Cav-1 participates in the development of diabetic neuropathy pain through the TLR4 signaling pathway

This study aims to determine whether caveolin-1 (Cav-1) participates in the process of diabetic neuropathic pain by directly regulating the expression of toll-like receptor 4 (TLR4) and the subsequent phosphorylation of N-methyl-D-aspartate receptor 2B subunit (NR2B) in the spinal cord. Male Sprague-Dawley rats (120–150 g) were continuously fed with high-fat and high-sugar diet for 8 weeks, and received a single low-dose of intraperitoneal streptozocin injection in preparation for the type-II diabetes model. Then, these rats were divided into five groups according to the level of blood glucose, and the mechanical withdrawal threshold and thermal withdrawal latency values. The pain thresholds were measured at 3, 7, and 14 days after animal grouping. Then, eight rats were randomly chosen from each group and killed. Lumbar segments 4–6 of the spinal cord were removed for western blot analysis and immunofluorescence assay. Cav-1 was persistently upregulated in the spinal cord after diabetic neuropathic pain in rats. The downregulation of Cav-1 through the subcutaneous injection of Cav-1 inhibitor daidzein ameliorated the pain hypersensitivity and TLR4 expression in the spinal cord in diabetic neuropathic pain (DNP) rats. Furthermore, it was found that Cav-1 directly bound with TLR4, and the subsequent phosphorylation of NR2B in the spinal cord contributed to the modulation of DNP. These findings suggest that Cav-1 plays a vital role in DNP processing at least in part by directly regulating the expression of TLR4, and through the subsequent phosphorylation of NR2B in the spinal cord.     

Inhibition of KHSRP sensitizes colorectal cancer to 5-fluoruracil through miR-501-5p-mediated ERRFI1 mRNA degradation

K-homology (KH)-type splicing regulatory protein (KHSRP) is an RNA binding protein that participates in RNA variable splicing and stability, and facilitates the biogenesis of miRNAs that target mRNA. However, to date, the role of KHSRP in colorectal cancer (CRC) progression has not been reported. In this study, the function of KHSRP in CRC proliferation and 5-fluoruracil (5-FU) resistance was investigated. The upregulation of KHSRP expression was confirmed in CRC patient tissues and two CRC cell lines. Manipulating KHSRP expression altered cell proliferation and 5-FU resistance in CRC cells. ERRFI1, a downstream effector of KHSRP in CRC cells, reduced CRC cell proliferation. Sensitivity to 5-FU mediated by KHSRP knockdown was reversed by ERRFI1 knockdown. We found that KHSRP decreased ERRFI1 mRNA expression indirectly. By screening KHSRP-regulated miRNAs, we further found that miR-501-5p directly combines with KHSRP in CRC cells. Mechanistically, the results of a luciferase assay suggested that miR-501-5p directly binds to the ERRFI1 3′-untranslated region. Taken together, our data indicated that modification of ERRFI1 by KHSRP occurs through miR-501-5p, an essential mechanism driving CRC proliferation and 5-FU resistance. Insight into this mechanism may provide novel targets for overcoming drug resistance in CRC.     

Biodiversity of stream insects in the Malaysian Peninsula: spatial patterns and environmental constraints

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Hydrogen sulfide reduces cell adhesion and relevant inflammatory triggering by preventing ADAM17‐dependent TNF‐α activation

H₂S is the third endogenous gaseous mediator, after nitric oxide and carbon monoxide, possessing pleiotropic effects, including cytoprotection and anti‐inflammatory action. We analyzed, in an in vitro model entailing monocyte adhesion to an endothelial monolayer, the changes induced by H₂S on various potential targets, including cytokines, chemokines, and proteases, playing a crucial role in inflammation and cell adhesion. Results show that H₂S prevents the increase in monocyte adhesion induced by tumor necrosis factor‐α (TNF‐α). Under these conditions, downregulation of monocyte chemoattractant protein‐1 (MCP‐1), chemokine C‐C motif receptor 2, and increase of cluster of differentiation 36 could be detected in monocytes. In endothelial cells, H₂S treatment reduces the increase in MCP‐1, inter‐cellular adhesion molecule‐1, vascular cell adhesion molecule‐1, and of a disintegrin and metalloproteinase metallopeptidase domain 17 (ADAM17), both at the gene expression and protein levels. Cystathionine γ‐lyase and 3‐mercaptopyruvate sulfurtransferase, the major H₂S forming enzymes, are downregulated in endothelial cells. In addition, H₂S significantly reduces activation of ADAM17 by PMA in endothelial cells, with consequent reduction of both ADAM17‐dependent TNF‐α ectodomain shedding and MCP‐1 release. In conclusion, H₂S is able to prevent endothelial activation by hampering endothelial activation, triggered by TNF‐α. The mechanism of this protective effect is mainly mediated by down‐modulation of ADAM17‐dependent TNF‐converting enzyme (TACE) activity with consequent inhibition of soluble TNF‐α shedding and its relevant MCP‐1 release in the medium. These results are discussed in the light of the potential protective role of H₂S in pro‐inflammatory and pro‐atherogenic processes, such as chronic renal failure. J. Cell. Biochem. 114: 1536–1548, 2013. © 2013 Wiley Periodicals, Inc.     

Exogenous high‐mobility group box 1 protein prevents postinfarction adverse myocardial remodeling through TGF‐β/Smad signaling pathway

High‐mobility group box 1 (HMGB1) has been reported to attenuate ventricular remodeling, but its mechanism remains mostly unresolved. Transforming growth factor‐beta (TGF‐β) is a crucial mediator in the pathogenesis of post‐infarction remodeling. Our study focused on the effects of HMGB1 on ventricular remodeling, and explored whether or not these effects were depended upon the TGF‐β signaling pathway. Rats underwent coronary artery ligation. An intramyocardium injection of phosphate buffered saline (PBS) with or without HMGB1 was administered 3 weeks after myocardial infarction (MI). At 4 weeks after the treatment, HMGB1 significantly increased the left ventricular ejection fraction (LVEF) (P < 0.05), decreased the left ventricular end diastolic dimension (LVEDD; P < 0.05), left ventricular end systolic dimension (LVESD) (P < 0.05) and the infarct size (P < 0.05) compared with control group. The expressions of collagen I, collagen III, and tissue inhibitor of metalloproteinase 2 (TIMP2) were also decreased, while the matrix metalloproteinases 2 (MMP2) and MMP9 expressions were upregulated by HMGB1 injection (P < 0.05) compared with control group. No effect on TIMP3 was observed. Furthermore, TGF‐β1 and phosphor‐Smad2 (p‐Smad2) were significantly suppressed and Smad7 was increased in HMGB1‐treated group (P < 0.05) compared with control group, no effects on p‐Smad3 and p‐p38 were observed. HMGB1 also upregulated Smad 7 expression and decreased the level of collagen I on cardiac fibroblasts (P < 0.05). Silencing of Smad7 gene by small interfering RNA abolished the fibrogenic effects of HMGB1 on cardiac fibroblasts (P < 0.05). These finding suggested that HMGB1 injection modulated ventricular remodeling may function through the possible inhibition of TGF‐β/Smad signaling pathway. J. Cell. Biochem. 114: 1634–1641, 2013. © 2013 Wiley Periodicals, Inc.     

Vegetative and reproductive phenology of the mangrove Kandelia obovata

Mangroves in the subtropical area of Japan are growing to their northern limits, yet little is known of their phenology. The aim of the present study was to understand both vegetative and reproductive phenology patterns, such as leaf emergence, leaf fall, bud setting, flowering, fruiting and propagule setting, in the mangrove Kandelia obovata. The phenology of this species was assessed using litter‐fall data for 5 years. Leaf and stipule litter‐falls continued with a clear monthly pattern throughout the years. New leaf production and leaf fall peaked in summer, immediately after the propagules fell. Leaf and stipule litter‐falls were linked to monthly sunshine hour, and monthly mean air temperature and monthly mean air relative humidity, respectively. Kandelia obovata had a distinct flowering period, with the flowering phenophase starting in spring and continuing into summer. Fruit initiation started at the end of summer and continued into autumn, whereas propagule production occurred during winter and spring. Flowering of K. obovata was influenced by monthly sunshine hour and monthly mean air temperature, whereas fruit and propagule litter‐falls were not linked to any climatic factors. The present results showed that a small portion (4.4%) of flowers developed into propagules. The average development period from flower buds to mature propagules was approximately 11 months. Kendall's consistency coefficient suggested that the monthly trends in vegetative and reproductive litter‐fall components, except for branches, did not change significantly among years.     

Adiponectin receptor agonist AdipoRon attenuates calcification of osteoarthritis chondrocytes by promoting autophagy

Cartilage calcification contributes to the development and progression of osteoarthritis (OA). It has been well-investigated adiponectin regulates vascular calcification. The purpose of this study is to investigate the therapeutic value and the molecular mechanism of AdipoRon, an adiponectin receptor agonist, on the chondrocytes calcification. Primary chondrocytes were isolated and cultured from normal cartilage and OA cartilage. The calcification in tissues was evaluated by inductively coupled plasma/atomic emission spectroscopy and alizarin red S staining. The calcification in chondrocytes was determined using the alkaline phosphatase (ALP) staining and an ALP assay kit. The cellular effects of AdipoRon were assessed by immunofluorescence staining and Western blot analysis. We found that calcification was significantly increased in OA cartilage tissues and cells. Importantly, the degree of calcification and ALP activity of the OA chondrocytes was decreased upon the treatment with AdipoRon. The AdipoRon-induced cellular effects, including the reduction of the calcification of chondrocytes and improvement of autophagy, were blocked by dorsomorphin, an 5′-adenosine monophosphate-activated protein kinase (AMPK) inhibitor. Moreover, autophagy activation by AdipoRon was mediated by the AMPK-mammalian target of rapamycin (mTOR) signaling pathway. Our results suggest that AdipoRon significantly alleviates the calcification of OA chondrocytes via activating AMPK-mTOR signaling to promote autophagy. Therefore, AdipoRon could be a potential therapeutic agent for the prevention and treatment of OA.     

Transganglionic degenerative atrophy in the substantia gelatinosa of the spinal cord after peripheral nerve transection in rhesus monkeys

Summary The effect of sciatic nerve transection on its centrally located terminals in the spinal cord was analyzed by electron microscopy in adult rhesus monkeys one and three months following lesion. Although the peripheral and intermediate portions of the dorsal roots, where the axons are enveloped by Schwann cells were normal, their central portion and their terminals in the substantia gelatinosa were remarkably altered. Transganglionic degenerative atrophy (TDA) is characterized by three distinct types of electronmicroscopic alterations. The first type exhibits a conspicuous electron density of the terminal and pre-terminal axoplasm. Importantly, shrinkage replaces fragmentation and glial engulfement of the terminal seen in the course of Wallerian degeneration. The second type is characterized by the disappearance of synaptic vesicles from the terminals. The third type of TDA consists of intricate labyrinthine structures, composed of flattened profiles of axonal, dendritic and glial elements. The complex and diverse cellular changes that occur in the upper dorsal horn following peripheral nerve injury may provide the structural basis of plasticity of the primary nociceptive system.