Photodynamic immunotherapy using ADU-S100-modified nanoparticles to treat triple-negative breast cancer.

Aim: STING agonists in immunotherapy show great promise and are currently in clinical trials. Combinations of STING agonists with other therapies remain underexplored. This study aimed to combine STING agonist-mediated immunotherapy with photodynamic therapy to treat breast cancer. Methods: STING agonist (ADU-S100)-functionalized porphyrin-based nanoparticles (NP-AS) were prepared and their antitumor properties in terms of cell apoptosis/necrosis and immune activation in triple-negative breast cancer were evaluated. Results: NP-AS induced tumor cell apoptosis/necrosis, activated the innate immune response and exhibited useful antitumor effects. Conclusion: NP-AS effectively treated breast cancer.

Resveratrol attenuates atherosclerotic endothelial injury through the Pin1/Notch1 pathway.

The present study investigates whether resveratrol could modulate the endothelial dysfunction of atherosclerosis via the Pin1/Notch1 signaling pathway. To assess the vascular endothelial cell (VECs) injury in mice, the levels of serum soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble E-selectin (sE-selectin), soluble thrombomodulin (sTM), and von Willebrand factor (vWF) were measured. Expressions of Pin1 and Notch1 intracellular domain (NICD1), both mRNA and protein, were also measured. Human umbilical vein endothelial cells (HUVECs) treated with 100 µg/mL oxidized low-density lipoprotein (ox-LDL) were incubated with resveratrol at doses from 10 µM to 40 µM. Cell function was evaluated by measuring apoptosis, cell viability, lipid accumulation, and adherent human myeloid leukemia mononuclear (THP-1) cells. Resveratrol intervention in AS mice decreased the expression of serum sVCAM-1, sICAM-1, sE-selectin, sTM, and vWF and dose-dependently down-regulated Pin1 and NICD1 mRNA and protein expression in endothelial cells. Resveratrol intervention reversed ox-LDL-induced cell dysfunction by increasing viability and decreasing apoptosis, lipid accumulation, and the adhesion of THP-1 cells. These beneficial effects were reversed by the overexpression of Pin1. Resveratrol regulates endothelial cell injury of atherosclerosis by inhibiting the Pin1/Notch1 signaling pathway, suggesting novel therapeutic targets for atherosclerosis treatment.

A PARylation-phosphorylation cascade promotes TOPBP1 loading and RPA-RAD51 exchange in homologous recombination.

The efficiency of homologous recombination (HR) in the repair of DNA double-strand breaks (DSBs) is closely associated with genome stability and tumor response to chemotherapy. While many factors have been functionally characterized in HR, such as TOPBP1, their precise regulation remains unclear. Here, we report that TOPBP1 interacts with the RNA-binding protein HTATSF1 in a cell-cycle- and phosphorylation-dependent manner. Mechanistically, CK2 phosphorylates HTATSF1 to facilitate binding to TOPBP1, which promotes S-phase-specific TOPBP1 recruitment to damaged chromatin and subsequent RPA/RAD51-dependent HR, genome integrity, and cancer-cell viability. The localization of HTATSF1-TOPBP1 to DSBs is potentially independent of the transcription-coupled RNA-binding and processing capacity of HTATSF1 but rather relies on the recognition of poly(ADP-ribosyl)ated RPA by HTATSF1, which can be blunted with PARP inhibitors. Together, our study provides a mechanistic insight into TOPBP1 loading at HR-prone DSB sites via HTATSF1 and reveals how RPA-RAD51 exchange is tuned by a PARylation-phosphorylation cascade.

Tumor-targeted biomimetic nanoplatform precisely integrates photodynamic therapy and autophagy inhibition for collaborative treatment of oral cancer.

Oral cancer is a common malignant tumor in the maxillofacial region. Surgical resection is the preferred treatment, but the severe functional impairment after surgery forces us to look for noninvasive treatments. As a promising noninvasive treatment method, photodynamic therapy (PDT) has received widespread attention in the field of cancer therapy, but the inefficient uptake capacity of tumor cells and the damage repair mechanisms limit the actual therapeutic effect. The establishment of a targeted therapy function and autophagy inhibition strategy is considered to be an important way to further enhance the effect of PDT. Based on this, we developed the biomimetic nanomaterial PCN-CQ@CCM. The metal-organic framework material PCN-224 was used as a carrier to load the autophagy inhibitor chloroquine (CQ) and it was coated onto the surface with isolated oral squamous cell carcinoma (OSCC) cell membranes. Owing to the immune evasion and homologous targeting ability of the biomimetic functionalized surface, PCN-CQ@CCM can escape macrophage phagocytosis and homologously adhere to tumor cells, enhancing the retention and uptake of nanomaterials in the tumor microenvironment. After being activated with a 660 nm laser, the generated reactive oxygen species (ROS) triggered the apoptosis pathway, as assessed by mitochondrial damage, and the released CQ further aggravated the ROS lethal pathway by effectively inhibiting the protective autophagic flux. Therefore, PCN-CQ@CCM achieves the precise synergy of PDT and autophagy inhibition through the biomimetic homologous targeting method, and the highly effective tumor suppression effect expands the field of vision for the noninvasive diagnosis and treatment of oral cancer.

Biological control agents colonize litchi fruit during storage and stimulate physiological responses to delay pericarp browning.

Introduction: Litchi is an economically important fruit in subtropical countries, but pericarp browning can limit its shelf life outside of controlled storage conditions. Effective and sustainable biological control strategies are needed to protect fruit against postharvest browning. Results and Discussion: In this study, we show that the four bacterial strains Bacillus licheniformis HS10, B. amyloliquefaciens LI24 and PP19, and Exiguobacterium acetylicum SI17 can delay fruit browning in both laboratory trials (LTs) and field plus laboratory trials (FLTs). Strains HS10, LI24, PP19 and SI17 showed 47.74%, 35.39%, 33.58% and 32.53% browning-inhibitory efficacy respectively at 180 h in LT. Litchi sarcocarp interior sourced isolate SI17 showed 74.05% inhibit-brown efficacy at 216 h in FLTs, performing better in FLT than in LT. Furthermore, strains PP19 and SI17 colonized the fruit pericarp and increased total phenolic and anthocyanin contents but decreased peroxidase and polyphenol oxidase activity. This is the first report of E. acetylicum (SI17) and B. licheniformis (HS10) strains acting as biological control agents (BCAs) to delay postharvest browning in litchi fruit. We conclude that PP19 and SI17 are promising BCAs against fruit browning, and their application could be effective for prolonging the shelf life of harvested litchi fruit.

Transcriptomic and Metabolomic Analyses Provide Insights into the Enhancement of Torulene and Torularhodin Production in Rhodotorula glutinis ZHK under Moderate Salt Conditions.

Carotenoids are a group of tetraterpene pigments widely used in the food, pharmaceutical, and cosmetic industries. Torulene, torularhodin, and ß-carotene, three principal carotenoids synthesized by Rhodotorula glutinis ZHK, possess strong health-promoting properties such as antioxidant, provitamin A, and antitumor. Here, the effect of different salt conditions on carotenoids production of R. glutinisZHK was investigated. The results showed that the total carotenoids were significantly enhanced in 0.5 M (3.91 mg/L) and 0.75 M (5.41 mg/L) NaCl treatments than that in 1.0 M (0.35 mg/L) and control (1.42 mg/L) after 120 h of cultivation. Of which, the increase in torulene and torularhodin production acts as the main contributor to the enhancement of total carotenoids. Transcriptome profiling revealed that salt stress efficiently promotes the gene expression of crtI, which could explain the molecular mechanisms of the enhanced torulene and torularhodin production under salt stress. Further experiments indicated that torulene and torularhodin play an important role in quenching excrescent reactive oxygen species induced by salt stress. Together, the present study reports an effective strategy for simultaneously improving torulene and torularhodin production in R. glutinis ZHK.

Intermediate dose cytarabine improves survival and relapse-free rate compared with standard-dose cytarabine as post-remission treatment for acute myeloid leukemia: A retrospection study.

ABSTRACT: The exact dose of cytarabine still remain controversial for the management of patients with acute myeloid leukemia (AML) after complete remission (CR), but recent studies favor lower doses. This study aimed to investigate the toxic effects of single-intermediate dose (ID) cytarabine in patients with AML after achieving CR, compared with standard-dose cytarabine.In this retrospective study, AML patients who achieved CR after consolidation therapy before enrollment between 07/2008 and 05/2019 were included. All patients were divided into single-ID cytarabine and standard-dose cytarabine. The Kaplan-Meier method was used to compare overall survival (OS) and relapse-free time (RFS). Cox regression models were used to assess factors independently associated with OS and RFS. The toxic side effects of hematology and non-hematology were observed.52 patients were enrolled. There were 33 in ID group, 19 in Standard dose group. The 3-year RFS rate (40.4% vs 22.2%, P = .031) was better in the ID group than in the standard-dose group, while the 3-year OS rate was not different between the 2 groups (50.2% vs 27.8%, P = .074). Treatment stratage of ID cytarabine chemotherapy significantly improve the prognosis of AML regardless of patient age, risk grade, WBC count. There were no significant differences between the 2 groups in grade 3 to 4 bone marrow suppression, gastrointestinal symptoms, blood transfusion, infections.Patients with AML receiving ID cytarabine showed better survival and similar toxicity profiles compared with patients who received standard-dose cytarabine.

NOL-mediated functional stay-green traits in perennial ryegrass (Lolium perenne L.) involving multifaceted molecular factors and metabolic pathways regulating leaf senescence.

Loss of chlorophyll (Chl) is a hallmark of leaf senescence, which may be regulated by Chl catabolic genes, including NON-YELLOW COLORING 1 (NYC1)-like (NOL). The objective of this study was to determine molecular factors and metabolic pathways underlying NOL regulation of leaf senescence in perennial grass species. LpNOL was cloned from perennial ryegrass (Lolium perenne L.) and found to be highly expressed in senescent leaves. Transient overexpression of LpNOL accelerated leaf senescence and Chl b degradation in Nicotiana benthamiana. LpNOL RNA interference (NOLi) in perennial ryegrass not only significantly blocked Chl degradation in senescent leaves, but also delayed initiation and progression of leaf senescence. This study found that NOL, in addition to functioning as a Chl b reductase, could enact the functional stay-green phenotype in perennial grass species, as manifested by increased photosynthetic activities in NOLi plants. Comparative transcriptomic analysis revealed that NOL-mediated functional stay-green in perennial ryegrass was mainly achieved through the modulation of Chl catabolism, light harvesting for photosynthesis, photorespiration, cytochrome respiration, carbohydrate catabolism, oxidative detoxification, and abscisic acid biosynthesis and signaling pathways.

Switchgrass PvDREB1C plays opposite roles in plant cold and salt tolerance in transgenic tobacco.

BACKGROUND: The C-repeat-binding factors/DRE-binding factors (CBF/DREBs) comprise a key transcription factor family involved in plant stress tolerance. Yet, there is limited information about switchgrass DREB genes and their functional roles. RESULTS: In this study, four cold-inducible PvDREB1s were identified from switchgrass (Panicum virgatum), among which PvDREB1C was the one responded to cold stress later than the other three PvDREB1s. Yet, ectopic overexpression of PvDREB1C led to significantly compromised, instead of improved cold tolerance in transgenic tobacco. On the other hand, PvDREB1C was transcriptionally down-regulated in response to salt stress, but overexpression of PvDREB1C improved plant salt tolerance in transgenic tobacco. The improved salt tolerance was associated with increased K+/Na+ ratio and Ca2+ content, higher cellular osmotic potential, and activation of stress-related functional genes in the leaves of transgenic plants under salt stress. CONCLUSIONS: The current results implied that PvDREB1C played opposite roles in plant cold and salt tolerance. Although DREB1s were known as positive stress regulators, particular attentions shall be paid to their potential negative regulatory role(s).

Functional characterization and hormonal regulation of the PHEOPHYTINASE gene LpPPH controlling leaf senescence in perennial ryegrass.

Chlorophyll (Chl) degradation occurs naturally during leaf maturation and senescence, and can be induced by stresses, both processes involving the regulation of plant hormones. The objective of this study was to determine the functional roles and hormonal regulation of a gene encoding pheophytin pheophorbide hydrolyase (PPH) that catabolizes Chl degradation during leaf senescence in perennial grass species. A PPH gene, LpPPH, was cloned from perennial ryegrass (Lolium perenne L.). LpPPH was localized in the chloroplast. Overexpressing LpPPH accelerated Chl degradation in wild tobacco, and rescued the stay-green phenotype of the Arabidopsis pph null mutant. The expression level of LpPPH was positively related to the extent of leaf senescence. Exogenous application of abscisic acid (ABA) and ethephon (an ethylene-releasing agent) accelerated the decline in Chl content in leaves of perennial ryegrass, whereas cytokinin (CK) and aminoethoxyvinylglycine (AVG; an ethylene biosynthesis inhibitor) treatments suppressed leaf senescence, corresponding to the up- or down-regulation of LpPPH expression. The promoters of five orthologous PPH genes were predicted to share conserved cis-elements potentially recognized by transcription factors in the ABA and CK pathways. Taken together, the results suggested that LpPPH-mediated Chl breakdown could be regulated positively by ABA and ethylene, and negatively by CK, and LpPPH could be a direct downstream target gene of transcription factors in the ABA and CK signaling pathways.

Acquired hemophilia A in a patient associated with community-acquired pneumonia.

Acquired hemophilia A (AHA) is a rare disease induced by autoantibodies to factor VIII (FVIII) and may be correlated with pregnancy, underlying malignancies, autoimmune diseases or drug administration. An 81-year-old man who presented with cough, expectoration, hemoptysis and multiple ecchymoses was diagnosed with community-acquired pneumonia by computed tomography scan. Respiratory symptoms were ameliorated after the application of antibiotics. Despite repeated infusion of fresh frozen plasma and cryoprecipitate, his prolonged activated partial thromboplastin time (APTT) maintained in the 75-110-s range and ecchymoses were not ameliorated. Then, he was transferred to the department of hematology. Based on a prolonged APTT, decreased level of FVIII and presence of antibodies against FVIII, the patient was diagnosed with AHA. Then the patient was treated with activated prothrombin complex concentrates, prednisone and intravenous immunoglobulin, resulting in a complete remission of the bleeding, recovering the FVIII level and negativity for FVIII antibody titers. Here, we investigate this novel case retrospectively and review the relevant literature.