Complete genome sequences of Klebsiella pneumoniae bacteriophages YMR1 and YMR2 isolated from sewage.

Two Klebsiella pneumoniae bacteriophages, YMR1 and YMR2, which form plaques with halos, were isolated from sewage in Seoul, South Korea. YMR1 and YMR2 have double-stranded DNA genomes of 40,338 bp and 40,756 bp with 49 and 52 predicted protein-coding genes, respectively. Both are predicted to be members of the family Autographiviridae.

Hyaluronic Acid-Bilirubin Nanoparticles as a Tumor Microenvironment Reactive Oxygen Species-Responsive Nanomedicine for Targeted Cancer Therapy.

Introduction: The tumor microenvironment (TME) has attracted considerable attention as a potential therapeutic target for cancer. High levels of reactive oxygen species (ROS) in the TME may act as a stimulus for drug release. In this study, we have developed ROS-responsive hyaluronic acid-bilirubin nanoparticles (HABN) loaded with doxorubicin (DOX@HABN) for the specific delivery and release of DOX in tumor tissue. The hyaluronic acid shell of the nanoparticles acts as an active targeting ligand that can specifically bind to CD44-overexpressing tumors. The bilirubin core has intrinsic anti-cancer activity and ROS-responsive solubility change properties. Methods & Results: DOX@HABN showed the HA shell-mediated targeting ability, ROS-responsive disruption leading to ROS-mediated drug release, and synergistic anti-cancer activity against ROS-overproducing CD44-overexpressing HeLa cells. Additionally, intravenously administered HABN-Cy5.5 showed remarkable tumor-targeting ability in HeLa tumor-bearing mice with limited distribution in major organs. Finally, intravenous injection of DOX@HABN into HeLa tumor-bearing mice showed synergistic anti-tumor efficacy without noticeable side effects. Conclusion: These findings suggest that DOX@HABN has significant potential as a cancer-targeting and TME ROS-responsive nanomedicine for targeted cancer treatment.

Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy.

BACKGROUND: Immunogenic cell death (ICD) is a crucial approach to turn immunosuppressive tumor microenvironment (ITM) into immune-responsive milieu and improve the response rate of immune checkpoint blockade (ICB) therapy. However, cancer cells show resistance to ICD-inducing chemotherapeutic drugs, and non-specific toxicity of those drugs against immune cells reduce the immunotherapy efficiency. METHODS: Herein, we propose cancer cell-specific and pro-apoptotic liposomes (Aposomes) encapsulating second mitochondria-derived activator of caspases mimetic peptide (SMAC-P)-doxorubicin (DOX) conjugated prodrug to potentiate combinational ICB therapy with ICD. The SMAC-P (AVPIAQ) with cathepsin B-cleavable peptide (FRRG) was directly conjugated to DOX, and the resulting SMAC-P-FRRG-DOX prodrug was encapsulated into PEGylated liposomes. RESULTS: The SMAC-P-FRRG-DOX encapsulated PEGylated liposomes (Aposomes) form a stable nanostructure with an average diameter of 109.1 ± 5.14 nm and promote the apoptotic cell death mainly in cathepsin B-overexpressed cancer cells. Therefore, Aposomes induce a potent ICD in targeted cancer cells in synergy of SMAC-P with DOX in cultured cells. In colon tumor models, Aposomes efficiently accumulate in targeted tumor tissues via enhanced permeability and retention (EPR) effect and release the encapsulated prodrug of SMAC-P-FRRG-DOX, which is subsequently cleaved to SMAC-P and DOX in cancer cells. Importantly, the synergistic activity of inhibitors of apoptosis proteins (IAPs)-inhibitory SMAC-P sensitizing the effects of DOX induces a potent ICD in the cancer cells to promote dendritic cell (DC) maturation and stimulate T cell proliferation and activation, turning ITM into immune-responsive milieu. CONCLUSIONS: Eventually, the combination of Aposomes with anti-PD-L1 antibody results in a high rate of complete tumor regression (CR: 80%) and also prevent the tumor recurrence by immunological memory established during treatments.

Antioxidative Hyaluronic Acid-Bilirubin Nanomedicine Targeting Activated Hepatic Stellate Cells for Anti-Hepatic-Fibrosis Therapy.

Liver fibrosis is a life-threatening and irreversible disease. The fibrosis process is largely driven by hepatic stellate cells (HSCs), which undergo transdifferentiation from an inactivated state to an activated one during persistent liver damage. This activated state is responsible for collagen deposition in liver tissue and is accompanied by increased CD44 expression on the surfaces of HSCs and amplified intracellular oxidative stress, which contributes to the fibrosis process. To address this problem, we have developed a strategy that combines CD44-targeting of activated HSCs with an antioxidative approach. We developed hyaluronic acid-bilirubin nanoparticles (HABNs), composed of endogenous bilirubin, an antioxidant and anti-inflammatory bile acid, and hyaluronic acid, an endogenous CD44-targeting glycosaminoglycan biopolymer. Our findings demonstrate that intravenously administered HABNs effectively targeted the liver, particularly activated HSCs, in fibrotic mice with choline-deficient l-amino acid-defined high-fat diet (CD-HFD)-induced nonalcoholic steatohepatitis (NASH). HABNs were able to inhibit HSC activation and proliferation and collagen production. Furthermore, in a murine CD-HFD-induced NASH fibrosis model, intravenously administered HABNs showed potent fibrotic modulation activity. Our study suggests that HABNs have the potential to serve as a targeted anti-hepatic-fibrosis therapy by modulating activated HSCs via CD44-targeting and antioxidant strategies. This strategy could also be applied to various ROS-related diseases in which CD44-overexpressing cells play a pivotal role.

Hyaluronic acid-bilirubin nanomedicine-based combination chemoimmunotherapy.

Despite significant advances in immune checkpoint blockade (ICB), immunosuppression mediated by tumor-associated myeloid cells (TAMCs) poses a major barrier to cancer immunotherapy. In addition, while immunogenic cell death (ICD) provides a viable approach to inducing anti-tumor immune response, it remains unknown how to effectively trigger ICD while addressing immunosuppressive TAMCs. Here, we show that SC144, a gp130 inhibitor that blocks the IL-6/gp130/STAT3 pathway, induces ICD of tumor cells and polarizes macrophages to M1-phenotype in vitro. However, as SC144 also induces killing of CD8+ T-cells, we sought to deliver SC144 selectively to tumor cells and TAMCs. Toward this goal, we have developed hyaluronic acid-bilirubin nanoparticles (HABN) that accumulate in CD44hi tumor cells and TAMCs. Systemic administration of SC144 loaded in HABN (SC144@HABN) induces apoptosis and ICD of tumor cells, increases the ratio of M1-like to M2-like macrophages, and decreases the frequency of myeloid-derived suppressor cells and CD4+ regulatory T-cells, while promoting anti-tumor CD8+ T-cells. Moreover, SC144@HABN combined with anti-PD-L1 ICB efficiently eliminates MC38 tumors and ICB-resistant 4T1 tumors. Overall, our work demonstrates a therapeutic strategy based on coordinated ICD induction and TAMC modulation and highlights the potential of combination chemoimmunotherapy.

Optic neuritis associated with seronegative autoimmune encephalitis: a case report.

Optic neuritis is an inflammatory demyelinating disorder that primarily affects the optic nerve and is often associated with multiple sclerosis. While it is rare for optic neuritis to be accompanied by autoimmune encephalitis, it can occur in some cases. A 65-year-old woman with bipolar disorder presented with a progressively altered mentality. Magnetic resonance imaging of the brain showed no definite abnormal findings. Electroencephalography revealed nonconvulsive status epilepticus. Cerebrospinal fluid study and autoimmune and paraneoplastic encephalitis antibodies were negative. The patient was diagnosed with seronegative autoimmune encephalitis and treated with methylprednisolone, intravenous immunoglobulin, and rituximab. Her condition gradually improved except for persistent blindness on the left side. This case highlights the importance of considering autoimmune encephalitis even in the absence of identifiable pathogenic antibodies when clinical manifestations and response to immunotherapy support such a diagnosis.

Oral Nanomedicines for siRNA Delivery to Treat Inflammatory Bowel Disease.

RNA interference (RNAi) therapies have significant potential for the treatment of inflammatory bowel diseases (IBD). Although administering small interfering RNA (siRNA) via an oral route is desirable, various hurdles including physicochemical, mucus, and cellular uptake barriers of the gastrointestinal tract (GIT) impede both the delivery of siRNA to the target site and the action of siRNA drugs at the target site. In this review, we first discuss various physicochemical and biological barriers in the GI tract. Furthermore, we present recent strategies and the progress of oral siRNA delivery strategies to treat IBD. Finally, we consider the challenges faced in the use of these strategies and future directions of oral siRNA delivery strategies.

Smart pH-responsive nanomedicines for disease therapy.

Background: Currently nanomedicines are the focus of attention from researchers and clinicians because of the successes of lipid-nanoparticles-based COVID-19 vaccines. Nanoparticles improve existing treatments by providing a number of advantages including protection of cargo molecules from external stresses, delivery of drugs to target tissues, and sustained drug release. To prevent premature release-related side effects, stable drug loading in nanoformulations is required, but the increased stability of the formulation could also lead to a poor drug-release profile at the target sites. Thus, researchers have exploited differences in a range of properties (e.g., enzyme levels, pH, levels of reduced glutathione, and reactive oxygen species) between non-target and target sites for site-specific release of drugs. Among these environmental stimuli, pH gradients have been widely used to design novel, responsive nanoparticles. Area covered: In this review, we assess drug delivery based on pH-responsive nanoparticles at the levels of tissues (tumor microenvironment, pH ~ 6.5) and of intracellular compartments (endosome and lysosome, pH 4.5-6.5). Upon exposure to these pH stimuli, pH-responsive nanoparticles respond with physicochemical changes to their material structure and surface characteristics. These changes include swelling, dissociation, or surface charge switching, in a manner that favors drug release at the target site (the tumor microenvironment region and the cytosol followed by endosomal escape) rather than the surrounding tissues. Expert opinion: Lastly, we consider the challenges involved in the development of pH-responsive nanomedicines.

Effectiveness of yoga training programs to reduce depression and improve resilience of single mothers.

Single mothers are vulnerable to mental health such as depression, but emotional support is insufficient. Yoga is known to be effective in reducing negative emotions and promoting resilience. This study was conducted in order to verify the effectiveness of yoga training programs in reducing depression and improving the resilience of single mothers. Participants in the study included 20 single mothers who belonged to the Single Mothers Association, who were randomly assigned to training (n=10) and nontraining (n=10) groups. The yoga training program for single mothers consisted of Asana yoga, meditation, and mind expression through expert meetings; a total of eight sessions were conducted once a week for 120 min. Testing for depression and resilience was performed before and after the program in order to verify the effectiveness of the program. According to the results of the study, depression in single mothers who participated in the yoga training program was significantly decreased, and resilience was significantly increased. Therefore, the effectiveness of the yoga training program in lowering the depression of single mothers and improving resilience was confirmed. In the future conduct of many studies will be required in order to help the mental health of single mothers.