MAD2B Blunts Chronic Unpredictable Stress and Corticosterone Stimulation-Induced Depression-Like Behaviors in Mice.

BACKGROUND: Depression is a prevalent and recurrent psychiatric disorder. Aberrant neural structure and activity play fundamental roles in the occurrence of depression. Mitotic arrest deficient protein (MAD2B) is highly expressed in neurons and may be implicated in synaptic plasticity in the central nervous system. However, the effect of MAD2B in depression, as well as the related molecular mechanism, is uncertain. METHODS: Here, we employed mouse models of depression induced by chronic unpredictable stress exposure or corticosterone (CORT) stimulation. Depression-like behaviors in mice were evaluated by sucrose preference, forced swimming, and tail suspension tests. Hippocampal MAD2B overexpression was mediated by adeno-associated virus 8 containing enhanced green fluorescent protein. In vitro primary neuronal cells were obtained from the hippocampus of rat embryos and were treated with CORT, and MAD2B overexpression was performed using lentivirus. MAD2B and glutamate metabotropic receptor 4 (GRM4) levels were evaluated by western blots and quantitative PCR. Primary neuronal miR-29b-3p expression was detected by quantitative PCR. RESULTS: MAD2B expression was reduced in the hippocampus in mice exhibiting depressive-like behaviors. However, hippocampal MAD2B overexpression protected mice from developing either chronic unpredictable stress- or CORT-induced depression-like behaviors, an effect associated with reduced expression of GRM4, a presynaptic receptor involved in depression. Moreover, MAD2B overexpression in primary neuronal cells also decreased GRM4 expression while enhancing the level of miR-29b-3p; this phenomenon was also observed under CORT stimulation. CONCLUSIONS: Our results suggest an important role of neuronal MAD2B in the pathogenesis of depression via the miR-29b-3p/GRM4 signaling pathway. MAD2B could be a potential therapeutic target for depressive disorders.

Inhibition of MAD2B alleviates venous neointimal formation by suppressing VSMCs proliferation and migration.

The proliferation and migration of vascular smooth muscle cells (VSMCs) are essential events in venous neointimal hyperplasia (VNH), a culprit of arteriovenous fistula (AVF) malfunction. Mitotic arrest-deficient protein 2B (MAD2B) is a critical regulator of cell proliferation and differentiation in many scenarios. To address the role of MAD2B in VSMCs proliferation and migration during VNH, AVFs from patients with end-stage renal disease (ESRD) and chronic kidney disease (CKD) mice were used to evaluate MAD2B expression. In cultured VSMCs treated with platelet-derived growth factor-BB (PDGF-BB), the effect of MAD2B on VSMCs proliferation and migration was detected by cell counting kit-8 (CCK8) assay, immunofluorescence, wound-healing scratch and transwell assays. Besides, we exploited different small interfering RNAs (siRNAs) to explore the potential mechanisms in the issue. Furthermore, rapamycin was applied to reveal whether MAD2B-associated pathways were involved in its inhibitory effect on VSMCs proliferation and migration. Accordingly, we found that MAD2B expression was enhanced in AVFs from patients with ESRD, CKD mice and VSMCs stimulated by PDGF-BB. Meanwhile, inhibition of MAD2B alleviated VSMCs proliferation and migration while the number of ski-related novel gene (SnoN)-positive VSMCs was also increased in vivo and in vitro. Moreover, gene deletion of MAD2B decreased the level of SnoN protein in PDGF-BB-stimulated VSMCs. Furthermore, rapamycin suppressed the increased expressions of MAD2B and SnoN induced by PDGF-BB. Thus, our study demonstrates that inhibition of MAD2B suppresses the proliferation and migration of VSMCs during VNH via reducing SnoN expression. Moreover, rapamycin exerts an inhibitory effect on intimal hyperplasia, possibly via the MAD2B-SnoN axis.

Ellagic Acid and Its Anti-Aging Effects on Central Nervous System.

Aging is an unavoidable biological process that leads to the decline of human function and the reduction in people's quality of life. Demand for anti-aging medicines has become very urgent. Many studies have shown that ellagic acid (EA), a phenolic compound widely distributed in dicotyledonous plants, has powerful anti-inflammation and antioxidant properties. Moreover, it has been demonstrated that EA can enhance neuronal viability, reduce neuronal defects, and alleviate damage in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and cerebral ischemia. This paper reviews the biochemical functions and neuroprotective effects of EA, showing the clinical value of its application.

Inflammasome activation in podocytes: a new mechanism of glomerular diseases.

INTRODUCTION: Inflammasome is a multi-protein complex which is an important constituent of innate immunity. It mainly consists of three parts, apoptosis-associated speck-like protein containing caspase recruitment domain (ASC), caspase protease, and a NOD-like receptor (NLR) family protein (such as NLRP1) or an HIN200 family protein (such as AIM2). Inflammasome is widely studied in many autoimmune diseases and chronic inflammatory reactions, such as familial periodic autoinflammatory response, type 2 diabetes, Alzheimer's disease, and atherosclerosis. Activation of inflammasome in the kidney has been widely reported in glomerular and tubular-interstitial diseases. Podocytes play a critical role in maintaining the normal structure and function of glomerular filtration barrier. Recently, it has been demonstrated that podocytes, as a group of renal residential cells, can express all necessary components of NLRP3 inflammasome, which is activated and contribute to inflammatory response in the local kidney. METHODS: Literature review was conducted to further summarize current evidence of podocyte NLRP3 inflammasome activation and related molecular mechanisms under different disease conditions. RESULTS: Podocytes are a key component of the glomerular filtration barrier, and the loss of podocyte regeneration is a major limiting factor in the recovery of proteinuria. Through a more comprehensive study of inflammasome in podocytes, it will provide new targets and possibilities for the treatment of kidney diseases.

Association between chronic kidney disease and Alzheimer's disease: an update.

It has been accepted that kidney function is connected with brain activity. In clinical studies, chronic kidney disease (CKD) patients have been found to be prone to suffering cognitive decline and Alzheimer's disease (AD). The cognitive function of CKD patients may improve after kidney transplantation. All these indicators show a possible link between kidney function and dementia. However, little is known about the mechanism behind the relation of CKD and AD. This review discusses the associations between CKD and AD from the perspective of the pathophysiology of the kidney and complications and/or concomitants of CKD that may lead to cognitive decline in the progression of CKD and AD. Potential preventive and therapeutic strategies for AD are also presented. Further studies are warranted in order to confirm whether the setting of CKD is a possible new determinant for cognitive impairment in AD.

Involvement of AMPK in regulating the degradation of MAD2B under high glucose in neuronal cells.

Although our recent study has demonstrated that mitotic spindle assembly checkpoint protein (MAD2B) mediates high glucose-induced neuronal apoptosis, the mechanisms for MAD2B degradation under hyperglycaemia have not yet been elucidated. In this study, we first found that the activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) was decreased in neurons, accompanied with the increased expression of MAD2B. Mechanistically, we demonstrated that activation of AMPK with its activators such as AICAR and metformin decreased the expression of MAD2B, indicating a role of AMPK in regulating the expression of MAD2B. Moreover, activation of AMPK prevented neuronal cells from high glucose-induced injury as demonstrated by the reduced expression of cyclin B1 and percentage of apoptosis as detected by TUNEL. We further found that when total protein synthesis was suppressed by chlorhexidine, the degradation of MAD2B was slower in high glucose-treated neurons and was mainly dependent on the ubiquitin-proteasome system. Finally, it was indicated that high glucose inhibited the ubiquitination of MAD2B, which could be reversed by activation of AMPK. Collectively, this study demonstrates that AMPK acts as a key regulator of MAD2B expression, suggesting that activation of AMPK signalling might be crucial for the treatment of high glucose-induced neuronal injury.

Activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain.

Background Paclitaxel is commonly used as a cancer chemotherapy drug that frequently causes peripheral neuropathic pain. Inflammasome is a multiprotein complex consisting of Nod-like receptor proteins (NLRPs), apoptosis-associated speck-like protein, and caspase-1, which functions to switch on the inflammatory process and the release of interleukin-1ß. Growing evidences have supported that peripheral interleukin-1ß is critical in enhancing paclitaxel-induced neuropathic pain. However, whether activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain is still unclear. Results Paclitaxel induced mechanical allodynia of rats from day 3 and worsened gradually till 3 weeks after injection. Paclitaxel resulted in expression of NLRP3 and activated fragments of caspase-1 and interleukin-1ß in L4-6 dorsal root ganglia and sciatic nerve three weeks after injection, indicating activation of NLRP3 inflammasome. The expression of NLRP3 was located in CD68-labeled macrophages infiltrating in L4-6 dorsal root ganglia and sciatic nerve, and paclitaxel increased the expression of NLRP3 in macrophage. Moreover, the paclitaxel elicited mitochondria damage, which became swollen and enlarged in macrophages and axons of sciatic nerve three weeks after injection. In vitro, paclitaxel increased the number of damaged mitochondria and mitochondrial reactive oxygen species production in the rat alveolar macrophage cell line NR8383. The administration of a non-specific reactive oxygen species scavenger, phenyl-N-tert-butylnitrone, markedly alleviated mechanical allodynia and inhibited the activation of NLRP3 inflammasome in L4-6 dorsal root ganglia and sciatic nerve of the paclitaxel-induced neuropathic pain model. Conclusions Paclitaxel induced mechanical allodynia and activation of NLRP3 inflammasome in infiltrated macrophages of L4-6 dorsal root ganglia and sciatic nerve. Paclitaxel elicited mitochondria damage and reactive oxygen species production may result in activation of NLRP3 inflammasome in peripheral nerve, which contributes to paclitaxel-induced neuropathic pain.

Activation and expression of µ-calpain in dorsal root contributes to RTX-induced mechanical allodynia.

Background Calpain is a calcium-dependent cysteine protease, and inhibition of calpain by pre-treatment with MDL28170 attenuated the rat mechanical allodynia in a variety of pain models. Postherpetic neuralgia (Shingles) is a neuropathic pain conditioned with the presence of profound mechanical allodynia. Systemic injection of resiniferatoxin can reproduce the clinical symptoms of postherpetic neuralgia. In this study, we determined to study whether activation of calpain contributes to cleave the myelin basic protein of dorsal root and is involved in resiniferatoxin-induced mechanical allodynia of postherpetic neuralgia animal model. Results Resiniferatoxin up-regulated the expression and activation of µ-calpain in dorsal root. The expression of µ-calpain was located in Schwann cell of dorsal root, and resiniferatoxin increased the expression of µ-calpain in Schwann cell in L4-L6 dorsal root at six weeks after injection. Resiniferatoxin also induced myelin basic protein degradation in L4-L6 dorsal root at six weeks after injection. Moreover, intraperitoneal injection of calpain inhibitor MDL28170 prevented the degradation of myelin basic protein and then reduced the sprouting of myelinated afferent fibers into spinal lamina II, thus relieving resiniferatoxin-induced mechanical allodynia. Conclusions Up-regulation and activation of µ-calpain located in Schwann cell may be the mechanism underlying resiniferatoxin-mediated proteolysis of myelin basic protein in dorsal root. Calpain inhibitor MDL28170 prevents resiniferatoxin-induced sprouting of myelinated afferent fibers and mechanical allodynia through inhibition of degradation of the myelin basic protein in dorsal root. Our results indicate that inhibition of pathological µ-calpain activation may present an interesting novel drug target in the treatment of postherpetic neuralgia.

Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B.

BACKGROUND/AIMS: Metformin, the common medication for type II diabetes, has protective effects on cerebral ischemia. However, the molecular mechanisms are far from clear. Mitotic arrest deficient 2-like protein 2 (MAD2B), an inhibitor of the anaphase-promoting complex (APC), is widely expressed in hippocampal and cortical neurons and plays an important role in mediating high glucose-induced neurotoxicity. The present study investigated whether metformin modifies the expression of MAD2B and to exert its neuroprotective effects in primary cultured cortical neurons during oxygen-glucose deprivation/reoxygenation (OGD/R), a widely used in vitro model of ischemia/reperfusion. METHODS: Primary cortical neurons were cultured, deprived of oxygen-glucose for 1 h, and then recovered with oxygen-glucose for 12 h and 24 h. Cell viability was measured by detecting the levels of lactate dehydrogenase (LDH) in culture medium. The levels of MAD2B, cyclin B and p-histone 3 were measured by Western blot. RESULTS: Cell viability of neurons was reduced under oxygen-glucose deprivation/reoxygenation (OGD/R). The expression of MAD2B was increased under OGD/R. The levels of cyclin B1, which is a substrate of APC, were also increased. Moreover, OGD/R up-regulated the phosphorylation levels of histone 3, which is the induction of aberrant re-entry of post-mitotic neurons. However, pretreatment of neurons with metformin alleviated OGD/R-induced injury. Metformin further decreased the expression of MAD2B, cyclin B1 and phosphorylation levels of histone 3. CONCLUSION: Metformin exerts its neuroprotective effect through regulating the expression of MAD2B in neurons under OGD/R.

Thioredoxin-interacting protein mediates NALP3 inflammasome activation in podocytes during diabetic nephropathy.

Numerous studies have shown that the NALP3 inflammasome plays an important role in various immune and inflammatory diseases. However, whether the NALP3 inflammasome is involved in the pathogenesis of diabetic nephropathy (DN) is unclear. In our study, we confirmed that high glucose (HG) concentrations induced NALP3 inflammasome activation both in vivo and in vitro. Blocking NALP3 inflammasome activation by NALP3/ASC shRNA and caspase-1 inhibition prevented IL-1ß production and eventually attenuated podocyte and glomerular injury under HG conditions. We also found that thioredoxin (TRX)-interacting protein (TXNIP), which is a pro-oxidative stress and pro-inflammatory factor, activated NALP3 inflammasome by interacting with NALP3 in HG-exposed podocytes. Knocking down TXNIP impeded NALP3 inflammasome activation and alleviated podocyte injury caused by HG. In summary, the NALP3 inflammasome mediates podocyte and glomerular injury in DN, moreover, TXNIP participates in the formation and activation of the NALP3 inflammasome in podocytes during DN, which represents a novel mechanism of podocyte and glomerular injury under diabetic conditions.

MAD2B contributes to podocyte injury of diabetic nephropathy via inducing cyclin B1 and Skp2 accumulation.

It is well documented that mitotic arrest deficiency (MAD)2B can inhibit the anaphase-promoting complex/cyclosome (APC/C) via cadherin (Cdh)1 and, consequently, can destroy the effective mitotic spindle checkpoint control. Podocytes have been observed to rapidly detach and die when being forced to bypass cell cycle checkpoints. However, the role of MAD2B, a cell cycle regulator, in podocyte impairment of diabetic nephropathy (DN) is unclear. In the present study, we investigated the significance of MAD2B in the pathogenesis of DN in patients, an animal model, and in vitro podocyte cultures. By Western blot and immunohistochemistry analyses, we found that MAD2B was evidently upregulated under high glucose milieu in vivo and in vitro, whereas Cdh1 was inhibited with high glucose exposure. Overexpression of MAD2B in podocytes by plasmid DNA transfection suppressed expression of Cdh1 and triggered the accumulation of cyclin B1 and S phase kinase-associated protein (Skp)2, two key molecules involving in cell cycle regulation, and the subsequent podocyte insult. In contrast, MAD2B deletion alleviated the high glucose-induced reduction of Cdh1 as well as the elevation of cyclin B1 and Skp2, which rescued the podocyte from damage. Taken together, our data demonstrate that MAD2B may play an important role in high glucose-mediated podocyte injury of DN via modulation of Cdh1, cyclin B1, and Skp2 expression.

Attenuation of glomerular endothelial cells from high glucose-induced injury by blockade of MAD2B.

BACKGROUND/AIMS: To assess the role of mitotic arrest-deficient 2-like protein 2 (MAD2B) in high glucose-induced injury in mouse glomerular endothelial cells (GEnCs). METHODS: GEnCs were cultured in vitro, and MAD2B protein levels were measured by Western blot in cells stimulated with high glucose (30 mM) for various periods of time. MAD2B and scrambled shRNA were introduced into GEnCs by liposomal transfection. Cell proliferation, apoptosis, nitric oxide (NO) production, and monolayer permeability were then measured in cells grown in the following conditions: control, high glucose treatment, MAD2B shRNA transfection with high glucose treatment, and scrambled shRNA transfection with high glucose treatment. RESULTS: High glucose increased the protein levels of MAD2B in GEnCs. Compared with control cells, apoptosis was increased by high glucose treatment, which was attenuated by transfection with MAD2B shRNA transfection. Cells treated with high glucose produced less NO than control cells, whereas MAD2B shRNA transfection increased NO production. Cell monolayer permeability was enhanced in high glucose treated cells, but MAD2B shRNA transfection reduced permeability. CONCLUSION: High glucose levels induced the expression of MAD2B in GEnCs, whereas suppressing its expression reduced high glucose-induced endothelial cell apoptosis and high permeability, and promoted cell proliferation and NO production.

The Expression and Significance of NLRP3 Inflammasome in Patients with Primary Glomerular Diseases.

BACKGROUND/AIMS: Primary glomerulonephritis (PGN) is the most common reason inducing end stage renal disease in China, however, its pathogenesis remains unclear. The present study was designed to test the hypothesis that the formation and activation of NLRP3 (Nod-like receptor family pyrin domain containing 3) inflammasomes is an important initiating mechanism resulting in PGN. METHODS: Serum samples and frozen sections were collected from 38 cases with PGN, and renal tissues were obtained from 22 of them. NLRP3 inflammasomes were detected by RT-PCR and immunofluoresence methods. The relationship between NLRP3 and clinical/pathologic indexes was analyzed. RESULTS: RT-PCR analyses demonstrated that the mRNA levels of NLRP3 and caspase-1 genes were elevated significantly in renal tissues of PGN patients compared to those from normal pericarcinoma tissues. Moreover, the increased level of NLRP3 mRNA was correlative with a decrease in nephrin mRNA level and an increase in desmin mRNA level, which indicates that NLRP3 participates in podocyte injury in PGN patients. Immunofluorescence analysis also showed the protein expressions of NLRP3 and caspase-1 were increased in the glomeruli of PGN patients. Neverthless, there was no obvious regularity was presented in further subgroup analysis according to pathological types. In addition, increased NLRP3 was associated with the deterioration of renal function and glomerulosclerosis. IL-1ß, a product of NLRP3 inflammasome activation, had a significant correlation with proteinuria. CONCLUSIONS: The formation and activation of NLRP3 inflammasomes in podocytes has been importantly implicated in the development of PGN-associated glomerular injury.

Protection of neurons from high glucose-induced injury by deletion of MAD2B.

Diabetic encephalopathy may lead to cognitive deficits in diabetic patients and diminish quality of life. It has been shown that protracted hyperglycaemia is directly associated with neuronal apoptosis, which is involved in diabetic encephalopathy. The anaphase-promoting complex (APC) is essential for the survival of post-mitotic neurons. In our previous study, we found that the mitotic arrest deficient protein MAD2B, one of APC inhibitors, was expressed in neurons in central nervous system. However, whether MAD2B is involved in hyperglycaemia-induced apoptosis and thus takes part in diabetic encephalopathy is still unknown. To address this issue, we first explored the expression of MAD2B and cyclin B1 detected by immunofluorescence and Western blot. It was found that hyperglycaemia remarkably increased the expression of MAD2B and accumulation of cyclin B1 in cortices of diabetes mellitus rat model and in cultured primary neurons. To further explore the role of MAD2B in hyperglycaemia-induced neuronal injury, we depleted MAD2B expression by a specifically targeted shRNA against MAD2B. We observed that MAD2B deficiency alleviated cyclin B1 expression and apoptotic neuronal death. These results demonstrate that MAD2B expression is the main culprit for accumulation of cyclin B1 and apoptosis in neurons under high glucose. Moreover, inhibition of the expression of MAD2B prevented neurons from entering an aberrant S phase that led differentiated neurons into apoptotic cell death. These results suggest that hyperglycaemia induced neuronal apoptosis through inducing expression of MAD2B, which represents a novel mechanism of diabetic encephalopathy.

Catechin Protects against Lipopolysaccharide-induced Depressive-like Behaviour in Mice by Regulating Neuronal and Inflammatory Genes.

BACKGROUND: Many studies have suggested that tea has antidepressant effects; however, the underlying mechanism is not fully studied. As the main anti-inflammatory polyphenol in tea, catechin may contribute to the protective role of tea against depression. OBJECTIVE: The objective of this study is to prove that catechin can protect against lipopolysaccharide (LPS)-induced depressive-like behaviours in mice, and then explore the underlying molecular mechanisms. METHODS: Thirty-one C57BL/6J mice were categorized into the normal saline (NS) group, LPS group, catechin group, and amitriptyline group according to their treatments. Elevated Plus Maze (EPM), Tail Suspension Test (TST), and Open Field Test (OFT) were employed to assess depressive- like behaviours in mice. RNA sequencing (RNA-seq) and subsequent Bioinformatics analyses, such as differential gene analysis and functional enrichment, were performed on the four mouse groups. RESULTS: In TST, the mice in the LPS group exhibited significantly longer immobility time than those in the other three groups, while the immobility times for the other three groups were not significantly different. Similarly in EPM, LPS-treated mice exhibited a significantly lower percentage in the time/path of entering open arms than the mice in the other three groups, while the percentages of the mice in the other three groups were not significantly different. In OFT, LPS-treated mice exhibited significantly lower percentages in the time/path of entering the centre area than those in the other three groups. The results suggested that the LPS-induced depression models were established successfully and catechin can reverse (LPS)-induced depressive-like behaviours in mice. Finally, RNA-seq analyses revealed 57 differential expressed genes (DEGs) between LPS and NS with 19 up-regulated and 38 down-regulated. Among them, 13 genes were overlapped with the DEGs between LPS and cetechin (in opposite directions), with an overlapping p-value < 0.001. The 13 genes included Rnu7, Lcn2, C4b, Saa3, Pglyrp1, Gpx3, Lyz2, S100a8, S100a9, Tmem254b, Gm14288, Hbb-bt, and Tmem254c, which might play key roles in the protection of catechin against LPS-induced depressive-like behaviours in mice. The 13 genes were significantly enriched in defense response and inflammatory response, indicating that catechin might work through counteracting changes in the immune system induced by LPS. CONCLUSION: Catechin can protect mice from LPS-induced depressive-like behaviours through affecting inflammatory pathways and neuron-associated gene ontologies.

Targeting MAD2B as a strategy for ischemic stroke therapy.

INTRODUCTION: Post-stroke cognitive impairment is one of the major causes of disability due to cerebral ischemia. MAD2B is an inhibitor of Cdh1/APC, and loss of Cdh1/APC function in mature neurons increases ROCK2 activity, leading to changes in synaptic plasticity and memory loss in mouse neurons. Whether MAD2B regulates learning memory capacity through ROCK2 in cerebral ischemia is not known. OBJECTIVES: We investigated the role and mechanism of MAD2B in cerebral ischemia-induced cognitive dysfunction. METHODS: The expression of MAD2B and its downstream related molecules was detected by immunoblotting and intervened with neuroprotectants after middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R). We constructed MAD2B-cKO-specific knockout mice, knocked down and overexpressed MAD2B in mouse hippocampus by lentiviral injection in brain stereotaxis, modeled cerebral ischemia by using MCAO, and explored the role of MAD2B in post-stroke cognitive impairment (PSCI) by animal behaviors such as Y-maze and Novel object recognition test. Then the expression of MAD2B/ROCK2, downstream molecules and apoptosis-related molecules was detected. Finally, ROCK2 expression was intervened using its inhibitor and shRNA-ROCK2 lentivirus. RESULTS: The expression of MAD2B and its downstream molecules increased after MCAO and OGD/R. Nonetheless, this expression underwent a decline post-therapy with neuroprotective agents. Deletion of MAD2B in the hippocampus ameliorated memory and learning deficits and improved motor coordination in MCAO mice. Conversely, the overexpression of MAD2B in the hippocampus exacerbated learning and memory deficits. Deletion of MAD2B resulted in the downregulation of ROCK2/LIMK1/cofilin. It effectively reduced ischemia-induced upregulation of BAX and cleaved caspase-3, which could be reversed by MAD2B overexpression. Inhibition or knockdown of ROCK2 expression in primary cultured neurons led to the downregulation of LIMK1/cofilin expression and reduced the expression of apoptosis-associated molecules induced by ischemia. CONCLUSIONS: Our findings suggest that MAD2B affects neuronal apoptosis via Rock2, which affects neurological function and cerebral infarction.

Deficiency of Nuclear Receptor Coactivator 3 Aggravates Diabetic Kidney Disease by Impairing Podocyte Autophagy.

Nuclear receptors (NRs) are important transcriptional factors that mediate autophagy, preventing podocyte injury and the progression of diabetic kidney disease (DKD). However, the role of nuclear receptor coactivators that are powerful enhancers for the transcriptional activity of NRs in DKD remains unclear. In this study, a significant decrease in Nuclear Receptor Coactivator 3 (NCOA3) is observed in injured podocytes caused by high glucose treatment. Additionally, NCOA3 overexpression counteracts podocyte damage by improving autophagy. Further, Src family member, Fyn is identified to be the target of NCOA3 that mediates the podocyte autophagy process. Mechanistically, NCOA3 regulates the transcription of Fyn in a nuclear receptor, PPAR-γ dependent way. Podocyte-specific NCOA3 knockout aggravates albuminuria, glomerular sclerosis, podocyte injury, and autophagy in DKD mice. However, the Fyn inhibitor, AZD0530, rescues podocyte injury of NCOA3 knockout DKD mice. Renal NCOA3 overexpression with lentivirus can ameliorate podocyte damage and improve podocyte autophagy in DKD mice. Taken together, the findings highlight a novel target, NCOA3, that protects podocytes from high glucose injury by maintaining autophagy.

Electroacupuncture improves thermal and mechanical sensitivities in a rat model of postherpetic neuralgia.

BACKGROUND: Electroacupuncture (EA) is effective in relieving pain in patients with postherpetic neuralgia (PHN). However, the mechanism underlying the therapeutic effect of EA in PHN is still unclear. Systemic injection of resiniferatoxin (RTX), an ultrapotent analog of TRPV1 agonist, in adult rats can reproduce the clinical symptoms of PHN by ablating TRPV1-expressing sensory neurons. In this study, we determined the beneficial effect of EA and the potential mechanisms in this rat model of PHN. METHODS: PHN was induced in rats by a single injection of RTX. Thermal hyperalgesia was tested with a radiant heat stimulus, and mechanical allodynia was quantified with von Frey filaments. TRPV1 receptors were shown by using immunofluorescence labeling. The ultrastructural changes of the sciatic nerve were assessed by electron microscopic examination. The sprouting of myelinated primary afferent terminals into the spinal dorsal horn was mapped by using the transganglionic tracer cholera toxin B-subunit (CTB). RESULTS: RTX injection diminished thermal sensitivity and gradually induced tactile allodynia within 3 weeks. EA applied to GB30 and GB34 at 2 and 15 Hz, but not 100 Hz, significantly increased the thermal sensitivity 4 weeks after treatment and decreased the tactile allodynia 2 weeks after treatment in RTX-treated rats. EA treatment at 2 and 15 Hz recovered the loss of TRPV1-positive dorsal root ganglion neurons and their central terminals of afferent fibers in the spinal superficial dorsal horn of RTX-treated rats. Moreover, EA significantly reduced the loss of unmyelinated fibers and the damage of the myelinated nerve fibers of RTX-treated rats. Furthermore, EA at 2 and 15 Hz inhibited the sprouting of myelinated primary afferent terminals into the spinal lamina II of RTX-treated rats. CONCLUSIONS: EA treatment improves thermal perception by recovering TRPV1-positive sensory neurons and nerve terminals damaged by RTX. EA Also reduces RTX-induced tactile allodynia by attenuating the damage of myelinated afferent nerves and their abnormal sprouting into the spinal lamina II. Our study provides new information about the mechanisms of the therapeutic actions of EA in the treatment of PHN.

Actin-associated Proteins in the Pathogenesis of Podocyte Injury.

Podocytes have a complex cellular architecture with interdigitating processes maintained by a precise organization of actin filaments. The actin-based foot processes of podocytes and the interposed slit diaphragm form the final barrier to proteinuria. The function of podocytes is largely based on the maintenance of the normal foot process structure with actin cytoskeleton. Cytoskeletal dynamics play important roles during normal podocyte development, in maintenance of the healthy glomerular filtration barrier, and in the pathogenesis of glomerular diseases. In this review, we focused on recent findings on the mechanisms of organization and reorganization of these actin-related molecules in the pathogenesis of podocyte injury and potential therapeutics targeting the regulation of actin cytoskeleton in podocytopathies.

Vitamin D and neurodegenerative diseases.

Neurodegenerative diseases, featured by progressive loss of structure or function of neurons, are considered incurable at present. Movement disorders like tremor and postural instability, cognitive or behavioral disorders such as memory impairment are the most common symptoms of them and the growing patient population of neurodegenerative diseases poses a serious threat to public health and a burden on economic development. Hence, it is vital to prevent the occurrence of the diseases and delay their progress. Vitamin D can be transformed into a hormone in vivo with both genomic and non-genomic actions, exerting diverse physiological effects. Cumulative evidence indicates that vitamin D can ameliorate neurodegeneration by regulating pertinent molecules and signaling pathways including maintaining Ca2+ homeostasis, reducing oxidative stress, inhibiting inflammation, suppressing the formation and aggregation of the pathogenic protein, etc. This review updates discoveries of molecular mechanisms underlying biological functions of vitamin D in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and vascular dementia. Clinical trials investigating the influence of vitamin D supplementation in patients with neurodegenerative diseases are also summarized. The synthesized information will probably provoke an enhanced understanding of the neuroprotective roles of vitamin D in the nervous system and provide therapeutic options for patients with neurodegenerative diseases in the future.