Knockdown of LOX-1 ameliorates bone quality and generation of type H blood vessels in diabetic mice.

Our previous studies have shown that lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) is expressed in liver sinusoidal endothelial cells, and oxidized low-density lipoprotein induces liver sinusoidal dysfunction and defenestration through the LOX-1/ROS/NF-kB pathway, revealing that LOX-1 can mediate liver sinusoidal barrier function, involved in the regulation of non-alcoholic fatty liver disease. Here, we investigated whether, in the context of bone metabolic diseases, LOX-1 could affect bone quality and type H blood vessels in diabetic mice. We used db/db mice as model and found that LOX-1 knockdown can ameliorate bone quality and type H blood vessel generation in db/db mice. This further verifies our hypothesis that LOX-1 is involved in the regulation of bone quality and type H blood vessel homeostasis, thus inhibiting osteoporosis progression in db/db mice.

Synthesis of ethane-disulfonate pillared layered cobalt hydroxide towards the electrocatalytic oxygen evolution reaction.

We report the synthesis of a hybrid layered cobalt hydroxide sample and its redox behaviors in the electrochemical oxygen evolution reaction (OER). Compound Co7(OH)12(C2H4S2O6)·1.6H2O was synthesized via a homogeneous alkalization reaction using Co(SO3C2H4SO3) and hexamethylenetetramine. This compound comprises cationic host layers of {[Co7(OH)12]2+}∞, which comprise octahedrally (CoOh) and tetrahedrally (CoTd) coordinated Co cations at a CoOh : CoTd ratio of 5 : 2. The ethane-disulfonate ions are combined with the cationic host layers by electrostatic attractions and hydrogen bonding as a hybrid pillared layered framework. This hybrid sample can promote the OER in 1 M KOH with an overpotential as low as ∼410 mV (at a current density of 10 mA cm-2). In situ Raman spectroscopy showed that the sample first evolved into Co(III)-based phases comprising a mixture of layered CoOOH and spinel Co3O4, and the Co(III)-based compounds were converted into Co(IV)-O intermediates containing [CoO6] units at the onsite of the OER. The structural evolution behaviors suggest that the catalyst prefers a topotactic phase transition and the CoOh and CoTd units exhibit different activities in the electrochemical reaction. The electron transfer events involved in the electrochemical reaction were identified by Fourier-transformed alternating current voltammetry.

LOX-1 attenuates high glucose-induced autophagy via AMPK/HNF4α signaling in HLSECs.

Type 2 diabetes mellitus (T2DM) combined with nonalcoholic fatty liver disease (NAFLD) is a common cause of death. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved in the regulation of autophagy and associated with a variety of diseases, such as atherosclerosis, diabetes, and NAFLD. This study aimed to investigate the effect of LOX-1 on autophagy induced by high glucose levels in human liver sinusoidal endothelial cells (HLSECs) and whether it regulates autophagy through the adenosine monophosphate-activated protein kinase/hepatocyte nuclear factor 4α (AMPK/HNF4α) pathway. In this study, HLSECs cultured with high glucose medium showed increased expression of LOX-1, whereas autophagy was inhibited. High glucose levels decreased the AMPK phosphorylation, increased the HNF4α phosphorylation, and retained the HNF4α in the cytoplasm. By contrast, silencing of LOX-1 reversed the phenomenon induced by high glucose levels and restored the HNF4a localization. Taken together, our findings reveal a novel mechanism of high glucose-induced autophagy in HLSECs, namely, the LOX-1-mediated AMPK/HNF4α signaling pathway. Therefore, LOX-1 is an important target molecule for the regulation of autophagy in HLSECs.

Simultaneous Determination of Celecoxib, Dezocine and Dexmedetomidine in Beagle Plasma Using UPLC-MS/MS Method and the Application in Pharmacokinetics.

BACKGROUND: An efficient, fast and sensitive ultra high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method for simultaneous determination of celecoxib (CEL), dezocine (DEZ) and dexmedetomidine (DEX) in beagle plasma were established. METHODS: The beagle dogs plasmawas precipitated by acetonitrile. The column was Acquity UPLC BEH C18 column and the mobile phase was acetonitrile-formic acid with gradient mode, and the flow rate was set at 0.4 mL/min. Under the positive ion mode, CEL, DEZ, DEX and Midazolam (internal standard, IS) were monitored by multiple reaction monitoring (MRM) as the following mass transition pairs: m/z 381.10→282.10 for CEL, m/z 246.20→147.00 for DEZ, m/z 201.10→94.90 for DEX, and m/z 326.10→291.10 for IS. RESULTS: This UPLC-MS/MS method had good linearity for CEL, DEZ and DEX. The RSDs of inter-day and intra-day precision were the values of 0.31-7.66% and 0.11-9.63%, respectively; the RE values were from -6.05% to 10.98%. The extraction recovery was more than 79%, and the matrix effect was around 100%. The RSDs of stability were less than 8.96%. All of them met the acceptance standard of biological analysis method recommended by FDA. CONCLUSION: This UPLC-MS/MS method is an effective tool for the simultaneous determination of CEL, DEX and DEX, and has been successfully applied to the study of pharmacokinetics in beagle dogs.

Upregulation of the Purinergic Receptor Subtype P2X3 in the Trigeminal Ganglion Is Involved in Orofacial Pain Induced by Occlusal Interference in Rats.

AIMS: To evaluate whether the purinergic receptor subtype P2X3 (P2X3R) in trigeminal ganglion (TG) neurons is involved in hyperalgesia of the temporomandibular joints (TMJs) and masseter muscles associated with placement of an occlusal interference. METHODS: Forty-five rats were randomized into five groups (ie, for days 1, 3, 7, 14, or 28; nine rats per group). Six rats from each group were chosen to receive the occlusal interference, and the remaining three rats were sham-treated controls. On days 1, 3, 7, 14, and 28 after placement of the occlusal interference, the mechanical pain threshold (MPT) to stimulation of the TMJs or masseter muscles was examined using von Frey filaments. Seven days after the occlusal interference placement, changes in MPT were tested after administration of the P2X3R antagonist A-317491 into the TMJs and masseter muscles (60 µg/site) in six rats. The expression of P2X3R in the TGs was investigated by immunohistochemistry and quantitative polymerase chain reaction (qPCR). Retrograde tracing was combined with immunofluorescence to identify TMJ and masseter muscle afferent neurons in the TGs of six premature rats. RESULTS: The TMJ and masseter muscle MPTs were decreased after placement of the occlusal interference, and the P2X3R antagonist reversed the mechanical hyperalgesia that was caused by the occlusal interference placement. The frequency of P2X3R-immunoreactive cells increased in small-sized neurons in the TG after occlusal interference. By contrast, there was no increase in medium-sized TG neurons. P2X3R mRNA increased on day 3. Retrograde tracing indicated that the TMJ and masseter muscle afferent neurons in the TG expressed P2X3R. CONCLUSION: Upregulated P2X3R expression in the TG may contribute to orofacial pain development induced by an occlusal interference. P2X3R may be a therapeutic target for chronic TMJ or masseter muscle pain.