Boron- and Oxygen-Doped π-Extended Helical Nanographene with Circularly Polarised Thermally Activated Delayed Fluorescence.

Helical nanographenes have garnered substantial attention owing to their finely adjustable optical and semiconducting properties. The strategic integration of both helicity and heteroatoms into the nanographene structure, facilitated by a boron-oxygen-based multiple resonance (MR) thermally activated delayed fluorescence (TADF), elevates its photophysical and chiroptical features. This signifies the introduction of an elegant category of helical nanographene that combines optical (TADF) and chiroptical (CPL) features. In this direction, we report the synthesis, optical, and chiroptical properties of boron, oxygen-doped Π-extended helical nanographene. The π-extension induces distortion in the DOBNA-incorporated nanographene, endowing a pair of helicenes, (P)-B2NG, and (M)-B2NG exhibiting circularly polarized luminescence with glum of -2.3×10-3 and +2.5×10-3, respectively. B2NG exhibited MR-TADF with a lifetime below 5 µs, and a reasonably high fluorescence quantum yield (50 %). Our molecular design enriches the optical and chiroptical properties of nanographenes and opens up new opportunities in multidisciplinary fields.

Mitigation of acute radiation syndrome (ARS) with human umbilical cord blood.

PURPOSE: The growing concern over potential unintended nuclear accidents or malicious activities involving nuclear/radiological devices cannot be overstated. Exposure to whole-body doses of radiation can result in acute radiation syndrome (ARS), colloquially known as "radiation sickness," which can severely damage various organ systems. Long-term health consequences, such as cancer and cardiovascular disease, can develop many years post-exposure. Identifying effective medical countermeasures and devising a strategic medical plan represents an urgent, unmet need. Various clinical studies have investigated the therapeutic use of umbilical cord blood (UCB) for a range of illnesses, including ARS. The objective of this review is to thoroughly discuss ARS and its sub-syndromes, and to highlight recent findings regarding the use of UCB for radiation injury. UCB, a rich source of stem cells, boasts numerous advantages over other stem cell sources, like bone marrow, owing to its ease of collection and relatively low risk of severe graft-versus-host disease. Preclinical studies suggest that treatment with UCB, and often UCB-derived mesenchymal stromal cells (MSCs), results in improved survival, accelerated hematopoietic recovery, reduced gastrointestinal tract damage, and mitigation of radiation-induced pneumonitis and pulmonary fibrosis. Interestingly, recent evidence suggests that UCB-derived exosomes and their microRNAs (miRNAs) might assist in treating radiation-induced damage, largely by inhibiting fibrotic pathways. CONCLUSION: UCB holds substantial potential as a radiation countermeasure, and future research should focus on establishing treatment parameters for ARS victims.

Binaphthalene-Assisted Axial Chirality in Porphyrins: Toward Solid-State Circularly Polarized Luminescence from Self-Assembled Nanostructures.

Circularly polarized luminescence (CPL) is emerging as an effective tool to study the excited-state optical activity in molecules and their self-assembled nanostructures. Chiral porphyrins are a class of optically active molecules wherein the ground-state chirality has been extensively studied in recent times using circular dichroism (CD) spectroscopy. However, obtaining CPL from porphyrin nanostructures, which would have vast implications in biological applications, has remained an uphill task. In this work, we design and synthesize a pair of chiral porphyrin enantiomers functionalized by axially chiral binaphthalene units at the four meso-positions. The molecule undergoes self-assembly following an isodesmic polymerization model, leading to the formation of a spherical nanostructure possessing opposite chirality. Favorable thermodynamic parameters achieved through the controlled experimental conditions helped drive the self-assembly in the forward direction. The limitations imposed by a large nonradiative decay constant arising due to the aggregation-induced quenching could be overcome by fabricating self-standing polymeric films of the nanostructures. The films exhibited relatively high radiative decay and, more interestingly, good CPL activity with clear mirror image spectra for the nanostructures with opposite chirality. The work on CPL-active solid-state materials opens avenue for the design and synthesis of a variety of porphyrin-based chromophoric systems and their nanoaggregates that can find potential application in the field of chiral biosensing and bioimaging, security tags, and display devices.

The heme oxygenase system selectively enhances the anti-inflammatory macrophage-M2 phenotype, reduces pericardial adiposity, and ameliorated cardiac injury in diabetic cardiomyopathy in Zucker diabetic fatty rats.

Cardiac function is adversely affected by pericardial adiposity. We investigated the effects of the heme oxygenase (HO) inducer, hemin on pericardial adiposity, macrophage polarization, and diabetic cardiopathy in Zucker diabetic fatty rats (ZDFs) with use of echocardiographic, quantitative real-time polymerase chain reaction, Western immunoblotting, enzyme immunoassay, and spectrophotometric analysis. In ZDFs, hemin administration increased HO activity; normalized glycemia; potentiated insulin signaling by enhancing insulin receptor substrate 1(IRS-1), phosphatidylinositol-3-kinase (PI3K), and protein kinase B (PKB)/Akt; suppressed pericardial adiposity, cardiac hypertrophy, and left ventricular longitudinal muscle fiber thickness, a pathophysiological feature of cardiomyocyte hypertrophy; and correspondingly reduced systolic blood pressure, total peripheral resistance, and pro-inflammatory/oxidative mediators, including nuclear factor κB (NF-κB), cJNK, c-Jun-N-terminal kinase (cJNK), endothelin (ET-1), tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1ß, activating protein 1 (AP-1), and 8-isoprostane, whereas the HO inhibitor, stannous mesoporphyrin, nullified the effects. Furthermore, hemin reduced the pro-inflammatory macrophage M1 phenotype, but enhanced the M2 phenotype that dampens inflammation. Because NF-κB activates TNFα, IL-6, and IL-1ß and TNF-α, cJNK, and AP-1 impair insulin signaling, the high levels of these cytokines in obesity/diabetes would create a vicious cycle that, together with 8-isoprostane and ET-1, exacerbates cardiac injury, compromising cardiac function. Therefore, the concomitant reduction of pro-inflammatory cytokines and macrophage infiltration coupled to increased expressions of IRS-1, PI3K, and PKB may account for enhanced glucose metabolism and amelioration of cardiac injury and function in diabetic cardiomyopathy. The hemin-induced preferential polarization of macrophages toward anti-inflammatory macrophage M2 phenotype in cardiac tissue with concomitant suppression of pericardial adiposity in ZDFs are novel findings. These data unveil the benefits of hemin against pericardial adiposity, impaired insulin signaling, and diabetic cardiomyopathy and suggest that its multifaceted protective mechanisms include the suppression of inflammatory/oxidative mediators.

Catharanthine dilates small mesenteric arteries and decreases heart rate and cardiac contractility by inhibition of voltage-operated calcium channels on vascular smooth muscle cells and cardiomyocytes.

Catharanthine is a constituent of anticancer vinca alkaloids. Its cardiovascular effects have not been investigated. This study compares the in vivo hemodynamic as well as in vitro effects of catharanthine on isolated blood vessels, vascular smooth muscle cells (VSMCs), and cardiomyocytes. Intravenous administration of catharanthine (0.5-20 mg/kg) to anesthetized rats induced rapid, dose-dependent decreases in blood pressure (BP), heart rate (HR), left ventricular blood pressure, cardiac contractility (dP/dt(max)), and the slope of the end-systolic pressure-volume relationship (ESPVR) curve. Catharanthine evoked concentration-dependent decreases (I(max) >98%) in endothelium-independent tonic responses of aortic rings to phenylephrine (PE) and KCl (IC(50) = 28 µM for PE and IC(50) = 34 µM for KCl) and of third-order branches of the small mesenteric artery (MA) (IC(50) = 3 µM for PE and IC(50) = 6 µM for KCl). Catharanthine also increased the inner vessel wall diameter (IC(50) = 10 µM) and reduced intracellular free Ca(2+) levels (IC(50) = 16 µM) in PE-constricted MAs. Patch-clamp studies demonstrated that catharanthine inhibited voltage-operated L-type Ca(2+) channel (VOCC) currents in cardiomyocytes and VSMCs (IC(50) = 220 µM and IC(50) = 8 µM, respectively) of MA. Catharanthine lowers BP, HR, left ventricular systolic blood pressure, and dP/dt(max) and ESPVR likely via inhibition of VOCCs in both VSMCs and cardiomyocytes. Since smaller vessels such as the third-order branches of MAs are more sensitive to VOCC blockade than conduit vessels (aorta), the primary site of action of catharanthine for lowering mean arterial pressure appears to be the resistance vasculature, whereas blockade of cardiac VOCCs may contribute to the reduction in HR and cardiac contractility seen with this agent.

Considerations for application of benchmark dose modeling in radiation research: workshop highlights.

BACKGROUND: Exposure to different forms of ionizing radiation occurs in diverse occupational, medical, and environmental settings. Improving the accuracy of the estimated health risks associated with exposure is therefore, essential for protecting the public, particularly as it relates to chronic low dose exposures. A key aspect to understanding health risks is precise and accurate modeling of the dose-response relationship. Toward this vision, benchmark dose (BMD) modeling may be a suitable approach for consideration in the radiation field. BMD modeling is already extensively used for chemical hazard assessments and is considered statistically preferable to identifying low and no observed adverse effects levels. BMD modeling involves fitting mathematical models to dose-response data for a relevant biological endpoint and identifying a point of departure (the BMD, or its lower bound). Recent examples in chemical toxicology show that when applied to molecular endpoints (e.g. genotoxic and transcriptional endpoints), BMDs correlate to points of departure for more apical endpoints such as phenotypic changes (e.g. adverse effects) of interest to regulatory decisions. This use of BMD modeling may be valuable to explore in the radiation field, specifically in combination with adverse outcome pathways, and may facilitate better interpretation of relevant in vivo and in vitro dose-response data. To advance this application, a workshop was organized on June 3rd, 2022, in Ottawa, Ontario that brought together BMD experts in chemical toxicology and the radiation scientific community of researchers, regulators, and policy-makers. The workshop's objective was to introduce radiation scientists to BMD modeling and its practical application using case examples from the chemical toxicity field and demonstrate the BMDExpress software using a radiation dataset. Discussions focused on the BMD approach, the importance of experimental design, regulatory applications, its use in supporting the development of adverse outcome pathways, and specific radiation-relevant examples. CONCLUSIONS: Although further deliberations are needed to advance the use of BMD modeling in the radiation field, these initial discussions and partnerships highlight some key steps to guide future undertakings related to new experimental work.

Association mapping for pre-harvest sprouting resistance in white winter wheat.

Association mapping identified quantitative trait loci (QTLs) and the markers linked to pre-harvest sprouting (PHS) resistance in an elite association mapping panel of white winter wheat comprising 198 genotypes. A total of 1,166 marker loci including DArT and SSR markers representing all 21 chromosomes of wheat were used in the analysis. General and mixed linear models were used to analyze PHS data collected over 4 years. Association analysis identified eight QTLs linked with 13 markers mapped on seven chromosomes. A QTL was detected on each arm of chromosome 2B and one each on chromosome arms 1BS, 2DS, 4AL, 6DL, 7BS and 7DS. All except the QTL on 7BS are located in a location similar to previous reports and, if verified, the QTL on 7BS is likely to be novel. Principal components and the kinship matrix were used to account for the presence of population structure but had only a minor effect on the results. Although, none of the QTLs was highly significant across all environments, a QTL on the long arm of chromosome 4A was detected in three different environments and also using the best linear unbiased predictions over years. Although previous reports have identified this as a major QTL, its effects were minor in our biparental mapping populations. The results of this study highlight the benefits of association mapping and the value of using elite material in association mapping for plant breeding programs.

COVID-19: The Disease, the Immunological Challenges, the Treatment with Pharmaceuticals and Low-Dose Ionizing Radiation.

The year 2020 will be carved in the history books-with the proliferation of COVID-19 over the globe and with frontline health workers and basic scientists worldwide diligently fighting to alleviate life-threatening symptoms and curb the spread of the disease. Behind the shocking prevalence of death are countless families who lost loved ones. To these families and to humanity as a whole, the tallies are not irrelevant digits, but a motivation to develop effective strategies to save lives. However, at the onset of the pandemic, not many therapeutic choices were available besides supportive oxygen, anti-inflammatory dexamethasone, and antiviral remdesivir. Low-dose radiation (LDR), at a much lower dosage than applied in cancer treatment, re-emerged after a 75-year silence in its use in unresolved pneumonia, as a scientific interest with surprising effects in soothing the cytokine storm and other symptoms in severe COVID-19 patients. Here, we review the epidemiology, symptoms, immunological alterations, mutations, pharmaceuticals, and vaccine development of COVID-19, summarizing the history of X-ray irradiation in non-COVID diseases (especially pneumonia) and the currently registered clinical trials that apply LDR in treating COVID-19 patients. We discuss concerns, advantages, and disadvantages of LDR treatment and potential avenues that may provide empirical evidence supporting its potential use in defending against the pandemic.

Validation of the markers linked with drought tolerance related traits for use in MAS programme in chickpea.

Chickpea is an important cool season legume crop. The breeding efforts in chickpea are often hampered due to the narrow genetic base. Availability of diverse germplasm is an essential requirement for any crop improvement programme. This can facilitate development of desirable gene combinations and subsequently the improved cultivars. In any marker-assisted selection (MAS) programme, study of parental polymorphism using QTL linked markers is a pre-requisite for screening of desired genotypes. Any such study involving use of markers chosen randomly can only tell the diversity of the parents, but does not guarantee success of the MAS. The present study was undertaken to study the suitability of the SSR markers from the QTL-hotspot region linked with drought tolerance related traits in different genetic background. The study of polymorphism of the QTL-hotspot linked SSR markers NCPGR127, NCPGR21, TAA170, ICCM0249, STMS11, TR11 and GA24 between drought tolerant genotype ICC-4958 and remaining 32 chickpea genotypes revealed that most of the genotypes had monomorphic alleles as that of ICC-4958, while only a few genotypes showed polymorphic alleles. The markers that are found polymorphic between ICC-4958 and other chickpea genotypes can be used directly for foreground selection in MAS as they are mapped in the QTL-hotspot region. However, in cases where these are monomorphic, additional markers from QTL-hotspot region need to be screened. Besides validating the suitability of these markers, we also validated SSR markers that can be used for the background selection. Of the 21 SSR markers, 15 were found polymorphic between ICC-4958 and other genotypes suggesting their usefulness in the background selection.

Vasoactive Effects of Acute Ergot Exposure in Sheep.

Ergotism is a common and increasing problem in Saskatchewan's livestock. Chronic exposure to low concentrations of ergot alkaloids is known to cause severe arterial vasoconstriction and gangrene through the activation of adrenergic and serotonergic receptors on vascular smooth muscles. The acute vascular effects of a single oral dose with high-level exposure to ergot alkaloids remain unknown and are examined in this study. This study had two main objectives; the first was to evaluate the role of α1-adrenergic receptors in mediating the acute vasocontractile response after single-dose exposure in sheep. The second was to examine whether terazosin (TE) could abolish the vascular contractile effects of ergot alkaloids. Twelve adult female sheep were randomly placed into control and exposure groups (n = 6/group). Ergot sclerotia were collected and finely ground. The concentrations of six ergot alkaloids (ergocornine, ergocristine, ergocryptine, ergometrine, ergosine, and ergotamine) were determined using HPLC/MS at Prairie Diagnostic Services Inc., (Saskatoon, SK, Canada). Each ewe within the treatment group received a single oral treatment of ground ergot sclerotia at a dose of 600 µg/kg BW (total ergot) while each ewe in the control group received water. Animals were euthanized 12 h after the treatment, and the pedal artery (dorsal metatarsal III artery) from the left hind limb from each animal was carefully dissected and mounted in an isolated tissue bath. The vascular contractile response to phenylephrine (PE) (α1-adrenergic agonist) was compared between the two groups before and after TE (α1-adrenergic antagonist) treatment. Acute exposure to ergot alkaloids resulted in a 38% increase in vascular sensitivity to PE compared to control (Ctl EC50 = 1.74 × 10-6 M; Exp EC50 = 1.079 × 10-6 M, p = 0.046). TE treatment resulted in a significant dose-dependent increase in EC50 in both exposure and control groups (p < 0.05 for all treatments). Surprisingly, TE effect was significantly more pronounced in the ergot exposed group compared to the control group at two of the three concentrations of TE (TE 30 nM, p = 0.36; TE 100 nM, p < 0.001; TE 300 nM, p < 0.001). Similar to chronic exposure, acute exposure to ergot alkaloids results in increased vascular sensitivity to PE. TE is a more potent dose-dependent antagonist for the PE contractile response in sheep exposed to ergot compared to the control group. This study may indicate that the dry gangrene seen in sheep, and likely other species, might be related to the activation of α1-adrenergic receptor. This effect may be reversed using TE, especially at early stages of the disease before cell death occurs. This study may also indicate that acute-single dose exposure scenario may be useful in the study of vascular effects of ergot alkaloids.

Heme arginate therapy enhanced adiponectin and atrial natriuretic peptide, but abated endothelin-1 with attenuation of kidney histopathological lesions in mineralocorticoid-induced hypertension.

We investigated the role of heme oxygenase (HO), adiponectin, and atrial natriuretic peptide (ANP) in uninephrectomized (UnX) deoxycorticosterone-acetate (DOCA)-salt hypertensive rats, a volume-overload model characterized by elevated endothelin-1 (ET-1), mineralocorticoid-induced oxidative/inflammatory insults, fibrosis, hypertrophy, and severe renal histopathological lesions that closely mimic end-stage renal disease (ESRD). HO was enhanced with heme arginate (HA) or blocked with chromium mesoporphyrin (CrMP). Histological, morphological/morphometrical, quantitative reverse transcription-polymerase chain reaction, Western blot, enzyme immunoassay, and spectrophotometric analysis were used. Our experimental design included the following groups of rats: A, controls [surgery-free Sprague-Dawley, UnX-sham, UnX-salt (0.9% NaCl + 0.2% KCl), and UnX-DOCA]; B, UnX-DOCA-salt hypertensive; C, UnX-DOCA-salt + HA; D, UnX-DOCA-salt + HA + CrMP; E, UnX-DOCA-salt + CrMP; F, UnX-DOCA-salt + captopril; G, UnX-DOCA-salt + L-arginine; H, UnX-DOCA-salt + spironolactone; and I, UnX-DOCA-salt + vehicle. HA lowered blood pressure and abated kidney hypertrophy and renal lesions, including glomerulosclerosis, tubular dilation, tubular cast formation, interstitial mononuclear cell infiltration, glomerular hypertrophy, and renal-arteriolar thickening in UnX-DOCA hypertension. Correspondingly, HO activity, adiponectin, adenosine monophosphate-activated protein kinase (AMPK), ANP, cGMP, antioxidants such as bilirubin, ferritin, superoxide dismutase, and catalase, and total antioxidant capacity were increased, whereas ET-1, transforming growth factor beta (TGF-beta), fibronectin, and 8-isoprostane were abated. These were accompanied by reduced proteinuria/albuminuria, but increased creatinine clearance. Interestingly, HA was more renoprotective than sipronolactone, L-arginine, and captopril, whereas the HO blocker CrMP exacerbated oxidative injury, aggravating renal lesions and function. Because 8-isoprostane stimulates ET-1 to potentiate oxidative stress and fibrosis, up-regulating HO-1 enhanced tissue antioxidant status alongside cellular targets such as adiponectin, AMPK, ANP, and cGMP to suppress ET-1, TGF-beta, and fibronectin with a corresponding decline of renal lesions, proteinuria/albuminuria, and thus improved renal function. The potent renoprotection of HA could be explored to combat renal hypertrophy and histopathological lesions characteristic of ESRD.

The heme oxygenase system attenuates pancreatic lesions and improves insulin sensitivity and glucose metabolism in deoxycorticosterone acetate hypertension.

Recent clinical reports indicate that impaired glucose tolerance is a common phenomenon in primary aldosteronism. Aldosterone stimulates NF-kappaB and activating protein-1 (AP-1) to cause oxidative injury. Elevated oxidative stress impairs insulin signaling. We recently showed that the heme oxygenase (HO) system lowers blood pressure (BP) in deoxycorticosterone-acetate (DOCA)+salt hypertension, a model of primary aldosteronism. However, the effect of the HO system on insulin sensitivity in this model remains largely unclear. Here we report the effects of the HO-inducer hemin and the HO-blocker [chromium mesoporphyrin (CrMP)] on insulin sensitivity/glucose metabolism. Our experimental design included the following 10 groups: (A) controls [(i) surgery-free or normal Sprague-Dawley (SD), (ii) uninephrectomized (UnX)-sham, (iii) UnX+salt (0.9%NaCl+0.2%KCl) and (iv) UnX+DOCA]; (B) DOCA+salt; (C) hemin+DOCA+salt; (D) hemin+CrMP+DOCA+salt; (E) CrMP+DOCA+salt; (F) vehicle-treated rats and (G) normal SD+hemin. Hemin therapy lowered BP and increased plasma insulin and the insulin-sensitizing protein adiponectin with slight but significant reduction of glycemia, while CrMP abolished the hemin effects. Furthermore, hemin improved intraperitoneal glucose and insulin tolerance, suggesting that although DOCA+salt-hypertensive rats were normoglycemic, insulin signaling may be impaired. In contrast, the HO-inhibitor CrMP aggravated insulin resistance and exacerbated glucose and insulin tolerance. Interestingly, the enhanced insulin sensitization in hemin-treated animals was accompanied by reduced urinary/gastrocnemius muscle 8-iso-prostaglandin F(2alpha) (8-isoprostane), inflammatory/oxidative transcription factors like NF-kappaB, AP-1, JNK, and heme content, whereas HO-1, HO-activity, cGMP, and plasma/gastrocnemius muscle antioxidants including bilirubin, ferritin, SOD, catalase, and the total antioxidant capacity were increased. Similarly, hemin enhanced pancreatic HO, cGMP, and cAMP but suppressed 8-isoprostane and attenuated pancreatic histopathological lesions including fibrosis, interstitial edema, acinar cell necrosis, vacuolization, and mononuclear cell infiltration, with corresponding improvement of insulin production. Our results suggest that impaired insulin signaling may be a forerunner to hyperglycemia in aldosteronism. By preserving pancreatic morphology, potentiating insulin signaling, and lowering BP, the HO system may prevent metabolic and cardiovascular complications in aldosteronism.

Template Assisted Generation of Chiral Luminescence in Organic Fluorophores.

Development of efficient ways of fabricating chiral light emitting materials is an active area of research due to the vast potential offered by these materials in the field of optoelectronic devices, data storage, and asymmetric synthesis. Among the various methods employed, template assisted generation of chiral luminescence is gaining enormous attention due to its simplicity, applicability over a wide range of fluorescent molecules/dyes, and the display of high anisotropic values.

Upregulating the heme oxygenase system suppresses left ventricular hypertrophy in adult spontaneously hypertensive rats for 3 months.

BACKGROUND: Aldosterone and phospholipase C (PLC) stimulate nuclear factor-kappaB (NF-kappaB) and activating-protein (AP-1), causing fibrosis and hypertrophy. Besides harboring binding sites for NF-kappaB and AP-1, heme oxygenase (HO-1) generates cytoprotective products, including bilirubin and ferritin. The multifaceted interaction between HO-1 and aldosterone-PLC profibrotic axis in cardiac hypertrophy of spontaneously hypertensive rats (SHR) was studied. METHODS AND RESULTS: HO-1 was induced with hemin or blocked with chromium mesoporphyrin (CrMP). The study groups included: (A) controls (SHR, WKY, and SD), (B) SHR+hemin, (C) SHR+hemin+CrMP, (D) SHR+CrMP, and (E) SHR+vehicle. Histological and morphological/morphometrical, quantitative reverse transcription-polymerase chain reaction, Western blot, enzyme immunoassay, and spectrophotometric assays were used to assess the effect of the HO system on cardiac hypertrophy. Hemin therapy evoked a 3-month enduring cardioprotection in adult SHR by lowering blood pressure, and reducing left-to-right ventricular ratio, left ventricular wall-thickness, and left ventricle-to-body-weight ratio, whereas CrMP exacerbated cardiac fibrosis/hypertrophy. The cardioprotection was accompanied by reduced aldosterone, PLC, inositol-triphosphate, NF-kappaB, AP-1, heme, and 8-isoprostane, a marker of oxidative stress, whereas HO-1, HO activity, cGMP, bilirubin, ferritin, superoxide dismutase, and the total antioxidant capacity were increased. Correspondingly, extracellular matrix/remodeling proteins such as fibronectin, collagen-1, collagen-IV, alongside cardiac histopathological lesions including fibrosis, scarring, muscular-hypertrophy, coronary-arteriolar thickening, and interstitial/perivascular collagen deposition were attenuated. CONCLUSIONS: Our study unveils sustained cardioprotection by hemin that may have clinical relevance.

Heme arginate suppresses cardiac lesions and hypertrophy in deoxycorticosterone acetate-salt hypertension.

In hypertension, elevated levels of oxidative/inflammatory mediators including nuclear factor kappaB (NF-kappaB), activating protein (AP-1), c-Jun-NH2-terminal kinase (JNK), and cell-regulatory proteins such as transforming growth factor beta (TGF-beta), trigger the mobilization of extracellular matrix (ECM) leading to fibrosis, hypertrophy and impairment of cardiac function. Although the heme oxygenase (HO) system is cytoprotective, its effects on cardiac fibrosis and hypertrophy in deoxycorticosterone acetate (DOCA-salt) hypertension are not completely elucidated. Here, we report cardioprotection by the HO inducer, heme arginate against histopathological lesions in DOCA-hypertension. Treatment with heme arginate restored physiological blood pressure, and abated cardiac hypertrophy (3.75 +/- 0.12 vs. 3.19 +/- 0.09 g/kg body wt; n =16, P < 0.01), left-to-right ventricular ratio (6.67 +/- 0.62 vs. 4.39 +/- 0.63; n = 16, P < 0.01), left ventricular mass (2.48 +/- 0.14 vs. 2.01 +/- 0.09 g/kg body wt; n = 16, P < 0.01) and left-ventricular wall thickness (2.82 +/- 0.16 vs. 1.98 +/- 0.14 mm; n = 16, P < 0.01), whereas the HO inhibitor, chromium mesoporphyrin, exacerbated hypertrophy and cardiac lesions. The suppression of cardiac hypertrophy was accompanied by a robust increase in HO-1, HO activity, cyclic guanosine monophosphate (cGMP), ferritin and the total antioxidant capacity, whereas 8-isoprostane, NF-kappaB, JNK, AP-1, TGF-beta, fibronectin and collagen-I were significantly abated. Correspondingly, histopathological parameters that depict progressive cardiac damage, including fibrosis, interstitial/perivascular collagen deposition, scarring, muscle-fiber thickness, muscular hypertrophy and coronary-arteriolar thickening were abated. Our study suggests that upregulating the HO system lowers blood pressure, potentiates the antioxidant status in tissues, suppresses oxidative stress/mediators such as NF-kappaB, AP-1 and cJNK, and suppresses the mobilization of ECM proteins like TGF-beta, collagen and fibronectin, with corresponding reduction of cardiac histopathological lesion and hypertrophy.

Cataloguing of blast resistance genes in landraces and breeding lines of rice from India.

The rice blast caused by the fungus Magnaporthe oryzae is one of the most devastating diseases of rice and can lead to complete failure of the crop under severe cases. The first step in breeding for blast resistance in rice is therefore to identify the novel sources of resistance and cataloguing different blast resistant genes in these genotypes. In the present study, a set of 37 rice genotypes comprising of landraces, advanced breeding lines and released varieties were first characterized for blast resistance under epiphytotic conditions and subsequently different blast resistant genes were catalogued with the help of markers tightly linked to these genes. A total of 22 different blast resistant genes were catalogued in these genotypes. Lot of diversity was found to be present for different genes in the rice genotypes studied. In addition, a set of 2-3 markers were identified which could distinguish genotypes of a particular geographic area from each other.The results are useful for identifying the right combination of genotypes in the resistance breeding programme.

Crosstalk between the heme oxygenase system, aldosterone, and phospholipase C in hypertension.

BACKGROUND: Aldosterone is a mineral corticoid hormone that is produced in response to angiotensin-II, and like angiotensin-II, stimulates inflammation, oxidative stress, and fibrosis by activating nuclear factor-kappaB and activating protein-1. Recent evidence, however, indicates that aldosterone stimulates phospholipase C and activates nuclear factor-kappaB and activating protein-1. Although the heme oxygenase system is cytoprotective, its effects on aldosterone-phospholipase C signaling in deoxycorticosterone acetate (DOCA-salt) hypertension, a model of aldosteronism, and spontaneously hypertensive rat, a genetic model of human essential hypertension, have not been fully characterized. METHODS: In the present study, the heme oxygenase inducer, hemin, was given to spontaneously hypertensive and deoxycorticosterone acetate hypertensive rats, and the effects on blood pressure, aldosterone, nuclear factor-kappaB, activating protein-1, phospholipase C, and inositol 1,4,5-triphosphate were examined. RESULTS: Hemin therapy restored physiological blood pressure to spontaneously hypertensive rats (209.9 +/- 0.9 to 127.3 +/- 0.85 mmHg, n = 10, P < 0.01) and to deoxycorticosterone acetate salt hypertensive rats (195.7 +/- 1.8 vs.132.5 +/- 2.1 mmHg; P < 0.01, n = 10), but had no effect on age-matched normotensive Wistar-Kyoto or Sprague-Dawley strains. The antihypertensive effect was accompanied by enhanced heme oxygenase activity, upregulated cyclic guanosine monophosphate-protein kinase G signaling, increased superoxide dismutase activity, and the potentiation of total antioxidant capacity, whereas aldosterone, activating protein-1, and nuclear factor-kappaB were reduced. Furthermore, hemin suppressed phospholipase C activity, attenuated inositol 1,4,5-triphosphate, and reduced resting intracellular calcium in the aorta. CONCLUSION: Collectively, our results suggest that the concomitant depletion of aldosterone, phospholipase C-inositol 1,4,5-triphosphate activity, resting intracellular calcium and the corresponding decline of inflammatory, and oxidative insults may account for the antihypertensive effects of hemin in deoxycorticosterone acetate hypertension and spontaneously hypertensive rats.

Hormonal regulation of oil accumulation in Brassica seeds: metabolism and biological activity of ABA, 7'-, 8'- and 9'-hydroxy ABA in microspore derived embryos of B. napus.

Developing seeds of Brassica napus contain significant levels of ABA and products of oxidation at the 7'- and 9'-methyl groups of ABA, 7'- and 9'-hydroxy ABA, as well stable products of oxidation of the 8'-methyl group, phaseic acid and dihydrophaseic acid. To probe the biological roles of the initially formed hydroxylated compounds, we have compared the effects of supplied ABA and the hydroxylated metabolites in regulating oil synthesis in microspore-derived embryos of B. napus, cv Hero that accumulate long chain fatty acids. Uptake into the embryos and metabolism of each of the hormone metabolites was studied by using deuterium labeled analogs. Supplied ABA, which was rapidly metabolized, induced expression of oleosin and fatty acid elongase genes and increased the accumulation of triacylglycerols and very long chain fatty acids. The metabolites 7'- and 9'-hydroxy ABA had similar effects, with the 9'-hydroxy ABA having even greater activity than ABA. The principal catabolite of ABA, 8'-hydroxy ABA, also had hormonal activity and led to increased oil synthesis but induced the genes weakly. These results indicate that all compounds tested could be involved in lipid synthesis in B. napus, and may have hormonal roles in other ABA-regulated processes.

Prevention and treatment of atherosclerosis with flaxseed-derived compound secoisolariciresinol diglucoside.

Atherosclerosis is the primary cause of coronary artery disease, heart attack, strokes, and peripheral vascular disease. Alternative/complimentary medicines, although are unacceptable by medical community, may be of great help in suppression, slowing of progression and regression of atherosclerosis. Numerous natural products are in use for therapy in spite of lack of evidence. This paper discusses the basic mechanism of atherosclerosis, risk factors for atherosclerosis, and prevention, slowing of progression and regression of atherosclerosis with flaxseed-derived secoisolariciresinol diglucoside (SDG). SDG content of flaxseed varies from 6mg/g to 18 mg/g. Flaxseed is the richest source of SDG. SDG possesses antioxidant, antihypertensive, antidiabetic, hypolipidemic, anti-inflammatory and antiatherogenic activities. SDG content of some commonly used food has been described. SDG in very low dose (15 mg/ kg) suppressed the development of hypercholesterolemic atherosclerosis by 73 % and this effect was associated with reduction in serum total cholesterol, LDL-C, and oxidative stress, and an increase in the levels HDL-C. A summary of the effects of flaxseed and its components on hypercholesterolemic atherosclerosis has been provided. Reduction in hypercholesterolemic atherosclerosis by flaxseed, CDC-flaxseed, flaxseed oil, flax lignan complex and SDG are 46 %, 69 %, 0 %, 34 % and 73 % respectively in dietary cholesterol -induced rabbit model of atherosclerosis. SDG slows the progression of atherosclerosis in animal model. Long-term use of SDG regresses hypercholesterolemic atherosclerosis. It is interesting that regular diet following high cholesterol diet accelerates in this animal model of atherosclerosis. In conclusion SDG suppresses, slow the progression and regresses the atherosclerosis. It could serve as an alternative medicine for the prevention, slowing of progression and regression of atherosclerosis and hence for the treatment of coronary artery disease, stroke and peripheral arterial vascular diseases.

Hemin therapy improves kidney function in male streptozotocin-induced diabetic rats: role of the heme oxygenase/atrial natriuretic peptide/adiponectin axis.

Diabetic nephropathy is characterized by elevated macrophage infiltration and inflammation. Although heme-oxygenase (HO) is cytoprotective, its role in macrophage infiltration and nephropathy in type 1 diabetes is not completely elucidated. Administering the HO inducer, hemin, to streptozotocin-diabetic rats suppressed renal proinflammatory macrophage-M1 phenotype alongside several proinflammatory agents, chemokines, and cytokines including macrophage inflammatory protein 1α (MIP-1α), macrophage-chemoattractant protein-1 (MCP-1), TNF-α, IL-1ß, IL-6, nuclear factor-κB (NF-κB), and aldosterone, a stimulator of the inflammatory/oxidative transcription factor, NF-κB. Similarly, hemin therapy attenuated extracellular matrix/profibrotic proteins implicated in renal injury including fibronectin, collagen-IV, and TGF-ß1 and reduced several renal histopathological lesions such as glomerulosclerosis, tubular necrosis, tubular vacuolization, and interstitial macrophage infiltration. Furthermore, hemin reduced markers of kidney dysfunction like proteinuria and albuminuria but increased creatinine clearance, suggesting improved kidney function. Correspondingly, hemin significantly enhanced the antiinflammatory macrophage-M2 phenotype, IL-10, adiponectin, HO-1, HO activity, and atrial natriuretic-peptide (ANP), a substance that abates TNF-α, IL-6, and IL-1ß, with parallel increase of urinary cGMP, a surrogate marker of ANP. Contrarily, coadministering the HO inhibitor, chromium-mesoporphyrin with the HO-inducer, hemin nullified the antidiabetic and renoprotective effects, whereas administering chromium-mesoporphyrin alone abrogated basal HO activity, reduced basal adiponectin and ANP levels, aggravated hyperglycemia, and further increased MCP-1, MIP-1α, aldosterone, NF-κB, TNF-α, IL-6, IL-1ß, proteinuria/albuminuria, and aggravated creatinine clearance, thus exacerbating renal dysfunction, suggesting the importance of the basal HO-adiponectin-ANP axis in renoprotection and kidney function. Collectively, these data suggest that hemin ameliorates diabetic nephropathy by selectively enhancing the antiinflammatory macrophage-M2 phenotype and IL-10 while concomitantly abating the proinflammatory macrophage-M1 phenotype and suppressing extracellular matrix/profibrotic factors with reduction of renal lesions including interstitial macrophage infiltration. Because aldosterone stimulate NF-κB, which activates cytokines like TNF-α, IL-6, IL-1ß that in turn stimulate chemokines such as MCP-1 and MIP-1α to promote macrophage-M1 infiltration, the hemin-dependent potentiation of the HO-adiponectin-ANP axis may account for reduced macrophage infiltration and inflammatory insults in streptozotocin-diabetic rats.