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Thalidomide causes teratogenic effects in several animal species and in humans. Accordingly, the World Health Organization banned thalidomide when mothers who took thalidomide during pregnancy delivered abnormal fetuses. After four decades, thalidomide underwent drug “re-purposing” since its antiangiogenic and immunomodulatory effects were therapeutic for multiple myeloma. There are no reports of thalidomide’s effects on prokaryotes, but it showed teratogenic effects in Arabidopsis thaliana, an ancestor of the plant kingdom. This proof of concept study clearly shows that thalidomide caused a significant and reproducible decrease in germination rate, nitric oxide (NO) production, and chlorophyll content of fennel plantlets. Thalidomide also induced the formation of abnormal fennel plantlets with stunting, wrinkling, and curling of fennel shoots and leaves. Notably, quantitative analysis showed that thalidomide caused a 50% increase in the formation of abnormal fennel plantlets and that these negative effects of thalidomide showed a 2.50- to 4-fold decrease when fennel seeds were co-incubated with an NO donor (Spermine NoNoate) or a stable cGMP analog 8-bromo Guanosine 3′,5′-cyclic monophosphate (8-Bromo-cGMP). This study is important because it confirms that thalidomide’s negative effects on fennel seed germination and growth are mediated by attenuation of NO and disruption of NO signaling. This reproducible model of thalidomide-induced, NO-dependent damage in a plant system can be used to further investigate the molecular mechanisms of thalidomide action in plants. Importantly, this study establishes a link between the evolution of development of higher plants and mammals.

Plant-derived phenolics are utilized as chemopreventive agents to abate adverse toxic responses associated with drug-induced damages. Tamoxifen (TAM)—a chemotherapeutic agent—is used in managing all stages of hormone-dependent breast cancer. Notwithstanding TAM’s clinical side effect—including hepatic toxicity—its use is commonplace. The present study investigates the effect of Chlorogenic acid (CGA: 25 and 50 mg kg−1; per os (p.o)) reported to exhibit various beneficial properties, including antioxidative effect against TAM (50 mg/kg; p.o.)-induced hepatorenal toxicities in rats treated as follows: Control, CGA, or TAM alone, and rats co-treated with CGA and TAM for 2 weeks. Biomarkers of hepatorenal function, oxido-inflammatory stress, and hepatorenal histopathology were performed. We observed that TAM alone decreased relative organ weights (ROW), marginally impacted rat’s survivability, and significantly (P

To improve assessment of risks associated with pharmaceutical contamination of the environment, it is crucial to understand effects and mode of action of drugs in non-target species. The evidence is accumulating that species with well-conserved drug targets are prone to be at risk when exposed to pharmaceuticals. An interesting group of pharmaceuticals released into the environment is imidazoles, antifungal agents with inhibition of ergosterol synthesis as a primary mode of action in fungi. However, imidazoles have also been identified as competitive antagonists of calmodulin (CaM), a calcium-binding protein with phylogenetically conserved structure and function. Therefore, imidazoles would act as CaM inhibitors in various organisms, including those with limited capacity to synthesize sterols, such as arthropods. We hypothesized that effects observed in crustaceans exposed to imidazoles are related to the CaM inhibition and CaM-dependent nitric oxide (NO) synthesis. To test this hypothesis, we measured (i) CaM levels and its gene expression, (ii) NO accumulation and (iii) gene expression of NO synthase (NOS1 and NOS2), in the cladoceran Daphnia magna exposed to miconazole, a model imidazole drug. Whereas significantly increased CaM gene expression and its cellular allocation were observed, supporting the hypothesized mode of action, no changes occurred in either NO synthase expression or NO levels in the exposed animals. These findings suggest that CaM inhibition by miconazole leads to protein overexpression that compensates for the loss in the protein activity, with no measurable downstream effects on NO pathways. The inhibition of CaM in D. magna may have implications for effect assessment of exposure to mixtures of imidazoles in aquatic non-target species.

Significance: Photobiomodulation (PBM) refers to the beneficial effects of low-energy light absorption. Although there is a large body of literature describing downstream physiological benefits of PBM, there is a limited understanding of the molecular mechanisms underlying these effects. At present, the most popular hypothesis is that light absorption induces release of nitric oxide (NO) from the active site of cytochrome c oxidase (COX), allowing it to bind O2 instead. This is believed to increase mitochondrial respiration, and result in greater overall health of the cell due to increased adenosine triphosphate production. Aim: Although NO itself is a powerful signaling molecule involved in a host of biological responses, less attention has been devoted to NO mechanisms in the context of PBM. The purpose of our work is to investigate wavelength-specific effects on intracellular NO release in living cells. Approach: We have conducted in-depth dosimetry analyses of NO production and function in an in vitro retinal model in response to low-energy exposure to one or more wavelengths of laser light. Results: We found statistically significant wavelength-dependent elevations (10% to 30%) in intracellular NO levels following laser exposures at 447, 532, 635, or 808 nm. Sequential or simultaneous exposures to light at two different wavelengths enhanced the NO modulation up to 50% of unexposed controls. Additionally, the immediate increases in cellular NO levels were independent of the function of NO synthase, depended greatly on the substrate source of electrons entering the electron transport chain, and did not result in increased levels of cyclic guanosine monophosphate. Conclusions: Our study concludes the simple model of light-mediated release of NO from COX is unlikely to explain the wide variety of PBM effects reported in the literature. Our multiwavelength method provides a novel tool for studying immediate and early mechanisms of PBM as well as exploring intracellular NO signaling networks.

A point-of-care, non-invasive, low-cost and sensitive nano-biodiagnostic is needed in today's age for rapid and accurate self-diagnosis as well as for the management of asthma, which is advantageous for low resource areas where asthma is prevalent. The objective of this research work was to prepare the miniature, nanosponges coated paper strip to detect the asthma using certain biomarkers present in exhaled air. The asthma biomarker, nitric oxide present in exhaled air (FeNO) was chosen, which on reaction with nanosponges of diazotizing agent gave significant color change. The pyromellitic anhydride cross-linked β-cyclodextrin-based nanosponges of sulfanilamide and N-(1-naphthyl) ethylenediamine dihydrochloride were prepared using a polymer condensation method and coated on Whatman filter paper strip (1 × 5 cm2). The thickness of coating was found to be uniform (400 ± 50 μm) which was determined using SEM analysis. The Hue-Saturation-Value scale was used to detect the color change using a smartphone app. We also investigated the performance of a nano-engineered paper strip by comparing this with commercially available, FDA approved FeNO analyzer-NIOX MINO. Our findings demonstrated no significant difference in results obtained using both the techniques. Besides good repeatability, the paper strip showed increasing saturation with NO concentration and the capacity to detect the biomarker down to mean value of 20.33 ppb level. The successful validation and method comparison indicated that a bioinspired strip can provide on-site analysis and daily monitoring for diagnosis and management of asthma.

Significance: Photobiomodulation is a well-established therapeutic modality. However, the mechanism of action is poorly understood, due to lack of research in the causal relationship between the near-infrared (NIR) light irradiation and its specific biological effects, hindering broader applications of this technology. Aim: Since biological chromophores typically show several absorption peaks, we determined whether specific effects of photobiomodulation are induced with a combination of two wavelengths at a certain range of irradiance only, rather than a single wavelength of NIR light. Approach: In order to analyze a wide array of combinations of multispectral NIR light at various irradiances efficiently, we developed a new optical platform equipped with two distinct wavelengths of NIR lasers by high-throughput multiple dosing for single-cell live imaging. Two wavelengths of 1064 and 1270 nm were selected based on their photobiomodulatory effects reported in the literature. Results: A specific combination of wavelengths at low irradiances (250 to 400 mW/cm2 for 1064 nm and 55 to 65 mW/cm2 for 1270 nm) modulates mitochondrial retrograde signaling, including intracellular calcium and reactive oxygen species in T cells. The time-dependent density functional theory computation of binding of nitric oxide (NO) to cytochrome c oxidase indicates that the illumination with NIR light could result in the NO release, which might be involved in these changes. Conclusions: This optical platform is a powerful tool to study causal relationship between a specific parameter of NIR light and its biological effects. Such a platform is useful for a further mechanistic study on not only photobiomodulation but also other modalities in photomedicine.

There is evidence that homocysteine contributes to various neurodegenerative disorders, and elevated plasma homocysteine levels have been observed in patients with multiple sclerosis (MS).To investigate if and why plasma homocysteine levels are increased in MS, and whether they play a role in the disease course.We compared plasma levels of homocysteine in 88 patients with MS and 57 healthy controls. In the MS group, 28 had a benign course, 37 were secondary progressive, and 23 primary progressive. To explore the underlying mechanisms, we measured serum levels of vitamins B6 and B12, folate, interleukin (IL)-12, tumour necrosis factor (TNF)-alpha, leukocyte nitric oxide production, and plasma diene conjugate levels (measure of oxidative stress).Mean (SD) plasma homocysteine concentration was higher in patients (13.8 (4.9) micromol/l) than in controls (10.1 (2.5) micromol/l; p0.0001). However, there were no significant differences in homocysteine levels between the three clinical subgroups of MS. Serum concentrations of vitamin B6, vitamin B12, and folate were not different between patients with MS and controls. In the MS group, there were no correlations between plasma homocysteine levels and the serum concentrations of IL-12 or TNF-alpha, leukocyte nitric oxide production, or plasma diene conjugate levels.Elevated plasma homocysteine occurs in both benign and progressive disease courses of MS, and seems unrelated to immune activation, oxidative stress, or a deficiency in vitamin B6, vitamin B12, or folate.

Bacterial enteric infections exact a heavy toll on the human population, particularly among children. Despite the explosion of knowledge on the pathogenesis of enteric diseases experienced during the past decade, the number of diarrhoeal episodes and human deaths reported worldwide remains of apocalyptic dimensions. However, our better understanding of the pathogenic mechanisms involved in the onset of diarrhoea is finally leading to preventive interventions, such as the development of enteric vaccines, that may have a significant impact on the magnitude of this human plague. The application of a multidisciplinary approach to study bacterial pathogenesis, along with the recent sequencing of entire microbial genomes, have made possible discoveries that are changing the way scientists view the bacterium-host interaction. Today, research on the molecular basis of the pathogenesis of infective diarrhoeal diseases of necessity transcends established boundaries between microbiology, cell biology, intestinal pathophysiology, and immunology. This review focuses on the most recent outcomes of this multidisciplinary effort.

New therapies for inflammatory bowel disease are needed, because standard therapies fail to induce remission in about 30% of patients, and because of the relative inefficacy of current maintenance therapies. This review summarises the current status of the development of small therapeutic molecules for inflammatory bowel disease.

Characteristics and catalytic properties of a series of carbon-based catalysts (CBCs) produced from paper mill sludge were evaluated. The major processes involved in the production of the catalysts were chemical activation, impregnation, pyrolysis, and post pyrolysis rinsing. The porous structure, catalytic activity and thermostability of the catalysts were tailored during the production stage by introducing hetero-atoms (zinc chloride, and ferric nitrate) in the carbon structure. Characterization of the produced CBCs included determination of the surface area, pore size, and pore size distribution (PSD) from standard N2-adsorption isotherm data. The extent of graphitization and the presence of metal crystals were identified from X-ray diffraction (XRD). The limit of the catalyst gasification was estimated from thermogravimetric analysis (TGA) conducted in an oxidized environment. The NOx reduction capability of the produced catalysts was evaluated in the presence of carbon monoxide using a fixed bed reactor. The reaction temperature ranged from 300 to 500 degrees C. It was shown that paper mill sludge is an excellent precursor for the production of CBCs with NOx removal capability of 66-94%. The catalytic capability of the produced CBCs varied according to the method of production, catalyst surface properties (surface area, pore structure, PSD), metal composition and reaction temperature. The highest NOx removal capacity was observed for the catalytic reactions carried out at 400 degrees C. The mesoporous catalyst produced with a Zn:Fe molar ratio of 1:0.5 exhibited the maximum NOx removal catalytic activity of 94%.

The aim of the study was to investigate whether measurement of nitric oxide in exhaled air could be used for assessing the effects of irritants on the respiratory system, in this case recurrent ozone gassing in an occupational setting. The study population comprised bleachery workers (n=56) from a Swedish pulpmill carrying out ozone-based pulp bleaching since 1992 and controls (n=39). Both groups were investigated by measuring NO in exhaled air, methacholine challenge test and answers to a questionnaire concerning history of respiratory symptoms and accidental exposure to ozone peaks. There was no significant difference in NO output between exposed subjects and controls (median 67.2 versus 55.0 nL x min(-1), p=0.64). However, among bleachery workers reporting ozone gassings, the median NO output was 90.0 nL x min(-1) compared to 58.8 nL x min(-1) among those not reporting such incidents (p=0.019). There was no relation between exhaled NO and the prevalence of respiratory symptoms or bronchial hyperresponsiveness. In a multiple regression model, only reported ozone gassings were associated (p=0.016) with NO output. The results indicate an association between previous response to ozone gassing and nitric oxide output. The increased nitric oxide output among the bleachery workers reporting peak ozone exposure may indicate that chronic airway inflammation is present. Further studies are needed to evaluate the extent to which nitric oxide can be used for biological monitoring of respiratory health effects, and to relate it to other markers of airway inflammation.