Synthesis,antioxidant and carbonic anhydrase I and II inhibitory activities of novel sulphonamide-substituted coumarylthiazole derivatives

New secondary benzenesulphonamide-substituted coumarylthiazole derivatives were synthesized and their inhibitory effects on purified carbonic anhydrase I and II were evaluated using CO₂ as a substrate. The result showed that all the synthesized compounds exhibited inhibitory activity on both hCA I and hCA II with N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)naphthalene-2-sulphonamide (5f, IC₅₀ value of 5.63 and 8.48?µM, against hCA I and hCA II, respectively) as the strongest inhibitor revealed from this study. Structure–activity relationship revealed that the inhibitory activity of the synthesized compounds is related to the type of the halogen and bulky substituent on the phenyl ring. In addition, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the synthesized compounds were assayed. 4-methoxy-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)benzenesulphonamide (5e) exhibited the strongest ABTS and CUPRAC activity with IC₅₀ value of 48.83?µM and A_0.50 value of 23.29?µM, respectively.     

Cochliomycin A inhibits the larval settlement of Amphibalanus amphitrite by activating the NO/cGMP pathway

Cochliomycin A is a compound with anti-barnacle settlement activity and low toxicity, but the molecular mechanism of the compound is unknown. Here, isobaric tags for the relative or absolute quantitation (iTRAQ) labeling proteomic method were applied to analyze changes in the proteome of Amphibalanus（=Balanus） amphitrite cyprids in response to cochliomycin A treatment. Cochliomycin A affected the cytochrome P450, glutathione S-transferase (GST) and NO/cGMP pathways, among which the NO/cGMP pathway was considered to play a key role in barnacle larval settlement, while the cytochrome P450 and the GST pathways are mainly for detoxification. The results of real-time PCR further suggested the NO/cGMP pathway was activated in response to cochliomycin A. Larval settlement assays revealed that S-methylisothiourea sulfate (SMIS) and 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) rescued cyprids from cochliomycin A-induced inhibition of larval settlement. The findings supported the hypothesis that cochliomycin A inhibited barnacle larval settlement by stimulating the NO/cGMP pathway.     

Immunohistochemical localization of irisin in skin,eye, and thyroid and pineal glands of the crested porcupine (Hystrix cristata)

Irisin was first identified in muscle cells. We detected irisin immunoreactivity in various organs of the crested porcupine (Hystrix cristata). In the epidermis, irisin immunoreactivity was localized mainly in stratum basale, stratum spinosum and stratum granulosum layers; immunoreactivity was not observed in the stratum corneum. In the dermis, irisin was found in the external and internal root sheath, cortex and medulla of hair follicles, and in sebaceous glands. Irisin immunoreactivity was found in the neural retina and skeletal muscle fibers associated with the eye. The pineal and thyroid glands also exhibited irisin immunoreactivity.     

Vascular progenitor cell senescence in patients with Marfan syndrome

Vascular progenitor cells (VPCs) present in the adventitia of the vessel wall play a critical role in the regulation of vascular repair following injury. This study aimed to assess the function of VPCs isolated from patients with Marfan syndrome (MFS). VPCs were isolated from control and MFS donors and characterized. Compared with control‐VPCs, MFS‐VPCs exhibited cellular senescence as demonstrated by increased cell size, higher SA‐β‐gal activity and elevated levels of p53 and p21. RNA sequencing showed that several cellular process‐related pathways including cell cycle and cellular senescence were significantly enriched in MFP‐VPCs. Notably, the expression level of TGF‐β1 was much higher in MFS‐VPCs than control‐VPCs. Treatment of control‐VPCs with TGF‐β1 significantly enhanced mitochondrial reactive oxidative species (ROS) and induced cellular senescence whereas inhibition of ROS reversed these effects. MFS‐VPCs displayed increased mitochondrial fusion and decreased mitochondrial fission. Treatment of control‐VPCs with TGF‐β1 increased mitochondrial fusion and reduced mitochondrial fission. Nonetheless, treatment of mitofusin2 (Mfn2)‐siRNA inhibited TGF‐β1‐induced mitochondrial fusion and cellular senescence. Furthermore, TGF‐β1‐induced mitochondrial fusion was mediated by the AMPK signalling pathway. Our study shows that TGF‐β1 induces VPC senescence in patients with MFS by mediating mitochondrial dynamics via the AMPK signalling pathway.     

Genetic analysis of craniofacial traits in the medaka

Family and twin studies suggest that a substantial genetic component underlies individual differences in craniofacial morphology. In the current study, we quantified 444 craniofacial traits in 100 individuals from two inbred medaka (Oryzias latipes) strains, HNI and Hd-rR. Relative distances between defined landmarks were measured in digital images of the medaka head region. A total of 379 traits differed significantly between the two strains, indicating that many craniofacial traits are controlled by genetic factors. Of these, 89 traits were analyzed via interval mapping of 184 F(2) progeny from an intercross between HNI and Hd-rR. We identified quantitative trait loci for 66 craniofacial traits. The highest logarithm of the odds score was 6.2 for linkage group (LG) 9 and 11. Trait L33, which corresponds to the ratio of head length to head height at eye level, mapped to LG9; trait V15, which corresponds to the ratio of snout length to head width measured behind the eyes, mapped to LG11. Our initial results confirm the potential of the medaka as a model system for the genetic analysis of complex traits such as craniofacial morphology.     

A microsatellite linkage map of Barramundi, Lates calcarifer

Barramundi (Lates calcarifer) is an important farmed marine food fish species. Its compact genome (approximately 700 Mb) is among the smallest genomes of food fish species. We established a first-generation genetic linkage map of Barramundi with a mapping panel containing three parents (two males and one female) and 93 progeny. A total of 240 microsatellite markers were mapped into 24 linkage groups. Among these markers, 10 were located in ESTs and known genes. The total lengths of the female and male maps were 873.8 and 414.5 cM with an average marker spacing of 6.20 and 4.70 cM, respectively. Comparing the flanking sequences of the 240 Barramundi microsatellites with the assembled whole-genome sequences of Tetraodon nigrovidiris revealed 55 homologous sequences located in 19 of the 21 chromosomes of T. nigrovidiris. The map will not only enable the mapping of quantitative trait loci, but also provide new resources for understanding the evolution of fish genomes.     

Disulfide bond mediates aggregation, toxicity, and ubiquitylation of familial amyotrophic lateral sclerosis-linked mutant SOD1

Mutations in the Cu/Zn-superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS) through the gain of a toxic function; however, the nature of this toxic function remains largely unknown. Ubiquitylated aggregates of mutant SOD1 proteins in affected brain lesions are pathological hallmarks of the disease and are suggested to be involved in several proposed mechanisms of motor neuron death. Recent studies suggest that mutant SOD1 readily forms an incorrect disulfide bond upon mild oxidative stress in vitro, and the insoluble SOD1 aggregates in spinal cord of ALS model mice contain multimers cross-linked via intermolecular disulfide bonds. Here we show that a non-physiological intermolecular disulfide bond between cysteines at positions 6 and 111 of mutant SOD1 is important for high molecular weight aggregate formation, ubiquitylation, and neurotoxicity, all of which were dramatically reduced when the pertinent cysteines were replaced in mutant SOD1 expressed in Neuro-2a cells. Dorfin is a ubiquityl ligase that specifically binds familial ALS-linked mutant SOD1 and ubiquitylates it, thereby promoting its degradation. We found that Dorfin ubiquitylated mutant SOD1 by recognizing the Cys(6)- and Cys(111)-disulfide cross-linked form and targeted it for proteasomal degradation.     

Age and gender effect on alexithymia in large, Japanese community and clinical samples: a cross-validation study of the Toronto Alexithymia Scale (TAS-20)

Background  

The construct validity of alexithymia and its assessment using the 20-item Toronto Alexithymia Scale (TAS-20) in Japan is unknown. Low reliability has been found for the third factor of the TAS-20 in some cultures, and the factor structure for psychosomatic disorder patients has not been adequately investigated. Although alexithymia most likely has certain developmental aspects, this has infrequently been investigated.