasibility of identifying a group of bi-risk ACS patients after PCI using the OPT-BIRISK criteria, emphasizing extended DAPT treatment safety and efficacy beyond 12 months in these bi-risk ACS after PCI in real-world conditions. Methods: This analysis compared extended DAPT and single antiplatelet therapy (SAPT) at 12-24 months in ACS patients undergoing PCI complicated with both ischemic and bleeding risk as defined by OPT-BIRISK criteria without premature DAPT discontinuation before 9 months or major clinical adverse events within 12 months. This was a post hoc analysis of the Optimal antiPlatelet Antiplatelet Therapy for Chinese Patients with Coronary Artery Disease (OPT-CAD) study. The main research outcome was the incidence of ischemic events within 12-24 months, which was determined as a composite of stroke, myocardial infarction, and cardiac death events. Through propensity score matching (PSM), groups were balanced. For the external validation of the OPT-BIRISK criteria to identify a bi-risk ACS patient, ischemic events, BARC 2, 3, 5 bleeding events, and BARC 3, 5 bleeding events at 5 years were analyzed. Results: The total number of ACS patients analyzed in this analysis was 7,049, of whom 4,146 (58.8%) were bi-risk patients and 2,903 (41.2%) were not. The frequency of ischemic events was significantly different between the two groups at 5 years (11.70% vs. 5.55%, P < 0.001), and the incidence of BARC 2,3,5 bleeding was significantly higher in the bi-risk group (6.90% vs. 4.03%, P < 0.001) than in the non-bi-risk group. Among the bi-risk patients without any clinical adverse events within 12 months that underwent extended DAPT treatment (n = 2,374, 75.7%) exhibited a lower risk of stroke at 12-24 months (1.10% vs. 2.10%, P = 0.036) relative to those that underwent SAPT (n = 763, 24.3%), while bleeding risk did not differ significantly between these groups. PSM cohort analysis results were consistent with those of overall group analyses. Conclusion: In conclusion, the findings showed that using the OPT-BIRISK criteria could help physicians identify ACS patients at a high risk of developing recurrent ischemia and bleeding episodes after PCI. Compared to antiplatelet monotherapy, a strategy of extended DAPT may offer potential benefits in lowering the risk of stroke without carrying a disproportionately high risk of serious bleeding problems among these patients who were event-free after a year of DAPT.

Synergistic Approach of Antibody-Photosensitizer Conjugate Independent of KRAS-Mutation and Its Downstream Blockade Pathway in Colorectal Cancer.

Here, a novel approach is presented to improve the efficacy of antibody-drug conjugates (ADC) by integrating antibody-mediated immunotherapy and photodynamic therapy (PDT) in a combination therapy system utilizing an antibody-photosensitizer conjugate (APC) platform based on a poloxamer polymer linker. To specifically target Kirsten rat sarcoma 2 viral oncogene homolog (KRAS)-mutated cancer cells, an antibody antiepidermal growth factor receptor (EGFR), cetuximab, with a poloxamer linker coupled with the photosensitizer chlorin e6 through click chemistry (cetuximab-maleimide-poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide)-chlorine e6 conjugate, CMPXC) is synthesized. CMPXC is cytotoxic upon laser treatment, achieving a 90% cell death by suppressing KRAS downstream signaling pathways associated with ERK and AKT proteins, confirmed using RNA sequencing analysis. In KRAS-mutated colorectal cancer mouse models, CMPXC significantly enhances antitumor efficacy compared with cetuximab treatment alone, resulting in an 86% reduction in tumor growth. Furthermore, CMPXC treatment leads to a 2.24- and 1.75-fold increase in dendritic and priming cytotoxic T cells, respectively, highlighting the immune-activating potential of this approach. The findings suggest that the APC platform addresses the challenges associated with ADC development and EGFR-targeted therapy, including the synergistic advantages of antibody-mediated immunotherapy and PDT.

Nanoparticle platform comprising lipid-tailed pH-sensitive carbon dots with minimal drug loss.

Herein, we synthesized a lipid-mimicking organic material (PCD_FA) that can surpass the efficacy of lipid-based nanoparticles and demonstrated its potential as a delivery vehicle for various hydrophilic drugs. PCD_FA is a conjugate of pH-sensitive carbon dots (PCDs) and fatty acids (FAs) and has potential applications in several fields owing to various combinations of carbon dots (CDs) and FAs. Similar to phospholipids, PCD-FAs have hydrophilic heads and hydrophobic tails that allow them to self-form nanoparticles (Coposomes) in the aqueous phase. Coposomes can easily combine various hydrophilic head and hydrophobic tail combinations, and several drugs can be encapsulated, or drug release patterns can be controlled according to each property. We analyzed the differences in size, drug loading efficiency, and drug release patterns of Coposomes depending on the type of FAs and characteristics of the encapsulated drugs. Additionally, cell entry and intracellular drug release mechanisms of the Coposomes were identified. The applicability of Coposomes as drug delivery carriers for tumor treatment has been demonstrated in comparison with that of liposomes formulation in tumor-bearing mouse models. Consequently, this study presents possibilities for the synthesis and application of various amphiphilic lipid-mimicking organic materials via the combination of CDs and FAs with various functions.

pH-Responsive Zinc Ion Regulating Immunomodulatory Nanoparticles for Effective Cancer Immunotherapy.

Herein, we introduce a novel approach involving the utilization of a human serum albumin-coated zeolite imidazolate framework-8 containing a photosensitizer (HPZ) that exhibits targeted recognition of the tumor microenvironment, enabling the rapid elevation of zinc ion concentrations while facilitating the controlled release of an encapsulated photosensitizer (PS). At a physiological pH of 7.4, HPZ demonstrates a size of approximately 170 nm, significantly decreasing to less than 10 nm under pH 6.5 acidic conditions. Acid-induced decomposition of HPZ triggers a rapid increase in zinc ion concentration, eliciting potent cytotoxic effects against colorectal, breast, and pancreatic cancers. Additionally, upon laser irradiation, the encapsulated PS within HPZ initiates the generation of reactive oxygen species, synergistically augmenting the cytotoxicity induced by zinc ions. Intravenous administration of HPZ in a CT26 tumor-bearing mouse model resulted in a notable expansion of CD3+CD4+ helper T cells and CD3+CD8+ cytotoxic T cells, accompanied by a reduction in the CD4+CD25+Foxp3+ regulatory T-cell population. These changes led to significant inhibition of tumor growth, highlighting the efficacy of HPZ in this experimental model. Importantly, HPZ exhibits favorable safety characteristics, displaying no toxicity toward vital organs and inducing no weight loss. Thus, HPZ holds immense promise as a standalone treatment or in combination with diverse anticancer immunotherapies, underscoring its potential in the field of anticancer immunotherapy.

Contemporary Use of Ticagrelor vs Clopidogrel in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: A GRACE Risk Score Stratification-Based Analysis in a Large-Scale, Real-World Study From China.

OBJECTIVE: To evaluate potential gains in outcomes from ticagrelor-based strategy according to risk stratification by Global Registry of Acute Coronary Events (GRACE) score. METHODS: A total of 19,704 patients discharged alive post-acute coronary syndrome who underwent percutaneous coronary intervention and received ticagrelor or clopidogrel between March 2016 and March 2019 were included in the study. The primary endpoint was ischemic events at 12 months, composed of cardiac death, myocardial infarction, and/or stroke. Secondary outcomes included all-cause mortality and Bleeding Academic Research Consortium type 2 to 5 and 3 to 5 bleeding. RESULTS: The ticagrelor group comprised 6432 (32.6%) patients and the clopidogrel group comprised 13,272 (67.4%) patients. During the follow-up period, there was a significant reduction in the incidence of ischemic events in patients treated using ticagrelor who had excessive risk of bleeding. According to the GRACE score, among low-risk patients, ticagrelor use compared with clopidogrel was not associated with decreased ischemic events (HR, 0.82; 95% CI, 0.57 to 1.17; P=.27) with excessive risk of Bleeding Academic Research Consortium type 3 to 5 bleeding (HR, 1.59; 95% CI, 1.16 to 2.17; P=.004). The risk of ischemic events (HR, 0.60; 95% CI, 0.41 to 0.89; P=.01) were lower in the intermediate- to high-risk patients treated with ticagrelor without significant difference in BARC type 3 to 5 bleeding risk (HR, 1.11; 95% CI, 0.75 to 1.65; P=.61). CONCLUSION: There was still a gap between guideline-indicated therapy and the clinical practice in a sizable subset of patients with acute coronary syndrome who underwent percutaneous coronary intervention. The GRACE risk score could identify patients who would derive benefit from the ticagrelor-based antiplatelet strategy.

Nanoparticle oral absorption and its clinical translational potential.

Oral administration of pharmaceuticals is the most preferred route of administration for patients, but it is challenging to effectively deliver active ingredients (APIs) that i) have extremely high or low solubility in intestinal fluids, ii) are large in size, iii) are subject to digestive and/or metabolic enzymes present in the gastrointestinal tract (GIT), brush border, and liver, and iv) are P-glycoprotein substrates. Over the past decades, efforts to increase the oral bioavailability of APIs have led to the development of nanoparticles (NPs) with non-specific uptake pathways (M cells, mucosal, and tight junctions) and target-specific uptake pathways (FcRn, vitamin B12, and bile acids). However, voluminous findings from preclinical models of different species rarely meet practical standards when translated to humans, and API concentrations in NPs are not within the adequate therapeutic window. Various NP oral delivery approaches studied so far show varying bioavailability impacted by a range of factors, such as species, GIT physiology, age, and disease state. This may cause difficulty in obtaining similar oral delivery efficacy when research results in animal models are translated into humans. This review describes the selection of parameters to be considered for translational potential when designing and developing oral NPs.

Photoactive intragastric satiety-inducing device using polymeric photosensitizers for minimally invasive weight loss treatment.

An intragastric satiety-inducing device (ISD) located in the stomach induce satiety and fullness in the absence of food by continuously pressing on the distal esophagus and cardia of the stomach. To improve the therapeutic function of ISD, Chlorin e6 (Ce6) was embedded in a disk portion of ISD, generating reactive oxygen species and stimulating endocrine cells under the laser irradiation. Since Ce6 has remarkable light efficiency but poor solubility in various solvents, it is essential to use a polymeric photosensitizer and optimize a suitable coating solution composition. Methoxy polyethylene glycol-Ce6 was uniformly coated and the spontaneous release amount of the Ce6 from the device could be reduced, which induced photo-responsive cell death and reduced ghrelin levels in vitro. In mini pigs operated single therapy (PDT or ISD) or combination therapy (Photoreactive ISD), there were differences in body weight (control: 28% vs. Photoreactive ISD: 4%, P < 0.001), ghrelin (control: 4% vs. Photoreactive ISD: 35%, P < 0.001), and leptin levels (control: 8% vs. Photoreactive PDT: 35%, P < 0.001) at 4 weeks.

Corrigendum: Untargeted metabolomics identified kynurenine as a predictive prognostic biomarker in acute myocardial infarction.

[This corrects the article DOI: 10.3389/fimmu.2022.950441.].

Nanocracker capable of simultaneously reversing both P-glycoprotein and tumor microenvironment.

Here, we describe a multidrug-resistant nanocracker (MDRC) that can treat multi-drug resistant (MDR) cancer by recognizing the acidic microenvironment and inhibiting two mechanisms of MDR such as P-glycoprotein (P-gp) and vacuolar-type ATPase (V-ATPase). MDRC is a liposome formulation co-loading pantoprazole (PZ) and paclitaxel (PTX). PZ acts as a chemosensitizer that enhances the MDR cancer treatment effect of PTX by disrupting the pH gradient and inhibiting P-gp. MDRC-encapsulated PZ and PTX have different release rates, with PZ released within 12 h and PTX sustained release for 48 h in the plasma. MDRC could increase cell uptake by inhibiting the P-gp overexpressed MCF-7/mdr cells and UV-2237M cells, which are human breast MDR cancer cells and murine fibrosarcoma cells, respectively. MDRC can also increase the cytotoxic efficacy of PTX by increasing intracellular pH. MDRC has a 10.5-fold reduced IC50 value in the P-gp overexpressed human breast adenocarcinoma and a 6.3- to 9.5-fold reduced IC50 value in the P-gp non-expressed human breast adenocarcinoma compared to the mixture of PZ and PTX, respectively. Intravenous injection of MDRC did not cause weight loss, liver dysfunction, or major organ toxicity. MDRC exhibited 80% complete remission of murine fibrosarcoma. The excellent therapeutic effect of MDRC on MDR tumors was accompanied by an increase in dendritic cell maturation and cytotoxic T cells. In other words, MDRC has the potential to terminate MDR therapy through the complete remission of MDR tumors.