Iron accelerates the conversion of dopamine-oxidized intermediates into melanin and provides protection in SH-SY5Y cells

Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN), and it has been suggested that dopamine is one of the main endogenous toxins in the genesis of PD. We demonstrated that thiol antioxidants (the reduced form of glutathione, N-acetyl-L-cysteine, and L-cysteine), which conjugate with one dopamine oxidation intermediate, o-quinone, provided almost complete protection from dopamine-mediated toxicity in SH-SY5Y, a human neuroblastoma cell line. In contrast, catalase partially provided protection against cell death caused by dopamine. These data suggest that the generation of dopamine oxidation intermediates, rather than hydrogen peroxide, plays a pivotal role in dopamine-induced toxicity. Iron accumulated in the SN of patients with PD can cause dopaminergic neuronal degeneration by enhancing oxidative stress. However, we found that iron reduced the total amounts of dopamine oxidation intermediates and enhanced the formation of melanin, a final product of dopamine oxidation. Also, addition of iron inhibited dopamine-induced cytotoxicity. These results suggest that iron can provide protection when it accelerates the conversion of dopamine oxidation intermediates.     

Muscular amyloid angiopathy with amyloidgenic transthyretin Ser50Ile and Tyr114Cys

Among patients with familial amyloid polyneuropathy (FAP), those with transthyretin Val30Met mainly show distally predominant weakness and atrophy, whereas some FAP patients, including those with transthyretin Ser50Ile and Tyr114Cys, show muscle weakness and atrophy that is dominant proximally, simulating myopathy. To clarify the cause of proximally dominant muscular atrophy in patients with FAP transthyretin Ser50Ile and Tyr114Cys, we investigated the distinctive features of muscle specimens of patients with FAP, 3 of who had Val30Met, 2 Ser50Ile, and 2 Tyr114Cys transthyretin. All specimens showed transthyretin amyloid around blood vessels and perimysium, and neurogenic denervation patterns. The amount of amyloid around the vessels was much greater in patients with FAP Ser50Ile and Tyr114Cys than in Val30Met patients. Muscular amyloid angiopathy may contribute to motor nerve injury that, in turn, may lead to amyotropic changes in patients with FAP Ser50Ile and Tyr114Cys.     

Selective embolization of the splenic vein in patients with hepatic encephalopathy and splenorenal shunt

Obliteration of portal-systemic shunts is effective for portosystemic encephalopathy but is often associated with complications such as retention of ascites and worsening of esophageal varices. Selective embolization of the splenic vein was performed on six patients with hepatic encephalopathy and splenorenal shunts. Hepatic encephalopathy was not observed in four patients after the procedure. Neither retention of ascites nor rupture of esophageal varices was observed because postoperative elevation of portal venous pressure was not as great as that seen when shunt obliteration is performed. This procedure can be an effective and safe treatment option for hepatic encephalopathy with a splenorenal shunt.     

Glucose attenuating local anesthetic-induced hemolysis

BACKGROUND: The effect of glucose on local anesthetic-induced neural damage has not been fully studied. We examined the effect of glucose on hemolysis induced by local anesthetics. METHODS: The mean EC50 values (the local anesthetic level that causes destruction of half of the red blood cells in vitro) of lidocaine HCl, tetracaine HCl and dibucaine HCl were determined with 0% and 7.5% glucose contained in Krebs solution at pH 6.4. RESULTS: The mean EC50 values of lidocaine HCl, tetracaine HCl, and dibucaine HCl in 0%-glucose Krebs solution were 6.51%, 0.45%, 0.17%, respectively, which increased significantly to 7.05%, 0.64% and 0.23%, in 7.5% glucose Krebs solution at pH 6.4. CONCLUSIONS: Glucose may have a protective role in local anesthetic-induced neural damage.     

Decision-making process about sex assignment in the neonate with ambiguous genitalia

Although diagnoses and etiologies of underlying disorders of sexual differentiation can be carefully delineated through biochemical, imagine, and chromosomal analyses, the decision-making process about sex assignment in the newborn with ambiguous genitalia is in a state of controversy. The conventional way for the approach to these neonates consists of 4 principles; 1) Urgency of diagnosis and sex assignment, so that early surgical reconstruction could obviate the fear of the parents with each diaper change. 2) Adequacy of the phallus as a male. 3) Fertility, especially 46XX female are sex assigned female because of potential fertility. 4) Cosmetic appearance of the reconstructed genitalia based on the recognition that external female genitalia are generally easier to construct than male. Contrary to these conventional methods, some researchers insist on flexibility in the clinical approach to provide the best possible outcome. It is getting apparent that the quantity, timing, and duration of androgen exposure will play a role in determining the degree of masculinization of the brain, which may potentially decide gender identity before 18 months of age or even in utero, and may influence the psychosexual development of the child. Flexibility in decision-making will allow for options not to remove any tissues including gonads and internal sex organs, or to reconstruct the genitalia until he or she is sure of the gender. This new approach must be proved in the future.     

PKC412 induces apoptosis through a caspase-dependent mechanism in human keloid-derived fibroblasts

There is no established pharmacological therapy for skin keloids, a wound healing disorder. In this study, we investigated the effect of N-benzoyl staurosporine (PKC412), a protein kinase C inhibitor, on human keloid-derived fibroblasts to examine whether this agent is applicable for the treatment of keloid formation. Although PKC412 induced apoptosis in keloid fibroblasts in a time- and dose-dependent manner, the effective concentration of this agent was much higher than that of staurosporine. Western blotting showed that both PKC412 (10 microM) and staurosporine (100 nM) cleaved pro-caspase-3 to active forms. An in vitro caspase assay also showed that PKC412 and staurosporine elevated caspase-3 activities. Carbobenzoxy-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK), a caspase inhibitor with a broad spectrum, inhibited caspase-3 activities stimulated by PKC412 and staurosporine; however, only PKC412-induced apoptosis, but not staurosporine-induced apoptosis, was prevented by Z-VAD-FMK. These results suggested that PKC412-induced apoptosis, but not staurosporine-induced apoptosis, is mainly mediated by the caspase-dependent mechanism.     

Plasminogen activator inhibitor-1 is a downstream mediator of the PGP9.5-related oncogenic pathway in esophageal squamous cell carcinoma

BACKGROUND & MATERIALS AND METHODS: Recently, it has been proved that PGP9.5 is an oncogene candidate for squamous cell carcinomas. To examine the PGP9.5-related oncogenic pathway, we tested for global patterns of gene expression in cancer cells following PGP9.5 gene introduction using an oligonucleotide microarray approach. RESULTS: Plasminogen activator inhibitor-1 (PAI-1) was identified as an overexpressed gene in a PGP9.5-expressed esophageal squamous cancer cell line. To confirm the data obtained, we performed Northern analysis using a PGP9.5 or a PAI-1 cDNA probe and found that PAI-1 mRNA was induced by PGP9.5 expression in NUEC1 cells. We further examined endogenous PGP9.5 and PAI-1 expression in 6 esophageal cancer cell lines. One cell line (NUEC2) with PGP9.5 expression exhibited PAI-1 expression, suggesting the possibility that PGP9.5 might induce PAI-1 directly or indirectly. CONCLUSION: These results suggested that PAI-1 might be a novel downstream mediator of PGP9.5 in esophageal squamous cell carcinomas.     

A devised method of hepatic and splenic arterial infusion chemotherapy after transcatheter peripancreatic arterial embolization for patients with advanced pancreatic cancer

We previously reported the clinical efficacy based on hepatic and splenic arterial infusion chemotherapy (HSAIC) for patients with advanced pancreatic cancer after transcatheter peripancreatic arterial embolization (TPPAE). However, this medical treatment pointed out a few problems in which the method had its complexity and a limited use of embolus micro-coil numbers. Then, we tried to improve the method in solving those problems. In order to reduce the embolus micro-coil numbers for TPPAE, we divided the micro-coil into several parts. We also devised the method of HSAIC. We used one catheter with a side hole, so that the catheter was able to supply a therapeutic drug for arterial infusion chemotherapy, both to the common hepatic artery and splenic artery. The effective rate for eleven cases was 72.7%, and there were no significant differences from the cases treated with the conventional method of TPPAE-HSAIC. Therefore, the devised treatment was considered to be an easy and useful method for TPPAE and HSAIC.     

Endogenous factors regulating neuronal death induced by radical stress

Neurons in the central nervous system (CNS) are vulnerable to radical stress caused by reactive oxygen species, including nitric oxide (NO). Those radicals play crucial roles in glutamate neurotoxicity associated with ischemic brain injury and a wide range of neurodegenerative disorders. In our previous studies, we have shown evidence suggesting that glutamate neurotoxicity is regulated by certain endogenous substances such as neurotrophins, nicotinic acetylcholine, prostanoids and vitamins. Based on those findings, we have used the term 'neuroprotective factor' for endogenous substances possessing protective activity against glutamate neurotoxicity, and have further searched for a candidate with unique structure. We isolated a novel neuroprotective substance named 'serofendic acid' derived from fetal calf serum. The compound exhibited potent protective action against neurotoxicity induced by glutamate and by an NO donor without inhibiting glutamate receptors. Electron spin resonance analysis demonstrated that serofendic acid had no direct scavenging activity on NO, but was capable of inhibiting the generation of a hydroxyl radical, a presumed 'executor' radical in the nitric oxide-mediated neurotoxic cascade. The chemical structure was determined by mass spectrometry and nuclear magnetic resonance spectroscopy, and was confirmed by synthesis. The structure was unique among known endogenous substances because the compound was a sulfur-containing atisane type diterpenoid. The discovery of serofendic acid may provide a new scope for the investigation of low-molecular weight bioactive factors promoting the survival of CNS neurons.