Therapeutic potential of breakers of advanced glycation end product-protein crosslinks

Long-lived structural proteins, collagen and elastin, undergo continual non-enzymatic crosslinking during aging and in diabetic individuals. This abnormal protein crosslinking is mediated by advanced glycation end products (AGEs) generated by non-enzymatic glycosylation of proteins by glucose. The AGE-derived protein crosslinking of structural proteins contributes to the complications of long-term diabetes such as nephropathy, retinopathy, and neuropathy. AGE-crosslinks have also been implicated in age-related cardiovascular diseases. Potential treatment strategies for these AGE-derived complications include prevention of AGE-formation and breaking of the existing AGE-crosslinks. The therapeutic potential of the AGE-inhibitor, pimagedine (aminoguanidine), has been extensively investigated in animal models and in Phase 3 clinical trials. This review presents the pre-clinical and clinical studies using ALT-711, a highly potent AGE-crosslink breaker that has the ability to reverse already-formed AGE-crosslinks. Oral administration of ALT-711 has resulted in a rapid improvement in the elasticity of stiffened myocardium in experimental animals. Topical administration of ALT-711 was effective in improving the skin hydration of aged rats. The therapeutic potential of crosslink breakers for cardiovascular complications and dermatological alterations associated with aging and diabetes is discussed.     

Apoptosis during spontaneous and prostaglandin F(2alpha)-induced luteal regression in the buffalo cow (Bubalus bubalis): involvement of mitogen-activated protein kinases

The present study was conducted to evaluate whether the corpus luteum (CL) of the water buffalo (Bubalus bubalis) cow undergoes luteal regression by the process of apoptosis and to examine the involvement of mitogen-activated protein (MAP) kinases during prostaglandin (PG) F(2alpha)-induced luteolysis. Sections of CL from late in the estrous cycle, i.e., during spontaneous luteolysis, stained for 4',6'-diamidino-2-phenylindole revealed increased numbers of condensed nuclei, indicating cell death by apoptosis, which was confirmed further by the occurrence of pronounced oligonucleosome formation. For morphological and biochemical characterization during PGF(2alpha)-induced apoptosis, CL were collected at 0, 4, 12, and 18 h after injection of 750 micro g of Tiaprost, a synthetic analogue of PGF(2alpha), to midestrous buffalo cows. Serum progesterone concentrations fell within 4 h and decreased (P < 0.05) maximally by 18 h. Concomitant decreases (P < 0.05) in the levels of steroidogenic acute regulatory mRNA and protein were observed in CL during 12-18 h, with the more profound effect on mRNA levels. Quantitative analysis of the genomic DNA showed a >5-fold increase (P < 0.05) in the low molecular weight DNA fragments by 18 h postinjection. Immunoblot analysis of CL tissue lysates showed increased (P < 0.05) levels of phospho-Jun N-terminal kinase (JNK) 1 (4- to 14-fold during 4-18 h) and phospho-p38 (2- to 4-fold at 18 h). Immunohistochemical evaluation of CL sections revealed an increased nuclear localization of phospho-JNK after treatment. These findings demonstrate that the CL of the buffalo cow undergoes cell death by the process of apoptosis both during spontaneous and PGF(2alpha)-induced luteolysis and that MAP kinases are involved during PGF(2alpha)-mediated apoptosis in the CL.     

ERRATUM: A review of the genus Eodiaptomus Kiefer, 1932, with the description of E. sanuamuangae n.sp. from Thailannd, and a redescriptionn of E.lumholtzi (Sars, 1889) from Australia (Copepoda, Calanoida)

Hydrobiologia 361: 169–189, 1998. Due to technical problems, Figures 73–84 and Figures 85–94 were unfortunately omitted from pages 182 and 183, respectively, of the above volume, duplicates of Figures 1–6 appearing in their place. We now present the correct Figures with their captions, on pages 214 and 215 of this volume. Additionally there are four corrections to Table 1, which appeared on pages 186-188     

Two flavonoids from tephrosia purpurea

Purpurenone, a new β-hydroxychalcone; (+)-purpurin, a diastereoisomer of(?)purpurin; dehydroisoderricin, and (?)-maackiain have been isolated from the roots of Tephrosio purpurea in addition to the earlier reported flavonoids [1, 2]. Pseudosemiglabrin was obtained in admixture with (?)-semiglabrin     

An analysis of association of components of yield and oil in safflower (Carthamus tinctorius L.)

Summary Inter-relationships of various component characters with yield and oil content were analysed using 215 entries of safflower from India and U.S.A. Correlation of capsule number per plant and capsule weight with yield per plant was pronounced and they showed large direct effects on yield. All other components influenced seed yield mainly through these two components. Seed size had little effect on yield while seed number exerted a positive influence. The proportion of hull expressed as per cent of the whole seed revealed a highly significant and inverse relationship with oil content and was mainly responsible for the observed variability in oil content in the material. Although negative association was indicated between seed size and oil content, it was observed to be due to the indirect effect of hull content and not due to direct effect of seed size. Interestingly, yield per plant and its major components, number of capsules and capsule weight, revealed a negligible relationship with oil content. Both direct as well as indirect effects of hull percent and yield per plant were responsible for the favourable effect of seed number on oil content. The correlation of plant height, days to first flowering and total crop growth period with yield and oil content was either negligible or low, offering scope for developing early maturing and dwarf varieties with high yield and oil content. Spine index showed a non-significant association with yield and oil content. Capsule number, capsule weight and hull per cent were observed to be the most important components in breeding for higher yield and oil content.     

Heterogeneity of proteoglycans in developing chick limb cartilage.

Proteoglycan heterogeneity was studied during the maturation of embryonic-chick limb cartilage in vivo. The results suggest that during the differentiation of limb-bud cartilage the aggregated forms of proteoglycans increase between stages 24 and 35, whereas the non-aggregated or monomeric forms decrease. Only one link protein is found in stage-24 limb buds, whereas two are present at stage 35. Evidence suggests that the synthesis of link proteins may be a regulatory factor in limb chondrogenesis.     

Weakened coupling of conserved arginine to the proteorhodopsin chromophore and its counterion implies structural differences from bacteriorhodopsin

In wild-type proteorhodopsin (pR), titration of the chromophore's counterion Asp(97) occurs with a pK(a) of 8.2+/-0.1. R94C mutation reduces this slightly to 7.0+/-0.2, irrespective of treatment with ethylguanidinium. This contrasts with the homologous archaeal protein bacteriorhodopsin (bR), where R82C mutation was previously shown to elevate the pK(a) of Asp(85) by approximately 5 units, while reconstitution with ethylguanidinium restores it nearly to the wild-type value of 2.5. We conclude there is much weaker electrostatic coupling between Arg(94) and Asp(97) in the unphotolyzed state of pR, in comparison to Arg(82) and Asp(85) in bR. Therefore, while fast light-driven H(+) release may depend on these two residues in pR as in bR, no tightly conserved pre-photolysis configuration of them is required.     

Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression

Dysregulation of central serotonin neurotransmission has been widely suspected as an important contributor to major depression. Here, we identify a (G1463A) single nucleotide polymorphism (SNP) in the rate-limiting enzyme of neuronal serotonin synthesis, human tryptophan hydroxylase-2 (hTPH2). The functional SNP in hTPH2 replaces the highly conserved Arg441 with His, which results in approximately 80% loss of function in serotonin production when hTPH2 is expressed in PC12 cells. Strikingly, SNP analysis in a cohort of 87 patients with unipolar major depression revealed that nine patients carried the mutant (1463A) allele, while among 219 controls, three subjects carried this mutation. In addition, this functional SNP was not found in a cohort of 60 bipolar disorder patients. Identification of a loss-of-function mutation in hTPH2 suggests that defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression.     

Human umbilical cord tissue stem cells and neuronal lineages in an injectable caffeic acid–bioconjugated gelatin hydrogel for transplantation

Present-day scaffolds are useful in cell therapy to a reasonable extent, but in pursuit of improvising the scaffold to improve the outcome, we tested a new injectable caffeic acid–bioconjugated gelatin hydrogel scaffold (CBGH; with tunable stiffness −10%). Two-dimensional (2D) form of human umbilical cord tissue-derived mesenchymal stem cells (HUCMSCs) culture performed based on our previously reported methods and characterized by using multipotent and pluripotent analysis. In addition, neurogenesis was induced in the presence of retinoic acid or neural growth factor or epidermal growth factor categorized by neuronal markers. The viability, proliferation rate, and vascular endothelial growth factor expression of HUCMSCs increased significantly in the CBGH scaffold. In addition, there was an increase in CD90 and TRA-1-81 phenotypic expressions and SOX-2, MAP-2, TAU, NeuN, and NF, which confirmed the neurogenesis of encapsulated HUCMSCs. Topographical elucidation by scanning electron microscopy data showed that the HUCMSCs proliferated and migrated inside the construct. Hematoxylin and eosin staining demonstrated a more viable structural pattern and cresyl violet staining showed the Nissl synthesis, confirming the presence of functional neurons in the encapsulated form. The molecular-level analysis further substantiated that HUCMSCs cultured in CBGH expressed significantly greater upregulation of stemness, neuronal genes, and protein expression compared with the adherent culture. Correspondingly, this is the first time that we have measured the fluorescence intensity variation of the HUCMSCs-stained cell segmentation process using customized MATLAB code execution to reduce the background noise and autofluorescence. We conclude that this novel CBGH scaffold increases the viability, proliferation, stemness, and also neuronal transdifferentiation of HUCMSCs in a three-dimensional culture than the 2D plastic adherent culture.