Mitochondria and Mitochondrial DNA: Key Elements in the Pathogenesis and Exacerbation of the Inflammatory State Caused by COVID-19.

Background and Objectives. The importance of mitochondria in inflammatory pathologies, besides providing energy, is associated with the release of mitochondrial damage products, such as mitochondrial DNA (mt-DNA), which may perpetuate inflammation. In this review, we aimed to show the importance of mitochondria, as organelles that produce energy and intervene in multiple pathologies, focusing mainly in COVID-19 and using multiple molecular mechanisms that allow for the replication and maintenance of the viral genome, leading to the exacerbation and spread of the inflammatory response. The evidence suggests that mitochondria are implicated in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which forms double-membrane vesicles and evades detection by the cell defense system. These mitochondrion-hijacking vesicles damage the integrity of the mitochondrion's membrane, releasing mt-DNA into circulation and triggering the activation of innate immunity, which may contribute to an exacerbation of the pro-inflammatory state. Conclusions. While mitochondrial dysfunction in COVID-19 continues to be studied, the use of mt-DNA as an indicator of prognosis and severity is a potential area yet to be explored.

Hyperglycemia and Angiotensin-Converting Enzyme 2 in Pulmonary Function in the Context of SARS-CoV-2 Infection.

Since the appearance of the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 in China, diabetes mellitus (DM) and hyperglycemia in patients infected with SARS-CoV, represent independent predictors of mortality. Therefore, metabolic control has played a major role in the prognosis of these patients. In the current pandemic of coronavirus disease 19 (COVID-19), multiple studies have shown that DM is one of the main comorbidities associated with COVID-19 and higher risk of complications and death. The incidence and prevalence of COVID-19 complications and death related with hyperglycemia in patients with or without DM are high. There are many hypotheses related with worse prognosis and death related to COVID-19 and/or hyperglycemia. However, the information about the interplay between hyperglycemia and angiotensin-converting enzyme 2 (ACE2), the critical receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in the context of SARS-CoV-2 infection, is almost null, but there is enough information to consider the possible participation of hyperglycemia in the glycation of this protein, unleashing a pool of reactions leading to acute respiratory distress syndrome and death in patients with COVID-19. In this document we investigated the current evidence related with ACE2 as a key element within the pathophysiological mechanism related with hyperglycemia extrapolating it to context of SARS-CoV-2 infection and its relationship with worse prognosis and death for COVID-19.

Matrix metalloproteinase multiplex screening identifies increased MMP-2 urine concentrations in women predicted to develop preeclampsia.

BACKGROUND: Preeclampsia, a pregnancy disorder characterized by hypertension and proteinuria, represents the leading cause of fetal and maternal morbidity and mortality in developing countries. The identification of novel and accurate biomarkers that are predictive of preeclampsia is necessary to improve the prognosis of patients with preeclampsia. OBJECTIVE: The objective of this study is to evaluate the usefulness of nine urinary metalloproteinases to predict the risk of preeclampsia development. METHODS: MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12 and MMP-13 were analyzed in urine (early-pregnancy) from 17 women predicted to develop preeclampsia and 48 controls using the Bio-Plex Pro-Human MMP panel (Bio-Rad, Hercules, CA). RESULTS: Urinary MMP-2 showed differences between groups which allowed us to calculate an increased risk for PE development of up to 20 times among the study population. CONCLUSION: Increased urinary concentration of MMP-2 at 12 and 16 weeks of gestation predicted an increased risk of developing preeclampsia in the study population.

Circulating levels of specific members of chromosome 19 microRNA cluster are associated with preeclampsia development.

PURPOSE: To perform serum microRNA expression profiling to identify members of chromosome 19 miRNA cluster involved in preeclampsia development. METHODS: Serum chromosome 19 miRNA cluster microRNA expression profiling was evaluated at 12, 16, and 20 gestational weeks and at the time of preeclampsia diagnosis, in women who developed preeclampsia (WWD-PE; n = 16) and controls (n = 18) using TaqMan low density array plates. RESULTS: A total of 51 chromosome 19 microRNA cluster members were evaluated. The circulating hsa-miRs 512-3p, 518f-3p, 520c-3p, and 520d-3p, were differentially expressed between groups (P < 0.05). Compared with controls, serum levels of hsa-miR-518f-3p at 20 GW were useful for identifying WWD-Mild-PE (P = 0.035) and WWD-Severe-PE (P = 0.007). CONCLUSIONS: Serum hsa-miRs 512-3p, 518f-3p, 520c-3p, and 520d-3p, are differentially expressed between WWD-PE and controls and their role in the development of preeclampsia should be investigated further.

Doppler ultrasound evaluation in preeclampsia.

BACKGROUND: Worldwide preeclampsia (PE) is the leading cause of maternal death and affects 5 to 8% of pregnant women. PE is characterized by elevated blood pressure and proteinuria. Doppler Ultrasound (US) evaluation has been considered a useful method for prediction of PE; however, there is no complete data about the most frequently altered US parameters in the pathology. The aim of this study was to evaluate the uterine, umbilical, and the middle cerebral arteries using Doppler US parameters [resistance index (RI), pulsatility index (PI), notch (N), systolic peak (SP) and their combinations] in pregnant women, in order to make a global evaluation of hemodynamic repercussion caused by the established PE. RESULTS: A total of 102 pregnant Mexican women (65 PE women and 37 normotensive women) were recruited in a cases and controls study. Blood velocity waveforms from uterine, umbilical, and middle cerebral arteries, in pregnancies from 24 to 37 weeks of gestation were recorded by trans-abdominal examination with a Toshiba Ultrasound Power Vision 6000 SSA-370A, with a 3.5 MHz convex transducer. Abnormal general Doppler US profile showed a positive association with PE [odds ratio (OR) = 2.93, 95% confidence interval (CI) = 1.2 - 7.3, P = 0.021)], and a specificity and predictive positive value of 89.2% and 88.6%, respectively. Other parameters like N presence, RI and PI of umbilical artery, as well as the PI of middle cerebral artery, showed differences between groups (P values < 0.05). CONCLUSION: General Doppler US result, as well as N from uterine vessel, RI from umbilical artery, and PI from umbilical and middle cerebral arteries in their individual form, may be considered as tools to determine hemodynamic repercussion caused by PE.

Antiviral mode of action of bovine dialyzable leukocyte extract against human immunodeficiency virus type 1 infection.

BACKGROUND: Bovine dialyzable leukocyte extract (bDLE) is derived from immune leukocytes obtained from bovine spleen. DLE has demonstrated to reduce transcription of Human Immunodeficiency Virus Type 1 (HIV-1) and inactivate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Therefore, we decided to clarify the mode of antiviral action of bDLE on the inhibition of HIV-1 infection through a panel of antiviral assays. RESULTS: The cytotoxicity, HIV-1 inhibition activity, residual infectivity of bDLE in HIV-1, time of addition experiments, fusion inhibition of bDLE for fusogenic cells and the duration of cell protection even after the removal of bDLE were all assessed in order to discover more about the mode of the antiviral action.HIV-1 infectivity was inhibited by bDLE at doses that were not cytotoxic for HeLa-CD4-LTR-ß-gal cells. Pretreatment of HIV-1 with bDLE did not decrease the infectivity of these viral particles. Cell-based fusion assays helped to determine if bDLE could inhibit fusion of Env cells against CD4 cells by membrane fusion and this cell-based fusion was inhibited only when CD4 cells were treated with bDLE. Infection was inhibited in 80% compared with the positive (without EDL) at all viral life cycle stages in the time of addition experiments when bDLE was added at different time points. Finally, a cell-protection assay against HIV-1 infection by bDLE was performed after treating host cells with bDLE for 30 minutes and then removing them from treatment. From 0 to 7 hours after the bDLE was completely removed from the extracellular compartment, HIV-1 was then added to the host cells. The bDLE was found to protect the cells from HIV-1 infection, an effect that was retained for several hours. CONCLUSIONS: bDLE acted as an antiviral compound and prevented host cell infection by HIV-1 at all viral life cycle stages. These cell protection effects lingered for hours after the bDLE was removed. Interestingly, bDLE inhibited fusion of fusogenic cells by acting only on CD4 cells. bDLE had no virucidal effect, but could retain its antiviral effect on target cells after it was removed from the extracellular compartment, protecting the cells from infection for hours.bDLE, which has no reported side effects or toxicity in clinical trials, should therefore be further studied to determine its potential use as a therapeutic agent in HIV-1 infection therapy, in combination with known antiretrovirals.