Nanomaterials-based precision sonodynamic therapy enhancing immune checkpoint blockade: A promising strategy targeting solid tumor.

Burgeoning is an evolution from conventional photodynamic therapy (PDT). Thus, sonodynamic therapy (SDT) regulated by nanoparticles (NPs) possesses multiple advantages, including stronger penetration ability, better biological safety, and not reactive oxygen species (ROS)-dependent tumor-killing effect. However, the limitation to tumor inhibition instead of shrinkage and the incapability of eliminating metastatic tumors hinder the clinical potential for SDT. Fortunately, immune checkpoint blockade (ICB) can revive immunological function and induce a long-term immune memory against tumor rechallenges. Hence, synergizing NPs-based SDT with ICB can provide a promising therapeutic outcome for solid tumors. Herein, we briefly reviewed the progress in NPs-based SDT and ICB therapy. We highlighted the synergistic anti-tumor mechanisms and summarized the representative preclinical trials on SDT-assisted immunotherapy. Compared to other reviews, we provided comprehensive and unique perspectives on the innovative sonosensitizers in each trial. Moreover, we also discussed the current challenges and future corresponding solutions.

Development of a nomogram for predicting the high-risk groups of solid-pseudopapillary neoplasms of the pancreas.

Background: Solid pseudopapillary neoplasms (SPNs) of the pancreas are indolent rare tumors with malignant potential. The risk factors associated with the malignant behavior of SPNs are still unclear. Methods: A retrospective analysis of patients with SPNs who underwent surgical treatment in the First Hospital of Jilin University from January 2010 to January 2022 was conducted. The clinical baseline data, pathology, imaging, and laboratory indicators of the patients were analyzed by univariate and multivariate logistic regression to identify the independent risk factors associated with the high-risk groups, and a predictive model was established in the form of a nomogram. Results: In multivariate analysis, clinical symptoms (P < 0.001), unclear tumor margins (P = 0.001), incomplete tumor capsules (P = 0.005), maximum tumor diameters ≥ 7.2 cm (P = 0.003), and prognostic nutritional index values < 47.45 (P = 0.007) were independent risk factor for SPNs with high-risk groups. A nomogram model was successfully established to predict high-risk groups of SPNs. The area under the receiver operating characteristic curve was 0.856. The calibration prediction curve was in good agreement with the standard curve. Conclusion: The nomogram model based on clinical symptoms, inflammatory markers, and imaging features had a high application value in the preoperative prediction of the high-risk groups of SPNs. A novel nomogram of the affiliated hospital of Jilin University-SPNs risk model was proposed for routine application to guide the patient counseling in clinical practice.

Ataxia telangiectasia mutated inhibitor-loaded copper sulfide nanoparticles for low-temperature photothermal therapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and is ranked the sixth most common neoplasm and the third leading cause of cancer-related deaths. Photothermal therapy (PTT) for thermal ablation of local tumors has recently emerged as a therapeutic strategy. However, the relatively high temperature of over 50 °C may lead to unexpected heat-related damage to tumor-adjacent normal tissues. Herein, we designed and synthesized ataxia telangiectasia mutated (ATM) inhibitor loaded hollow-structured CuS NPs with surface modification with anti-TGF-ß antibody (CuS-ATMi@TGF-ß NPs). CuS-ATMi@TGF-ß NPs are highly photo-stable, can release encapsulated drugs, and increase the temperature to an effective level in a near-infrared (NIR)-responsive manner. Moreover, CuS-ATMi@TGF-ß NPs specifically target tumors and thereby significantly inhibit tumor growth on contribution to synergistic low-temperature PTT and chemotherapy. This system not only achieved low-temperature PTT but also resulted in reduced damage to normal tissues. Modification with anti-TGF-ß antibody enhanced target specificity and immune activation. The combination of PTT and ATM inhibitor showed synergistic effects and significantly attenuated the growth of the HCC via down regulation of heat shock protein (HSP). CuS-ATMi@TGF-ß NPs are a highly promising platform for targeted tumor ablation via hyperthermia-mediated tumor death with minimal damage to normal tissues at a low temperature. STATEMENT OF SIGNIFICANCE: We constructed ataxia telangiectasia mutated (ATM) inhibitor-loaded hollow-structured CuS NPs with surface modification with anti-TGF-ß antibody (CuS-ATMi@TGF-ß NPs). CuS-ATMi@TGF-ß NPs not only achieved low-temperature photothermal therapy (PTT) but also resulted in reduced damage to normal tissues and sufficient biocompatibility. The modification with anti-TGF-ß antibody enhanced targeted specificity, cell endocytosis, and immune activation. In addition, the combination of PTT and ATM inhibitor synergistically attenuated the growth of the HCC via downregulation of heat shock protein (HSP). This study provided proof-of-concept for the ATM inhibitor that mediated low-temperature PTT with a potential for future clinical applications.

Astragalus mongholicus (Fisch.) Bge Improves Peripheral Treg Cell Immunity Imbalance in the Children With Viral Myocarditis by Reducing the Levels of miR-146b and miR-155.

Viral myocarditis (VMC) is a common cardiac disease, however, there still lacks an effective therapeutic strategy for VMC. Astragalus mongholicus (Fisch.) Bge (AB), a Chinese herb with some functional metabolites, may have some pharmacological effects on VMC. AB ingredients were measured by a full-scan LCQ mass spectrum. We aimed to explore the effects of AB on the VMC children by investigating peripheral Treg cell homeostasis. A total of 68 VMC children were random and evenly assigned into an AG group (received 10-mL AB oral liquid daily), and a CG group (received placebo daily). Peripheral blood mononuclear cells (PBMC) were obtained from peripheral blood and Treg cells were isolated. The levels of miR-146b, miR-155, Treg immunity activity and myocarditis biomarkers were measured in Treg cells. There were four main components (sucrose, calycosin, Astragaloside IV and calycosin-7-glucoside) in AB. The cases sinus tachycardia, frequent premature ventricular contractions, and supraventricular tachycardia were significantly reduced in the AG group (P < 0.05). Meanwhile, the myocardial enzymes and cardiac function indexes were improved in the AG group when compared with the CG group (P < 0.05). The time of electrocardiogram recovery, symptom duration and hospital stay was shorter in the AG group than in the CG group (P < 0.05). The levels of miR-146b and miR-155 were higher in the CG group than in the AG group (P < 0.05). The levels of ROR-γt (retinoic acid receptor-related orphan nuclear receptor gamma), FoxP3 (forkhead transcription factor), IL-10 (interleukin-11) and TGF-ß (transforming growth factor beta) were lower in the CG group than in the AG group (P < 0.05). In contrast, the levels of IL-17, IL-21, CK-MB (creatine kinase-MB), cTnI (cardiac troponin I), GrB (granzyme B), sFasL (soluble fas ligand) and caspase-3 were higher in the CG group than in the AG group (P < 0.05). Furthermore, the levels of ROR-γt, FoxP3, IL-10, and TGF-ß were positively, whereas the levels of IL-17, IL-21, CK-MB, cTnI, GrB, sFasL and caspase-3 were negatively, associated with the levels of miR-146b and miR-155 (P < 0.05). AB treatment improved cardiac functions, peripheral Treg cell immunity imbalance in the children with VMC by reducing the levels of miR-146b and miR-155.

Study of Staphylococcus aureus N315 Pathogenic Genes by Text Mining and Enrichment Analysis of Pathways and Operons.

BACKGROUND: Staphylococcus aureus (S. aureus) is a versatile pathogen found in many environments and can cause nosocomial infections in the community and hospitals. S. aureus infection is an increasingly serious threat to global public health that requires action across many government bodies, medical and health sectors, and scientific research institutions. METHODS: In the present study, S. aureus N315 genes that have been shown in the literature to be pathogenic were extracted using a bibliometric method for functional enrichment analysis of pathways and operons to statistically discover novel pathogenic genes associated with S. aureus N315. RESULTS: A total of 383 pathogenic genes were mined from the literature using bibliometrics, and subsequently a few new pathogenic genes of S. aureus N315 were identified by functional enrichment analysis of pathways and operons. CONCLUSIONS: The discovery of these novel S. aureus N315 pathogenic genes is of great significance to treat S. aureus induced diseases and identify potential diagnostic markers, thus providing theoretical fundamentals for epidemiological prevention.

Development of a sensitive LC-MS/MS method for quantification of coniferyl ferulate and its metabolite coniferyl alcohol in rat plasma: Application to a pharmacokinetic study.

A rapid and simple LC-MS/MS method was developed and validated for the simultaneous determination of coniferyl ferulate (CF) and its metabolite coniferyl alcohol (CA) using bavachromene as an internal standard (IS). A TSQ Quantum Access mass spectrometer was operated under selected-reaction monitoring mode using negative electrospray ionization. Extraction with ether was used in sample preparation. The plasma samples were prepared and then chromatographed on a Phenomenex Luna C18 column (2.1mm×50mm, 1.7µm; Torrance, USA) at 35°C, using acetonitrile: water (65:35, v/v) in an isocratic mode at a flow rate of 0.3mL/min. Method validation was performed as per the FDA guidelines and calibration curves showed good linearity over the concentration range of 2.5-1000ng/mL for both CF and CA. The intra- and inter-day precision and accuracy were within the acceptable limits. The developed assay was successfully applied to a pharmacokinetic study of CA in rats.

TSA protects H9c2 cells against thapsigargin-induced apoptosis related to endoplasmic reticulum stress-mediated mitochondrial injury.

Endoplasmic reticulum stress (ERS) activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. Recently, TSA has shown protective effects on ERS and its mechanisms related to ER pathway has been previously characterized. However, whether TSA exerts its protective role via metabolic events remain largely undefined. Objectives: To explore the possible involvement of the metabolic changes during ERS and to better understand how TSA influence mitochondrial function to facilitate cellular adaptation. Results: TSA is an inhibitor of histone deacetylase which could significantly inhibit H9c2 cell apoptosis induced by Thapsigargin (TG). It also intervene the decrease of mitochondrial membrane potential. By immunofluorescence staining, we have shown that GRP78 was concentrated in the perinuclear region and co-localized with ER. However, treatments with TG and TSA could let it overlap with the mitochondrial marker MitoTracker. Cellular fractionation also confirmed the location of GRP78 in mitochondrion. CONCLUSIONS: TSA decreases ERS-induced cell apoptosis and mitochondrial injury may related to enhance the location of GRP78 in mitochondrion.

Inhibitory effect of trans-caryophyllene (TC) on leukocyte-endothelial attachment.

trans-Caryophyllene (TC) is a major component found in the essential oils of many spices and foods/medicinal plants. It is a natural sesquiterpene and has been the subject of numerous studies. However, the effects of TC on vascular inflammation remain unknown. In this study, we reported that TC treatment in human umbilical vein endothelial cells (HUVECs) prevented attachment of monocytic leukemia cell line THP-1 cells to endothelial cells. In addition, in vivo results indicate that TC inhibited macrophage infiltration to the aortic surface and reduced total serum levels of cholesterol and triglycerides. Importantly, administration of TC could inhibit the induction of vascular cell adhesion molecule-1 (VCAM-1) both in vitro and in vivo. Notably, our data indicate that the inhibitory effects of TC on the expression of VCAM-1 are mediated by the JAK2/STAT1/IRF-1 pathway. TC is a specific agonist of the type 2 cannabinoid receptor (CB2R). Importantly, we further verified that the inhibitory effects of TC on the expression of IRF-1 and VCAM-1 are dependent on activation of CB2R. Inhibition of CB2R by either specific inhibitors or RNA interference abolished the inhibitory effects of TC on the expression of IRF-1 and VCAM-1. Our results suggest that TC might have a capacity to suppress the development of atherosclerosis.