Integration of National Health Insurance claims data and animal models reveals fexofenadine as a promising repurposed drug for Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a common and costly progressive neurodegenerative disease of unclear etiology. A disease-modifying approach that can directly stop or slow its progression remains a major unmet need in the treatment of PD. A clinical pharmacology-based drug repositioning strategy is a useful approach for identifying new drugs for PD. METHODS: We analyzed claims data obtained from the National Health Insurance Service (NHIS), which covers a significant portion of the South Korean population, to investigate the association between antihistamines, a class of drugs commonly used to treat allergic symptoms by blocking H1 receptor, and PD in a real-world setting. Additionally, we validated this model using various animal models of PD such as the 6-hydroxydopmaine (6-OHDA), α-synuclein preformed fibrils (PFF) injection, and Caenorhabditis elegans (C. elegans) models. Finally, whole transcriptome data and Ingenuity Pathway Analysis (IPA) were used to elucidate drug mechanism pathways. RESULTS: We identified fexofenadine as the most promising candidate using National Health Insurance claims data in the real world. In several animal models, including the 6-OHDA, PFF injection, and C. elegans models, fexofenadine ameliorated PD-related pathologies. RNA-seq analysis and the subsequent experiments suggested that fexofenadine is effective in PD via inhibition of peripheral immune cell infiltration into the brain. CONCLUSION: Fexofenadine shows promise for the treatment of PD, identified through clinical data and validated in diverse animal models. This combined clinical and preclinical approach offers valuable insights for developing novel PD therapeutics.

GPR40 agonist ameliorates neurodegeneration and motor impairment by regulating NLRP3 inflammasome in Parkinson's disease animal models.

Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra (SN) and accumulation of intracellular α-synuclein (ɑ-syn) aggregates known as Lewy bodies and Lewy neurites. Levels of polyunsaturated fatty acids (PUFAs) have previously been shown to be reduced in the SN of PD patients. G protein-coupled receptor 40 (GPR40) serves as a receptor for PUFAs, playing a role in neurodevelopment and neurogenesis. Additionally, GPR40 has been implicated in several neuropathological conditions, such as apoptosis and inflammation, suggesting its potential as a therapeutic target in PD. In this study, we investigated the neuroprotective effects of the GPR40 agonist, TUG469 in PD models. Our results demonstrated that TUG469 reduces the neurotoxicity induced by 6-OHDA in SH-SY5Y cells. In 6-OHDA-induced PD model mice, TUG469 treatment improved motor impairment, preserved dopaminergic fibers and cell bodies in the striatum (ST) or SN, and attenuated 6-OHDA-induced microgliosis and astrogliosis in the brain. Furthermore, in a PD model involving the injection of mouse ɑ-syn fibrils into the brain (mPFFs-PD model), TUG469 treatment reduced the levels of pSer129 ɑ-syn, and decreased microgliosis and astrogliosis. Our investigation also revealed that TUG469 modulates inflammasome activation, apoptosis, and autophagy in the 6-OHDA-PD model, as evidenced by the results of RNA-seq and western blotting analyses. In summary, our findings highlight the neuroprotective effects of GPR40 agonists on dopaminergic neurons and their potential as therapeutic agents for PD. These results underscore the importance of targeting GPR40 in PD treatment, particularly in mitigating neuroinflammation and preserving neuronal integrity.

The dual role of c-src in cell-to-cell transmission of α-synuclein.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons located in the substantia nigra pars compacta and the presence of proteinaceous inclusions called Lewy bodies and Lewy neurites in numerous brain regions. Increasing evidence indicates that Lewy pathology progressively involves additional regions of the nervous system as the disease advances, and the prion-like propagation of α-synuclein (α-syn) pathology promotes PD progression. Accordingly, the modulation of α-syn transmission may be important for the development of disease-modifying therapies in patients with PD. Here, we demonstrate that α-syn fibrils induce c-src activation in neurons, which depends on the FcγRIIb-SHP-1/-2-c-src pathway and enhances signals for the uptake of α-syn into neurons. Blockade of c-src activation inhibits the uptake of α-syn and the formation of Lewy body-like inclusions. Furthermore, the blockade of c-src activation also inhibits the release of α-syn via activation of autophagy. The brain-permeable c-src inhibitor, saracatinib, efficiently reduces α-syn propagation into neighboring regions in an in vivo model system. These results suggest a new therapeutic target against progressive PD.

Neuronal ApoE Regulates the Cell-to-Cell Transmission of α-Synuclein.

The presence of protein inclusions, called Lewy bodies (LBs) and Lewy neurites (LNs), in the brain is the main feature of Parkinson's disease (PD). Recent evidence that the prion-like propagation of α-synuclein (α-syn), as a major component of LBs and LNs, plays an important role in the progression of PD has gained much attention, although the molecular mechanism remains unclear. In this study, we evaluated whether neuronal ApoE regulates the cell-to-cell transmission of α-syn and explored its molecular mechanism using in vitro and in vivo model systems. We demonstrate that neuronal ApoE deficiency attenuates both α-syn uptake and release by downregulating LRP-1 and LDLR expression and enhancing chaperone-mediated autophagy activity, respectively, thereby contributing to α-syn propagation. In addition, we observed that α-syn propagation was attenuated in ApoE knockout mice injected with pre-formed mouse α-syn fibrils. This study will help our understanding of the molecular mechanisms underlying α-syn propagation.

Effects of Stromal Vascular Fraction on Breast Cancer Growth and Fat Engraftment in NOD/SCID Mice.

BACKGROUND: To overcome unpredictable fat graft resorption, cell-assisted lipotransfer using stromal vascular fraction (SVF) has been introduced. However, its effect on cancer growth stimulation and its oncological safety are debatable. We investigated the effect of SVF on adjacent breast cancer and transplanted fat in a mouse model. METHODS: A breast cancer xenograft model was constructed by injecting 2 × 106 MDA-MB-231-luc breast cancer cells into the right lower back of 40 NOD/SCID mice. Two weeks later, cancer size was sorted according to signal density using an in vivo optical imaging system, and 36 mice were included. Human fat was extracted from the abdomen, and SVFs were isolated using a component isolator. The mice were divided into four groups: A, controls; B, injected with 30 µl SVF; C, injected with 0.5 ml fat and 30 µl saline; group D, injected with 0.5 ml fat and 30 µl SVF. Magnetic resonance imaging and three-dimensional micro-computed tomography volumetric analysis were performed at 4 and 8 weeks. RESULTS: Tumor volume was 43.6, 42.3, 48.7, and 42.4 mm3 at the initial time point and 6780, 5940, 6080, and 5570 mm3 at 8 weeks in groups A, B, C, and D, respectively. Fat graft survival volume after 8 weeks was 49.32% and 62.03% in groups C and D, respectively. At 2-month follow-up after fat grafting in the xenograft model, SVF injection showed an increased fat survival rate and did not increase the adjacent tumor growth significantly. CONCLUSION: Fat grafting with SVF yields satisfactory outcome in patients who undergo breast reconstruction surgery. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Clinical Characteristics of Arteriovenous Malformations of the Head and Neck.

BACKGROUND: Arteriovenous malformation (AVM) of the head and neck regions show low incidence; hence, studies regarding the causative factors of onset, diagnostic criteria, clinical aspects, treatment methods, and outcomes remain lacking. OBJECTIVE: To share the diagnostic and treatment experiences at the center and to understand the treatments' effect through a retrospective analysis of cases in the past 15 years. MATERIALS AND METHODS: The authors included 60 patients with AVM in the head and neck area between January 1999 and September 2014 to investigate diagnostic methods, distributions and locations of lesions, clinical stage, and treatment methods by retrospective evaluation. RESULTS: In all, 3.7% were diagnosed with AVMs of the head and neck. No sex-related differences were observed, and the mean age at diagnosis was 27.6 ± 14.24 years. The left (26 patients, 43%) and V2 sections (33 patients, 55%) of the head and neck were the most frequent locations. Stage II (28 patients, 47%) had the largest distribution. Forty-four patients (73%) showed improvement after sclerotherapy, embolization, and surgical resection. CONCLUSION: The diagnosis and treatment of AVMs should be approached on a case-by-case basis by gathering opinions from specialists in each department using medical history, physical examination, and imaging results.

Artificial intelligence-driven drug repositioning uncovers efavirenz as a modulator of α-synuclein propagation: Implications in Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder with an unclear etiology. Despite significant research efforts, developing disease-modifying treatments for PD remains a major unmet medical need. Notably, drug repositioning is becoming an increasingly attractive direction in drug discovery, and computational approaches offer a relatively quick and resource-saving method for identifying testable hypotheses that promote drug repositioning. We used an artificial intelligence (AI)-based drug repositioning strategy to screen an extensive compound library and identify potential therapeutic agents for PD. Our AI-driven analysis revealed that efavirenz and nevirapine, approved for treating human immunodeficiency virus infection, had distinct profiles, suggesting their potential effects on PD pathophysiology. Among these, efavirenz attenuated α-synuclein (α-syn) propagation and associated neuroinflammation in the brain of preformed α-syn fibrils-injected A53T α-syn Tg mice and α-syn propagation and associated behavioral changes in the C. elegans BiFC model. Through in-depth molecular investigations, we found that efavirenz can modulate cholesterol metabolism and mitigate α-syn propagation, a key pathological feature implicated in PD progression by regulating CYP46A1. This study opens new avenues for further investigation into the mechanisms underlying PD pathology and the exploration of additional drug candidates using advanced computational methodologies.

Critical roles of parkin and PINK1 in coxsackievirus B3-induced viral myocarditis.

Viral myocarditis is an inflammatory disease of the myocardium, often leads to cardiac dysfunction and death. PARKIN (PRKN) and PINK1, well known as Parkinson's disease-associated genes, have been reported to be involved in innate immunity and mitochondrial damage control. Therefore, we investigated the role of parkin and PINK1 in coxsackievirus B3 (CVB3)-induced viral myocarditis because the etiology of myocarditis is related to abnormal immune response to viral infection and mitochondrial damage. After viral infection, the survival was significantly lower and myocardial damage was more severe in parkin knockout (KO) and PINK1 KO mice compared to wild-type (WT) mice. Parkin KO and PINK1 KO showed defective immune cell recruitment and impaired production of antiviral cytokines such as interferon-gamma, allowing increased viral replication. In addition, parkin KO and PINK1 KO mice were more susceptible to CVB3-induced mitochondrial damage than WT mice, resulting in susceptibility to viral-induced cardiac damage. Finally, using publicly available RNA-seq data, we found that pathogenic mutants of the PRKN gene are more common in patients with dilated cardiomyopathy and myocarditis than in controls or the general population. This study will help elucidate the molecular mechanism of CVB3-induced viral myocarditis.

Age-related increase in caveolin-1 expression facilitates cell-to-cell transmission of α-synuclein in neurons.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, with aging being considered the greatest risk factor for developing PD. Caveolin-1 (Cav-1) is known to participate in the aging process. Recent evidence indicates that prion-like propagation of misfolded α-synuclein (α-syn) released from neurons to neighboring neurons plays an important role in PD progression. In the present study, we demonstrated that cav-1 expression in the brain increased with age, and considerably increased in the brain of A53T α-syn transgenic mice. Cav-1 overexpression facilitated the uptake of α-syn into neurons and formation of additional Lewy body-like inclusion bodies, phosphorylation of cav-1 at tyrosine 14 was found to be crucial for this process. This study demonstrates the relationship between age and α-syn spread and will facilitate our understanding of the molecular mechanism of the cell-to-cell transmission of α-syn.

Regulation of cerebrospinal fluid production by caffeine consumption.

BACKGROUND: Caffeine is the most commonly consumed psycho-stimulant in the world. The effects of caffeine on the body have been extensively studied; however, its effect on the structure of the brain has not been investigated to date. RESULTS: In the present study we found that the long-term consumption of caffeine can induce ventriculomegaly; this was observed in 40% of the study rats. In the caffeine-treated rats with ventriculomegaly, there was increased production of CSF, associated with the increased expression of Na(+), K(+)-ATPase and increased cerebral blood flow (CBF). In contrast to the chronic effects, acute treatment with caffeine decreased the production of CSF, suggesting 'effect inversion' associated with caffeine, which was mediated by increased expression of the A1 adenosine receptor, in the choroid plexus of rats chronically treated with caffeine. The involvement of the A1 adenosine receptor in the effect inversion of caffeine was further supported by the induction of ventriculomegaly and Na+, K+-ATPase, in A1 agonist-treated rats. CONCLUSION: The results of this study show that long-term consumption of caffeine can induce ventriculomegaly, which is mediated in part by increased production of CSF. Moreover, we also showed that adenosine receptor signaling can regulate the production of CSF by controlling the expression of Na(+), K(+)-ATPase and CBF.

The role of hedgehog signaling during gastric regeneration.

BACKGROUND: Hedgehog signaling plays critical roles during embryonic development. It is also involved in tissue regeneration and carcinogenesis in various adult tissues. Moreover, it regulates the maintenance of cancer stem cells and adult stem cells. Although hedgehog signaling is important in gastric carcinogenesis, its role in gastric regeneration has not been previously examined. In the present study, we evaluated the expression and roles of hedgehog signaling during gastric regeneration. METHODS: Gastric ulcers were induced by serosal application of an acetic acid solution in mice. Sham-operated mice served as controls. The proliferation of gastric progenitor cells was studied using bromodeoxyuridine (BrdU). The expression of hedgehog signaling molecules and the differentiation of gastric progenitor cells were examined by immunohistochemical staining and Western blotting. RESULTS: One day after the induction of gastric ulcer, the proliferation of gastric progenitor cells increased; however, the expression of hedgehog signaling molecules, including sonic hedgehog (Shh), Indian hedgehog (Ihh), desert hedgehog (Dhh), and patched (Ptch1) decreased at the ulcer margin. From 5 days after the induction of gastric ulcer, newly generated gastric glands and their differentiation were observed at the ulcer margin. The expression of hedgehog signaling molecules gradually increased in the newly generated gastric glands of the ulcer margin. Cyclopamine, a specific inhibitor of hedgehog signaling, significantly inhibited the differentiation of mucous cells and parietal cells during the gastric regeneration process. CONCLUSION: The above results suggest that hedgehog signaling is involved in the differentiation of gastric progenitor cells during the gastric ulcer repair process.

Reduction of ischemia-induced cerebral injury by all-trans-retinoic acid.

Ischemia-induced cerebral injury evolves over a longer period than previously believed through post-ischemic inflammation. Retinoic acid (RA) has been shown to exert cytoprotective effects on several cells, but its effects on ischemia-induced cerebral injury have been poorly characterized. The aim of the present study was to examine the effects of all-trans-RA on ischemia-induced cerebral injury and elucidate the underlying mechanism. All-trans-RA treatment reduced the size of the ischemia-induced cerebral infarct. To elucidate the underlying mechanism, ischemia-induced cerebral inflammation was studied by examination of expressions of interleukin 1beta (IL-1beta) and ED-1. RA treatment significantly reduced the cerebral inflammation. Moreover, cerebral ischemic induction of cyclooxygenase-2 (COX-2) and CCAAT/enhancer binding protein beta (C/EBPbeta), which binds to the COX-2 promoter, was also inhibited by RA. These results suggest that RA can reduce ischemia-induced cerebral injury by an anti-inflammatory action, which may be effected via inhibition of C/EBPbeta-mediated COX-2 induction.

Hedgehog signaling regulates the survival of gastric cancer cells by regulating the expression of Bcl-2.

Gastric cancer is the second most common cause of cancer deaths worldwide. The underlying molecular mechanisms of its carcinogenesis are relatively poorly characterized. Hedgehog (Hh) signaling, which is critical for development of various organs including the gastrointestinal tract, has been associated with gastric cancer. The present study was undertaken to reveal the underlying mechanism by which Hh signaling controls gastric cancer cell proliferation. Treatment of gastric cancer cells with cyclopamine, a specific inhibitor of Hh signaling pathway, reduced proliferation and induced apoptosis of gastric cancer cells. Cyclopamine treatment induced cytochrome c release from mitochondria and cleavage of caspase 9. Moreover, Bcl-2 expression was significantly reduced by cyclopamine treatment. These results suggest that Hh signaling regulates the survival of gastric cancer cells by regulating the expression of Bcl-2.

Utility of Two Surgical Techniques Using a Lateral Intercostal Artery Perforator Flap after Breast-Conserving Surgery: A Single-Center Retrospective Study.

BACKGROUND: Immediate partial breast reconstruction after breast-conserving surgery has become a new paradigm in treating breast cancer. Among the volume replacement techniques used for small to moderate-sized breasts, the perforator flap method has many advantages. The authors present anatomical studies and two surgical techniques using lateral intercostal artery perforator flaps. METHODS: Data from 40 patients who underwent breast reconstruction using the lateral intercostal artery perforator flap between January of 2011 and June of 2016 were included. The authors conducted comparative analyses of the propeller flap and the turnover flap. They used three-dimensional computed tomography in lateral intercostal artery perforator flap anatomical studies, analyzing the distribution probability of the dominant perforator, the vertical distance from the axillary fold, and the horizontal distance from the anterior border of the latissimus dorsi. RESULTS: The most dominant perforator used for lateral intercostal artery perforator flaps was the sixth lateral intercostal artery perforator (43.6 percent of cases), followed by the seventh lateral intercostal artery perforator (39.1 percent of cases); their mean distances from the latissimus dorsi and the axillary folds were determined and reported. Complications included three cases requiring additional treatment for fat necrosis (propeller method, two cases; turnover method, one case) and venous congestion in only two cases that used the propeller method. Cosmetic satisfaction was 90 percent or greater for both techniques, indicating that results were rated as either excellent or good. CONCLUSION: The authors believe that their study results can broaden the application of partial breast reconstruction by using the lateral intercostal artery perforator flap after breast-conserving surgery, with three-dimensional computed tomography for anatomical studies, and using one of the authors' two described surgical techniques. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Up-regulation of VEGF expression by NGF that enhances reparative angiogenesis during thymic regeneration in adult rat.

Angiogenesis is important for adult tissue regeneration as well as normal development. Vascular endothelial growth factor (VEGF) is a unique potent angiogenic factor, and plays an essential role in regulating angiogenesis during embryonic development, normal tissue growth, and tissue regeneration. Recent evidence shows that nerve growth factor (NGF) also plays a role as an angiogenic regulator as well as a well-known neurotrophic factor. The aim of this study was to investigate whether thymus regeneration accompanies reparative angiogenesis and also to evaluate whether the thymic expression of VEGF is regulated by NGF in vivo and in vitro. Here, we show that high VEGF mRNA and protein levels are concomitant with reparative angiogenesis that occurs dramatically during regeneration following acute involution induced by cyclophosphamide (CY) in the rat thymus. Fluorescent thymus angiography using FITC-dextran showed that thymic regeneration is associated with a much denser capillary network compared with normal control thymus. Furthermore, the expressions of NGF and TrkA were highly increased during thymic regeneration. We also show that NGF mediates thymic epithelial induction of VEGF expression in vitro and in vivo. Taken together, our results suggest that NGF-mediated VEGF up-regulation in thymic epithelial cells may contribute to reparative angiogenesis during thymic regeneration in adult.

RANKL stimulates proliferation, adhesion and IL-7 expression of thymic epithelial cells.

In many clinical situations which cause thymic involution and thereby result in immune deficiency, T cells are the most often affected, leading to a prolonged deficiency of T cells. Since only the thymic-dependent T cell production pathway secures stable regeneration of fully mature T cells, seeking strategies to enhance thymic regeneration should be a key step in developing therapeutic methods for the treatment of these significant clinical problems. This study clearly shows that receptor activator of NF-kappaB ligand (RANKL) stimulates mouse thymic epithelial cell activities including cell proliferation, thymocyte adhesion to thymic epithelial cells, and the expression of cell death regulatory genes favoring cell survival, cell adhesion molecules such as ICAM-1 and VCAM-1, and thymopoietic factors including IL-7. Importantly, RANKL exhibited a significant capability to facilitate thymic regeneration in mice. In addition, this study demonstrates that RANKL acts directly on the thymus to activate thymus regeneration regardless of its potential influences on thymic regeneration through an indirect or systemic effect. In light of this, the present study provides a greater insight into the development of novel therapeutic strategies for effective thymus repopulation using RANKL in the design of therapies for many clinical conditions in which immune reconstitution is required.

Nerve growth factor stimulates proliferation, adhesion and thymopoietic cytokine expression in mouse thymic epithelial cells in vitro.

Thymic epithelial cells, which constitute a major component of the thymic microenvironment, provide a crucial signal for intrathymic T cell development and selection. Neuroimmune networks in the thymic microenvironment are thought to be involved in the regulation of T cell development. NGF is increasingly recognized as a potent immunomodulator, promoting "cross-talk" between various types of immune system cells. The present study clearly shows that NGF stimulates mouse thymic epithelial cell activities in vitro including cell proliferation, thymocyte adhesion to thymic epithelial cells, and the expression of cell adhesion molecules such as ICAM-1 and VCAM-1, and thymopoietic factors including IL-7, GM-CSF, SDF-1, TARC and TECK. Thus, our data are of considerable clinical importance showing that trophic NGF activity could be used to enhance the thymus regeneration and develop methods to improve host immunity when the immune function is depressed due to thymic involution.

Prion-like Propagation of α-Synuclein Is Regulated by the FcγRIIB-SHP-1/2 Signaling Pathway in Neurons.

Recent evidence of prion-like propagation of α-synuclein (α-syn) into neighboring neurons set up a paradigm to elucidate the mechanism of progression of Parkinson's disease (PD) and to develop therapeutic strategies. Here, we show that FcγRIIB expressed in neurons functions as a receptor for α-syn fibrils and mediates cell-to-cell transmission of α-syn. SHP-1 and 2 are activated downstream by α-syn fibrils through FcγRIIB and play an important role in cell-to-cell transmission of α-syn. Also, taking advantage of a co-culture system, we show that cell-to-cell transmission of α-syn induces intracellular Lewy body-like inclusion body formation and that the FcγRIIB/SHP-1/2 signaling pathway is involved in it. Therefore, the FcγRIIB-SHP-1/-2 signaling pathway may be a therapeutic target for the progression of PD. The in vitro system is an efficient tool for further high-throughput screening that can be used for developing a therapeutic intervention in PD.

The usefulness of pedicled perforator flap in partial breast reconstruction after breast conserving surgery in Korean women.

BACKGROUND: The emergence of breast-conserving surgery combined with radiotherapy as the treatment of choice for early stage breast cancer has resulted in greater focus on oncoplastic breast surgery. The use of perforator flaps has particularly gained in reputation for its effectiveness in the reconstruction of partial breast defects in Korean women. Herein, we present our experience with the use of thoracodorsal artery perforator (TDAP) and lateral intercostal artery perforator (LICAP) flaps. METHODS: This study included 33 patients who underwent breast reconstruction using TDAP or LICAP flaps at our hospital from January 2011 to December 2014. Data from patient medical records, and patient satisfaction surveys, which were conducted 12 months postoperatively, were retrospectively evaluated. RESULTS: TDAP and LICAP flap-based reconstructions were performed in 14 and 19 patients, respectively. Five patients developed complications that required additional intervention. Overall patient satisfaction was observed to be excellent in 15 (46%) patients, and good in 12 (36%). CONCLUSIONS: Based on our experience, oncoplastic breast surgery using TDAP or LICAP flap is an effective remodeling technique for small-to-moderate breast defects in Korean women with smaller breasts.