Aldimine to ketoamine isomerization (Amadori rearrangement) potential at the individual nonenzymic glycation sites of hemoglobin a: Preferential inhibition of glycation by nucleophiles at sites of low isomerization potential

The relative roles of the two structural aspects of nonenzymic glycation sites of hemoglobin A, namely the ease with which the amino groups could form the aldimine adducts and the propensity of the microenvironments of the respective aldimines to facilitate the Amadori rearrangement, in dictating the site selectivity of nonenzymic glycation with aldotriose has been investigated. The chemical reactivity of the amino groups of hemoglobin A forin vitro reductive glycation with aldotriose is distinct from that in the nonreductive mode. The reactivity of amino groups of hemoglobin A toward reductive glycation (i.e., propensity for aldimine formation) decreases in the order Val-1(), Val-1(), Lys-66(), Lys-61(), and Lys-16(). The overall reactivity of hemoglobin A toward nonreductive glycation decreased in the order Lys-16(), Val-1(), Lys-66(), Lys-82(), Lys-61(), and Val-1(). Since the aldimine is the common intermediate for both the reductive and nonreductive modification, the differential selectivity of protein for the two modes of glycation is clearly a reflection of the propensity of the microenvironments of nonenzymic glycation sites to facilitate the isomerization reaction (i.e., Amadori rearrangement). A semiquantitative estimate of this propensity of the microenvironment of the nonenzymic glycation sites has been obtained by comparing the nonreductive (nonenzymic) and reductive modification at individual glycation sites. The microenvironment of Lys-16() is very efficient in facilitating the rearrangement and the relative efficiency decreases in the order Lys-16(), Lys-82(), Lys-66(), Lys-61(), Val-1(), and Val-1(). The propensity of the microenvironment of Lys-16() to facilitate the Amadori rearrangement of the aldimine is about three orders of magnitude higher than that of Val-1() and is about 50 times higher than that of Val-1(). The extent of nonenzymic glycation at the individual sites is modulated by various factors, such as thepH, concentration of aldotriose, and the concentration of the protein. The nucleophiles—such as tris, glycine ethyl ester, and amino guanidine—inhibit the glycation by trapping the aldotriose. The nonenzymic glycation inhibitory power of nucleophile is directly related to its propensity to form aldimine. Thus, the extent of inhibition of nonenzymic glycation at a given site by a nucleophile directly reflects the relative role ofpK _a of the site in dictating the glycation at that site. The nonenzymic glycation of an amino group of a protein is an additive/synergestic consequence of the propensity of the site to form aldimine adducts on one hand, and the propensity of its microenvironment to facilitate the isomerization of the aldimines to ketoamines on the other. The isomerization potential of microenvironment plays the dominant role in dictating the site specificity of the nonenzymic glycation of proteins.     

Iron(III) complexes of certain meridionally coordinating tridentate ligands as models for non-heme iron enzymes: the role of carboxylate coordination

The iron(III) complexes [Fe(pda)Cl(H(2)O)(2)] (1), [Fe(tpy)Cl(3)] (2), and [Fe(bbp)Cl(3)] (3), where H(2)pda is pyridine-2,6-dicarboxylic acid, tpy is 2,2':6,2'-terpyridine and bbp is 2,6-bis(benzimidazolyl)pyridine, have been isolated and studied as functional models for the intradiol-cleaving catechol dioxygenase enzymes. Mixed ligand complexes of H(2)pda with the bidentate ligands 2,2'-bipyridine (bpy) and 1,10-phenanthroline (phen) have been also prepared and studied. All the complexes have been characterized using absorption spectral and electrochemical methods. The spectral changes in the catecholate adducts of the complexes generated in situ have been investigated. Upon interacting the complexes with catecholate anions a low energy catecholate to iron(III) charge transfer band appears, which is similar to that observed for enzyme-substrate complexes. All the complexes catalyze the oxidative intradiol cleavage of 3,5-di-tert-butylcatechol (H(2)dbc) in the presence of dioxygen. Interestingly, on replacing the pyridyl groups in 2 and the bulky benzimidazole groups in 3 by the carboxylate groups, the yields of the intradiol cleavage products of dioxygenation increases, 1 (50%)>2 (20%)>3 (10%). The higher intradiol yield for 1 has been ascribed to the meridional coordination of two carboxylate groups of pda(2-). In contrast to the trend in the intradiol cleavage yields, a tremendous decrease in the rate (200 times) is observed on replacing the two pyridyl moieties in 2 by two carboxylates as in 1 and a significant decrease in rate is observed on replacing the pyridyl moieties in 2 by strongly sigma-donating benzimidazole moieties as in 3. This is in conformity with the decrease in Lewis acidities of the iron(III) centers.     

Marine natural pigments as potential sources for therapeutic applications

In recent years, marine natural pigments have emerged as a powerful alternative in the various fields of food, cosmetic, and pharmaceutical industries because of their excellent biocompatibility, bioavailability, safety, and stability. Marine organisms are recognized as a rich source of natural pigments such as chlorophylls, carotenoids, and phycobiliproteins. Numerous studies have shown that marine natural pigments have considerable medicinal potential and promising applications in human health. In this review, we summarize the marine natural pigments as potential sources for therapeutic applications, including: antioxidant, anticancer, antiangiogenic, anti-obesity, anti-inflammatory activities, drug delivery, photothermal therapy (PTT), photodynamic therapy (PDT), photoacoustic imaging (PAI), and wound healing. Marine natural pigments will offer a better platform for future theranostic applications.     

Effect of female group size on harem male roosting behavior of the Indian short-nosed fruit bat <Emphasis Type="Italic">Cynopterus sphinx</Emphasis>

Mate guarding has been known to incur costs and cause constraints for harem males in many polygynous species. However, the effect of female group size on the harem male’s time budget in bats has received very limited attention. The Indian short-nosed fruit bat, Cynopterus sphinx, exhibits resource defense polygyny, in which tent roosting males construct tents and defend multiple female bats. We studied the effect of female group size on three aspects of harem male behavior: social grooming by reciprocal licking, tent maintenance, and tent guarding in the mast tree Polyalthia longifolia. In the process of reciprocal licking, all the bats in the harem were drenched in saliva before emergence, and this activity was positively and significantly correlated with female group size. Once females departed for foraging, harem males remained in their respective tents at night-time between intermittent foraging bouts and engaged in tent maintenance and tent guarding. Time invested by harem male bats in tent maintenance and tent guarding were positively and significantly correlated with female group size. Harem males extended their presence in tent by utilizing tents as feeding roosts. Female group size also influenced the emergence time of harem male bats, where males with largest group emerged later than did the smallest group. Likewise, harem male with the smallest group had more time available for foraging than the male with the largest group. Findings of this study suggest that having a larger harem may indeed be costly for the males by reducing their foraging time.     

Relative deficiency in interferon-γ-secreting CD4+ T cells is strongly associated with poorer COVID-19 vaccination responses in older adults

Although the two-dose mRNA vaccination regime provides protection against SARS-CoV-2, older adults have been shown to exhibit poorer vaccination responses. In addition, the role of vaccine-induced T-cell responses is not well characterised. We aim to assess the impact of age on immune responses after two doses of the BNT162b2 mRNA vaccine, focussing on antigen-specific T-cells. A prospective 3-month study was conducted on 15 young (median age 31 years, interquartile range (IQR) 25–35 years) and 14 older adults (median age 72 years, IQR 70–73 years). We assessed functional, neutralising antibody responses against SARS-CoV-2 variants using ACE-2 inhibition assays, and changes in B and T-cell subsets by high-dimensional flow cytometry. Antigen-specific T-cell responses were also quantified by intracellular cytokine staining and flow cytometry. Older adults had attenuated T-helper (Th) response to vaccination, which was associated with weaker antibody responses and decreased SARS-CoV-2 neutralisation. Antigen-specific interferon-γ (IFNγ)-secreting CD4+ T-cells to wild-type and Omicron antigens increased in young adults, which was strongly positively correlated with their neutralising antibody responses. Conversely, this relationship was negative in older adults. Hence, older adults' relative IFNγ-secreting CD4+ T cell deficiency might explain their poorer COVID-19 vaccination responses. Further exploration into the aetiology is needed and would be integral in developing novel vaccination strategies and improving infection outcomes in older adults.     

Chromium picolinate attenuates hyperglycemia-induced oxidative stress in streptozotocin-induced diabetic rats

Chromium picolinate is advocated as an anti-diabetic agent for impaired glycemic control. It is a transition metal that exists in various oxidation states and may thereby act as a pro-oxidant. The present study has been designed to examine the effect of chromium picolinate supplementation on hyperglycemia-induced oxidative stress. Diabetes was induced in male Wistar rats by a single intraperitoneal injection of streptozotocin (50 mg/kg body weight) and chromium was administered orally as chromium picolinate (1 mg/kg body weight) daily for a period of four weeks after the induction of diabetes. As is characteristic of diabetic condition, hyperglycemia was associated with an increase in oxidative stress in liver in terms of increased lipid peroxidation and decreased glutathione levels. The activity of antioxidant enzymes like superoxide dismutase, catalase and glutathione reductase were significantly reduced in liver of diabetic animals. Levels of α-tocopherol and ascorbic acid were found to be considerably lower in plasma of diabetic rats. Chromium picolinate administration on the other hand was found to have beneficial effect in normalizing glucose levels, lipid peroxidation and antioxidant status. The results from the present study demonstrate potential of chromium picolinate to attenuate hyperglycemia-induced oxidative stress in experimental diabetes.     

Stable coordination of the inhibitory Ca2+ ion at the metal ion-dependent adhesion site in integrin CD11b/CD18 by an antibody-derived ligand aspartate: implications for integrin regulation and structure-based drug design

A central feature of integrin interaction with physiologic ligands is the monodentate binding of a ligand carboxylate to a Mg(2+) ion hexacoordinated at the metal ion-dependent adhesion site (MIDAS) in the integrin A domain. This interaction stabilizes the A domain in the high-affinity state, which is distinguished from the default low-affinity state by tertiary changes in the domain that culminate in cell adhesion. Small molecule ligand-mimetic integrin antagonists act as partial agonists, eliciting similar activating conformational changes in the A domain, which has contributed to paradoxical adhesion and increased patient mortality in large clinical trials. As with other ligand-mimetic integrin antagonists, the function-blocking mAb 107 binds MIDAS of integrin CD11b/CD18 A domain (CD11bA), but in contrast, it favors the inhibitory Ca(2+) ion over the Mg(2+) ion at MIDAS. We determined the crystal structures of the Fab fragment of mAb 107 complexed to the low- and high-affinity states of CD11bA. Favored binding of the Ca(2+) ion at MIDAS is caused by the unusual symmetric bidentate ligation of a Fab-derived ligand Asp to a heptacoordinated MIDAS Ca(2+) ion. Binding of the Fab fragment of mAb 107 to CD11bA did not trigger the activating tertiary changes in the domain or in the full-length integrin. These data show that the denticity of the ligand Asp/Glu can modify the divalent cation selectivity at MIDAS and hence integrin function. Stabilizing the Ca(2+) ion at MIDAS by bidentate ligation to a ligand Asp/Glu may provide one approach for designing pure integrin antagonists.     

Role of quercetin (a natural herbal compound) in allergy and inflammation

An investigated flavonoid, quercetin, is reviewed in this article. Quercetin is a bioflavonoid found in red wine, grapefruit, onions, apples, black tea, and, in lesser amounts, in leafy green vegetables and beans. Quercetin has an antioxidant and anti-inflammatory activity and prevents cancer. Quercitin inhibits the growth of certain malignant cells in vitro, and histamine and most cyclin-dependent kinases and also displays unique anticancer properties. Quercetin is a natural compound that blocks substances involved in allergies and is able to act as an inhibitor of mast cell secretion, causes a decrease in the release of tryptase, MCP-1 and IL-6 and the down-regulation of histidine decarboxylase (HDC) mRNA from few mast cell lines. Quercetin is a safe, natural therapy that may be used as primary therapy or in conjunction with conventional methods.     

Understanding the evolutionary relationship of hemagglutinin protein from influenza viruses using phylogenetic and molecular modeling studies

The existing H1N1 (2009) swine flu is pandemic in nature and is responsible for global economic losses and fatalities. Among the eight gene segments of H1N1, hemagglutinin (HA) plays a major role in the attachment of the virus to the host cell surface and entry of viral RNA into the host cell leads to infection. In this study, sequence and phylogenetic analysis of the H1N1 (2009) HA, from Mexico City along with 1952 sequences, from different subtypes of pandemic influenza A virus were studied and results showed that the closest relationship of H1N1 (2009) Mexico strain was with the H1N1 (2007) Mallard Norway strain. Analysis of secondary structures predicted from the protein sequence revealed that diminishing of alpha helixes was observed in many areas of the sequences between the years 2005 to 2010. Conversely, analysis at the structural level is necessary to critically assess the functional significance. Structural level investigation was therefore done for the above said proteins by constructing the 3D structure of these proteins through homology modeling. The models were validated and structural level similarities were evaluated through superimposition. Subsequently, docking studies were done to find the binding mode of the sialic acid (SA) with influenza HA. Molecular dynamics simulations were executed to study the interactions of SA molecule with the HA. Energetic analysis reveals that van der Waal interaction is more favorable for binding of HA with SA of the whole influenza virus. Binding pocket analysis shows that intensities of H-bond donor and acceptor are more in H1N1 (2009).