COVID-19 Infection during Pregnancy: Disruptions in Lipid Metabolism and Implications for Newborn Health (preprint)

The COVID-19 pandemic has raised questions about indirect impact in pregnant women on the development of their future children. Investigating the characteristics of lipid metabolism in the "mother-placenta-fetus" system can give information about the pathophysiology of COVID-19 infection during pregnancy. 234 women were included in study. Maternal plasma, cord blood, amniotic fluid lipidome were analyzed using HPLC-MS/MS. Differences in lipid profile were searched by Manna-Whitney and Kruskall-Wallis test, diagnostic model based on logistic regres-sion were bilt by AIC. Elevation levels of lysophospholipids, triglycerides, sphingomyelins, and oxidized lipids was registered in patients’ after COVID-19 maternal and cord plasma. An increase in maternal plasma sphingomyelins and oxidized lipids was observed in cases of infection during the second trimester. In amniotic fluid, compared to the control group, nine lipids are reduced, six lipids are elevated. Levels of phosphoglycerides, lysophosphoglycerides, and phosphatidylinosi-tols decreased during infection in the second and third trimesters of pregnancy. Newborn’s health diagnostic model based on maternal plasma were developed for each group and exhibit good di-agnostic value (AUC> 0.85). Maternal and cord plasma’s lipidome changes during delivery, asso-ciated with Covid-19 infection during pregnancy, are synergistic. The most significant disturbances occur with infections in the second trimester of pregnancy.

Increased Incidence of Pancreatic Steatosis Detected Using Computed Tomography at Initial Diagnosis of Coronavirus Disease 2019.

BACKGROUND: It is known that hepatic steatosis, diabetes, obesity, and metabolic syndrome are poor prognostic criteria for coronavirus disease 2019. Closely associated with these factors, pancreatic steatosis has yet to be clarified regarding its incidence in patients with coronavirus disease 2019 and its effect on prognosis. This study aimed to compare the incidence of pancreatic steatosis detected in non-contrast chest computed tomography examinations of patients with coronavirus disease 2019 pneumonia at the time of diagnosis with that of the general population. METHODS: In the present retrospective study, which included 399 patients, densities of 5 different regions of the pancreas and 4 different regions of the spleen were measured, and the mean value of the measured densities was obtained. The difference between the mean pancreatic attenuation and splenic attenuation was defined as pancreatic steatosis if pancreatic attenuation-splenic attenuation ≤-5. RESULTS: The median pancreatic density in patients with coronavirus disease 2019 was significantly lower than in those who tested negative (P = .034). In patients who were coronavirus disease 2019 positive, the incidence of pancreatic steatosis was statistically significantly higher (54.3% vs. 43.0%, P = .031). CONCLUSIONS: According to the non-contrast chest computed tomography examination of the patients with coronavirus disease 2019 performed at the time of admission, the incidence of pancreatic steatosis was higher than that of the normal population of a similar age group. Given that patients with pancreatic steatosis and the accompanying metabolic syndrome are more prone to inflammation, the findings suggest that these patients underwent more chest computed tomography examinations at the time of diagnosis. Therefore, pancreatic steatosis may be a poor prognostic factor in coronavirus disease 2019.

Weight loss in patients with COVID-19 and Influenza in comorbidity with NCDs: a pilot prospective clinical trial. (preprint)

Background COVID and Influenza with non-communicable chronic diseases (NCDs) complicate the diagnosis, treatment, prognosis, and increase mortality rate. The aim: to evaluate the effects of the fast weight loss on clinic and laboratory inflammation profile, metabolic profile, reactive oxygen species (ROS) and body composition in patients with COVID and Influenza in comorbidity with NCDs. Methods A 6-week open, pilot prospective clinical trial including 62 adult patients with COVID (n=27) and influenza (n=35) in comorbidity with T2D, hypertension, and NASH. Overweight in 33 patients (53.2%) with BMI 28.14{+/-}0.39 kg/m2, and 29 patients without overweight with BMI 23.37 {+/-} 0.38 kg/m2. T2D in 26 (41.9%); Hypertension in 38 (61.3%) (incl. 12 patients with T2D); NASH in 51 patients (82.2%) (incl. 8 patients with NASH, T2D and Hypertension; 6 patients with NASH and T2D; 18 patients with NASH and Hypertension; 19 patients with only NASH). Primary endpoints Clinic/infectious/inflammation tests for COVID and Influenza; weight loss during 14 days. Secondary endpoints: fasting blood glucose, HbA1c, blood insulin; systolic/diastolic BP; blood lipids; ALT, AST, chest CT-scan. Results The patients with overweight lost -12,4% from baseline or BMI= -4.2 kg/m2, and patients without overweight lost -9,14% from baseline or BMI= -2.2 kg/m2 (-9.7{+/-}0.7 kg vs. -6.4{+/-}0.6 kg, respectively; P<0.001) at 14-day of the treatment. Weight loss in both groups was due to reduction of fat mass (P<0.0001). Sputum production increased in 1.0-1.5 liter/day on 2-3 days, decreased in 7-9 days. Body temperature normalized in 6-9 days. On 3-5 days, in most patients their urine became turbid/muddy/intensively colored. Urine microscopy showed organic and non-organic salts, and leukocyturia (20-35/sight). White blood cells, lymphocytes, NLR normalized at 14 days (P<0.0001). Total-fibrinogen, C-reactive-protein, and Erythrocyte-sedimentation-rate, ROS normalized at 14-day of treatment (P<0.0001). COVID and Influenza were a negative in >96.3% patients at 14-day. Systolic/diastolic BP decreased (161.3{+/-}1.31/101.6{+/-}0.85 vs. 118.3{+/-}0.46/80.89{+/-}0.66, P<0.0001), glucose and lipids metabolism in patients with T2D (n=26) (P<0.0001); ALT and AST in patients with NASH (n=51) were significantly normalized (from baseline 134.3{+/-}5.4 and 166.5{+/-}5.5 U/L, respectively, and at 14-day to 78.4{+/-}4.2 and 92.4{+/-}4.9 U/L, respectively (P<0.0001)), platelets increased from baseline (186.5{+/-}4.6, x109/L) at 14-day of treatment (238.5{+/-}5.8, x109/L) (P<0.0001), and at 6-week follow-up (278.3{+/-}6.9, x109/L) (P<0.0001). The mean score of chest-CT for the patients (n=44) was 13.12{+/-}0.38 from baseline, and at 14-day the score was 1.72{+/-}0.12 (P<0.0001). ROS level normalized at 14-day treatment and 6-week follow-up from baseline (P<0.0001). The previous antidiabetic, antihypertensive, antiinflammatory and hepatoprotective, and other symptomatic medications were adequately decreased in 2-5 days to completely stopping by 5-8 days treatment. Conclusions The fast weight loss is clinical/laboratory benefit in treatment of patients with COVID-19 and Influenza in comorbidity with T2D, hypertension, and NASH.

Obesity and lipid metabolism disorders determine the risk for development of long COVID syndrome: a cross-sectional study from 50,402 COVID-19 patients.

PURPOSE: Metabolic disorders have been identified as major risk factors for severe acute courses of COVID-19. With decreasing numbers of infections in many countries, the long COVID syndrome (LCS) represents the next major challenge in pandemic management, warranting the precise definition of risk factors for LCS development. METHODS: We identified 50,402 COVID-19 patients in the Disease Analyzer database (IQVIA) featuring data from 1056 general practices in Germany. Multivariate logistic regression analysis was used to identify risk factors for the development of LCS. RESULTS: Of the 50,402 COVID-19 patients included into this analysis, 1,708 (3.4%) were diagnosed with LCS. In a multivariate regression analysis, we identified lipid metabolism disorders (OR 1.46, 95% CI 1.28-1.65, p < 0.001) and obesity (OR 1.25, 95% CI 1.08-1.44, p = 0.003) as strong risk factors for the development of LCS. Besides these metabolic factors, patients' age between 46 and 60 years (compared to age ≤ 30, (OR 1.81 95% CI 1.54-2.13, p < 0.001), female sex (OR 1.33, 95% CI 1.20-1.47, p < 0.001) as well as pre-existing asthma (OR 1.67, 95% CI 1.39-2.00, p < 0.001) and depression (OR 1.27, 95% CI 1.09-1.47, p = < 0.002) in women, and cancer (OR 1.4, 95% CI 1.09-1.95, p = < 0.012) in men were associated with an increased likelihood of developing LCS. CONCLUSION: Lipid metabolism disorders and obesity represent age-independent risk factors for the development of LCS, suggesting that metabolic alterations determine the risk for unfavorable disease courses along all phases of COVID-19.

Mitochondrial dysfunction is associated with lipid metabolism disorder and upregulation of angiotensin-converting enzyme 2.

Thymidine kinase 2 (TK2) deficiency in humans leads to a myopathic form of mitochondrial DNA (mtDNA) deficiency. Here we present a skeletal and cardiac muscle specific TK2 knockout mouse (mTk2 KO). The mice showed dilated hearts and markedly reduced adipose tissue during week 12 to 16. A severe decrease of mtDNA was found only in skeletal muscle and heart tissue in mTk2 KO mice. Expression analysis of key metabolic genes of 16 weeks knockout mice showed significant changes of genes involved in lipid metabolism, with different patterns in heart and skeletal muscle. Our study further suggests that lipoprotein lipase (LPL) from liver supports the metabolism when heart and skeletal muscle were impaired due to mitochondrial dysfunction. The angiotensin-converting enzyme 2 (ACE2), which is involved in glucose homeostasis, was also affected by mtDNA deficiency in our study. Interestingly, both the gene and protein expression of ACE2 were increased in cardiac tissue of mTk2 KO mice. Since ACE2 is a receptor for the SARS-CoV-2 virus, its regulation in relation to mitochondrial function may have important clinical implications.

The Spike protein of SARS-CoV-2 impairs lipid metabolism and increases susceptibility to lipotoxicity: implication for a role of Nrf2 (preprint)

Background/objectives Coronavirus disease 2019 (COVID-19) patients exhibit lipid metabolic alterations, but the mechanism remains unknown. In this study, we aimed to investigate whether the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs lipid metabolism in host cells. Methods A Spike cell line in HEK293 was generated using the pcDNA vector carrying the Spike gene expression cassette. A control cell line was generated using the empty pcDNA vector. Gene expression profiles related to lipid metabolic, autophagic, and ferroptotic pathways were investigated. Palmitic acid (PA)-overload was used to assess lipotoxicity-induced necrosis. Results As compared with controls, the Spike cells showed a significant increase in lipid depositions on cell membranes as well as dysregulation of expression of a panel of molecules involved lipid metabolism, autophagy, and ferroptosis. The Spike cells showed an upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a multifunctional transcriptional factor, in response to PA. Furthermore, the Spike cells exhibited increased necrosis in response to PA-induced lipotoxicity compared to control cells in a time- and dose-dependent manner via ferroptosis, which could be attenuated by the Nrf2 inhibitor trigonelline. Conclusions The Spike protein impairs lipid metabolic and autophagic pathways in host cells, leading to increased susceptibility to lipotoxicity via ferroptosis which can be suppressed by a Nrf2 inhibitor. This data also suggests a central role of Nrf2 in Spike-induced lipid metabolic impairments.

Weakly activated core inflammation pathways were identified as a central signaling mechanism contributing to the chronic neurodegeneration in Alzheimer’s disease (preprint)

Neuro-inflammation signaling has been identified as an important hallmark of Alzheimer’s disease (AD) in addition to amyloid β plaques (Aβ) and neurofibrillary tangles (NFTs). However, our knowledge of neuro-inflammation is very limited; and the core signaling pathways associated with neuro-inflammation are missing. From a novel perspective, i.e., investigating weakly activated molecular signals (rather than the strongly activated molecular signals), in this study, we uncovered the core neuro-inflammation signaling pathways in AD. Our novel hypothesis is that weakly activated neuro-inflammation signaling pathways can cause neuro-degeneration in a chronic process; whereas, strongly activated neuro-inflammation often cause acute disease progression like in COVID-19. Using the two large-scale genomics datasets, i.e., Mayo Clinic (77 control and 81 AD samples) and RosMap (97 control and 260 AD samples), our analysis identified 7 categories of signaling pathways implicated on AD and related to virus infection: immune response, x-core signaling, apoptosis, lipid dysfunctional, biosynthesis and metabolism, and mineral absorption signaling pathways. More interestingly, most of genes in the virus infection, immune response and x-core signaling pathways, are associated with inflammation molecular functions. Specifically, the x-core signaling pathways were defined as a group of 9 signaling proteins: MAPK, Rap1, NF-kappa B, HIF-1, PI3K-Akt, Wnt, TGF-beta, Hippo and TNF, which indicated the core neuro-inflammation signaling pathways responding to the low-level and weakly activated inflammation and hypoxia, and leading to the chronic neuro-degeneration. The core neuro-inflammation signaling pathways can be used as novel therapeutic targets for effective AD treatment and prevention.

The aging transcriptome and cellular landscape of the human lung in relation to SARS-CoV-2 (preprint)

Since the emergence of SARS-CoV-2 in December 2019, Coronavirus Disease-2019 (COVID-19) has rapidly spread across the globe. Epidemiologic studies have demonstrated that age is one of the strongest risk factors influencing the morbidity and mortality of COVID-19. Here, we interrogate the transcriptional features and cellular landscapes of the aging human lung through integrative analysis of bulk and single-cell transcriptomics. By intersecting these age-associated changes with experimental data on host interactions between SARS-CoV-2 or its relative SARS-CoV, we identify several age-associated factors that may contribute to the heightened severity of COVID-19 in older populations. We observed that age-associated gene expression and cell populations are significantly linked to the heightened severity of COVID-19 in older populations. The aging lung is characterized by increased vascular smooth muscle contraction, reduced mitochondrial activity, and decreased lipid metabolism. Lung epithelial cells, macrophages, and Th1 cells decrease in abundance with age, whereas fibroblasts, pericytes and CD4+ Tcm cells increase in abundance with age. Several age-associated genes have functional effects on SARS-CoV replication, and directly interact with the SARS-CoV-2 proteome. Interestingly, age-associated genes are heavily enriched among those induced or suppressed by SARS-CoV-2 infection. These analyses illuminate potential avenues for further studies on the relationship between the aging lung and COVID-19 pathogenesis, which may inform strategies to more effectively treat this disease.