Carbon Monoxide as a Therapeutic for Airway Diseases: Contrast and Comparison of Various CO Delivery Modalities

: The quest to find novel strategies to tackle respiratory illnesses has led to the exploration of the potential therapeutic effects of carbon monoxide (CO) as an endogenous signaling molecule and a cytoprotective agent. Further, several studies have demonstrated the pharmacological efficacy of CO in animal models of respiratory disorders such as acute lung injury and pulmonary hypertension. Because of the gaseous nature of CO and its affinity for multiple targets, its controlled delivery has been a challenge. Past studies have employed different delivery modalities including CO gas, HO-1 inducers, and CO donors, sometimes leading to substantive variations of the resulting pharmacological effects for various reasons. Herein, this review summarizes and analyzes the differences among the profiles of various CO-delivery modalities in terms of their efficacy, dosing regimen, and pharmacokinetics in airways models. We believe that analysis of these issues will help in understanding the fundamental roles of CO in airways and eventually contribute to its development as a medicine for respiratory diseases.

Cytoprotective effects of garlic on spermatozoa quality and fertilizing ability of extended porcine semen

Fertilizing potential of spermatozoa is pivotal for successful artificial insemination. Preservation of boar semen is associated with the production of reactive oxygen species which leads to decline of spermatozoa quality and decrease in fertilizing ability. The study aimed at investigating the effects of Ethanolic Allium sativum Extracts (EASE) as a cytoprotective agent on the quality and fertilizing potential of spermatozoa in extended boar semen. Semen was collected and aliquot portions were divided into 60 sample bottles comprising of five treatments with replicates. T1 served as the control (Beltsville Thawing Solution (BTS) + semen) in ratio 1:3 semen-extender, while other treatments T2 to T5 contained semen-extender at the same ratio, but supplemented with EASE at varying concentrations of 50, 75, 100 and 125 μg/L respectively stored at 17 °C and were evaluated at 0, 24, 48 and 72 hours for pH, normal spermatozoa (NS) (%), liveability (%), acrosome integrity (AI) (%) in a completely randomized design. Data obtained were subjected to descriptive statistics and analysed using one way ANOVA and means were separated using Duncan Multiple Range Test. Treated semen samples (75, 100 and 125 μg/L) gave superior (P<0.05) liveability than control, up to 72 hours. Similar (P>0.05) mean values were observed for NS from all treatments except 50 μg/L at 24 hours. At 72 hours, treated samples (75, 100 and 125 μg/L) gave superior (P<0.05) NS. Significant differences (P<0.05) in mean values for pH were observed among treatments through the extension period. However, all values were within accepted range for quality semen. Acrosome integrity were similar (P>0.05) among treatments from 0 to 72 hours, but reduced (P<0.05). Results suggest that the supplementation of BTS with EASE 125 μg/L, gave better cytoprotection to the spermatozoa compared to the control. L'ablitédes spermatozoïdes de fertiliserest essentiel pour une insémination artificielle réussie. La conservation de la semence de l'our est associée à la production d'espèces réactives de l'oxygène, ce qui entraîne un déclin de la qualité des spermatozoïdes et une diminution de la capacité de fertilisation. L'étude visait à étudier les effets des extraits éthanoliques d'Allium sativum (EEAS) en tant qu'agent cytoprotecteur sur la qualité et le potentiel fertilisant des spermatozoïdes dans le sperme de sanglier étendu. Le sperme a été collecté et les portions aliquotes ont été divisées en 60 bouteilles d'échantillons comprenant cinq traitements avec des répliques. T1 a servi de contrôle (BeltsvilleThawing Solution (BTS) + sperme) dans un rapport 1: 3 sperme-extenseur, tandis que d'autres traitements T2 à T5 contenaient sperme-extenseur au même rapport, mais complété avec EEAS à des concentrations variables de 50, 75 , 100 et 125 μg / L respectivement conservés à 17 ° C et ont été évalués à 0, 24, 48 et 72 heures pour le pH, les spermatozoïdes normaux (SN) (%), l'habitabilité (%), l'intégrité de l'acrosome (IA) (%) dans une conception complètement aléatoire. Les données obtenues ont été soumises à des statistiques descriptives et analyses en utilisant une méthode ANOVA et les moyennes ont été séparées en utilisant le test Duncan Multiple Range. Les échantillons de sperme traités (75, 100 et 125 μg / L) ont donné une habitabilité supérieure (P <0.05) à celle des témoins, jusqu'à 72 heures. Des valeurs moyennes similaires (P> 0.05) ont été observées pour le SN pour tous les traitements, sauf 50 μg / L à 24 heures. A 72 heures, les échantillons traités (75, 100 et 125 ug / L) ont donné une SN supérieure (P <0.05). Des différences significatives (P <0.05) dans les valeurs moyennes du pH ont été observées entre les traitements pendant la période d'extension. Cependant, toutes les valeurs se situaient dans la plage acceptée pour le sperme de qualité. L'intégrité des acrosomes était similaire (P> 0.05) parmi les traitements de 0 à 72 heures, mais réduite (P <0.05). Les résultats suggèrent que la supplémentation en BTS avec EEAS 125 μg / L, a donné une meilleure cytoprotection des spermatozoïdes par rapport au témoin.

Heme Oxygenase-1 in Gastrointestinal Tract Health and Disease

Heme oxygenase 1 (HO-1) is the rate-limiting enzyme of heme oxidative degradation, generating carbon monoxide (CO), free iron, and biliverdin. HO-1, a stress inducible enzyme, is considered as an anti-oxidative and cytoprotective agent. As many studies suggest, HO-1 is highly expressed in the gastrointestinal tract where it is involved in the response to inflammatory processes, which may lead to several diseases such as pancreatitis, diabetes, fatty liver disease, inflammatory bowel disease, and cancer. In this review, we highlight the pivotal role of HO-1 and its downstream effectors in the development of disorders and their beneficial effects on the maintenance of the gastrointestinal tract health. We also examine clinical trials involving the therapeutic targets derived from HO-1 system for the most common diseases of the digestive system.

Can Melatonin Be a Potential “Silver Bullet” in Treating COVID-19 Patients?

The therapeutic potential of melatonin as a chronobiotic cytoprotective agent to counteract the consequences of COVID-19 infections has been advocated. Because of its wide-ranging effects as an antioxidant, anti-inflammatory, and immunomodulatory compound, melatonin could be unique in impairing the consequences of SARS-CoV-2 infection. Moreover, indirect evidence points out to a possible antiviral action of melatonin by interfering with SARS-CoV-2/angiotensin-converting enzyme 2 association. Melatonin is also an effective chronobiotic agent to reverse the circadian disruption of social isolation and to control delirium in severely affected patients. As a cytoprotector, melatonin serves to combat several comorbidities such as diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases, which aggravate COVID-19 disease. In view of evidence on the occurrence of neurological sequels in COVID-19-infected patients, another putative application of melatonin emerges based on its neuroprotective properties. Since melatonin is an effective means to control cognitive decay in minimal cognitive impairment, its therapeutic significance for the neurological sequels of SARS-CoV-2 infection should be considered. Finally, yet importantly, exogenous melatonin can be an adjuvant capable of augmenting the efficacy of anti-SARS-CoV-2 vaccines. We discuss in this review the experimental evidence suggesting that melatonin is a potential “silver bullet” in the COVID 19 pandemic.

In Vitro Evaluation of a Novel Synthetic Bilirubin Analog as an Antioxidant and Cytoprotective Agent for Pancreatic Islet Transplantation

Bilirubin is a natural cytoprotective agent and physiologic doses have proven to be beneficial in various models of organ and cellular transplantation. Recently, we showed that bilirubin has protective effects in models of pancreatic islet transplantation, preventing cell death associated with islet stress and suppressing the release of damage-associated molecular patterns. Despite these promising therapeutic attributes, the natural bilirubin used in these research studies is animal-derived (porcine), making it unsuitable for clinical application. In the current study, we synthesized two bilirubin analogs that can be produced without the use of animal-derived products. Antioxidant activity for the analogs was measured using the ferric-reducing-ability-of-plasma (FRAP) and 2,2V-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) assays. Dose-dependent cytotoxicity and cytoprotective effects were then demonstrated in isolated rat islets. Compound 1 showed similar antioxidant activity to natural bilirubin. Dose-dependent cytotoxicity was seen following treatment with Compound 1 and natural bilirubin at doses >40 μM, resulting in significantly increased cell death when compared to control islets ( P < 0.05) or islets treated with doses ≤20 μM ( P < 0.05). Following hypoxic challenge, islet cell death was reduced in islets treated with Compound 1 at 10 μM (17.27% ± 0.26%) compared to natural bilirubin at 10 μM (51.36% ± 0.71%; P < 0.0001) or 20 μM (59.02% ± 0.83%; P < 0.0001) and control islets (36.51% ± 0.44%; P < 0.0001). Compound 1 was found to have promising antioxidant and cytoprotective effects, limiting islet cell death in a model of islet transplantation hypoxic stress. Compound 1 may serve as a synthetic drug lead for clinical islet transplantation and further evaluation of this molecule and its analogs is warranted.