Potentiating dual-directional immunometabolic regulation with nanomedicine to enhance anti-tumor immunotherapy following incomplete photothermal ablation.

Photothermal therapy (PTT) is a promising cancer treatment method due to its ability to induce tumor-specific T cell responses and enhance therapeutic outcomes. However, incomplete PTT can leave residual tumors that often lead to new metastases and decreased patient survival in clinical scenarios. This is primarily due to the release of ATP, a damage-associated molecular pattern that quickly transforms into the immunosuppressive metabolite adenosine by CD39, prevalent in the tumor microenvironment, thus promoting tumor immune evasion. This study presents a photothermal nanomedicine fabricated by electrostatic adsorption among the Fe-doped polydiaminopyridine (Fe-PDAP), indocyanine green (ICG), and CD39 inhibitor sodium polyoxotungstate (POM-1). The constructed Fe-PDAP@ICG@POM-1 (FIP) can induce tumor PTT and immunogenic cell death when exposed to a near-infrared laser. Significantly, it can inhibit the ATP-adenosine pathway by dual-directional immunometabolic regulation, resulting in increased ATP levels and decreased adenosine synthesis, which ultimately reverses the immunosuppressive microenvironment and increases the susceptibility of immune checkpoint blockade (aPD-1) therapy. With the aid of aPD-1, the dual-directional immunometabolic regulation strategy mediated by FIP can effectively suppress/eradicate primary and distant tumors and evoke long-term solid immunological memory. This study presents an immunometabolic control strategy to offer a salvage option for treating residual tumors following incomplete PTT.

The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis.

Kaempferol (KA), an natural antioxidant of traditional Chinese medicine (TCM), is extensively used as the primary treatment for inflammatory digestive diseases with impaired redox homeostasis. Severe acute pancreatitis (SAP) was exacerbated by mitochondrial dysfunction and abundant ROS, which highlights the role of antioxidants in targeting mitochondrial function. However, low bioavailability and high dosage of KA leading to unavoidable side effects limits clinical transformation. The mechanisms of KA with poor bioavailability largely unexplored, hindering development of the efficient strategies to maximizing the medicinal effects of KA. Here, we engineered a novel thioketals (TK)-modified based on DSPE-PEG2000 liposomal codelivery system for improving bioavailability and avoiding side effects (denotes as DSPE-TK-PEG2000-KA, DTM@KA NPs). We demonstrated that the liposome exerts profound impacts on damaging intracellular redox homeostasis by reducing GSH depletion and activating Nrf2, which synergizes with KA to reinforce the inhibition of inadequate fission, excessive mitochondrial fusion and impaired mitophagy resulting in inflammation and apoptosis; and then, the restored mitochondrial homeostasis strengthens ATP supply for PAC renovation and homeostasis. Interestingly, TK bond was proved as the main functional structure to improve the above efficacy of KA compared with the absence of TK bond. Most importantly, DTM@KA NPs obviously suppresses PAC death with negligible side effects in vitro and vivo. Mechanismly, DTM@KA NPs facilitated STAT6-regulated mitochondrial precursor proteins transport via interacting with TOM20 to further promote Drp1-dependent fission and Pink1/Parkin-regulated mitophagy with enhanced lysosomal degradation for removing damaged mitochondria in PAC and then reduce inflammation and apoptosis. Generally, DTM@KA NPs synergistically improved mitochondrial homeostasis, redox homeostasis, energy metabolism and inflammation response via regulating TOM20-STAT6-Drp1 signaling and promoting mitophagy in SAP. Consequently, such a TCM's active ingredients-based nanomedicine strategy is be expected to be an innovative approach for SAP therapy.

Downregulation of circular RNA 00091761 protects against heart failure after myocardial infarction via microRNA-335-3p/ ASCL4 axis.

Our research tended to explore the biological roles and expression status of circ_00091761 in HF after MI. The hypoxia reoxygenation (H/R) injured H9c2 cells model was constructed to simulate HF after MI. The expression of circ_0091761 was examined in H/R injured H9c2 cells by qRT-PCR. Then, the effect of circ_0091761 expression on the proliferation of H/R injured H9c2 cells was evaluated by CCK-8 along with TUNEL assay. Secretion of lactate dehydrogenase (LDH), reactive oxygen species (ROS), Fe2+, glutathione (GSH), and malondialdehyde (MDA) was measured to evaluate cell ferroptosis of H/R injured H9c2 cells, along with protein levels of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and transferrin receptor protein (TFRC). Luciferase reporter as well as RNA pull-down assays revealed the binding relationship between miR-335-3p and circ_0091761 or ASCL4. Circ_0091761 was upregulated in H/R injured H9c2 cells. Knockdown of circ_0091761 promoted cell proliferation and suppressed ferroptosis of H/R injured H9c2 cells. Interestingly, circ_0091761 sponges miR-335-3p to upregulate acyl-CoA synthetase long-chain family member 4 (ACSL4) expression. miR-335-3p inhibitor attenuated the effects of circ_0091761 knockdown on cell proliferation and ferroptosis in H/R injured H9c2 cells. Additionally, upregulated ACSL4 abrogated elevated miR-335-3p-induced effects on H/R injured H9c2 cells. Circ_0091761 inhibited cell proliferation and accelerated ferroptosis of H/R injured H9c2 cells by sponging miR-335-3p to upregulated TFRC axis. Therefore, Inhibition of circ_0091761 may protect against HF after MI.

Association between serum uric acid levels of patients with gout and their complications and examination fees: A cross-sectional analysis.

OBJECTIVE: Correlation influence factor analysis of gout patients' serum uric acid (SUA) levels, their examination fees, and various complications were explored. METHODS: From January 2017 to December 2021, 17 666 patients with gout were obtained. Conduct quartile grouping according to gout patients' SUA levels was used to compare the differences between groups in terms of examination fees and complications. Kernel density estimation method was adopted to analyze the data distribution, Spearman and Mantel-Haenszel χ2 tests were used to analyze the correlation between SUA levels and examination fees and complications. Binary logistic regression analysis was used to analyze the correlation influence factor between SUA levels and complications. RESULTS: Of the 17 666 gout cases, 85.46% were male. Among them, 7637 (43.23%) were inpatients and 10 029 (56.77%) were outpatients. Compared with outpatients, age, SUA levels, and examination fees were significantly higher, and there were more complications among inpatients (P < 0.05). Correlation analysis revealed that outpatients and SUA levels of patients with gout were positively correlated with examination fees, cardiovascular diseases, pulmonary diseases, liver diseases, and kidney diseases (P < 0.01). Binary logistic regression analysis showed that SUA level is an independent influence factor for cardiovascular diseases, pulmonary diseases, liver diseases, and kidney diseases (odds ratio [95% confidence interval]: 1.002 [1.002-1.002], 1.001 [1.000-1.001], 1.003 [1.002-1.003], and 1.001 [1.001-1.002], respectively). CONCLUSIONS: As SUA levels increased, examination fees, cardiovascular disease, pulmonary disease, liver disease, and kidney disease complications increased. SUA level is an independent influence factor for the combination of gout with cardiovascular diseases, pulmonary diseases, liver diseases, and kidney diseases.

Analysis of Risk Factors for Changes in the Renal Two-Dimensional Image in Gout Patients.

OBJECTIVE: To explore the effects of different blood uric acid levels in gout patients on the two-dimensional image of the kidney and the risk factors for gout-related kidney damage for providing clinical evidence to enable early prevention and treatment of gout-related kidney damage. METHODS: We obtained information of 227 patients with primary gout and estimated the association between two-dimensional kidney images and clinical indicators using binary logistic regression. RESULTS: Our study showed that different uric acid levels, age, disease course, cystatin C (CysC) level, and γ-glutamyl transpeptidase level were correlated with echo of the renal medulla (P < 0.05). CysC level was correlated with the renal cortex thickness and kidney stones in different uric acid-level groups (P < 0.05). Disease course, aspartate transaminase (AST) level, creatinine (CREA) level, and tophi were risk factors for renal cortex thinning in gout patients (P = 0.045, 0.026, 0.004, 0.006, respectively). The disease course, platelet (PLT) count, and high-density lipoprotein (HDL-C) level were risk factors for kidney stone formation in gout patients (P = 0.037, 0.022, 0.023, respectively), while CysC level and C-reactive protein (CRP) level were risk factors for increased renal medulla echo in these patients (P = 0.022, 0.028, respectively). CONCLUSION: Our study revealed disease course, AST level, CREA level, tophi, PLT count, HDL-C level, CysC level and CRP level may be important predictors of renal image changes.

Differential Diagnosis of Acute and Chronic Gouty Arthritis by Multijoint Ultrasound.

To investigate whether multi-joint ultrasound (US) findings in patients with gouty arthritis could be used to distinguish between acute and chronic stages, we performed a retrospective study with 129 enrolled patients from the Rheumatology Department of the First Affiliated Hospital of Chengdu Medical College from September 1, 2018 to June 12, 2019. Patients with acute or non-acute gout were categorized using clinical data, and US imaging findings of the knees, ankles and first metatarsophalangeal joints were analyzed and compared between groups. Notably, we found that the most prevalent sign detected by US was the hyperechoic spot in the synovium, followed by arthrosynovitis, aggregates, double contour signs and tophi; meanwhile, bone erosions were the least common. Additionally, synovitis was more frequently detected in the acute joints of gouty arthritis (49%) compared with the non-acute joints (35%), whereas grade 1 or 2 blood flow classifications (97%), tophi and bone lesions were more often seen in the latter. Overall, our data suggest that multi-joint US scanning might be used to evaluate disease severity and discriminate between stages of gouty arthritis.

Clinical Value of Positron Emission Tomography-Computed Tomography Combined with Ultrasound in Detection of Primary Tumors in Patients with Malignant Ascites.

OBJECTIVE: To investigate and discuss the clinical value of positron emission tomography-computed tomography (PET-CT) combined with ultrasound in detection of primary tumors in patients with malignant ascites (MA). MATERIALS AND METHODS: A total of 122 malignant tumor patients with ascites as the initial symptom and 48 patients with benign ascites were enrolled in this study. All patients underwent PET-CT and abdominal B-ultrasound examinations. The corresponding specificity, sensitivity, accuracy rate, positive predictive value, and negative predictive value of PET-CT, abdominal B-ultrasound, and combined detection group were recorded, respectively, with pathological findings as the gold standards. Statistical Product and Service Solutions 17.0 software was used for statistical analysis. p < 0.05 suggested that the difference was statistically significant. RESULTS: The detection rate of primary foci through PET-CT was 79.5%, of which the detection rate of primary foci of MA derived from gastric cancer was the highest. The detection rate of primary foci through B-ultrasound was 62.5%, which is the highest for MA derived from ovarian cancer. B-ultrasound had the highest specificity in diagnosing the primary foci of MA (73.2%), PET-CT had the highest sensitivity in diagnosing the primary foci of MA (91.7%), and PET-CT combined with abdominal B-ultrasound had the highest sensitivity and accuracy in diagnosing the primary foci of MA (98.1% and 89.1%, respectively). The diagnostic accuracy rate of B-ultrasound was the highest in detecting tumors >5 cm (77.0%), whereas that of PET-CT was the highest in detecting tumors of 3-5 cm (84.2%). CONCLUSION: The PET-CT combined with ultrasound is conducive to improving the diagnostic efficiency for primary tumors in patients with MA.