Irbesartan ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing NLRP3 inflammasomes in vivo and in vitro.

OBJECTIVES: Diabetic nephropathy (DN) is characterized by albuminuria and renal dysfunction caused by diabetes. At present there is no specific treatment for DN. Irbesartan (IRB) is an angiotensin receptor inhibitor indicated for the treatment of hypertension and DN. However, the underlying molecular mechanisms of IRB on DN remains obscure. METHODS: RAW264.7 macrophages were incubated in RPMI-1640, cell viability was evaluated by CCK-8 assays, transcriptional level of proinflammatory cytokines and was measured by ELISA and qPCR, NLRP3 inflammasome and Nrf2/Keap1 related proteins were measured by Western blotting and immunohistochemistry. Streptozotocin (STZ)-induced diabetic male C57BL/6 mice were used to evaluate the therapeutic effect of IRB on DN. Key findings First, we found that IRB improved high glucose-induced cell inflammation by inhibiting the transcription of IL-1ß and IL-18. IRB activated the Nrf2/Keap1 pathway and decreased the release of reactive oxygen species (ROS). IRB also suppressed the expression of NLRP3 and caspase-1. IRB combined with the N-acetylcysteine (NAC) significantly inhibited the activation of NLRP3 inflammasomes. Conversely, IRB combined with the Nrf2-related inhibitor ML385 enhanced NLRP3 inflammasome activation, suggesting that IRB suppressed NLRP3 inflammasome via the Nrf2 pathway. In vivo study, HE staining and immunohistochemistry analysis further showed that IRB ameliorated high glucose-induced renal injury by elevating the expression of the Nrf2/Keap1 signaling pathway and suppressing the proinflammatory cytokine and NLRP3 inflammasome activation. CONCLUSIONS: Our results suggested that IRB ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing the NLRP3 inflammasomes in vivo and in vitro. These findings provide new therapeutic strategies of diabetic nephropathy.

Inhibition of NLRP3 and Golph3 ameliorates diabetes-induced neuroinflammation in vitro and in vivo.

Golgi stress has been observed in various neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Whether Golgi stress participates in hyperglycemia-induced neuroinflammation, and how it is regulated remain unclear. First, we found that high glucose (HG) could induce dispersed Golgi apparatus (GA) in BV2 cells, which can be reversed by knockout of NLRP3. Next, we discovered that HG could promote the interaction of NLRP3 and VPS35 and then enhances the interaction of VPS35 and Golph3; knockout of NLRP3 suppressed the expression of VPS35 and Golph3; knockout of VPS35 reduced the expression of Golph3 but not NLRP3, indicating that HG induced the activation of NLRP3/VPS35/Golph3 pathway in BV2 cells. Further, we elucidated the signaling pathway that Golph3 mediated GA stress in HG condition. We used GST-pulldown and Co-IP experiments methods to show that HG promoted the interaction of Golph3 and Vimentin, knockout of Golph3 alleviated the expression of Vimentin. Knockout out of Golph3 and Vimentin both ameliorated HG induced dispersed Golgi apparatus. Collectively, our study demonstrated that HG regulates GA stress through NLRP3/VPS35/Golph3/Vimentin pathway. At last, we found that a combination of small molecular inhibitors targeting NLRP3 and Golph3 selected by molecular docking could alleviate HG-induced neuroinflammation in vitro and in vivo. Therefore, the molecular inhibitors targeting NLRP3 and Golph3 have great potential for use in the development of anti-diabetes neuroinflammatory therapies.

TREM2 Regulates High Glucose-Induced Microglial Inflammation via the NLRP3 Signaling Pathway.

Background: TREM2 expressed on microglia plays an important role in modulating inflammation in neurodegenerative diseases. It remains unknown whether TREM2 modulates hyperglycemia-induced microglial inflammation. Methods: We investigated the molecular function of TREM2 in high glucose-induced microglial inflammation using western blotting, qPCR, ELISA, pulldown, and co-IP methods. Results: Our data showed that in high glucose-induced BV2 cells, TREM2 was increased, and the proinflammatory cytokine IL-1ß was increased. TREM2 knockout (KO) attenuated the proinflammatory cytokine IL-1ß; conversely, TREM2 overexpression (OE) exacerbated IL-1ß expression. Furthermore, we found that high glucose promoted the interaction of TREM2 with NLRP3. TREM2 KO abolished the interaction of TREM2 with NLRP3, while TREM2 OE enhanced the interaction. Moreover, TREM2 KO reduced high glucose-induced NLRP3 inflammasome activation, and TREM2 OE augmented high glucose-induced NLRP3 inflammasome activation, indicating that high glucose enhances the expression of TREM2, which activates the NLRP3 inflammasome. To further clarify whether the NLRP3 signaling pathway mediates the TREM2-regulated inflammatory response, we blocked the NLRP3 inflammasome by knocking out NLRP3 and treating cells with a caspase1 inhibitor, which decreased the levels of the IL-1ß proinflammatory cytokine but did not affect the high glucose-induced expression of TREM2. Conclusions: TREM2 modulates high glucose-induced microglial inflammation via the NLRP3 signaling pathway.

Single posterior debridement, interbody fusion, and fixation on patients with continuous multivertebral lumbar spine tuberculosis (CMLSTB).

BACKGROUND: Patients with continuous multi-vertebral lumbar spine tuberculosis (CMLSTB) were subjected to single posterior debridement, interbody fusion, and fixation to explore their clinical outcomes. METHODS: Sixty-seven CMLSTB patients who underwent single posterior debridement interbody fusion and fixation between January 2008 to December 2017 were studied. The operation time, blood loss, perioperative complication rate, cure rate, Visual Analog Scale (VAS), Oswetry disability index (ODI), Japanese Orthopedic Association (JOA), Erythrocyte Sedimentation Rate (ESR), C-reactive protein (CRP), kyphotic Cobb's angle and time of interbody fusion were analyzed to understand their therapeutic effects on CMLSTB patients. RESULTS: The patients were followed up for 20-48 months, with a mean of 24.3 months. The mean operation time was 215.5 min (range, 120-280 min), whereas 818.0 ml of blood was lost (range, 400-1500 ml) with a perioperative complication rate of 6.0% and a cure rate of 95.5%. During the last phase of follow-up, the mean preoperative VAS score (5.7) and ODI (72.0%) decreased significantly to 1.4 (t = 31.4, P<0.01) and 8.4% (t = 48.4, P<0.01), respectively. Alternatively, the mean preoperative ESR and CRP (74.7 mm /h and 69.3 mg/L, respectively) decreased to average values (tESR = 39.7, PESR<0.001; tCRP = 50.2, PCRP<0.001), while the JOA score (13.9) significantly increased to 23.0 (t = - 11.6, P<0.01). The preoperative kyphotic Cobb's angle (20.5°) decreased to 4.8° after the operation (t = 14.0, P<0.01); however, the kyphotic correction remained intact at the time of follow-up (t = - 0.476, P = 0.635). Furthermore, the mean of interbody fusion time was identified to be 8.8 months (range, 6-16 months). CONCLUSION: Single posterior debridement, interbody fusion, and fixation may be one of the surgical choices for the treatment of CMLSTB patients.

Tracing photon transmission in dye-doped DNA-CTMA optical nanofibers.

We experimentally demonstrate the novel phenomena of photoluminescence (PL) and fluorescence resonance energy transfer (FRET) assisted three-color PL separating in DNA optical nanofibers consisting of the stretched and connected DNA-cetyltrimethyl ammonium wires. The PL experiments are performed to comparatively trace photon transmission between single dye-doped DNA-CTMA optical nanofiber and PMMA optical nanofiber. A cascade FRET including DNA minor groove binder and DNA intercalators is used to further trace photon transmission inside DNA-CTMA wire. These experimental results will help to intrigue the new applications of DNA-CTMA as molecular waveguide in optobioelectronics area.

DNA optical nanofibers: preparation and characterization.

We demonstrate the preparation and characterization of DNA optical nanofibers. The prepared DNA optical nanofibers with strong strength and high flexibility are tested. Coupled with silica fiber tapers, their optical characteristics including light transmission performance, group delay and chromatic dispersion are experimentally investigated. The visible and near infrared light waveguiding properties of the DNA optical nanofibers with and without R6G doping are also studied. It is expected that the DNA optical nanofibers may be potential for building the miniaturized biomedical photonic devices.

Enhanced fast light in microfiber ring resonator with a Sagnac loop reflector.

We fabricate a microfiber knot-type ring resonator with a Sagnac loop reflector, and control the light velocity using the device. In this structure, light is reflected by the Sagnac loop and passes through the ring resonator twice. Thus, it possesses doubled transmission and group delay comparing with the microfiber ring resonator without the Sagnac loop. We experimentally demonstrate pulse advancement in an under-coupled microfiber knot-type ring resonator with a Sagnac loop reflector. In the experiment, a maximum of approximately 25 ps pulse advancement was achieved for a 5-Gb/s RZ signal.

A universal microarray for detection of SARS coronavirus.

Severe acute respiratory syndrome (SARS) is caused by the SARS coronavirus (SARS-CoV). There are many point mutations among SARS-CoV genome sequences. Previous studies suggested that the mutations are correlated closely with the SARS epidemic. It was found that the bases of six nucleotide positions (nt9404, nt9479, nt19838, nt21721, nt22222 and nt27827) with high-mutation rate have an important relationship with the SARS epidemic. For viral detection as well as genotyping, a universal microarray system was developed that combines RT-PCR and ligase detection reaction (LDR). The Zip Codes attached covalently to a slide remain constant and their complementary Zip Codes (cZip Codes) can be used for tagging target sequence, making the microarrays universal. The discriminating oligonucleotides contain on the 5' end "cZip Codes" that are used to direct LDR product to specific Zip Codes attached covalently to a slide. Since Zip Codes have no homology to either the target sequence or to other sequences in the genomes of both human host and SARS-CoV, there was no false signal due to mismatch hybridizations. 20 samples assayed with the universal microarray were confirmed by DNA sequencing, demonstrating that this microarray system is a promising diagnostic tool for detection and genotyping of the SARS-CoV.

[Prognostic analysis of advanced non small cell lung cancer treated by sequential chemo-radiation therapy combined with traditional Chinese medicine: a report of 54 cases].

OBJECTIVE: To evaluate the influence of fewer courses and prolonged intervals of chemotherapy on survival rate of advanced non small cell lung cancer (NSCLC) patients treated by sequential chemo-radiation therapy combined with traditional Chinese medicine (TCM). METHODS: From Jan. 2000 to Dec. 2001, 54 untreated advanced NSCLC patients (2 stage IIIa, 18 stage IIIb, 34 stage IV) were treated by sequential chemo-radiation therapy combined with TCM. The courses of chemotherapy were reduced and the intervals of chemotherapy were longer than that of the standard regimen. The efficacy and survival rate were documented and the prognostic factors were analyzed. RESULTS: Complete remission (CR) was observed in 1 case and partial remission (PR) in 20 cases. The overall objective response rate was 40.4%. Median survival was 15.3 months, 1-, 2- and 3-year survival rate were 53.7%, 28.9% and 9.6% respectively. The median survival of stage III and IV were 21.8 months and 12.5 months respectively. The 1-, 2-, and 3-year survival rates of stage III were 65.0%, 49.5%, 24.7% and that of stage IV were 47.0%, 23.3%, 0%, respectively. The quality of life was improved in most of the patients. Cox's proportional hazards regression showed that improved quality of life and treatment of TCM were the significant prognostic factors of overall survival. CONCLUSION: Chemotherapy and radiotherapy combined with TCM is beneficial to extending the interval of chemotherapy, improving the quality of life, and increasing the survival rate of advanced NSCLC patients.