Cholesterol-Modified DNA Nanostructures Serve as Effective Non-Viral Carriers for Delivering siRNA to the Kidneys to Prevent Acute Kidney Injury.

With the emergence of gene therapy utilizing viral vectors, the potential risks associated with these vectors have prompted increased attention toward non-viral alternatives. DNA nanotechnology enables the assembly of specific oligonucleotide chains into nanostructures possessing defined spatial configurations. Due to their inherent characteristics, DNA nanostructures possess natural advantages as carriers for regulating gene expression in a non-viral manner. Cholesterol modification can convert DNA nanostructures from hydrophilic materials to amphiphilic materials, thereby extending their systemic circulation time. In this study, the high-dimensional design and cholesterol modification are shown to prolong the systemic circulation half-life of DNA nanostructures in mice. Specifically, the tetrahedron structure modified with three cholesterol molecules (TDN-3Chol) exhibit excellent circulation time and demonstrate a preference for renal uptake. The unique characteristics of TDN-3Chol can effectively deliver p53 siRNA to the mouse renal tubular tissue, resulting in successful knockdown of p53 and demonstrating its potential for preventing acute kidney injury. Furthermore, TDN-3Chol is not exhibited significant toxicity in mice, highlighting its promising role as a non-viral vector for targeted gene expression regulation in the kidneys. The designed non-viral vector as a prophylactic medication shows potential in addressing the current clinical challenges associated with nephrotoxic drugs.

Clinical application of 3DSlicer and Sina in minimally invasive puncture drainage of elderly patients with spontaneous intracerebral hemorrhage under local anesthesia.

BACKGROUND: Decreased organ function and poor physical compensatory capacity in elderly patients diagnosed with spontaneous intracerebral hemorrhage (ICH) can make surgical treatment procedures challenging and risky. Minimally invasive puncture drainage (MIPD) combined with urokinase infusion therapy is a safe and feasible method of treating ICH. This study aimed to compare the treatment efficacy of MIPD conducted under local anesthesia using either 3DSlicer + Sina application or computer tomography (CT)-guided stereotactic localization of hematomas in elderly patients diagnosed with ICH. METHODS: The study sample included 78 elderly patients (≥ 65 years of age) diagnosed with ICH for the first time. All patients exhibited stable vital signs and underwent surgical treatment. The study sample was randomly divided into two groups, either receiving 3DSlicer+Sina or CT-guided stereotactic assistance. The preoperative preparation time; hematoma localization accuracy rate; satisfactory hematoma puncture rate; hematoma clearance rate; postoperative rebleeding rate; Glasgow Coma Scale (GCS) score after 7 days; and modified Rankin scale (mRS) score 6 months after surgery were compared between the two groups. RESULTS: No significant differences in gender, age, preoperative GCS score, preoperative hematoma volume (HV), and surgical duration were observed between the two groups (all p-values > 0.05). However, the preoperative preparation time was shorter in the group receiving 3DSlicer + Sina assistance compared to that receiving CT-guided stereotactic assistance (p-value < 0.001). Both groups exhibited significant improvement in GCS scores and reduction in HV after surgery (all p-values < 0.001). The accuracy of hematoma localization and puncture was 100% in both groups. There were no significant differences in surgical duration, postoperative hematoma clearance rate, rebleeding rate, postoperative GCS and mRS scores between the two groups (all p-values > 0.05). CONCLUSIONS: A combination of 3DSlicer and Sina is effective in accurately identifying hematomas in elderly patients with ICH exhibiting stable vital signs, thus simplifying MIPD surgeries conducted under local anesthesia. This procedure may also be preferred over CT-guided stereotactic localization in clinical practice due to its ease of use and accuracy in hematoma localization.

Nifuroxazide Activates the Parthanatos to Overcome TMPRSS2:ERG Fusion-Positive Prostate Cancer.

Fusion of the E-26 transformation-specific (ETS)-related gene (ERG) with transmembrane serine protease 2 (TMPRSS2) is a crucial step in the occurrence and progression of approximately 50% of prostate cancers. Despite significant progress in drug discovery, ERG inhibitors have yet to be approved for the clinical treatment of prostate cancer. In this study, we used computer-aided drug design (CADD)-based virtual screening to screen for potential inhibitors of ERG. In vivo and in vitro methods revealed that nifuroxazide (NFZ) inhibited the proliferation of a TMPRSS2:ERG fusion-positive prostate cancer cell line (VCaP) with an IC50 lower than that of ERG-negative prostate cancer cell lines (LNCaP, DU145, and WPMY cells). Poly [ADP-ribose] polymerase 1, the critical mediator of parthanatos, is known to bind ERG and is required for ERG-mediated transcription. NFZ blocked this interaction and overly activated PARP1, leading to cell death that was reduced by olaparib, a PARP1 inhibitor. These results show that NFZ inhibits ERG, leading to parthanatic cell death.

Silencing of H19 alleviates oxygen-glucose deprivation/reoxygenation-triggered injury through the regulation of the miR-1306-5p/BCL2L13 axis.

Cerebral ischemia/reperfusion (I/R) injury remains a leading cause of death and disability. Long noncoding RNAs (lncRNAs) exert key functions in cerebral I/R injury. Here, we sought to elucidate the mechanism underlying the regulation of H19 in cerebral I/R cell injury. An in vitro model of cerebral I/R injury was created using oxygen-glucose deprivation/reoxygenation (OGD/R). The levels of H19, miR-1306-5p and B cell lymphoma-2 (Bcl-2)-like 13 (BCL2L13) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Cell viability and apoptosis were determined by the Cell Counting-8 Kit (CCK-8) assay and flow cytometry, respectively. The levels of lactate dehydrogenase (LDH) and cytokines were evaluated by enzyme-linked immunosorbent assays (ELISA). Direct relationships among H19, miR-1306-5p and BCL2L13 were verified by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pulldown assays. Our data showed that H19 and BCL2L13 were highly expressed in the cerebral I/R injury rats and OGD/R-triggered SK-N-SH and IMR-32 cells. The knockdown of H19 or BLC2L13 alleviated OGD/R-triggered injury in SK-N-SH and IMR-32 cells. Moreover, H19 silencing protected against OGD/R-triggered cell injury by down-regulating BCL2L13. H19 acted as a sponge of miR-1306-5p and BCL2L13 was a direct target of miR-1306-5p. H19 mediated BCL2L13 expression by sequestering miR-1306-5p. Furthermore, miR-1306-5p was a molecular mediator of H19 function. These results suggested that H19 silencing alleviated OGD/R-triggered I/R injury at least partially depending on the regulation of the miR-1306-5p/BCL2L13 axis.