The major variant of concerns (VOCs) have shared mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins, mostly on the S1 unit and resulted in higher transmissibility rate and affect viral virulence and clinical outcome. The spike protein mutations and other non-structural protein mutations in the VOCs may lead to escape approved vaccinations in certain extend. We will discuss these VOC mutations and discuss the need for combination therapeutic strategies targeting viral cycle and immune host responses.

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■ AbstractBACKGROUND: Diabetes mellitus is a systemic disorder associated with inflammation and oxidative stress which may target many organs such as the kidney, retina, and the vascular system. The pathophysiology, mechanisms, and consequences of diabetes on these organs have been studied widely. However, no work has been done on the concept of the lung as a target organ for diabetes and its implications for lung diseases. AIM: In this review, we aimed to investigate the effects of diabetes and hypoglycemic agent on lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, pulmonary hypertension, and lung cancer. We also reviewed the potential mechanisms by which these effects may affect lung disease patients. RESULTS: Our results suggest that diabetes can affect the severity and clinical course of several lung diseases. CONCLUSIONS: Although the diabetes-lung association is epidemiologically and clinically well-established, especially in asthma, the underlying mechanism and pathophysiology are not been fully understood. Several mechanisms have been suggested, mainly associated with the proinflammatory and proliferative properties of diabetes, but also in relation to micro-and macrovascular effects of diabetes on the pulmonary vasculature. Also, hypoglycemic drugs may influence lung diseases in different ways. For example, metformin was considered a potential therapeutic agent in lung diseases, while insulin was shown to exacerbate lung diseases; this suggests that their effects extend beyond their hypoglycemic properties.Keywords: diabetes · asthma · chronic obstructive pulmonary disease · COPD · idiopathic pulmonary fibrosis · pulmonary hypertension · lung cancer · hypoglycemic drugs

BACKGROUND: Diabetes mellitus is a systemic disorder associated with inflammation and oxidative stress which may target many organs such as the kidney, retina, and the vascular system. The pathophysiology, mechanisms, and consequences of diabetes on these organs have been studied widely. However, no work has been done on the concept of the lung as a target organ for diabetes and its implications for lung diseases. AIM: In this review, we aimed to investigate the effects of diabetes and hypoglycemic agent on lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, pulmonary hypertension, and lung cancer. We also reviewed the potential mechanisms by which these effects may affect lung disease patients. RESULTS: Our results suggest that diabetes can affect the severity and clinical course of several lung diseases. CONCLUSIONS: Although the diabetes-lung association is epidemiologically and clinically well-established, especially in asthma, the underlying mechanism and pathophysiology are not been fully understood. Several mechanisms have been suggested, mainly associated with the proinflammatory and proliferative properties of diabetes, but also in relation to micro-and macrovascular effects of diabetes on the pulmonary vasculature. Also, hypoglycemic drugs may influence lung diseases in different ways. For example, metformin was considered a potential therapeutic agent in lung diseases, while insulin was shown to exacerbate lung diseases; this suggests that their effects extend beyond their hypoglycemic properties.

These findings provide a framework linking interactions among cellular signalling pathways associated with reactive oxygen species production, macrophage cholesterol biosynthesis, and cellular PON2 expression in vascular pathophysiology.

Upregulation of macrophage PON2 may provide a compensatory protective mechanism against uPA-stimulation of macrophage oxidative stress during atherogenesis.

Objective-The atherosclerotic lesion is characterized by lipid peroxide accumulation. Paraoxonase 1 (PON1) reduces atherosclerotic lesion oxidative stress, whereas urokinase-type plasminogen activator (uPA) increases oxidative stress in atherosclerotic lesions and contributes to the progression and complications of atherosclerosis. We hypothesized that uPA may promote oxidative stress in the arterial wall via modulation of PON1 activity. Because the liver is the main site for PON1 production, in the present study, we tested whether uPA influences PON1 expression in hepatocytes. Methods and Results-HuH7 hepatocytes were incubated in culture with increasing concentrations of uPA. uPA decreased PON1 gene expression and activity in a dose-dependent manner and accordingly suppressed PON1 secretion from hepatocytes. This effect required uPA/uPA receptor interaction. uPA downregulated PON1 gene expression via inactivation of peroxisome proliferator-activated receptor-␥ (PPAR␥) activity, and this effect was dependent on uPA-mediated mitogen-activated protein kinase kinase activation. Mechanistic studies showed that uPA enhanced mitogen-activated protein kinase kinase-PPAR␥ interaction, resulting in PPAR␥ nuclear export to the cytosol. Conclusion-This study provides the first evidence that uPA interferes with PPAR␥ transcriptional activity in hepatocytes, resulting in downregulation of PON1 expression and its secretion to the medium. This may explain, at least in part, the prooxidative effect of uPA in the vascular wall. Key Words: Hepatocytes Ⅲ PPAR␥ Ⅲ paraoxonase 1 (PON1) Ⅲ urokinase T he atherosclerotic lesion is dominated by accumulation of lipid peroxides, along with the progression of early plaque development. 1 Paraoxonase 1 (PON1) is a calciumdependent, high-density lipoprotein (HDL)-bound lipolactonase with antioxidative properties, which are associated with the enzyme's capability to decrease oxidative stress in atherosclerotic lesions 2 and to attenuate atherosclerosis development. Immunohistochemical analysis has revealed accumulation of PON1 in the human atherosclerotic lesion as it progresses from fatty streak to advanced lesion. 3 Recently, it was demonstrated that PON1 acts to reduce the oxidizing potency of lipids in atherosclerotic lesions, thus providing protection against oxidation. 4 Epidemiological evidence demonstrates that low PON1 activity is associated with increased risk of cardiovascular events and cardiovascular disease 5 and is an independent risk factor for coronary artery disease. 6 A primary determinant of serum PON1 levels is the availability of the enzyme for release by the liver, the principal site of PON1 production. 7 Urokinase-type plasminogen activator (uPA) is a serine protease enzyme of the fibrinolytic system, and uPA binding to its receptor (uPAR) is implicated in plasmin generation. The uPA/uPAR system has also a nonproteolytic role that extends beyond its role in fibrinolysis. 8 uPA is expressed in human atherosclerotic vessel wall, mainly in association with macrophages, 9 a...

BACKGROUND: Diabetes mellitus is a systemic disorder associated with inflammation and oxidative stress which may target many organs such as the kidney, retina, and the vascular system. The pathophysiology, mechanisms, and consequences of diabetes on these organs have been studied widely. However, no work has been done on the concept of the lung as a target organ for diabetes and its implications for lung diseases. AIM: In this review, we aimed to investigate the effects of diabetes and hypoglycemic agent on lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, pulmonary hypertension, and lung cancer. We also reviewed the potential mechanisms by which these effects may affect lung disease patients. RESULTS: Our results suggest that diabetes can affect the severity and clinical course of several lung diseases. CONCLUSIONS: Although the diabetes-lung association is epidemiologically and clinically well-established, especially in asthma, the underlying mechanism and pathophysiology are not been fully understood. Several mechanisms have been suggested, mainly associated with the proinflammatory and proliferative properties of diabetes, but also in relation to micro-and macrovascular effects of diabetes on the pulmonary vasculature. Also, hypoglycemic drugs may influence lung diseases in different ways. For example, metformin was considered a potential therapeutic agent in lung diseases, while insulin was shown to exacerbate lung diseases; this suggests that their effects extend beyond their hypoglycemic properties.