Cholecystokinin B receptor antagonists for the treatment of depression via blocking long-term potentiation in the basolateral amygdala.

Depression is a common and severe mental disorder. Evidence suggested a substantial causal relationship between stressful life events and the onset of episodes of major depression. However, the stress-induced pathogenesis of depression and the related neural circuitry is poorly understood. Here, we investigated how cholecystokinin (CCK) and CCKBR in the basolateral amygdala (BLA) are implicated in stress-mediated depressive-like behavior. The BLA mediates emotional memories, and long-term potentiation (LTP) is widely considered a trace of memory. We identified that the cholecystokinin knockout (CCK-KO) mice impaired LTP in the BLA, while the application of CCK4 induced LTP after low-frequency stimulation (LFS). The entorhinal cortex (EC) CCK neurons project to the BLA and optogenetic activation of EC CCK afferents to BLA-promoted stress susceptibility through the release of CCK. We demonstrated that EC CCK neurons innervate CCKBR cells in the BLA and CCK-B receptor knockout (CCKBR-KO) mice impaired LTP in the BLA. Moreover, the CCKBR antagonists also blocked high-frequency stimulation (HFS) induced LTP formation in the BLA. Notably, CCKBR antagonists infusion into the BLA displayed an antidepressant-like effect in the chronic social defeat stress model. Together, these results indicate that CCKBR could be a potential target to treat depression.

RNF152 negatively regulates Wnt/ß-catenin signaling in Xenopus embryos.

The Wnt/ß-catenin signaling plays crucial roles in early development, tissue homeostasis, stem cells, and cancers. Here, we show that RNF152, an E3 ligase localized to lysosomes, acts as a negative regulator of the Wnt/ß-catenin pathway during Xenopus early embryogenesis. Overexpression of wild-type (WT) RNF152 inhibited XWnt8-induced stabilization of ß-catenin, ectopic expression of target genes, and activity of a Wnt-responsive promoter. Likewise, an E3 ligase-defective RNF152 had repressive effects on the Wnt-dependent gene responses but not its truncation mutant lacking the transmembrane domain. Conversely, knockdown of RNF152 further enhanced the transcriptional responses induced by XWnt8. RNF152 morphants exhibited defects in craniofacial structures and pigmentation. In line with this, the gain-of-RNF152 function interfered with the expression of neural crest (NC) markers, whereas its depletion up-regulated NC formation in the early embryo. Mechanistically, RNF152 inhibits the polymerization of Dishevelled, which is key to Wnt signaling, in an E3 ligase-independent manner. Together, these results suggest that RNF152 controls negatively Wnt/ß-catenin signaling to fine-tune its activity for NC formation in Xenopus embryo. [BMB Reports 2022; 55(5): 232-237].

Wip1 regulates Smad4 phosphorylation and inhibits TGF-ß signaling.

The tumor suppressor Smad4, a key mediator of the TGF-ß/BMP pathways, is essential for development and tissue homeostasis. Phosphorylation of Smad4 in its linker region catalyzed by the mitogen-activated protein kinase (MAPK) plays a pivotal role in regulating its transcriptional activity and stability. In contrast, roles of Smad4 dephosphorylation as a control mechanism of TGF-ß/BMP signaling and the phosphatases responsible for its dephosphorylation remain so far elusive. Here, we identify Wip1 as a Smad4 phosphatase. Wip1 selectively binds and dephosphorylates Smad4 at Thr277, a key MAPK phosphorylation site, thereby regulating its nuclear accumulation and half-life. In Xenopus embryos, Wip1 limits mesoderm formation and favors neural induction by inhibiting TGF-ß/BMP signals. Wip1 restrains TGF-ß-induced growth arrest, migration, and invasion in human cells and enhances the tumorigenicity of cancer cells by repressing the antimitogenic activity of Smad4. We propose that Wip1-dependent dephosphorylation of Smad4 is critical for the regulation of TGF-ß signaling.

New Absorbable Microvascular Anastomotic Devices Representing a Modified Sleeve Technique: Evaluation of Two Types of Source Material and Design.

The purpose of this study was to create a new absorbable vascular anastomotic coupler and evaluate the patency and degradation degree. Vascular anastomosis was performed in the jugular vein in 31 New Zealand white female rabbits. The coupler consisted of an inner and outer ring. One side of the jugular vein was passed through and overlapped the inner ring. The opposite side of the jugular vein overlapped the everted jugular vein on the inner ring. Then, the outer ring engaged with the inner ring and completed the anastomosis. The outer rings were also constructed with two shapes including an O-type that had no slit and a C-type with a slit on the outer ring of the O-type coupler to allows expandability of the diameter. A Phase I experiment was performed to evaluate the degradability of the source materials, including the poly (lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL) couplers. A Phase II experiment was performed to evaluate the patency and anastomosis time of the O-type PLGA and PCL couplers. A Phase III experiment was performed to evaluate the patency and anastomosis time of suture anastomosis (control) and the C-type PLGA coupler. The patency was determined by ultrasonography and open exploration. Histological analysis was performed to determine the degradability of the couplers. In Phase I, the PLGA couplers were completely degraded with good vascular wall remodeling at 8 months, while the PCL couplers demonstrated incomplete degradation. In Phases II and III, the anastomosis time was significantly shorter in the coupler groups than that in the control group. All of the coupler groups demonstrated complete patency of the anastomoses on ultrasonography. In Phase III, the C-type PLGA coupler also demonstrated patency and complete degradation at 8 months. PLGA is a suitable source material for absorbable couplers due to its fast degradability. We devised the O-shaped outer ring for the C-shaped outer ring to increase flexibility, which also demonstrated complete patency during the experimental period. Our absorbable microvascular anastomosis devices could provide rapid and reliable microvascular anastomosis without anastomotic failure.

Role of dipeptidyl peptidase-4 as a potentiator of activin/nodal signaling pathway.

DPP4 (dipeptidyl peptidase-4), a highly conserved transmembrane glycoprotein with an exo-peptidase activity, has been shown to contribute to glucose metabolism, immune regulation, signal transduction, and cell differentiation. Here, we show that DPP4 is involved in control of activin/nodal signaling in Xenopus early development. In support of this, gain of function of DPP4 augmented Smad2 phosphorylation as well as expression of target genes induced by activin or nodal signal. In addition, Dpp4 and Xnr1 showed synergistic effect on induction of ectopic dorsal body axis, when co-injected at suboptimal doses in early embryos. Conversely, saxagliptin, a DPP4 inhibitor repressed activin induction of Smad2 phosphorylation. Notably, overexpression of Dpp4 disrupted specification of dorsal body axis of embryo, leading to malformed phenotypes such as spina bifida and a shortened and dorsally bent axis. Together, these results suggest that DPP4 functions as a potentiator of activin/nodal signaling pathway. [BMB Reports 2018; 51(12): 636-641].

Radiation Therapy Following Total Keloidectomy: A Retrospective Study over 11 Years.

BACKGROUND: Radiotherapy treatment after keloidectomy is known to be an effective method for reducing the rate of recurrence. However, to date, the appropriate total radiation dose and fractionation have not yet been confirmed. The authors performed a retrospective analysis to identify the appropriate radiation dose and fractionation in post-keloidectomy radiotherapy. METHODS: From May 2000 to February 2011, postoperative radiotherapy was performed on 39 lesions in 28 patients after total keloidectomy. The keloid lesions were confined to the ear lobes. Between May 2000 and May 2004, 14 keloids were treated with surgical excision, followed by a total radiation dose of 1,200 cGy in three fractions over four to five days (group 1). Between June 2004 to February 2011, 25 keloids were treated with surgical excision, followed by a total radiation dose of 1,500 cGy in three fractions over four to five days (group 2). Patients were given a survey asking them to report their experiences regarding reoperation, recurrence of symptoms, recurrence of the lesion, and satisfaction with the operation. RESULTS: Of the 28 patients who were treated, 20 underwent follow-up. Group 2 had more cases showing elevation with erythematous changes, whereas group 1 had more cases showing progressive stages of elevation than group 2. These differences were statistically significant. Moreover, a correlation was observed between the level of keloid elevation and the extent of symptoms. CONCLUSIONS: We suggest 1,500 cGy of radiation in three fractions following keloidectomy for ear lobe keloids. A further randomized study is needed to assess the recurrence of keloids after radiotherapy.