Antidiabetic Drugs and their Potential Use in COVID-19: A Mechanistic Approach.

Many therapies have been developed against COVID-19 since it first appeared in December 2019. Antivirals, antimalarials, cephalosporins, colchicine, anticoagulants, and corticosteroids, among others, have been evaluated as protecting agents against antibacterial complications due to their anti-inflammatory and immunomodulatory effects against thrombosis and cell death caused by infection with SARS-CoV-2. Nevertheless, the overall balance in their application has not been found to be satisfactory. On the other hand, developing and applying several vaccines against this virus have marked an important watershed in preventive and prophylactic medicine in the new millennium. However, given the regular efficacy reported of some of them, the still scarce affordability, and the emergency of new strains for which no drug has been evaluated, the search for new pharmacological therapy alternatives still represents an essential component in the clinical management of COVID-19, and the rapid identification of drugs with potential antiviral and/or immunomodulatory properties is needed. In the present review, a potential therapeutic effect of metformin and other antidiabetic therapies for the management of COVID-19 are proposed and discussed from the viewpoint of their in vitro and in vivo immunomodulatory effects. Given that acute inflammation is an important component of COVID-19, antidiabetic therapies could be promising alternatives in its management and reducing the disease's severity. In order to understand how metformin and other antidiabetic therapies could work in the context of COVID-19, here we review the possible mechanisms of action through a detailed description of cellular and molecular events.

Physiological and Molecular Responses of Vitis vinifera cv. Tempranillo Affected by Esca Disease.

Esca is a multi-fungal disease affecting grapevines. The objective of the study was to evaluate the physiological and molecular response of the grapevine cv. Tempranillo to esca disease, carried out in a vineyard under Mediterranean climatic conditions in western Spain. The photosynthetic pigments in the leaves decreased, with a strong decrease in the photosynthetic efficiency. The proline content increased significantly in the early stages of affected leaves, being possibly involved in the maintenance of lipid peroxidation levels in leaves, which do not increase. The phenol, flavonoid, and phenylpropanoid content decreased in esca-affected leaves, as does the total antioxidant capacity (FRAP), while the polyphenol oxidase (PPO) activity suffers a strong increase with the development of the disease. In affected grapes, the lipid peroxidation and the total phenol content decrease, but not the anthocyanin content. The ascorbate pool decreases with the disease and with time. On the other hand, pool GSH + GSSG is lower in affected leaves, but increases with time. These alterations show a clear change in the redox homeostasis. The expression of genes phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO), superoxide dismutase (SOD), and chalcone synthase (ChaS1 and ChaS3) become considerably higher in response to esca, being even higher when the infection time increases. The alteration of AsA and GSH levels, phenolic compounds, PPO activity, proline content, and FRAP, together with the increase of the PAL, PPO, SOD,ChaS1, and ChaS3 gene expression, are clearly implicated in the esca response in plants. The expression of these genes, similar to the PPO activity, can be used as markers of state in the development of the disease.

Effect of Water Supplementation on Oxidant/Antioxidant Activities and Total Phenol Content in Growing Olives of the Morisca and Manzanilla Varieties.

The objective of this work was to analyse, using a time series analysis, the effect of water regime for two cultivars at three stages of ripeness, during three consecutive years. Fruit and oil yield; O2- production and NADH oxidation activities; polyphenol oxidase (PPO), superoxide dismutase (SOD) and peroxidase (POX) activities; total phenols, flavonoid and phenylpropanoid glycoside content; and total antioxidant capacity (FRAP) were determined. All these parameters were found to depend on variety, irrigation and year. The results showed that the fruit and oil yields were strongly dependent on both irrigation and variety. The DW/FW ratio was practically constant during ripening, with small variety-dependent changes due to irrigation. Total amino acid and protein contents increased with ripening, with a close dependence on variety but not on irrigation. The SOD and POX activities appeared closely related, and related to the NADH oxidation and the amount of O2-. The evolution of phenols and FRAP during ripening was complementary to that of NADH oxidation, O2- production as well as SOD and POX activities. The determining factors of the SOD, POX and PPO activities were the variety and the ripening; the determining factor of the yield, ROS production, total phenols and antioxidant capacity was the water regime. Inverse correlations were observed between maximum temperature and total phenols (-0.869), total flavonoids (-0.823), total PPGs (-0.801) and FRAP (-0.829); and between DW/FW and irrigation (-0.483). The remaining significant correlations were positive.

Influence of cultivar, irrigation, ripening stage, and annual variability on the oxidant/antioxidant systems of olives as determined by MDS-PTA.

The phenolic composition and content of olive fruit are some of the attributes that determine oil quality. This composition depends on the olive variety, the cultivation system, and the fruit's ripeness. This study considered two olive varieties (Manzanilla and Morisca), under two water regimes (irrigated and rainfed), harvested at three stages of maturation (S1, S2, and S3), over three consecutive campaigns (2011, 2012, and 2013). The accumulation of phenols in the fruit was found to depend only on the stage of ripeness, while the flavonoid and phenylpropanoid contents depended also on the variety and the water regime. Superoxide dismutase (SOD) activity was linked to O2- production, which in turn depended on water regime, variety, and stage of maturation (this last being a process involving ROS). The peroxidase (POX) activity seemed only to depend on ripeness, while polyphenol oxidase (PPO) activity varied from year to year as well as presenting a strong ripeness dependence that was in clear coherence with the levels of phenolic compounds that the olives accumulate. All these relationships between the variables and the factors conform a dataset with the structure of a multidimensional array that is difficult to interpret using conventional techniques of statistical analysis. This work takes a novel approach (MultiDimensional Scaling associated with a Partial Triadic Analysis, MDS-PTA) to the analysis of this type of data structure which allows its correct interpretation. The analysis showed that the state of maturation of the olives is the most clearly discriminating factor, far more so than the cultivar, water regime, or year. Thus, the phenols and the total antioxidant activity (FRAP) showed strong clustering, being closely related in all three years studied. The oxidant and antioxidant activities showed a certain tendency to cluster, although in these cases the year also had an influence as a factor, indicating that these parameters depend more on external factors and less on ripeness.

The Evolution of Total Phenolic Compounds and Antioxidant Activities during Ripening of Grapes (Vitis vinifera L., cv. Tempranillo) Grown in Semiarid Region: Effects of Cluster Thinning and Water Deficit.

A study was made of how water status (rainfed vs. irrigated) and crop load (no cluster thinning vs. cluster thinning) can together affect the grapes of Vitis vinifera cv. Tempranillo vines growing in a semiarid zone of Extremadura (Spain). The grapes were monitored at different stages of ripening, measuring the peroxidase (POX) and superoxide dismutase (SOD) antioxidant activities and the phenolic content (flavonoids and phenylpropanoids), together with other parameters. The irrigation regime was adjusted to provide 100% of crop evapotranspiration (ETc). The findings confirmed previous results that both thinning and water deficit advance ripening, while irrigation and high crop load (no thinning) lengthen the growth cycle. The SOD activity remained practically constant throughout ripening in the thinned treatments and was always lower than in the unthinned treatments, an aspect which could have been the cause of the observed greater level of lipid peroxidation in the water deficit, thinned treatment. The nonspecific peroxidase activity was very low, especially in the thinned treatments. The effect of thinning was enhanced when combined with water deficit, inducing increases in phenylpropanoids and, above all, flavonoids at the harvest stage of ripening, while leaving the polyphenol oxidase activity (PPO) unaffected.

Fatty Acid and Phenolic Compound Concentrations in Eight Different Monovarietal Virgin Olive Oils from Extremadura and the Relationship with Oxidative Stability.

Olive oils have been shown to be more resistant to oxidation than other vegetable fats, mainly due to their fatty acid (FA) profile which is rich in oleic acid and to their high content of antioxidants, principally phenols and tocopherols. This has situated virgin olive oils (VOOs) among the fats of high nutritional quality. However, it is important to stress that the oil's commercial category (olive oil, virgin olive oil, extra-virgin olive oil), the variety of the source plant, and the extraction-conservation systems all decisively influence the concentration of these antioxidants and the oil's shelf-life. The present work studied the fatty acid (FA) and phenolic composition and the oxidative stability (OS) of eight olive varieties grown in Extremadura (Arbequina, Cornicabra, Manzanilla Cacereña, Manzanilla de Sevilla, Morisca, Pico Limón, Picual, and Verdial de Badajoz), with the olives being harvested at different locations and dates. The Cornicabra, Picual, and Manzanilla Cacereña VOOs were found to have high oleic acid contents (>77.0%), while the VOOs of Morisca and Verdial de Badajoz had high linoleic acid contents (>14.5%). Regarding the phenol content, high values were found in the Cornicabra (633 mg·kg-1) and Morisca (550 mg·kg-1) VOOs, and low values in Arbequina (200 mg·kg-1). The OS was found to depend upon both the variety and the date of harvesting. It was higher in the Cornicabra and Picual oils (>55 h), and lower in those of Verdial de Badajoz (26.3 h), Arbequina (29.8 h), and Morisca (31.5 h). In relating phenols and FAs with the OS, it was observed that, while the latter, particularly the linoleic content (R = -0.710, p < 0.001, n = 135), constitute the most influential factors, the phenolic compounds, especially o-diphenols, are equally influential when the oils' linoleic content is ≥12.5% (R = 0.674, p < 0.001, n = 47). The results show that VOOs' resistance to oxidation depends not only on the FA or phenolic profile, but also on the interaction of these compounds within the same matrix.