Hollow copper sulfide nanoparticles carrying ISRIB for the sensitized photothermal therapy of breast cancer and brain metastases through inhibiting stress granule formation and reprogramming tumor-associated macrophages.

As known, the benefits of photothermal therapy (PTT) are greatly limited by the heat tolerance of cancer cells resulting from overexpressed heat shock proteins (HSPs). Then HSPs further trigger the formation of stress granules (SGs) that regulate protein expression and cell viability under various stress conditions. Inhibition of SG formation can sensitize tumor cells to PTT. Herein, we developed PEGylated pH (low) insertion peptide (PEG-pHLIP)-modified hollow copper sulfide nanoparticles (HCuS NPs) encapsulating the SG inhibitor ISRIB, with the phase-change material lauric acid (LA) as a gate-keeper, to construct a pH-driven and NIR photo-responsive controlled smart drug delivery system (IL@H-PP). The nanomedicine could specifically target slightly acidic tumor sites. Upon irradiation, IL@H-PP realized PTT, and the light-controlled release of ISRIB could effectively inhibit the formation of PTT-induced SG to sensitize tumor cells to PTT, thereby increasing the antitumor effect and inducing potent immunogenic cell death (ICD). Moreover, IL@H-PP could promote the production of reactive oxygen species (ROS) by tumor-associated macrophages (TAMs), repolarizing them towards the M1 phenotype and remodeling the immunosuppressive microenvironment. In vitro/vivo results revealed the potential of PTT combined with SG inhibitors, which provides a new paradigm for antitumor and anti-metastases.

Hsp70-Targeting and Size-Tunable Nanoparticles Combine with PD-1 Checkpoint Blockade to Treat Glioma.

Invasive glioma usually disrupts the integrity of the blood-brain barrier (BBB), making the delivery of nanodrugs across the BBB possible, but sufficient targeting ability is still avidly needed to improve drug accumulation in glioma. Membrane-bound heat shock protein 70 (Hsp70) is expressed on the membrane of glioma cells rather than adjacent normal cells, therefore it can serve as a specific glioma target. Meanwhile, prolonging the retention in tumors is important for active-targeting nanoparticles to overcome receptor-binding barriers. Herein, the Hsp70-targeting and acid-triggered self-assembled gold nanoparticles (D-A-DA/TPP) are proposed to realize selective delivery of doxorubicin (DOX) to glioma. In the weakly acidic glioma matrix, D-A-DA/TPP formed aggregates to prolong retention, improve receptor-binding efficiency and facilitate acid-responsive DOX release. DOX accumulation in glioma induced immunogenic cell death (ICD) to promote antigen presentation. Meanwhile, combination with the PD-1 checkpoint blockade further activate T cells and provokes robust anti-tumor immunity. The results showed that D-A-DA/TPP can induce more glioma apoptosis. Furthermore, in vivo studies indicated D-A-DA/TPP plus PD-1 checkpoint blockade significantly improved median survival time. This study offeres a potential nanocarrier combining size-tunable strategy with active targeting ability to increase drug enrichment in glioma and synergizes with PD-1 checkpoint blockade to achieve chemo-immunotherapy.

Human cytomegalovirus-encoded microRNAs expression profile in plasma of patients with aortic dissection.

BACKGROUND: Aortic dissection (AD) is a rare disease with high mortality for which no effective diagnostic biomarkers are available. Human cytomegalovirus (HCMV) infection is an important cause of the occurrence and progression of many diseases, but the relationship between HCMV infection and AD is not clear. METHODS: In this study, we first used quantitative reverse transcription polymerase chain reaction (qRT-PCR) to determine the expression profile of 25 HCMV-encoded microRNAs (HCMV miRNAs) in the plasma within a training set consisting of 20 AD patients and 20 healthy controls. Then, abnormal expressed HCMV miRNAs were verified in a validation set of 12 AD patients and 12 healthy controls. In addition, HCMV infection was detected in the third cohort consisting of 20 AD patients and 20 healthy controls. RESULTS: The 95% quantile of the expression levels of HCMV miRNAs in the training set was used as the threshold for distinction between AD patients and healthy controls. The proportion of individuals with high level of five types of HCMV miRNAs was significantly different between AD patients and healthy controls. In the validation set, only the proportion of individuals with high levels of hcmv-miR-UL112-5p and hcmv-miR-UL22A-5p, two of the five HCMV miRNAs obtained in the preliminary screening, showed significant difference between AD patients and healthy controls. In the third cohort, there was no significant difference in HCMV DNA levels and anti-HCMV IgG concentrations between AD patients and healthy controls. CONCLUSIONS: The HCMV miRNAs levels in plasma differed in AD patients and healthy controls. This finding may contribute to a further understanding of the relationship between HCMV infection and AD and are worthy of future research on the diagnosis and etiology of AD.

Co-delivery of ibrutinib and hydroxychloroquine by albumin nanoparticles for enhanced chemotherapy of glioma.

Ibrutinib (IBR) is an oral covalent inhibitor of Bruton's tyrosine kinase (BTK) that has been approved for the treatment of hematological malignancies. It was reported that IBR exhibited great therapeutic potential for glioma. However, the poor water solubility and high hepatic first-pass effect restrict its anti-glioma application. Meanwhile, IBR induces cytoprotective autophagy through Akt/mTOR signaling pathway, thus leading to a compromised antitumor effect. Herein, we aimed to develop a human serum albumin (HSA) based co-delivery system (IBR&HCQ HSA NPs) encapsulating IBR and hydroxychloroquine (HCQ). The bioavailability of IBR was largely improved, and enhanced sensitivity of glioma to IBR was achieved due to inhibition effect of HCQ on IBR-induced pro-survival autophagy. The physicochemical properties of IBR&HCQ HSA NPs were characterized to optimize the formulation. Biodistribution investigation revealed that HSA NPs (20 mg/kg, i.v.) dramatically increased the accumulation of IBR in glioma, which was 5.59 times higher than that of free IBR (100 mg/kg, i.g.). CCK-8 and apoptosis assays demonstrated that IBR&HCQ HSA NPs showed maximal cytotoxicity to C6 cells. In vivo studies indicated that the survival time was significantly prolonged in IBR&HCQ HSA NPs treated mice compared to those treated with IBR HSA NPs. Taken together, the HSA-based drug delivery system of IBR and HCQ opens a new avenue for efficient treatment of glioma.

Diminazene aceturate mitigates cardiomyopathy by interfering with renin-angiotensin system in a septic rat model.

BACKGROUND: There were limited studies investigating treatments of septic cardiomyopathy (SCM), which is a common complication during sepsis. A septic rat model created by cecal ligation and puncture (CLP) was used to investigate the effects of diminazene aceturate (DIZE) in SCM. METHODS: A total of 151 Wistar rats were randomly assigned into the sham, CLP, or CLP + DIZE group. Data evaluated postoperatively at 6, 12, 24, and 48 hours included: cardiac function; plasma concentrations of tumor necrosis factor-alpha (TNF-α), interleukin-6, angiotensin-(1-7) [Ang-(1-7)], angiotensin II (AngII), troponin I, and brain natriuretic peptide; expression levels of myocardial Ang-(1-7), angiotensin-converting enzyme (ACE), ACE2, and angiotensin type 1 and Mas receptors; and histological changes. RESULTS: We found that the CLP + DIZE group had a lower mortality compared to the CLP group (38.5% versus 61.5%) within 48 h postoperatively, although without statistical significance. In contrast to the sham group, the CLP group had decreased cardiac functions, increased myocardial injuries, and higher TNF-α levels, which were ameliorated in the CLP + DIZE group. Furthermore, administration of DIZE could reverse the decreases of myocardial Ang-(1-7) and ACE2 expressions in the CLP group, which finally minimized the myocardial microstructure disruptions. CONCLUSIONS: It was concluded that DIZE could mitigate the development of SCM and preserve cardiac function during sepsis possibly by interfering with the renin-angiotensin system through promoting myocardial ACE2 expression and restoring local Ang-(1-7) levels.

The impact of Flavourzyme on flavor, antioxidant activity, and sensory attributes of salted grass carp by brine injection and brining.

BACKGROUND: Enzyme injection is vital for improving the sensory attributes and processing characteristics of meat products by enhancing proteolysis. However, studies regarding the appropriate dose addition for accelerating protein degradation in grass carp are minimal. This study aimed to investigate the impact of Flavourzyme® on the flavor quality and antioxidant activity of salted grass carp via brine injection and brining. RESULTS: Flavourzyme was added at doses of 0, 5, 10, 20, and 30 leucine aminopeptidase units (LAPU) per kilogram of raw meat. The results indicated that adding Flavourzyme promoted proteolysis, which was reflected by the enhanced total free amino acid content (from 3.7414 g kg-1 to 4.9160 g kg-1 in the brining group and from 3.8039 g kg-1 to 5.4061 g kg-1 in the injection group) and a decrease in salt soluble and insoluble protein (P < 0.05). The antioxidant activity was improved, and the thiobarbituric acid reactive substance value in salted carp decreased due to the higher content of the protein hydrolysis product (P < 0.05). All sensory attributes were improved significantly, especially when using brine injection (P < 0.05). Brine injection was helpful to diffuse the Flavourzyme, resulting in stronger proteolysis. CONCLUSION: The appropriate Flavourzyme dose was 10 LAPU kg-1 in the injection group and 20 LAPU kg-1 in the brining group. Therefore, moderate Flavourzyme addition was excellent in improving sensory attributes and storage characteristics, whereas injection represented a novel method to obtain a similar fish meat quality in a shorter time and with less added Flavourzyme. © 2021 Society of Chemical Industry.