Hyperbaric Lidocaine Aggravates Diabetic Neuropathic Pain by Targeting p38 MAPK/ERK and PINK1/Parkin-Mediated Mitophagy Signaling Pathway.

BACKGROUND: Diabetic neuropathic pain (DNP) is a complication of diabetes mellitus (DM). Hyperbaric lidocaine (HL), a local anesthetics drug, has neurotoxicity. The present study aims to study the effect and molecular mechanisms of HL on spinal nerve injury in DNP. METHODS: The DNP rat model was established through a high-fat-glucose diet in combination with Streptozotocin (STZ) administration. SB203580 and PD98059 were utilized to inhibit p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK). The mechanical paw withdrawal threshold (PWT) and the thermal paw withdrawal latency (PWL) were tested to evaluate rats' mechanical allodynia and thermal hyperalgesia. Hematoxylin-eosin (H&E) and terminal deoxynucleotidyltransferase-mediated dUTP nick-end Labeling (TUNEL) staining were performed to evaluate the pathological changes and neuron apoptosis in spinal cord tissues of L4-5. Western blotting analysis and reverse transcription-polymerase chain reaction (RT-qPCR) assay were used to measure the levels of proteins and mRNAs, respectively. RESULTS: PWT and PWL were decreased in DNP rats with serious spinal nerve injury. HL administration downregulated the PWT and PWL and aggravated spinal nerve injury in DNP rats, but isobaric lidocaine had no effects on these changes. Meanwhile, p38 MAPK/ERK signaling and PTEN-induced kinase 1 (PINK1)-mediated mitophagy were activated in DNP, which was enhanced by HL but not isobaric lidocaine. Blocking p38 MAPK/ERK signaling could effectively attenuate HL-induced spinal nerve injury and inhibit mitophagy. CONCLUSION: In summary, HL can aggravate spinal cord tissue damage in DNP rats by inducing PINK1-mediated mitophagy via activating p38 MAPK/ERK signaling. Our data provide a novel insight that supports the potential role of p38 MAPK/ERK signaling in acting as a therapeutic target for HL-induced neurotoxicity.

Synthesis, biological evaluation, and structure-activity relationships of new tubulin polymerization inhibitors based on 5-amino-1,2,4-triazole scaffold.

Based on our previous research, thirty new 5-amino-1H-1,2,4-triazoles possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities. Among them, compounds IIa, IIIh, and IIIm demonstrated significant antiproliferative activities against a panel of tumor cell lines, and the promising compound IIIm dose-dependently caused G2/M phase arrest in HeLa cells. Furthermore, analogue IIa exhibited the most potent tubulinpolymerization inhibitory activity with an IC50 value of 9.4 µM, and molecular modeling studies revealed that IIa formed stable interactions in the colchicine-binding site of tubulin, suggesting that 5-amino-1H-1,2,4-triazole scaffold has potential for further investigation to develop novel tubulin polymerization inhibitors with anticancer activity.

A novel NFIA gene nonsense mutation in a Chinese patient with macrocephaly, corpus callosum hypoplasia, developmental delay, and dysmorphic features.

BACKGROUND: NFIA gene (OMIM*600727) has been shown to be associated with a syndrome of central nervous system malformations (corpus callosum and ventriculomegaly) with or without urinary tract defects(BRMUTD) (OMIM#613735) with a low incidence. METHODS AND RESULTS:   We presented the clinical data of a 3-month-old Chinese infant with clinical features such as thin corpus callosum, ventriculomegaly, development delay, and dysmorphic features (macrocephaly, hypertelorism, slightly pointed chin, broad forehead, and large ears). Genomic DNA was extracted for Trio Whole Exome Sequencing. Preliminary genetic tests revealed one de novo heterozygous nonsense mutation c.220 C>T (p.Arg74Ter) of the NFIA gene (NM_005595). CONCLUSION: Genetic DNA sequencing is a crucial method for diagnosing BRMUTD. This approach enriches the genotype and spectrum of BRMUTD syndrome and the outcome of the patient.

C.292G>A, a novel glycine receptor alpha 1 subunit gene (GLRA1) mutation found in a Chinese patient with hyperekplexia: A case report.

INTRODUCTION: Hyperekplexia is a rare hereditary neurological disorder; only 5 glycine receptor alpha 1 subunit gene (GLRA1) mutations have been reported in 5 Chinese patients. We report a Chinese infant with hyperekplexia and a novel mutation at c.292G > A. PATIENT CONCERNS: A Chinese infant with hyperekplexia and a novel mutation at c.292G > A. DIAGNOSIS: All exons of GLRA1 were sequenced in her parents and her, which revealed a mutation at c.1030C > T and another novel mutation at c.292G > A. Her diagnosis was confirmed as hereditary hyperekplexia with GlRA1 hybrid gene mutations based on the sequencing results. INTERVENTIONS: She was treated with clonazepam. OUTCOMES: Her muscle hypertonia recovered rapidly and the excessive startle reflex to unexpected stimuli was significantly reduced. CONCLUSION: Genetic DNA sequencing is a crucial method for diagnosing hyperekplexia-related gene mutation.

[Distribution Characteristics and Fluxes of Nitrogen and Phosphorus at the Sediment-water Interface of Yuqiao Reservoir].

Yuqiao Reservoir is an important source of drinking water in Tianjin. In recent years, the eutrophication status is becoming more and more serious, but its internal loading and distribution characteristics of nitrogen and phosphorus is not clear. The profiles of nitrogen and phosphorus at the sediment-water interface were analyzed using the Peeper (pore water equilibrium) technique and the spatial distribution was investigated. The existing forms of the released nitrogen and phosphorus were investigated by the static intact sediment cores, and the fluxes of nitrogen and phosphorus at the sediment-water interface were estimated by static incubations with intact sediment cores. The results demonstrated the following. ① The contents of PO43--P, NH4+-N, NO3--N, and NO2--N in sediments were 0.5-6.5, 0.5-10.9, 2.2-16.2, and 0.05-0.6 mg ·kg-1, respectively. The contents of nutrient were lower as depth increased, and horizontal distribution characteristics indicated significant differences. ② The contents of PO43--P and NH4+-N in the interstitial water were much higher than in the overlying water, suggesting that the interstitial water had the potential to diffuse nutrients to the overlying water. The concentrations of PO43--P and NH4+-N in the interstitial water increased rapidly at 0-5 cm and then decreased gradually. ③ PO43--P and NH4+-N diffused from the sediment to the overlying water, and the fluxes of them were 1.1-13.3 mg ·(m2 ·d)-1 and 20.6-250.5 mg ·(m2 ·d)-1, respectively. The exchange fluxes of NO3--N and NO2--N ranged from -20.4 to 33.4 mg ·(m2 ·d)-1 and from -7.4 to 0.4 mg ·(m2 ·d)-1, respectively. PO43--P and NH4+-N were the main nutrients in the sediment released to the overlying water. The fluxes were high in the south and low in the north, and also high in the mouth of the Linhe River and downstream of the reservoir. Compared with similar studies, the fluxes at the sediment-water interface of Yuqiao Reservoir were relatively high, indicating that the sediment was an important source of nutrients for the overlying water in Yuqiao Reservoir.

[Characteristics of N2O Release and Influencing Factors in Grass-type and Algae-type Zones of Taihu Lake During Summer].

Spatial heterogeneity of N2O generation and emissions in multi-ecotype lakes limited the accurate estimation of the N2O fluxes in lakes, but few studies on the characteristics of N2O generation and emissions have been conducted. In this study, N2O flux at the water-gas interface, dissolved N2O concentration in the water column, and N2O flux at the sediment-water interface in typical grass-type and algal-type zones of Taihu Lake were analyzed during summer, and indoor micro-environment experiments were conducted to illustrate the main factors affecting the generation and emissions of N2O. The results showed that the N2O fluxes at the water-gas interface, dissolved N2O concentration, and N2O fluxes at the sediment-water interface of the emergent macrophyte type area was higher than the algae-type area and submerged macrophyte area during the summer., with N2O fluxes at the water-gas interface of (115.807±7.583), (79.768±1.842), and (3.685±0.295) µmol ·(m2 ·h)-1, respectively. The dissolved N2O concentration in the water column were (0.051±0), (0.029±0.001), and (0.018±0) µmol ·L-1, respectively; and the N2O fluxes at the sediment-water interface were (178.275±3.666), (160.685±0.642), and (75.665±1.016) µmol ·(m2 ·h)-1, respectively. The spatial difference could be attributed to dominant plants and the concentration of inorganic nitrogen in the water column. The results of micro-environment experiments showed that nitrate and organic carbon sources could significantly increase the N2O production potential of sediments, the high concentration of NH4+-N in the water column might inhibit the N2O production in sediments, and the production rates of N2O in the sediment increased remarkably when the incubation temperature increased, suggesting that the generation and emissions of N2O were mainly restricted by nitrate, organic carbon, and temperature in summer.

A ratiometric fluorescent probe for hypochlorous acid determination: Excitation and the dual-emission wavelengths at NIR region.

An interesting ratiometric fluorescent probe with unique optical performance was reported in this work. By modifying on the bridge-head of heptamethine cyanine chromophore with an N-phenyl-N'-ethylene amine thiourea substituent as a chemodosimetric recognition unit, the probe exhibited ratiometric fluorescent response towards hypochlorous acid (HClO). Upon addition of HClO, the absorbance spectra showed a great red shift as large as 150nm from 650nm to 800nm. Employing the isosbestic absorption point at 730nm as an excitation wavelength, a ratiometric fluorescent sensing mode with two long emission wavelengths at 760nm and 820nm was acquired, and thus the probe displayed significant behavior with both the excitation wavelength and the dual-emission wavelengths located at NIR (650-900nm) region exclusively. Also, the probe showed excellent performance in high sensitivity and good selectivity towards HClO over other reactive oxygen species and a wide variety of coexist species in biological pH condition and had been successfully used to detect hypochlorous acid in serum samples and tap water samples.