Reactive Oxygen Species Contributes to Type 2 Diabetic Neuropathic Pain via the Thioredoxin-Interacting Protein-NOD-Like Receptor Protein 3- N -Methyl-D-Aspartic Acid Receptor 2B Pathway.

BACKGROUND: The number of patients with diabetic neuropathic pain (DNP) continues to increase, but available treatments are limited. This study aimed to examine the influence of reactive oxygen species (ROS)-thioredoxin-interacting protein (TXNIP)-NOD-like receptor protein 3 (NLRP3)- N -methyl-D-aspartic acid receptor 2B (NR2B) pathway on type 2 DNP. METHODS: Male Sprague-Dawley rats were fed with a high-fat and high-sugar diet for 8 weeks. Then, rats were intraperitoneally injected with streptozotocin (STZ, 35 mg/kg) to induce type 2 diabetes mellitus in rats. Diabetic rats with <85% of their basic levels in mechanical withdrawal threshold and thermal withdrawal latency were classified as DNP rats on day 14 after STZ injection. DNP rats were treated with ROS scavenger N-tert-Butyl-α-phenylnitrone (PBN, 100 mg·kg -1 ·d -1 ) or TXNIP small interfering ribonucleic acid (10 µg/d) once daily for 14 days. The level of ROS, protein levels of NLRP3, TXNIP, cysteinyl aspartate-specific proteinase-1 (caspase-1), interleukin-1ß (IL-1ß), NR2B phosphorylation at Tyr1472 (p-NR2B), total NR2B (t-NR2B), and distribution of NLRP3 in the spinal cord were examined. In vitro experiments, BV2 cells and PC12 cells were individually cultured and cocultured in a high-glucose environment (35 mmol/L D-glucose). The level of ROS and protein levels of NLRP3, TXNIP, caspase-1, and IL-1ß in BV2 cells, and p-NR2B, t-NR2B in PC12 cells were detected. The level of ROS was detected by the flow cytometry approach. The protein levels were detected by the Western blot technique. The location of NLRP3 was observed by immunofluorescent staining. The interaction between TXNIP and NLRP3 was detected by coimmunoprecipitation assay. RESULTS: The level of spinal ROS increased in DNP rats. The mechanical allodynia and thermal hyperalgesia of DNP rats were alleviated after systemic administration of PBN. This administration decreased protein levels of NLRP3, TXNIP, caspase-1, IL-1ß, and p-NR2B and the coupling of TXNIP to NLRP3 in spinal cords of DNP rats. Furthermore, knockdown of spinal TXNIP alleviated nociceptive hypersensitivity and decreased protein levels of NLRP3, TXNIP, caspase-1, IL-1ß, and p-NR2B in DNP rats. The level of ROS and protein levels of NLRP3, TXNIP, caspase-1, IL-1ß, the coupling of TXNIP to NLRP3, and the IL-1ß secretion increased in BV2 cells, and the protein expression of p-NR2B increased in cocultured PC12 cells in a high-glucose environment. All of these in vitro effects were significantly blocked after treatment of PBN. CONCLUSIONS: Our findings suggest that spinal ROS can contribute to type 2 DNP through TXNIP-NLRP3-NR2B pathway.

Enhanced Protein Damage Clearance Induces Broad Drug Resistance in Multitype of Cancers Revealed by an Evolution Drug-Resistant Model and Genome-Wide siRNA Screening.

Resistance to therapeutic drugs occurs in virtually all types of cancers, and the tolerance to one drug frequently becomes broad therapy resistance; however, the underlying mechanism remains elusive. Combining a whole whole-genome-wide RNA interference screening and an evolutionary drug pressure model with MDA-MB-231 cells, it is found that enhanced protein damage clearance and reduced mitochondrial respiratory activity are responsible for cisplatin resistance. Screening drug-resistant cancer cells and human patient-derived organoids for breast and colon cancers with many anticancer drugs indicates that activation of mitochondrion protein import surveillance system enhances proteasome activity and minimizes caspase activation, leading to broad drug resistance that can be overcome by co-treatment with a proteasome inhibitor, bortezomib. It is further demonstrated that cisplatin and bortezomib encapsulated into nanoparticle further enhance their therapeutic efficacy and alleviate side effects induced by drug combination treatment. These data demonstrate a feasibility for eliminating broad drug resistance by targeting its common mechanism to achieve effective therapy for multiple cancers.

Modification of the right subclavian vein catheterization and its anatomic basis and techniques.

BACKGROUND: Several million subclavian-vein catheters are placed in patients each year to enable caregivers to administer chemotherapy, total parenteral nutrition, or long-term antibiotics or to manage preoperative fluids. Subclavian venipuncture requires the position of a deep vein to be identified with only surface landmarks. But the traditional right subclavian vein (RSV) catheterization (primitive procedures) is not the answer for all patients. The precise location of the vein is not known, and it is important to select the most appropriate method to achieve central venous access safely in any given patient. To modify the primitive procedures of the RSV catheterization for greater success and reduce the complications, anatomic studies and ultrasonography were conducted and clinical applications were validated. METHODS: Anatomical observation and measurement of the RSV and its adjacent structures were performed on 20 adult cadavers according to modified procedures. The RSV catheterization of 2900 cases was carried out by the modified procedure, 500 of these cases were observed by ultrasonography after the operation. RESULTS: The anatomical studies and clinical application showed that the insertion point differs from the bodily form of fatness or leptosome. The clinical data revealed that in the 2900 cases which were performed with the modified approach, the success rate was 98.90% (2868 cases), the failure rate was 1.10% (32 cases), and the complication rate is 0.79% (23 cases), and the catheterization time is (31.2 +/- 10.5) minutes. Five hundred and sixty cases of the RSV catheterization were carried out by the recommended insertion procedure; the results were compared with the modified approach and the traditional approach. The successful rate of the traditional approach was 73.0%, of which the complication rate was 6.1%; the two approaches were significantly different (successful rate: chi(2) = 626.642, P < 0.01; complication rate: chi(2) = 80.708, P< 0.01). CONCLUSIONS: The modified RSV catheterization is characterized with a higher success rate and less complications, and the insertion procedure differs from the bodily form of fatness or leptosome.