Horizontally Transferred DNA in the Genome of the Fungus Pyricularia oryzae is Associated With Repressive Histone Modifications.

Horizontal gene transfer (HGT) is a means of exchanging genetic material asexually. The process by which horizontally transferred genes are domesticated by the host genome is of great interest but is not well understood. In this study, we determined the telomere-to-telomere genome sequence of the wheat-infecting Pyricularia oryzae strain Br48. SNP analysis indicated that the Br48 strain is a hybrid of wheat- and Brachiaria-infecting strains by a sexual or parasexual cross. Comparative genomic analysis identified several megabase-scale "insertions" in the Br48 genome, some of which were possibly gained by HGT-related events from related species, such as P. pennisetigena or P. grisea. Notably, the mega-insertions often contained genes whose phylogeny is not congruent with the species phylogeny. Moreover, some of the genes have a close homolog even in distantly related organisms, such as basidiomycetes or prokaryotes, implying the involvement of multiple HGT events. Interestingly, the levels of the silent epigenetic marks H3K9me3 and H3K27me3 in a genomic region tended to be negatively correlated with the phylogenetic concordance of genes in the same region, suggesting that horizontally transferred DNA is preferentially targeted for epigenetic silencing. Indeed, the putative HGT-derived genes were activated when MoKmt6, the gene responsible for H3K27me3 modification, was deleted. Notably, these genes also tended to be up-regulated during infection, suggesting that they are now under host control and have contributed to establishing a fungal niche. In conclusion, this study suggests that epigenetic modifications have played an important role in the domestication of HGT-derived genes in the P. oryzae genome.

Noisy galvanic vestibular stimulation effect on center of pressure sway during one-legged standing.

Noisy galvanic vestibular stimulation (nGVS) involves the application of a weak, noisy, electrical current to the vestibular end organs and their afferent nerves, through electrodes placed bilaterally over the mastoid process. Center of pressure (COP) sway was shown to decrease during nGVS under conditions of static standing posture. However, whether nGVS can improve balance functions other than the static standing posture remains unclear. This study aimed to elucidate the effects of nGVS on COP sway during one-legged standing. We randomly assigned 36 participants to either a control group (sham stimulation), a 0.2 mA group (nGVS at 0.2 mA), or a 0.4 mA group (nGVS at 0.4 mA). All participants were measured for COP sway standing on one leg, with open eyes, both before and during stimulation. In the 0.2 mA group, the sway path length, mediolateral mean velocity, and anteroposterior mean velocity decreased during stimulation compared with before stimulation. Conversely, no significant differences in COP sway were detected for either the control group or the 0.4 mA group. The stimulation effects for all COP sway parameters were significantly higher in the 0.2 mA group than in either the control group or the 0.4 mA group. The results of this study suggested that nGVS not only decreases COP sway during static standing postures but can also reduce COP sway during one-legged standing.

Acute Management of Gamma Knife Radiosurgery for Asymptomatic Obstructive Hydrocephalus Associated with Posterior Fossa Metastases.

OBJECTIVE: We retrospectively assessed the effectiveness and safety of Gamma Knife radiosurgery (GKRS) for asymptomatic obstructive hydrocephalus associated with posterior fossa metastases, which was known empirically but not well discussed. METHODS: We reviewed the medical records of 27 patients who underwent GKRS for asymptomatic obstructive hydrocephalus related to posterior fossa metastases. RESULTS: Cumulative control rates of hydrocephalus were 11.1%, 51.9%, 70.4%, and 74.6% at 1, 2, 3, and 6 months after GKRS. Primary gastrointestinal tract cancer (P = 0.001) was significantly correlated with unfavorable management. Evans ratio at GKRS (median 0.31) improved significantly compared with that at 1-3 months after GKRS (median 0.26) (P < 0.0001) and maintained at 6 to 12 months. Cumulative local tumor control rates were 91.7%, 70.8%, and 64.4% at 3, 6, and 12 months after GKRS. Primary gastrointestinal tract cancer (P = 0.018) and no conventional systemic agents (P = 0.027) were significantly correlated with unfavorable control. Cumulative incidence rates of adverse radiation effects were 0.0%, 16.7%, and 24.2% at 6, 9, and 12 months after GKRS. Primary gastrointestinal tract cancer (P < 0.0001) and single and 2- or 3-fraction GKRS (P < 0.0001) were significantly correlated with unfavorable outcomes. All but 1 patient avoided surgical procedure for hydrocephalus after GKRS. CONCLUSIONS: The present findings suggest that GKRS is an effective and safe treatment for asymptomatic obstructive hydrocephalus caused by posterior fossa metastases, and all but 1 could avoid invasive surgical procedures for hydrocephalus. Posterior fossa metastases from gastrointestinal tract cancer resulted in unsatisfactory outcomes for control of hydrocephalus, tumor progression, and adverse radiation effects.

Albumin fusion at the N-terminus or C-terminus of human lactoferrin leads to improved pharmacokinetics and anti-proliferative effects on cancer cell lines.

Human lactoferrin (hLF), a soluble factor of the innate immune system, exhibits various biological functions and therefore has potential as a therapeutic protein. However, the clinical applications of hLF are limited by its low stability in blood. We therefore attempted to resolve this by producing recombinant hLF fused to human serum albumin (HSA). Two HSA-fused hLFs with different fusion orientations (hLF-HSA and HSA-hLF) were produced in Chinese hamster ovary (CHO) DG44 cells. hLF-HSA revealed higher thermal stability, resistance to peptic degradation, and stability during the process of cellular uptake and release in an intestinal enterocyte model (Caco-2 cells) than HSA-hLF. The lower stability of HSA-hLF is presumably due to the steric hindrance imposed by HSA fusion to the N-terminus of hLF. Both HSA fusion proteins, especially HSA-hLF, displayed improved pharmacokinetic properties despite the lower protein stability of HSA-hLF. hLF-HSA and HSA-hLF exhibited approximately 3.3- and 20.7-fold longer half-lives (64.0 and 403.6 min), respectively, than holo-rhLF (19.5 min). Both HSA fusion proteins were found to exert enhanced growth inhibition effects on cancer cells in vitro, but not normal cells. Their enhanced growth inhibitory activities were considered to be due to the synergetic effects of hLF and HSA because hLF alone or HSA alone failed to exert such an effect. Altogether, Fusion of HSA to hLF yielded superior pharmacokinetics and anti-proliferative activities against cancer cells. HSA-fused hLF is a novel candidate for further application of hLF as biopharmaceuticals for intravenous administration.

Stenting Combined with Coil Embolization of a Dissecting Aneurysm after Traumatic Vertebral Artery Injury.

Objective: We report a case of dissecting aneurysm developed after traumatic vertebral artery dissection (VAD) treated by stenting combined with coil embolization. Case Presentation: A 47-year-old man was injured in a fall and presented with left VAD associated with central spinal injury due to C2 fracture. One week after admission, magnetic resonance imaging (MRI) demonstrated contralateral VAD with a dissecting aneurysm. Due to bilateral VAD, we employed coil embolization and stenting for the dissecting aneurysm to prevent rupture and embolic events, and to maintain the patency of the dominant right VA. There were no complications during the perioperative period. The follow-up angiogram 6 months after embolization confirmed obliteration of the dissecting aneurysm and patency of the parent artery. Conclusion: Stenting combined with coil embolization is an effective treatment for traumatic VAD with a dissecting aneurysm.

Interaction Effects of Behavioral Inhibition System/Behavioral Activation System and Cost/Probability Biases on Social Anxiety.

INTRODUCTION: Social anxiety disorder (SAD) symptoms are maintained by cognitive biases, which are overestimations of the severity and likelihood of negative social events (cost/probability biases), and by sensitivity to rewards and punishments that are determined according to behavioral inhibition/behavioral activation systems (BIS/BAS). Cost/probability biases might activate the behavioral immune system and exacerbate the avoidance of social events. Earlier studies have proposed that low BIS or high BAS decrease SAD symptoms; BIS/BAS may even change the effects of cognitive biases on SAD symptoms. Hence, the current study investigates the interaction effects of BIS/BAS and cost/probability biases on SAD symptoms. METHOD: Seventy-six Japanese undergraduate students completed the Japanese version of the Liebowitz Social Anxiety Scale (LSAS), which comprises Fear and Avoidance subscales, the BIS/BAS Scale, and the Social Cost Probability Scale. RESULTS: A multiple regression analysis was performed to examine whether cost/probability biases, BIS/BAS, and their interactions affected SAD symptoms; following this, the main effects of cost bias and BIS were determined for LSAS-Fear (ß = 0.64, p < 0.001; ß = 0.33, p < 0.01) and LSAS-Avoidance (ß = 0.49, p < 0.001; ß = 0.35, p < 0.01). The interaction effect between cost bias and BAS was significant for LSAS-Avoidance (ß = -0.32, p < 0.05). Simple slope analysis showed that the slope of cost bias was significant for low-BAS individuals (ß = 0.77, p < 0.001) but not for high-BAS individuals (ß = -0.21, n.s.). The interaction effect between probability bias and BAS was significant for LSAS-Avoidance (ß = 0.40, p < 0.01) as well. Further, simple slope analysis revealed that the slope of probability bias was significant for low-BAS individuals (ß = -0.53, p < 0.05) but not for high-BAS individuals (ß = 0.17, n.s.). DISCUSSION: The study found interesting results with respect to the avoidance of social events. Low-BAS individuals with high cost or low probability biases regarding social events may have a tendency to avoid social events. In contrast, if high-BAS individuals overestimate the cost of social events or underestimate the probability of social events, their anticipation of rewards might prevent them from avoiding social events.

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Cancer of Unknown Primary.

OBJECTIVE: We retrospectively analyzed treatment efficacy and identified prognostic factors impacting tumor control and survival in patients with brain metastases from cancer of unknown primary (CUP) treated with gamma knife radiosurgery (GKRS). METHODS: We retrospectively reviewed the medical records of 87 patients with 520 tumors who underwent GKRS for brain metastases from CUP. RESULTS: The median overall survival time after initial GKRS was 6 months. The 6- and 12-month overall survival rates were 79.3% and 14.9%, respectively. Older age (P = 0.002), lower Karnofsky Performance Status Index score (P = 0.026), extracranial metastases (P = 0.013), and multiple brain metastases (P = 0.007) were significantly correlated with shorter survival periods. The 6- and 12-month neurologic death rates were 25.3% and 32.2%, respectively. The 6- and 12-month neurologic deterioration rates were 24.1% and 27.6%, respectively. The 6- and 12-month distant brain control failure rates were 21.8% and 24.1%, respectively. The median tumor volume was 1.7 cm3. The median marginal prescription dose was 18 Gy. The 6- and 12-month tumor recurrence rates were 5.1% and 15.7%, respectively. Larger tumor volume (P < 0.0001) and lower prescription dose (P = 0.001) were significantly correlated with local tumor control failure. Seven patients had symptomatic radiation injury. The 6- and 12-month GKRS-related complication rates were both 6.9%. CONCLUSIONS: Our findings suggest that GKRS is a relatively effective and safe treatment for control of tumor progression in patients with brain metastases from CUP. Overall and neurologic survivals were short, but we recommend GKRS treatment to prevent early neurologic dysfunction and death in patients with CUP.

Esterification of PQQ Enhances Blood-Brain Barrier Permeability and Inhibitory Activity against Amyloidogenic Protein Fibril Formation.

Several neurodegenerative diseases have a common pathophysiology where selective damage to neurons results from the accumulation of amyloid oligomer proteins formed via fibrilization. Considering that the formation of amyloid oligomers leads to cytotoxicity, the development of chemical compounds that are able to effectively cross the blood-brain barrier (BBB) and inhibit this conversion to oligomers and/or fibrils is essential for neurodegenerative disease therapy. We previously reported that pyrroloquinoline quinone (PQQ) prevented aggregation and fibrillation of α-synuclein, amyloid ß1-42 (Aß1-42), and mouse prion protein. To develop a novel drug against neurodegenerative diseases based on PQQ, it is necessary to improve the insufficient BBB permeability of PQQ. Here, we show that an esterified compound of PQQ, PQQ-trimethylester (PQQ-TME), has twice the BBB permeability than PQQ in vitro. Moreover, PQQ-TME exhibited greater inhibitory activity against fibrillation of α-synuclein, Aß1-42, and prion protein. These results indicated that esterification of PQQ could be a useful approach in developing a novel PQQ-based amyloid inhibitor.

Endoscopic third ventriculostomy for hydrocephalus in brainstem glioma: a case series.

OBJECT: A brainstem glioma is an incurable brain tumor that can be complicated by hydrocephalus. A ventriculoperitoneal (VP) shunt is generally performed for the control of hydrocephalus. This study aimed to reveal the safety and efficacy of an endoscopic third ventriculostomy (ETV) for hydrocephalus in brainstem gliomas. METHODS: Six patients who had pontine glioma with hydrocephalus underwent an ETV between May 2010 and November 2015. In all the cases, there were one or more symptoms of hydrocephalus (headache, nausea, vomiting, or lethargy). Retrospective review of these patients was performed using the medical records and neuroimagings. RESULT: The ETV was performed safely and there were no intraoperative complications in all patients. The mean follow-up period was 12.3 months. An immediate symptomatic relief of hydrocephalus and an adequate control of symptoms were achieved without a VP shunt in all patients. CONCLUSIONS: The ETV is considered to be an effective and safe procedure for the treatment of hydrocephalus in brainstem gliomas. Determining the ventriculostomy site according to the preoperative MRI in each case is considered to be important for the safe procedure.

Orbital Abducens Nerve Schwannoma: A Case Report and Review of the Literature.

Intraorbital schwannoma is a rare tumor which accounts for about 1-2% of all neoplasms of the orbit. Orbital schwannomas most commonly arise from the sensory branches of the trigeminal nerve. On the other hand, intraorbital abducens nerve schwannomas are extremely rare, with a search of the English literature identifying only four cases of intraorbital abducens nerve schwannoma. This is the 5th reported case of an orbital schwannoma arising from the terminal branch of the abducens nerve to the lateral rectus muscle. We report a case of an intraorbital abducens nerve schwannoma in a 51-year-old man with no signs of neurofibromatosis. The tumor was totally excised with functional preservation of the nerve by a zygomatic approach with lateral orbitotomy. With knowledge of these anatomic features, total removal of the tumor with preservation of the abducens nerve function might be possible.

A nucleoprotein-enriched diet suppresses dopaminergic neuronal cell loss and motor deficit in mice with MPTP-induced Parkinson's disease.

Parkinson's disease (PD) is an obstinate progressive neurodegenerative disease and characterized by locomotor impairment and dopaminergic neuronal degeneration in the substantia nigra pars compacta (SNc). We examined in here the dietary effect of nucleoprotein (NP) extracted from salmon soft roe on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected PD-like mice model to prevent the symptom as an alternative medicine. Male C57/BL6 mice were given either an artificially modified NP-free diet (NF) or NF supplied with 1.2% NP for 1 week. Then, mice were injected intraperitoneally four times with 20 mg/kg MPTP. Seven days later, locomotor activity was examined, and the brains were immunostained with tyrosine hydroxylase (TH) and Iba1 antibodies. Moreover, in situ detection of superoxide anion (O2(-)) and gene expression of mitochondrial electron transfer chain gene, Cox8b was evaluated in midbrains. NP-fed animals showed significantly reduced locomotor impairment and an increased number of TH-positive cells in the SNc compared with NF animals. The NP-fed animals also showed reduced lower levels of O2(-) and up-regulation of Cox8b levels and Iba1 immunoreactivity, suggesting that inflammation and oxidative stress were suppressed and mitochondrial impairment was relieved in these animals. Supplementation of the diet with NP may serve as a useful preventive measure to slow the onset of PD.

Carboplatin-induced severe hypersensitivity reaction: role of IgE-dependent basophil activation and FcεRI.

Basophil activation was observed in patients with a history of carboplatin-induced severe hypersensitivity reaction (HR). However, the precise mechanism by which carboplatin induces basophil activation and the associated surrogate markers remains to be elucidated. To investigate whether IgE-dependent mechanisms, including the overexpression of FcεRI, participate in carboplatin-induced basophil activation, 13 ovarian cancer patients were enrolled: 5 with a history of carboplatin-induced severe hypersensitivity reaction within the past 2 years, and 8 with no such history. The expression levels of FcεRI, IgE, and CD203c on basophils were measured using a flow cytometer. Immunoglobulin E-dependent basophil activation was evaluated by testing for IgE passive sensitization using lactic acid, and by testing for phosphatidylinositol 3-kinase inhibition, using wortmannin. In three patients positive for carboplatin hypersensitivity, pretreatment with wortmannin almost completely inhibited carboplatin-induced basophil activation (P < 0.05). In a healthy control subject, whose own IgE showed no response to carboplatin, acquired reactivity to carboplatin when exposed to plasma from patients positive for carboplatin hypersensitivity. This did not occur when the same experiment was carried out using plasma from the patients negative for carboplatin hypersensitivity. Moreover, pretreatment with omalizumab, a monoclonal anti-IgE antibody, almost completely blocked carboplatin-induced basophil activation in the plasma of patients positive for carboplatin hypersensitivity. On further investigation, the HR-positive group had significantly higher levels of FcεRI compared with the negative group (P < 0.05). In conclusion, an IgE-dependent mechanism incorporating FcεRI overexpression participates in carboplatin-induced severe HR. These results establish the relevance of monitoring the pharmacodynamic changes of basophils to prevent carboplatin-induced severe HR.

Pathological and Clinical Features and Management of Central Nervous System Hemangioblastomas in von Hippel-Lindau Disease.

Central nervous system (CNS) hemangioblastoma is the most common manifestation of von Hippel-Lindau (VHL) disease. It is found in 70-80% of VHL patients. Hemangioblastoma is a rare form of benign vascular tumor of the CNS, accounting for 2.0% of CNS tumors. It can occur sporadically or as a familial syndrome. CNS hemangioblastomas are typically located in the posterior fossa and the spinal cord. VHL patients usually develop a CNS hemangioblastoma at an early age. Therefore, they require a special routine for diagnosis, treatment and follow-up. The surgical management of symptomatic tumors depend on many factors such as symptom, location, multiplicity, and progression of the tumor. The management of asymptomatic tumors in VHL patients are controversial since CNS hemangioblastomas grow with intermittent quiescent and rapid-growth phases. Preoperative embolization of large solid hemangioblastomas prevents perioperative hemorrhage but is not necessary in every case. Radiotherapy should be reserved for inoperable tumors. Because of complexities of VHL, a better understanding of the pathological and clinical features of hemangioblastoma in VHL is essential for its proper management.

Partial peptide of α-synuclein modified with small-molecule inhibitors specifically inhibits amyloid fibrillation of α-synuclein.

We have previously reported that pyrroloquinoline quinone (PQQ) prevents the amyloid formation of α-synuclein, amyloid ß(1-42) (Aß(1-42)), and mouse prion protein. Moreover, PQQ-modified α-synuclein and a proteolytic fragment of the PQQ-modified α-synuclein are able to inhibit the amyloid formation of α-synuclein. Here, we identified the peptide sequences that play an important role as PQQ-modified specific peptide inhibitors of α-synuclein. We demonstrate that the PQQ-modified α-Syn(36-46) peptide, which is a partial sequence of α-synuclein, prevented α-synuclein amyloid fibril formation but did not inhibit Aß(1-42) fibril formation. In addition, the α-synuclein partial peptide modified with other small-molecule inhibitors, Baicalein and epigallocatechin gallate (EGCG), prevented α-synuclein fibril formation. Currently reported quinone amyloid inhibitors do not have selectivity toward protein molecules. Therefore, our achievements provide a novel strategy for the development of targeted specific amyloid formation inhibitors: the combination of quinone compounds with specific peptide sequence from target proteins involved in amyloid formation.

Rapid cytotoxicity screening platform for amyloid inhibitors using a membrane-potential sensitive fluorescent probe.

The growing interest in membrane interactions of amyloidogenic proteins indicates that lipid binding and the regulation of membrane potential are critical to the onset and progression of neurodegenerative diseases such as Parkinson's (PD), Alzheimer's (AD), and prion diseases. Advancing the understanding of this field requires the application of varied biophysical and biological techniques designed to probe the characteristics and underlying mechanisms of membrane-peptide interactions. Therefore, the development of a rapid cytotoxicity evaluation system using a membrane potential-sensitive bis-oxonol fluorescent dye, DiBAC4(3) is reported here. The exposure of C-terminal truncated α-synuclein 119 (α-Syn119) and amyloid-ß(1-42) (Aß(1-42)) to U2-OS cell cultures resulted in an immediate, significant, and concentration-dependent increase in fluorescence response of DiBAC4(3). This response was strongly correlated with the cytotoxicity of α-Syn119 and Aß(1-42) as determined by conventional CC8 and ATP assays. Furthermore, the capacity of well-defined polyphenolic antioxidants (i.e., pyrroloquinoline quinone (PQQ), baicalein, (-)-epigallocatechin-3-gallate (EGCG), and myricetin) to mitigate amyloid-induced cytotoxicity was evaluated using the developed biosensing system. We envisage that this work would accelerate the development of a rapid and cost-effective high-throughput screening platform in drug discovery for AD and PD.

Relaxin ameliorates salt-sensitive hypertension and renal fibrosis.

BACKGROUND: Although relaxin (RLX) has potent vasodilatory and anti-fibrotic properties, there is no information on its effects on salt-sensitive hypertension. METHODS: We investigated the effects of short-term treatment with RLX on blood pressure (BP) and nitric oxide synthase (NOS) protein in the kidneys of male Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rats after 1 week consumption of an 8% NaCl diet. We also evaluated the inhibitory effects of each specific NOS inhibitor on BP during 1-week RLX treatment under high-salt diet. Next, we examined the long-term effects of RLX treatment for 6 weeks on renal histology and transforming growth factor-beta1 (TGF-ß1) expression in male DS and DR rats placed on the 8-week high-salt diet. RESULTS: The short-term RLX treatment significantly attenuated the high-salt diet-induced rise in BP in DS rats with increasing neuronal NOS and endothelial NOS protein in kidneys. Selective inhibition of each of the three NOS isoforms significantly blocked the anti-hypertensive effects of RLX in DS rats after 1-week high-salt diet. The long-term treatment of DS rats with RLX for 6 weeks significantly reduced systolic BP, lessened glomerular and tubulointerstitial changes and reduced TGF-ß signaling compared to saline-treated controls. CONCLUSIONS: The results suggested that RLX converted salt sensitivity to salt resistance, at least in part, by up-regulating NOS. RLX is a potentially useful therapeutic agent for salt-sensitive hypertension.

The inhibitory effect of pyrroloquinoline quinone on the amyloid formation and cytotoxicity of truncated alpha-synuclein.

BACKGROUND: Parkinson's disease (PD) involves the selective damage of dopaminergic neuron cells resulting from the accumulation and fibril formation of alpha-synuclein. Recently, it has been shown that not only full-length alpha-synuclein, but also C-terminal truncated forms exist in the normal brain, as well as Lewy bodies, which are cytoplasmic inclusions in PD. It is known that truncated alpha-synuclein has a much higher ability to aggregate and fibrillate than full-length alpha-synuclein. Since the fibrils and precursor oligomers of alpha-synuclein are cytotoxic to the neuron, inhibitors that prevent the formation of oligomers and/or fibrils might open the way to a novel therapeutic approach to PD. However, no inhibitor for truncated alpha-synuclein has been reported yet. RESULTS: In this study, we first characterized the aggregation and cytotoxicity of C-truncated alpha-synuclein119 and alpha-synuclein133 which have been found in both the normal and the pathogenic brain. Alpha-synuclein119 aggregated more rapidly and enhanced significantly the fibril formation of alpha-synuclein. Although both of alpha-synuclein119 and alpha-synuclein133 showed a high cytotoxicity, alpha-synuclein133 showed a similar aggregation with full-length alpha-synuclein and no acceleration effect. We showed that PQQ dramatically inhibits the fibril formation of C-terminal truncated alpha-synuclein110119, and 133 as well as the mixtures of full-length alpha-synuclein with these truncated variants. Moreover, PQQ decreases the cytotoxicity of truncated alpha-synuclein. CONCLUSIONS: Our results demonstrate that PQQ inhibits the amyloid fibril formation and cytotoxicity of the C-truncated alpha-synuclein variants. We believe that PQQ is a strong candidate for a reagent compound in the treatment of PD.

Pyrroloquinoline quinone inhibits the fibrillation of amyloid proteins.

Several neurodegenerative diseases involve the selective damage of neuron cells resulting from the accumulation of amyloid fibril formation. Considering that the formation of amyloid fibrils as well as their precursor oligomers is cytotoxic, the agents that prevent the formation of oligomers and/or fibrils might allow the development of a novel therapeutic approach to neurodegenerative diseases. Here, we show pyrroloquinoline quinone (PQQ) inhibits the amyloid fibril formation of the amyloid proteins, amyloid beta (1-42) and mouse prion protein. The fibril formation of mouse prion protein in the presence of PQQ was dramatically prevented. Similarly, the fibril formation of amyloid beta (1-42) also decreased. With further advanced pharmacological approaches, PQQ may become a leading anti-neurodegenerative compound in the treatment of neurodegenerative diseases.

The effect of amino acid substitution in the imperfect repeat sequences of alpha-synuclein on fibrillation.

Human alpha-synuclein is the causative protein of several neurodegenerative diseases, such as Parkinson's disease (PD) and dementia with Lewy Bodies (DLB). The N-terminal half of alpha-synuclein contains seven imperfect repeat sequences. One of the PD/DLB-causing point mutations, E46K, has been reported in the imperfect repeat sequences of alpha-synuclein, and is prone to form amyloid fibrils. The presence of seven imperfect repeats in alpha-synuclein raises the question of whether or not mutations corresponding to E46K in the other imperfect KTKE(Q)GV repeats have similar effects on aggregation and fibrillation, as well as their propensities to form alpha-helices. To investigate the effect of E(Q)/K mutations in each imperfect repeat sequence, we substituted the amino acid corresponding to E46K in each of the seven repeated sequences with a Lys residue. The mutations in the imperfect KTKE(Q)GV repeat sequences of the N-terminal region were prone to decrease the lag time of fibril formation. In addition, AFM imaging suggested that the Q24K mutant formed twisted fibrils, while the other mutants formed spherical aggregates and short fibrils. These observations indicate that the effect of the mutations on the kinetics of fibril formation and morphology of fibrils varies according to their location.

Effects of relaxin on development of mesangial proliferative nephritis.

The involvement of relaxin (RLX) in nephritis has not been fully elucidated. In this study, we examined the expression of the RLX receptor and effects of RLX administration in antithymocyte serum (ATS) nephritis. The nephritic glomeruli showed an increased immunostaining for LGR7 compared to normal glomeruli. The administration of RLX for 7 days to rats with ATS nephritis did not cause an alteration in blood pressure or body weight. On the sixth day, however, a significant reduction in urinary protein was recognized in rats treated with RLX. Histological studies revealed the amelioration of glomerular accumulation of Periodic acid-Schiff stain-positive matrix in rats treated with RLX. Significant reductions of phosphorylated SMAD2, mesangial cell proliferation, and alpha-smooth muscle actin expression were observed in rats treated with RLX. These results suggest that RLX is a promising therapeutic tool for nephritic diseases.