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An Overview of Systematic Reviews of the Role of Vitamin D on Inflammation in Patients with Diabetes and the Potentiality of Its Application on Diabetic Patients with COVID-19.
Argano, C, Mallaci Bocchio, R, Lo Monaco, M, Scibetta, S, Natoli, G, Cavezzi, A, Troiani, E, Corrao, S
International journal of molecular sciences. 2022;(5)
Abstract
Almost two years have passed since the outbreak reported for the first time in Wuhan of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome (SARS)-CoV-2 coronavirus, rapidly evolved into a pandemic. This infectious disease has stressed global health care systems. The mortality rate is higher, particularly in elderly population and in patients with comorbidities such as hypertension, diabetes mellitus, cardiovascular disease, chronic lung disease, chronic renal disease, and malignancy. Among them, subjects with diabetes have a high risk of developing severe form of COVID-19 and show increased mortality. How diabetes contributes to COVID-19 severity remains unclear. It has been hypothesized that it may be correlated with the effects of hyperglycemia on systemic inflammatory responses and immune system dysfunction. Vitamin D (VD) is a modulator of immune-response. Data from literature showed that vitamin D deficiency in COVID-19 patients increases COVID-19 severity, likely because of its negative impact on immune and inflammatory responses. Therefore, the use of vitamin D might play a role in some aspects of the infection, particularly the inflammatory state and the immune system function of patients. Moreover, a piece of evidence highlighted a link among vitamin D deficiency, obesity and diabetes, all factors associated with COVID-19 severity. Given this background, we performed an overview of the systematic reviews to assess the association between vitamin D supplementation and inflammatory markers in patients with diabetes; furthermore, vitamin D's possible role in COVID-19 patients was assessed as well. Three databases, namely MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews, were reviewed to retrieve the pertinent data. The aim of this review is to provide insight into the recent advances about the molecular basis of the relationship between vitamin D, immune response, inflammation, diabetes and COVID-19.
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Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease.
Lakkireddy, M, Gadiga, SG, Malathi, RD, Karra, ML, Raju, ISSVPM, Ragini, , Chinapaka, S, Baba, KSSS, Kandakatla, M
Scientific reports. 2021;(1):10641
Abstract
COVID 19 is known to cause immune dysregulation and vitamin D is a known immunomodulator. This study aims to objectively investigate the impact of Pulse D therapy in reducing the inflammatory markers of COVID-19. Consented COVID-19 patients with hypovitaminosis D were evaluated for inflammatory markers (N/L ratio, CRP, LDH, IL6, Ferritin) along with vitamin D on 0th day and 9th/11th day as per their respective BMI category. Subjects were randomised into VD and NVD groups. VD group received Pulse D therapy (targeted daily supplementation of 60,000 IUs of vitamin D for 8 or 10 days depending upon their BMI) in addition to the standard treatment. NVD group received standard treatment alone. Differences in the variables between the two groups were analysed for statistical significance. Eighty seven out of one hundred and thirty subjects have completed the study (VD:44, NVD:43). Vitamin D level has increased from 16 ± 6 ng/ml to 89 ± 32 ng/ml after Pulse D therapy in VD group and highly significant (p < 0.01) reduction of all the measured inflammatory markers was noted. Reduction of markers in NVD group was insignificant (p > 0.05). The difference in the reduction of markers between the groups (NVD vs VD) was highly significant (p < 0.01). Therapeutic improvement in vitamin D to 80-100 ng/ml has significantly reduced the inflammatory markers associated with COVID-19 without any side effects. Hence, adjunctive Pulse D therapy can be added safely to the existing treatment protocols of COVID-19 for improved outcomes.
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MR-proADM as marker of endotheliitis predicts COVID-19 severity.
García de Guadiana-Romualdo, L, Calvo Nieves, MD, Rodríguez Mulero, MD, Calcerrada Alises, I, Hernández Olivo, M, Trapiello Fernández, W, González Morales, M, Bolado Jiménez, C, Albaladejo-Otón, MD, Fernández Ovalle, H, et al
European journal of clinical investigation. 2021;(5):e13511
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BACKGROUND Early identification of patients at high risk of progression to severe COVID-19 constituted an unsolved challenge. Although growing evidence demonstrates a direct association between endotheliitis and severe COVID-19, the role of endothelial damage biomarkers has been scarcely studied. We investigated the relationship between circulating mid-regional proadrenomedullin (MR-proADM) levels, a biomarker of endothelial dysfunction, and prognosis of SARS-CoV-2-infected patients. METHODS Prospective observational study enrolling adult patients with confirmed COVID-19. On admission to emergency department, a blood sample was drawn for laboratory test analysis. Primary and secondary endpoints were 28-day all-cause mortality and severe COVID-19 progression. Area under the curve (AUC) and multivariate regression analysis were employed to assess the association of the biomarker with the established endpoints. RESULTS A total of 99 patients were enrolled. During hospitalization, 25 (25.3%) cases progressed to severe disease and the 28-day mortality rate was of 14.1%. MR-proADM showed the highest AUC to predict 28-day mortality (0.905; [CI] 95%: 0.829-0.955; P < .001) and progression to severe disease (0.829; [CI] 95%: 0.740-0.897; P < .001), respectively. MR-proADM plasma levels above optimal cut-off (1.01 nmol/L) showed the strongest independent association with 28-day mortality risk (hazard ratio [HR]: 10.470, 95% CI: 2.066-53.049; P < .005) and with progression to severe disease (HR: 6.803, 95% CI: 1.458-31.750; P = .015). CONCLUSION Mid-regional proadrenomedullin was the biomarker with highest performance for prognosis of death and progression to severe disease in COVID-19 patients and represents a promising predictor for both outcomes, which might constitute a potential tool in the assessment of prognosis in early stages of this disease.
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Sustaining efficient immune functions with regular physical exercise in the COVID-19 era and beyond.
Furtado, GE, Letieri, RV, Caldo-Silva, A, Sardão, VA, Teixeira, AM, de Barros, MP, Vieira, RP, Bachi, ALL
European journal of clinical investigation. 2021;(5):e13485
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The new coronavirus (SARS-CoV-2) appearance in Wuhan, China, did rise the new virus disease (COVID-19), which spread globally in a short time, leading the World Health Organization to declare a new global pandemic. To contain and mitigate the spread of SARS-CoV-2, specific public health procedures were implemented in virtually all countries, with a significant impact on society, making it difficult to keep the regular practice of physical activity. It is widely accepted that an active lifestyle contributes to the improvement of general health and preservation of cardiovascular, respiratory, osteo-muscular and immune system capacities. The positive effects of regular physical activity on the immune system have emerged as a pivotal trigger of general health, underlying the beneficial effects of physical activity on multiple physiological systems. Accordingly, recent studies have already pointed out the negative impact of physical inactivity caused by the social isolation imposed by the public sanitary authorities due to COVID-19. Nevertheless, there are still no current narrative reviews evaluating the real impact of COVID-19 on active lifestyle or even discussing the possible beneficial effects of exercise-promoted immune upgrade against the severity or progression of COVID-19. Based on the consensus in the scientific literature, in this review, we discuss how an exercise adherence could adequately improve immune responses in times of the 'COVID-19 Era and beyond'.
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COVID-19, cytokines, inflammation, and spices: How are they related?
Kunnumakkara, AB, Rana, V, Parama, D, Banik, K, Girisa, S, Henamayee, S, Thakur, KK, Dutta, U, Garodia, P, Gupta, SC, et al
Life sciences. 2021;:119201
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BACKGROUND Cytokine storm is the exaggerated immune response often observed in viral infections. It is also intimately linked with the progression of COVID-19 disease as well as associated complications and mortality. Therefore, targeting the cytokine storm might help in reducing COVID-19-associated health complications. The number of COVID-19 associated deaths (as of January 15, 2021; https://www.worldometers.info/coronavirus/) in the USA is high (1199/million) as compared to countries like India (110/million). Although the reason behind this is not clear, spices may have some role in explaining this difference. Spices and herbs are used in different traditional medicines, especially in countries such as India to treat various chronic diseases due to their potent antioxidant and anti-inflammatory properties. AIM: To evaluate the literature available on the anti-inflammatory properties of spices which might prove beneficial in the prevention and treatment of COVID-19 associated cytokine storm. METHOD A detailed literature search has been conducted on PubMed for collecting information pertaining to the COVID-19; the history, origin, key structural features, and mechanism of infection of SARS-CoV-2; the repurposed drugs in use for the management of COVID-19, and the anti-inflammatory role of spices to combat COVID-19 associated cytokine storm. KEY FINDINGS The literature search resulted in numerous in vitro, in vivo and clinical trials that have reported the potency of spices to exert anti-inflammatory effects by regulating crucial molecular targets for inflammation. SIGNIFICANCE As spices are derived from Mother Nature and are inexpensive, they are relatively safer to consume. Therefore, their anti-inflammatory property can be exploited to combat the cytokine storm in COVID-19 patients. This review thus focuses on the current knowledge on the role of spices for the treatment of COVID-19 through suppression of inflammation-linked cytokine storm.
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Strategies to DAMPen COVID-19-mediated lung and systemic inflammation and vascular injury.
Bime, C, Casanova, NG, Nikolich-Zugich, J, Knox, KS, Camp, SM, Garcia, JGN
Translational research : the journal of laboratory and clinical medicine. 2021;:37-48
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Approximately 15%-20% of patients infected with SARS-CoV-2 coronavirus (COVID-19) progress beyond mild and self-limited disease to require supplemental oxygen for severe pneumonia; 5% of COVID-19-infected patients further develop acute respiratory distress syndrome (ARDS) and multiorgan failure. Despite mortality rates surpassing 40%, key insights into COVID-19-induced ARDS pathology have not been fully elucidated and multiple unmet needs remain. This review focuses on the unmet need for effective therapies that target unchecked innate immunity-driven inflammation which drives unchecked vascular permeability, multiorgan dysfunction and ARDS mortality. Additional unmet needs including the lack of insights into factors predicting pathogenic hyperinflammatory viral host responses, limited approaches to address the vast disease heterogeneity in ARDS, and the absence of clinically-useful ARDS biomarkers. We review unmet needs persisting in COVID-19-induced ARDS in the context of the potential role for damage-associated molecular pattern proteins in lung and systemic hyperinflammatory host responses to SARS-CoV-2 infection that ultimately drive multiorgan dysfunction and ARDS mortality. Insights into promising stratification-enhancing, biomarker-based strategies in COVID-19 and non-COVID ARDS may enable the design of successful clinical trials of promising therapies.
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The design and discovery of phospholipase A2 inhibitors for the treatment of inflammatory diseases.
Batsika, CS, Gerogiannopoulou, AD, Mantzourani, C, Vasilakaki, S, Kokotos, G
Expert opinion on drug discovery. 2021;(11):1287-1305
Abstract
AREAS COVERED This review article summarizes the most important synthetic PLA2 inhibitors developed to target each one of the four major types of human PLA2 (cytosolic cPLA2, calcium-independent iPLA2, secreted sPLA2, and lipoprotein-associated Lp-PLA2), discussing their in vitro and in vivo activities as well as their recent applications and therapeutic properties. Recent findings on the role of PLA2 in the pathobiology of COVID-19 are also discussed. EXPERT OPINION Although a number of PLA2 inhibitors have entered clinical trials, none has reached the market yet. Lipoprotein-associated PLA2 is now considered a biomarker of vascular inflammation rather than a therapeutic target for inhibitors like darapladib. Inhibitors of cytosolic PLA2 may find topical applications for diseases like atopic dermatitis and psoriasis. Inhibitors of secreted PLA2, varespladib and varespladib methyl, are under investigation for repositioning in snakebite envenoming. A deeper understanding of PLA2 enzymes is needed for the development of novel selective inhibitors. Lipidomic technologies combined with medicinal chemistry approaches may be useful tools toward this goal.
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Novel Systemic Inflammation Markers to Predict COVID-19 Prognosis.
Karimi, A, Shobeiri, P, Kulasinghe, A, Rezaei, N
Frontiers in immunology. 2021;:741061
Abstract
Coronavirus disease 2019 (COVID-19) has resulted in a global pandemic, challenging both the medical and scientific community for the development of novel vaccines and a greater understanding of the effects of the SARS-CoV-2 virus. COVID-19 has been associated with a pronounced and out-of-control inflammatory response. Studies have sought to understand the effects of inflammatory response markers to prognosticate the disease. Herein, we aimed to review the evidence of 11 groups of systemic inflammatory markers for risk-stratifying patients and prognosticating outcomes related to COVID-19. Numerous studies have demonstrated the effectiveness of neutrophil to lymphocyte ratio (NLR) in prognosticating patient outcomes, including but not limited to severe disease, hospitalization, intensive care unit (ICU) admission, intubation, and death. A few markers outperformed NLR in predicting outcomes, including 1) systemic immune-inflammation index (SII), 2) prognostic nutritional index (PNI), 3) C-reactive protein (CRP) to albumin ratio (CAR) and high-sensitivity CAR (hsCAR), and 4) CRP to prealbumin ratio (CPAR) and high-sensitivity CPAR (hsCPAR). However, there are a limited number of studies comparing NLR with these markers, and such conclusions require larger validation studies. Overall, the evidence suggests that most of the studied markers are able to predict COVID-19 prognosis, however NLR seems to be the most robust marker.
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The effect of glutamine supplementation on serum levels of some inflammatory factors, oxidative stress, and appetite in COVID-19 patients: a case-control study.
Mohajeri, M, Horriatkhah, E, Mohajery, R
Inflammopharmacology. 2021;(6):1769-1776
Abstract
BACKGROUND Malnutrition is seen in COVID-19 patients, and reducing malnutrition with appropriate therapies may improve these patients' health. This case-control study aimed to assess and compare serum levels of some inflammatory factors, oxidative stress, and appetite in COVID-19 patients with respiratory infections that receive glutamine treatment with a control group. METHODS In this study, patients who consented to use glutamine were considered as the case group and other patients who did not use glutamine were considered as a control group. Two hundred twenty-two COVID-19 patients (51.2 ± 6.7) using L-Glutamine and 230 COVID-19 patients (51.3 ± 8.2) with similar age, gender, and clinical status, as the control group, were included in the study. For 5 days, the case group consumed 10 g of glutamine supplement three times per day. At the end of the 5 days, blood samples were taken again to test for serum levels of IL1β, tumor necrosis factor-α, malondialdehyde, and total antioxidant capacity, then all data were analyzed. RESULTS Serum levels of β-1 interleukin, tumor necrosis factor-α and hs-CRP were significantly reduced with five days of glutamine supplementation (p < 0.05), and patients' appetite during 5 days of glutamine supplementation compared with the control group had a significant increase (p < 0.05). CONCLUSION Glutamine supplementation in COVID-19 patients with respiratory infection significantly reduces serum levels of interleukin-1 β, hs-CRP, and tumor necrosis factor-α and significantly increases appetite, so glutamine supplementation may be useful for COVID-19 patients in the hospital.
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Anti-inflammatory properties of antidiabetic drugs: A "promised land" in the COVID-19 era?
Katsiki, N, Ferrannini, E
Journal of diabetes and its complications. 2020;(12):107723
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Inflammation is implicated in the development and severity of the coronavirus disease 2019 (COVID-19), as well as in the pathophysiology of diabetes. Diabetes, especially when uncontrolled, is also recognized as an important risk factor for COVID-19 morbidity and mortality. Furthermore, certain inflammatory markers [i.e. C-reactive protein (CRP), interleukin-6 (IL-6) and ferritin] were reported as strong predictors of worse outcomes in COVID-19 positive patients. The same biomarkers have been associated with poor glycemic control. Therefore, achieving euglycemia in patients with diabetes is even more important in the era of the COVID-19 pandemic. Based on the above, it is clinically interesting to elucidate whether antidiabetic drugs may reduce inflammation, thus possibly minimizing the risk for COVID-19 development and severity. The present narrative review discusses the potential anti-inflammatory properties of certain antidiabetic drugs (i.e. metformin, pioglitazone, sitagliptin, linagliptin, vildagliptin, alogliptin, saxagliptin, liraglutide, dulaglutide, exenatide, lixisenatide, semaglutide, empagliflozin, dapagliflozin, canagliflozin), with a focus on CRP, IL-6 and ferritin.
