Impact of GADD34 on Apoptosis of Tonsillar Mononuclear Cells from IgA Nephropathy Patients by Regulating Eif2α Phosphorylation

Background/Aims: Tonsillectomy may be an important method to achieve a long-term remission of IgAN, but patients’ physical status may limit their access to this surgery. We proposed an encouraging solution through inhibiting GADD34 expression in order to promote tonsillar mononuclear cells (TMCs) apoptosis and reduce nephropathic IgA secretion. Methods: A total of 12 IgAN and 9 non-IgAN patients were involved from March 2015 to May 2016. After TMCs were extracted by density gradient centrifugation and stimulated by inactivated hemolytic streptococcus, the mRNA and protein expression of GADD34, GRP78, CHOP, Bcl-2, Bcl-XL, AID, Iα-Cα, and cleaved caspase-3 were examined by fluorescent RT-PCR and Western blotting. Guanabenz treatment and siRNA interference were applied to downregulate GADD34 in tonsillar mononuclear cells from IgAN patients, and P-eIF2α expression was examined by Western Blotting. Cell apoptosis was evaluated by Annexin V FITC/PI flowcytometry, and IgA secretion in cultural supernatant was inspected by enzyme linked immunosorbent assay. Results: After stimulation, the expression of GADD34 was significantly increased in IgAN patients (P< 0.05). Cell apoptosis was mitigated and IgA secretion level was elevated (P< 0.05). To be noticed, CHOP expression had no significant difference between two groups. After guanabenz treatment and siRNA interference, a prolonged elevation of P-eIF2α expression was observed. Cell apoptosis was reinforced and IgA secretion level was decreased (P< 0.05). Conclusion: GADD34 may be a potential therapeutic target for IgAN treatment due to its effect on cell apoptosis

Synaptic Targeting and Function of SAPAPs Mediated by Phosphorylation-Dependent Binding to PSD-95 MAGUKs

The PSD-95/SAPAP/Shank complex functions as the major scaffold in orchestrating the formation and plasticity of the post-synaptic densities (PSDs). We previously demonstrated that the exquisitely specific SAPAP/Shank interaction is critical for Shank synaptic targeting and Shank-mediated synaptogenesis. Here, we show that the PSD-95/SAPAP interaction, SAPAP synaptic targeting, and SAPAP-mediated synaptogenesis require phosphorylation of the N-terminal repeat sequences of SAPAPs. The atomic structure of the PSD-95 guanylate kinase (GK) in complex with a phosphor-SAPAP repeat peptide, together with biochemical studies, reveals the molecular mechanism underlying the phosphorylation-dependent PSD-95/SAPAP interaction, and it also provides an explanation of a PSD-95 mutation found in patients with intellectual disabilities. Guided by the structural data, we developed potent non-phosphorylated GK inhibitory peptides capable of blocking the PSD-95/SAPAP interaction and interfering with PSD-95/SAPAP-mediated synaptic maturation and strength. These peptides are genetically encodable for investigating the functions of the PSD-95/SAPAP interaction in vivo. Using structural biology, cell biology, and electrophysiology approaches, Zhu et al. demonstrate that phosphorylation of the N-terminal repeating sequences of SAPAPs is required for the SAPAP/PSD-95 complex formation and SAPAP's synaptic targeting and maturation functions. They also developed a potent non-phosphorylated PSD-95 GK inhibitory peptide that can effectively disrupt the SAPAP/PSD-95 complex formation and thus inhibit excitatory synaptic activities. Keywords: GK domain; PSD-95; SAPAP; MAGUK; postsynaptic density; synaptic scaffold proteins; synaptogenesis; synaptic plasticit

Unveiling the influence of methyl jasmonate on key sugar metabolism genes in developing loquat fruit

The evaluation of fruit quality greatly relies on the presence of soluble sugars. In this study, we investigated the dynamics of soluble sugars and basic fruit quality of 'Zaozhong 6' loquat after the application of methyl jasmonate (MeJA). As loquats approached full ripeness, the study unveiled a notable increase in their soluble sugar content, predominantly attributed to the rise in fructose levels. MeJA application accelerated sugar accumulation, suggesting its potential for expediting fruit maturation and enhancing sugar content. Importantly, MeJA-treated fully ripe loquats exhibited a significantly higher sugar-acid ratio. In addition to compositional analyses, the study delves into the molecular aspects of sugar metabolism. Despite the absence of detectable sucrose and glucose, the expressions of FK, HK, SPP, SPS, and SS genes were notably influenced, emphasizing the complex regulatory mechanisms governing sugar metabolism in loquat fruit. This research provides valuable insights into the temporal changes in sugar composition during loquat fruit development, underscores the role of MeJA in shaping these dynamics, and highlights the significance of the sugar-acid ratio in fruit quality determination

Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity

α-synuclein (α-syn) is a main component of Lewy bodies (LB) that occur in many neurodegenerative diseases, including Parkinson's disease (PD), dementia with LB (DLB) and multi-system atrophy. α-syn mutations or amplifications are responsible for a subset of autosomal dominant familial PD cases, and overexpression causes neurodegeneration and motor disturbances in animals. To investigate mechanisms for α-syn accumulation and toxicity, we studied a mouse model of lysosomal enzyme cathepsin D (CD) deficiency, and found extensive accumulation of endogenous α-syn in neurons without overabundance of α-syn mRNA. In addition to impaired macroautophagy, CD deficiency reduced proteasome activity, suggesting an essential role for lysosomal CD function in regulating multiple proteolytic pathways that are important for α-syn metabolism. Conversely, CD overexpression reduces α-syn aggregation and is neuroprotective against α-syn overexpression-induced cell death in vitro. In a C. elegans model, CD deficiency exacerbates α-syn accumulation while its overexpression is protective against α-syn-induced dopaminergic neurodegeneration. Mutated CD with diminished enzymatic activity or overexpression of cathepsins B (CB) or L (CL) is not protective in the worm model, indicating a unique requirement for enzymatically active CD. Our data identify a conserved CD function in α-syn degradation and identify CD as a novel target for LB disease therapeutics

Rapamycin Ameliorates Kidney Fibrosis by Inhibiting the Activation of mTOR Signaling in Interstitial Macrophages and Myofibroblasts

Interstitial fibrosis is an inevitable outcome of all kinds of progressive chronic kidney disease (CKD). Emerging data indicate that rapamycin can ameliorate kidney fibrosis by reducing the interstitial infiltrates and accumulation of extra cellular matrix (ECM). However, the cellular mechanism that regulates those changes has not been well understood yet. In this study, we revealed the persistent activation of mammalian target of rapamycin (mTOR) signaling in the interstitial macrophages and myofibroblasts, but rarely in injured proximal epithelial cells, CD4+ T cells, neutrophils, or endothelial cells, during the development of kidney fibrosis. Administration of rapamycin to unilateral ureteral obstruction (UUO) mice significantly suppressed the immunoreactivity of mTOR signaling, which decreased the inflammatory responses and ECM accumulation in the obstructed kidneys. Isolated macrophages from rapamycin-treated obstructed kidneys presented less inflammatory activity than vehicle groups. In vitro study confirmed that rapamycin significantly inhibited the fibrogenic activation of cultured fibroblasts (NIH3T3 cells), which was induced by the stimulation of TGF-β1. Further experiment revealed that rapamycin did not directly inhibit the fibrogenesis of HK2 cells with aristolochic acid treatment. Our findings clarified that rapamycin can ameliorate kidney fibrosis by blocking the mTOR signaling in interstitial macrophages and myofibroblasts

Descriptions of immature stages of Octodonta nipae (Maulik) (Coleoptera, Chrysomelidae, Cassidinae, Cryptonychini)

Volume: 764Start Page: 91End Page: 10

Azimuth Ambiguity Suppression in SAR Images Based on Compressive Sensing Recovery Algorithm

Azimuth ambiguities appear widely throughout spaceborne Synthetic Aperture Radar (SAR) images. If the ambiguous energy is relatively strong, a large number of brilliant areas or points will emerge, which may be erroneously judged as actual targets. This is a disadvantage in image interpretation. Due to the fact that ambiguous energy is mixed with energy from the main zone in the frequency and time domains, it is difficult to suppress azimuth ambiguity to a reasonable level using the existing approach without loss of resolution. This study proposes an innovative approach for suppressing azimuth ambiguity based on the compressive sensing recovery framework, in which the original image acts as prior information and the corresponding frequency spectrum truncated in a proper ratio acts as measurement information. With the proposed approach, highresolution low-ambiguity images can be obtained by iteration. We used simulation and satellite data to validate the effectiveness of this proposed approach in suppressing azimuth ambiguity

Role Of KAtp Channels In Protection Against Neuronal Excitatory Insults

ATP-sensitive K+ (KATP) channels that are gated by intracellular ATP/ADP concentrations are a unique subtype of potassium channels and play an essential role in coupling intracellular metabolic events to electrical activity. Opening of KATP channels during energy deficits in the CNS induces efflux of potassium ions and in turn hyperpolarizes neurons. Thus, activation of KATP channels is thought to be able to counteract excitatory insults and protect against neuronal death. In this review, we bring together recent studies about what kinds of molecules are needed to build and regulate arrays of KATP channel functions in the CNS neurons. We propose a model to explain how KATP channel activation regulates glutamate release from the pre-synaptic terminals and how this regulation protects against ischemic neuronal injury and epilepsy. © 2007 The Authors

Vibration Induces BAFF Overexpression and Aberrant O-Glycosylation of IgA1 in Cultured Human Tonsillar Mononuclear Cells in IgA Nephropathy

Objective. To investigate the influence of in vitro vibratory stimulation of human tonsillar mononuclear cells (TMCs). Methods. Fourteen IgA nephropathy (IgAN) patients with chronic tonsillitis (CT) and 12 CT patients with no renal pathology were enrolled. Group A TMCs were collected after 24 hours of culture and used to determine baseline levels. TMCs in groups B, C, D, E, and F were exposed to vibratory stimulation (60 Hz) for 0 (as the control group), 1, 3, 5, and 10 minutes, respectively. Results. Baseline concentrations of B-cell-activation factor (BAFF) and IgA1, BAFF mRNA expression, and aberrant O-glycosylation IgA1 level were higher in the IgAN group as compared to that in the CT group, and all increased after vibratory stimulation. Baseline mRNA expressions of core β1,3-galactosyltransferase (C1GALT1) and core β1,3GalT-specific molecular chaperone (Cosmc) were lower in the IgAN group; the levels decreased further after vibratory stimulation. Conclusion. In patients with IgAN, vibratory stimulation of TMCs appears to induce IgA1 secretion through activation of BAFF release and to aberrant O-glycosylation IgA1 by suppressing C1GALT1 and Cosmc expression. In vitro vibratory stimulation of human TMCs mimics the vibratory simulation of palatine tonsils produced by vocal cords during phonation