High-Density Lipoprotein function is modulated by the SARS-CoV-2 spike protein in a lipid-type dependent manner.

There is a close relationship between the SARS-CoV-2 virus and lipoproteins, in particular high-density lipoprotein (HDL). The severity of the coronavirus disease 2019 (COVID-19) is inversely correlated with HDL plasma levels. It is known that the SARS-CoV-2 spike (S) protein binds the HDL particle, probably depleting it of lipids and altering HDL function. Based on neutron reflectometry (NR) and the ability of HDL to efflux cholesterol from macrophages, we confirm these observations and further identify the preference of the S protein for specific lipids and the consequent effects on HDL function on lipid exchange ability. Moreover, the effect of the S protein on HDL function differs depending on the individuals lipid serum profile. Contrasting trends were observed for individuals presenting low triglycerides/high cholesterol serum levels (LTHC) compared to high triglycerides/high cholesterol (HTHC) or low triglycerides/low cholesterol serum levels (LTLC). Collectively, these results suggest that the S protein interacts with the HDL particle and, depending on the lipid profile of the infected individual, it impairs its function during COVID-19 infection, causing an imbalance in lipid metabolism.

[HDL-cholesterol concentration and risk of SARS-CoV-2 infection in people over 75 years of age: a cohort with half a million participants from the Community of Madrid]. / Concentración de colesterol-HDL y riesgo de infección por SARS-CoV-2 en personas mayores de 75 años: una cohorte con medio millón de participantes de la Comunidad de Madrid.

OBJECTIVE: The aim of this study was to analyze the relationship between HDL-cholesterol and the risk of SARS-CoV-2 infection in over 75-year-olds residing in the Community of Madrid. METHODS: Study of a population-based cohort, composed of all residents in Madrid (Spain) born before January 1, 1945 and alive on December 31, 2019. Demographic, clinical and analytical data were obtained from primary care electronic medical records from January 2015. Confirmed SARS-CoV-2 infection was defined as a positive RT-PCR or antigen test result. Infection data correspond to the period March 1, 2020 through December 31, 2020. RESULTS: Of the 593,342 cohort participants, 501,813 had at least one HDL-cholesterol determination in the past 5 years. Their mean age was 83.4±5.6 years and 62.4% were women. A total of 36,996 (7.4%) had a confirmed SARS-CoV2 infection during 2020. The risk of infection [odds ratio (95% confidence interval)] for SARS-CoV2 according to increasing quintiles of HDL-cholesterol was 1, 0.960 (0.915-1.007), 0.891 (0.848-0.935), 0.865 (0.824-0.909) and 0.833 (0.792-0.876), after adjusting for age, sex, cardiovascular risk factors and comorbidities. CONCLUSIONS: There is an inverse and dose-dependent relationship between HDL-cholesterol concentration and the risk of SARS-CoV2 infection in subjects aged over 75 years of age in the Community of Madrid.

Cardiovascular Disease in South Asian Immigrants: a Review of Dysfunctional HDL as a Potential Marker.

South Asians (SAs) account for a quarter of the world's population and are one of the fastest-growing immigrant groups in the United States (US). South Asian Immigrants (SAIs) are disproportionately more at risk of developing cardiovascular disease (CVD) than other ethnic/racial groups. Atherosclerosis is a chronic inflammatory disorder and is the major cause of CVD. Traditional CVD risk factors, though important, do not fully explain the elevated risk of CVD in SAIs. High-density lipoproteins (HDLs) are heterogeneous lipoproteins that modify their composition and functionality depending on physiological or pathological conditions. With its cholesterol efflux, anti-inflammatory, and antioxidant functions, HDL is traditionally considered a protective factor for CVD. However, its functions can be compromised under pathological conditions, such as chronic inflammation, making it dysfunctional (Dys-HDL). SAIs have a high prevalence of type 2 diabetes and metabolic syndrome, which may further promote Dys-HDL. This review explores the potential association between Dys-HDL and CVD in SAIs and presents current literature discussing the role of Dys-HDL in CVD.

The effect of omega-3 supplements on the serum levels of ACE/ACE2 ratio as a potential key in cardiovascular disease: A randomized clinical trial in participants with vitamin D deficiency.

Objective: The aim of this randomized controlled clinical trial was to determine the effect of the omega-3 fatty acid supplementations 300 mg per day for 8 weeks on the serum levels of ACE/ACE2 ratio in Jordanian participants with vitamin D deficiency (VDD). Methods: The physical and clinical characteristic of individuals in both intervention and control randomized controlled clinical trial were measured and analyzed. The comparisons between the two groups and the changes in each group before and after taking omega-3 doses were studied through independent t test and paired t test, respectively. Possible factors that have a role in the changes were determined by multivariate stepwise regression. Follow-up period lasted 10 weeks. Results: The sample consisted of 82 participants with VDD and a mean age of 37.85 ± 9.85 years. Omega-3 Supplements resulted in a significant decrease in serum ACE levels, ACE/ACE2 ratio and serum 25-hydroxy vitamin D (25OHD). While the change in serum ACE2 levels and serum triglycerides levels were insignificant. Also, a significant increase in serum LDL levels were observed. Conclusion: It is possible that taking high doses of omega-3 fatty acid supplementations have positive effects on the heart and circulatory system and could protect from COVID-19 or decrease disease severity, in connection with a decrease in the ACE/ACE 2 ratio. On the other hand, omega-3 supplement may have negative effect on cardiovascular system due to the significant increase in serum LDL levels.

Understanding the Role of HDL during COVID-19 Infection

Background: Recently emerged COVID-19 pandemic has caused a large number of deaths with lacs of confirmed cases worldwide posturing a grim situation and severe threat to public health. There is an imperative necessity of analyzing emerging clinical and laboratory data of COVID-19 pa-tients, which may contribute to elucidate the pathogenic mechanism and development of effective prevention and treatment countermeasures. Method(s): Under this article, the emerging role of High-Density Lipoprotein (HDL) was analyzed by collecting recently published articles related to this field having clinical data of COVID-19 patients. Result(s): Based on the recently published reports of laboratory-confirmed COVID-19 infected hospitalized patients it was consistently observed that levels of HDL were low at the time of admission to hospi-tal and remained relatively low during the disease course i.e., treatment, recovery, and discharge stage. It was also reported critically that levels of HDL in the patients, those did not survive, decreased continu-ously until death. Conclusion(s): These clinical reports of patients have risen the concern about probable infection and worsen the clinical outcome of a healthy person having a compromised level of HDL for COVID-19 infection. Eventually, these findings stated that there is a strong association of low HDL levels with a higher risk of COVID-19 infection and further severity of the illness. Proper attention is needed to understand the significance of altered quantity and quality of HDL in COVID-19 patients compared to healthy controls, so that appropriate therapies could be given at the right time to combat severity and mortality due to this infection.Copyright © 2021 Bentham Science Publishers.

A study of relationship between lipid profile and severity of SARS-CoV-2

COVID-19 is a severe acute respiratory disease caused by coronavirus 2. While many biochemical alterations have been studied in patients with COVID-19, only a few studies were available to explore the relationship between serum lipid profile values and the severity of SARS COVID-19 infection. A cross-sectional study was conducted at Chettinad Hospital and Research Institute on 128 patients infected with SARS COVID-19 from March 2020 to September 2020. It was an age and sex-matched study. Patients were categorized into mild and severe based on the signs and symptoms. A fasting serum lipid profile and IL-6 levels were measured and Pearson's correlation analysis was done. There was a highly significant decrease in the median and IQR levels of TC, HDL, and LDL in severe cases as compared to mild cases [TC - mild: (256,64), severe (125,44), HDL - mild (46,11), severe (25,13), and LDL - mild (170,48), severe (76,36)]. TGL showed a significant decrease [mild: (170,67), severe:(110,69)]. IL-6 showed a significant increase in severe cases when compared to mild cases [mild:(20,37), severe:(62,105)]. Pearson's correlation analysis showed a significant inverse relationship between the levels of TC, HDL, and IL-6. However, TGL and LDL showed inverse but no significant relationship with IL-6. As the severity of COVID-19 increases, lipid profile levels start decreasing. Hypolipidemia is a pathognomic finding in severe SARS COVID-19 infection.

Correlation of low HDL and high triglycerides with outcome in patients with COVID 19 infection

Background: The world is still experiencing corona virus disease-19 (COVID-19) pandemic. So far, we experienced a total of more than 23 crore cases and 47 lakh deaths from COVID 19 disease. Severe acute respiratory syndrome - corona virus - 2 (SARS-CoV-2) was believed to affect lipid metabolism, with many authors reporting an increase in triglycerides and a decrease in high density lipoprotein (HDL) levels. This study gave the clinical features of COVID-19 patients with various HDL-C levels and an interrelation between HDL-C levels and the risk for adverse outcome in the form of deaths. Methods: We conducted a cross sectional study on 100 COVID-19 adult patients diagnosed by reverse transcription - polymerase chain reaction (RT-PCR) test admitted to the medicine department, from January 2020 to December 2020, who were also tested for lipid parameters. The detailed history and lab parameters of the patients were collected and the severe outcome of the same was measured in terms of deaths. Results: The mean age of study participants was 57.92 +or- 12.41 years. Majority of the participants were from the age group of 41 to 60 years with 50 patients (50%). There were 73 males (73%) and 27 females (27%) in our study. We observed that a total of 36 patients had co-morbidities (36%), such as diabetes seen in 22 cases (22%), hypertension in 18 cases (18%), ischaemic heart disease (IHD) in 8 cases (8%). A significant association was seen between the presence of co-morbidities and deaths in our study (P = 0.043). A significant association was seen between the patients who required intensive care and deaths (P < 0.001). We found a significant difference between the triglycerides and HDL parameters of lipid profiles in patients who died as compared to those who survived. (P < 0.05) The mean triglyceride level in patients who died was 223.14 +or- 56.59, significantly higher than those who survived 134.43 +or- 96.16. (P = 0.003) Conclusions: The lipid profile evaluation in our study was found to be effective in detecting the correlation of severity and outcome in COVID-19 patients. We conclude that the severity of COVID-19 cases is associated with low HDL and high triglyceride levels.

Altered lipid profile in patients with COVID-19 infection

Background: In this study, we aimed to investigate the pathological alterations of LDL-cholesterol, HDL-cholesterol, total cholesterol and triglycerides in COVID-19 patients during the acute phase of infection, and after recovery. Method(s): A retrospective study was performed to examine serum levels of LDL-cholesterol, HDL-cholesterol, total cholesterol and triglycerides on 55 COVID-19 patients who were hospitalized in our center between February and April 2020. The lipid profile and the hematological parameters were analyzed in the same group of patients before (Group before) and after clinical management (Group after). The laboratory tests results were compared between these two groups, as well as with a group of healthy subjects (Healthy controls), matched for age and sex and selected among the blood donors. Result(s): LDL-cholesterol, HDL-cholesterol, total cholesterol levels were significantly lower in COVID-19 patients (Group before) as compared with normal subjects (P<0.0001). Comparing healthy controls and the group after, statistically significant differences were observed for all parameters except for total cholesterol (P=0.9006). Total cholesterol, HDL-cholesterol, LDL-cholesterol and triglyceride were found to be significantly higher after recovery than during the acute phase of infection (P<0.0001). C-reactive protein levels were found to be inversely correlated with those of LDL-cholesterol (rs =-0573, P<0.0001), total cholesterol (r=-0.732, P<0.0001), and HDL-cholesterol (r=-0.700, P<0.0001). Conclusion(s): The results of our study seemingly attest that lipids, especially cholesterol, may play an important role in viral replication, internalization and immune activation in patients with COVID-19 infection. Moreover, lipid abnormalities observed during and after this infection could be used for assessing indirectly the response to clinical treatment.Copyright © Journal of Laboratory and Precision Medicine. All rights reserved.

Low HDL-c levels at admission are associated with greater severity and worse clinical outcomes in patients with COVID-19 disease.

Background and aims: HDL particles may act to buffer host cells from excessive inflammatory mediators. The aim of this study is to investigate if the lipid profile provides a prognostic biomarker for COVID-19 outcomes. Methods: This was a prospective study of the characteristics of 125 adult COVID-19 patients with a lipid profile performed on the day of admission analyzed with regard to clinical outcomes. Results: Seventy-seven patients (61.2%) were men, with a mean age of 66.3 (15.6) years. 54.1% had bilateral pneumonia. The all-cause mortality rate during hospitalization was 20.8%. We found a direct association between more severe disease assessed by the WHO classification, admission to the ICU and death with more pronounced lymphopenia, higher levels of CRP, ferritin (p < 0.001), D-dímer and lactate dehydrogenase (LDH) all statistically significant. Lower leves of HDL-c and LDL-c were also associated with a worse WHO classification, ICU admission, and death,. HDL-c levels were inversely correlated with inflammatory markers CRP (r = -0.333; p < 0.001), ferritin (r = -0.354; p < 0.001), D-dímer (r = -0.214; p < 0.001), LDH (r = -0.209; p < 0.001. LDL-c levels were significantly associated with CRP (r = -0.320; p < 0.001) and LDH (r = -0.269; p < 0.001). ROC curves showed that HDL [AUC = 0.737(0.586-0.887), p = 0.005] and lymphocytes [AUC = 0.672(0.497-0.847], p < 0.043] had the best prognostic accuracy to predict death. In a multivariate analysis, HDL-c (ß = -0.146(0.770-0.971), p = 0.014) and urea (ß = 0.029(1.003-1.057), p = 0.027) predicted mortality. Conclusion: Hypolipidemia including HDL levels at admission identifies patients with a higher risk of death and worse clinical manifestations who may require more intensive care.

Plasma Apolipoprotein Concentrations Are Highly Altered in Severe Intensive Care Unit COVID-19 Patients: Preliminary Results from the LIPICOR Cohort Study.

SARS-CoV-2 infection goes beyond acute pneumonia, as it also impacts lipid metabolism. Decreased HDL-C and LDL-C levels have been reported in patients with COVID-19. The lipid profile is a less robust biochemical marker than apolipoproteins, components of lipoproteins. However, the association of apolipoprotein levels during COVID-19 is not well described and understood. The objective of our study is to measure plasma levels of 14 apolipoproteins in patients with COVID-19 and to evaluate the relationships between apolipoprotein levels, severity factors and patient outcomes. From November to March 2021, 44 patients were recruited on admission to the intensive care unit because of COVID-19. Fourteen apolipoproteins and LCAT were measured by LC-MS/MS in plasma of 44 COVID-19 patients on admission to the ICU and 44 healthy control subjects. Absolute apolipoprotein concentrations were compared between COVID-19 patients and controls. Plasma apolipoproteins (Apo) A (I, II, IV), C(I, II), D, H, J and M and LCAT were lower in COVID-19 patients, whereas Apo E was higher. COVID-19 severity factors such as PaO2/FiO2 ratio, SO-FA score and CRP were correlated with certain apolipoproteins. Lower Apo B100 and LCAT levels were observed in non-survivors of COVID-19 versus survivors. To conclude, in this study, lipid and apolipoprotein profiles are altered in COVID-19 patients. Low Apo B100 and LCAT levels may be predictive of non-survival in COVID-19 patients.

Effect of COVID-19 on Glycemic Control, Insulin Resistance, and pH in Elderly Patients With Type 2 Diabetes.

Background The coronavirus disease of 2019 (COVID-19) was spread all over the world, while diabetes mellitus (DM) remains the most prevalent chronic disease worldwide. Aims This study aims to investigate the effect of COVID-19 on glycemic control, insulin resistance (IR), and pH in elderly patients with type 2 diabetes. Methods  A retrospective study was conducted on patients with type 2 DM who were diagnosed with COVID-19 infection in the central hospitals of the Tabuk region. Patient data were collected from September 2021 to August 2022. Four non-insulin-based insulin resistance indexes were calculated for patients: the triglyceride-glucose (TyG) index, the triglyceride glucose-body mass index (TyG-BMI) index, the triglyceride to high-density lipoprotein cholesterol (TG/HDL) ratio, and the metabolic score for insulin resistance (METS-IR). Results Patients showed increased serum fasting glucose and blood HbA1c associated with a high TyG index, TyG-BMI index, TG/HDL ratio, and METS-IR as compared with results before COVID-19. Moreover, during COVID-19, patients revealed a reduction in pH, associated with a reduction in cBase and bicarbonate, and an elevation in PaCO2 as compared with their results before COVID-19. After complete remission, all patients' results turn back to their level before COVID-19. Conclusions Patients with type 2 DM who catch the COVID-19 infection suffer from dysregulation of glycemic control and elevated insulin resistance associated with a significant reduction in their pH.

Effect of evolocumab on fasting and post fat load lipids and lipoproteins in familial dysbetalipoproteinemia.

BACKGROUND: Familial dysbetalipoproteinemia (FD) is the second most common monogenic lipid disorder (prevalence 1 in 850-3500), characterized by postprandial remnant accumulation and associated with increased cardiovascular disease (CVD) risk. Many FD patients do not achieve non-HDL-C treatment goals, indicating the need for additional lipid-lowering treatment options. OBJECTIVES: To evaluate the effect of the PCSK9 monoclonal antibody evolocumab added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in patients with FD. METHODS: A randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. At the start and end of each treatment period patients received an oral fat load. The primary endpoint was the 8-hour post fat load non-HDL-C area under the curve (AUC). Secondary endpoints included fasting and post fat load lipids and lipoproteins. RESULTS: In total, 28 patients completed the study. Mean age was 62±9 years and 93% had an Ɛ2Ɛ2 genotype. Evolocumab reduced the 8-hour post fat load non-HDL-C AUC with 49% (95%CI 42-55) and apolipoprotein B (apoB) AUC with 47% (95%CI 41-53). Other fasting and absolute post fat load lipids and lipoproteins including triglycerides and remnant-cholesterol were also significantly reduced by evolocumab. However, evolocumab did not have significant effects on the rise above fasting levels that occurred after consumption of the oral fat load. CONCLUSIONS: Evolocumab added to standard lipid-lowering therapy significantly reduced fasting and absolute post fat load concentrations of non-HDL-C, apoB and other atherogenic lipids and lipoproteins in FD patients. The clinically significant decrease in lipids and lipoproteins can be expected to translate into a reduction in CVD risk in these high-risk patients.

The bidirectional interaction of COVID-19 infections and lipoproteins.

COVID-19 infections decrease total cholesterol, LDL-C, HDL-C, and apolipoprotein A-I, A-II, and B levels while triglyceride levels may be increased or inappropriately normal for the poor nutritional status. The degree of reduction in total cholesterol, LDL-C, HDL-C, and apolipoprotein A-I are predictive of mortality. With recovery lipid/lipoprotein levels return towards pre-infection levels and studies have even suggested an increased risk of dyslipidemia post-COVID-19 infection. The potential mechanisms for these changes in lipid and lipoprotein levels are discussed. Decreased HDL-C and apolipoprotein A-I levels measured many years prior to COVID-19 infections are associated with an increased risk of severe COVID-19 infections while LDL-C, apolipoprotein B, Lp (a), and triglyceride levels were not consistently associated with an increased risk. Finally, data suggest that omega-3-fatty acids and PCSK9 inhibitors may reduce the severity of COVID-19 infections. Thus, COVID-19 infections alter lipid/lipoprotein levels and HDL-C levels may affect the risk of developing COVID-19 infections.

Autoimmune Reaction Associated With Long COVID Syndrome and Cardiovascular Disease: A Genetic Case Report.

A 35-year-old woman with history of cardiovascular disease presented with shortness of breath, lightheadedness, fatigue, chest pain, and premature ventricular contractions 3 weeks after her second COVID-19 vaccine. Symptoms subsided following catheter ablation and ibuprofen except for chest pain and fatigue, which persisted following ablation and subsequent SARS-CoV-2 infection. The case suggests causal associations between COVID-19 vaccine/infection and recurrence of cardiovascular disease, including long-COVID-like symptoms. (Level of Difficulty: Advanced.).

Maternal fructose boosts the effects of a Western-type diet increasing SARS-COV-2 cell entry factors in male offspring.

Fructose-rich beverages and foods consumption correlates with the epidemic rise in cardiovascular disease, diabetes and obesity. Severity of COVID-19 has been related to these metabolic diseases. Fructose-rich foods could place people at an increased risk for severe COVID-19. We investigated whether maternal fructose intake in offspring affects hepatic and ileal gene expression of proteins that permit SARS-CoV2 entry to the cell. Carbohydrates were supplied to pregnant rats in drinking water. Adult and young male descendants subjected to water, liquid fructose alone or as a part of a Western diet, were studied. Maternal fructose reduced hepatic SARS-CoV2 entry factors expression in older offspring. On the contrary, maternal fructose boosted the Western diet-induced increase in viral entry factors expression in ileum of young descendants. Maternal fructose intake produced a fetal programming that increases hepatic viral protection and, in contrast, exacerbates fructose plus cholesterol-induced diminution in SARS-CoV2 protection in small intestine of progeny.

Evaluation of Tau, amyloid beta, dynorphin levels and number of biochemical variables in covid-19 patients

The study aimed to determine the levels of Tau, amyloid beta, dynorphin, and number of biochemical variables in men with COVID-19. The study groups included 30 men with COVID-19, 30 men who recovered from COVID -19, and 30 healthy men as a control group. Protein and biochemical assays include: tau, amyloid beta, dynorphin, zinc, triglycerides, HDL-C, VLDL-C and cholesterol. The results were a significant increase (P 0.05) in the levels of amyloid beta, dynorphin, HDL-C, cholesterol and LDL-C in patients. Those infected with COVID-19 compared to the control group, while in the recovery group, amyloid beta was low compared to the control group, while zinc and lipid profile were high in the recovered. While tau protein, zinc, triglycerides and VLDL-C showed a significant decrease at (P< 0.05) in the affected men group compared to the control group.

The rationale for the treatment of long-Covid symptoms - A cardiologist's view.

The ongoing coronavirus disease 2019 pandemic left us with thousands of patients suffering from neurological, cardiovascular, and psychiatric disorders named post-acute sequelae of COVID-19 or just long-Covid. In parallel, the vaccination campaigns against SARS-CoV-2 spike protein saved millions of lives worldwide but long-Covid symptoms also appeared rarely following vaccination with a strong overlap to the "canonical" long-Covid symptoms. A therapeutic strategy targeting both, post-VAC and post-SARS-CoV-2 long-Covid symptoms is warranted since exposure to the S-protein either by vaccination or SARS-CoV-2 infection may trigger identical immuno-inflammatory cascades resulting in long-Covid symptoms.

Low HDL Cholesterol Efflux Capacity Indicates a Fatal Course of COVID-19.

Plasma membrane cholesterol is required for proper trafficking and localization of receptors that facilitate severe acute respiratory syndrome coronavirus 2 infection. High-density lipoproteins (HDL) mobilize plasma membrane cholesterol, and HDL-cholesterol levels are associated with the severity of COVID-19 disease and mortality. However, HDL-cholesterol levels poorly reflect the function of this complex family of particles, and a detailed assessment of COVID-19-associated changes in HDL functionality and its prognostic value is lacking. In the present study, we assessed HDL cholesterol efflux capacity, HDL anti-inflammatory and antioxidant properties, and changes in HDL composition and metabolism in COVID-19 (n = 48) and non-COVID pneumonia patients (n = 32). COVID-19 infection markedly reduced the activity of lecithin-cholesteryl-acyltransferase and functional parameters of HDL, such as the cholesterol efflux capacity, arylesterase activity of paraoxonase 1, and anti-oxidative capacity of apoB-depleted serum when compared to non-COVID pneumonia at baseline, paralleled by markedly reduced levels of HDL-cholesterol. Of particular interest, low HDL cholesterol efflux capacity was associated with increased mortality risk in COVID-19 patients, independent of HDL-C levels. Our results highlight profound effects of COVID-19 infection on HDL function, metabolism, and composition. Low HDL cholesterol efflux capacity indicates a fatal course of COVID-19, independent of HDL-cholesterol levels.

The Influence of SARS-CoV-2 Infection on Lipid Metabolism-The Potential Use of Lipid-Lowering Agents in COVID-19 Management.

Several studies have indicated lipid metabolism alterations during COVID-19 infection, specifically a decrease in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) concentrations and an increase in triglyceride (TG) levels during the infection. However, a decline in triglycerides can also be observed in critical cases. A direct correlation can be observed between a decrease in serum cholesterol, HDL-C, LDL-C and TGs, and the severity of the disease; these laboratory findings can serve as potential markers for patient outcomes. The transmission of coronavirus increases proportionally with rising levels of cholesterol in the cell membrane. This is due to the fact that cholesterol increases the number of viral entry spots and the concentration of angiotensin-converting enzyme 2 (ACE2) receptor, crucial for viral penetration. Studies have found that lower HDL-C levels correspond with a higher susceptibility to SARS-CoV-2 infection and infections in general, while higher HDL-C levels were related to a lower risk of developing them. However, extremely high HDL-C levels in serum increase the risk of infectious diseases and is associated with a higher risk of cardiovascular events. Low HDL-C levels are already accepted as a marker for risk stratification in critical illnesses, and higher HDL-C levels prior to the infection is associated with a lower risk of death in older patients. The correlation between LDL-C levels and disease severity is still unclear. However, TG levels were significantly higher in non-surviving severe patients compared to those that survived; therefore, elevated TG-C levels in COVID-19 patients may be considered an indicator of uncontrolled inflammation and an increased risk of death.

Anti-Inflammatory Activity of CIGB-258 against Acute Toxicity of Carboxymethyllysine in Paralyzed Zebrafish via Enhancement of High-Density Lipoproteins Stability and Functionality.

Background: Hyperinflammation is frequently associated with the chronic pain of autoimmune disease and the acute death of coronavirus disease (COVID-19) via a severe cytokine cascade. CIGB-258 (Jusvinza®), an altered peptide ligand with 3 kDa from heat shock protein 60 (HSP60), inhibits the systemic inflammation and cytokine storm, but the precise mechanism is still unknown. Objective: The protective effect of CIGB-258 against inflammatory stress of N-ε-carboxymethyllysine (CML) was tested to provide mechanistic insight. Methods: CIGB-258 was treated to high-density lipoproteins (HDL) and injected into zebrafish and its embryo to test a putative anti-inflammatory activity under presence of CML. Results: Treatment of CML (final 200 µM) caused remarkable glycation of HDL with severe aggregation of HDL particles to produce dysfunctional HDL, which is associated with a decrease in apolipoprotein A-I stability and lowered paraoxonase activity. Degradation of HDL3 by ferrous ions was attenuated by a co-treatment with CIGB-258 with a red-shift of the Trp fluorescence in HDL. A microinjection of CML (500 ng) into zebrafish embryos resulted in the highest embryo death rate, only 18% of survivability with developmental defects. However, co-injection of CIGB-258 (final 1 ng) caused the remarkable elevation of survivability around 58%, as well as normal developmental speed. An intraperitoneal injection of CML (final 250 µg) into adult zebrafish resulted acute paralysis, sudden death, and laying down on the bottom of the cage with no swimming ability via neurotoxicity and inflammation. However, a co-injection of CIGB-258 (1 µg) resulted in faster recovery of the swimming ability and higher survivability than CML alone injection. The CML alone group showed 49% survivability, while the CIGB-258 group showed 97% survivability (p < 0.001) with a remarkable decrease in hepatic inflammation up to 50%. A comparison of efficacy with CIGB-258, Infliximab (Remsima®), and Tocilizumab (Actemra®) showed that the CIGB-258 group exhibited faster recovery and swimming ability with higher survivability than those of the Infliximab group. The CIGB-258 group and Tocilizumab group showed the highest survivability, the lowest plasma total cholesterol and triglyceride level, and the infiltration of inflammatory cells, such as neutrophils in hepatic tissue. Conclusion: CIGB-258 ameliorated the acute neurotoxicity, paralysis, hyperinflammation, and death induced by CML, resulting in higher survivability in zebrafish and its embryos by enhancing the HDL structure and functionality.