Alterations in microbiota of patients with COVID-19: implications for therapeutic interventions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently caused a global pandemic, resulting in more than 702 million people being infected and over 6.9 million deaths. Patients with coronavirus disease (COVID-19) may suffer from diarrhea, sleep disorders, depression, and even cognitive impairment, which is associated with long COVID during recovery. However, there remains no consensus on effective treatment methods. Studies have found that patients with COVID-19 have alterations in microbiota and their metabolites, particularly in the gut, which may be involved in the regulation of immune responses. Consumption of probiotics may alleviate the discomfort caused by inflammation and oxidative stress. However, the pathophysiological process underlying the alleviation of COVID-19-related symptoms and complications by targeting the microbiota remains unclear. In the current study, we summarize the latest research and evidence on the COVID-19 pandemic, together with symptoms of SARS-CoV-2 and vaccine use, with a focus on the relationship between microbiota alterations and COVID-19-related symptoms and vaccine use. This work provides evidence that probiotic-based interventions may improve COVID-19 symptoms by regulating gut microbiota and systemic immunity. Probiotics may also be used as adjuvants to improve vaccine efficacy.

Mitochondrial energy metabolism in diabetic cardiomyopathy: Physiological adaption, pathogenesis, and therapeutic targets.

ABSTRACT: Diabetic cardiomyopathy is defined as abnormal structure and function of the heart in the setting of diabetes, which could eventually develop heart failure and leads to the death of the patients. Although blood glucose control and medications to heart failure show beneficial effects on this disease, there is currently no specific treatment for diabetic cardiomyopathy. Over the past few decades, the pathophysiology of diabetic cardiomyopathy has been extensively studied, and an increasing number of studies pinpoint that impaired mitochondrial energy metabolism is a key mediator as well as a therapeutic target. In this review, we summarize the latest research in the field of diabetic cardiomyopathy, focusing on mitochondrial damage and adaptation, altered energy substrates, and potential therapeutic targets. A better understanding of the mitochondrial energy metabolism in diabetic cardiomyopathy may help to gain more mechanistic insights and generate more precise mitochondria-oriented therapies to treat this disease.

SEPSIS LEADS TO IMPAIRED MITOCHONDRIAL CALCIUM UPTAKE AND SKELETAL MUSCLE WEAKNESS BY REDUCING THE MICU1:MCU PROTEIN RATIO.

ABSTRACT: Purpose: Intensive care unit-acquired weakness (ICUAW) is a severe neuromuscular complication that frequently occurs in patients with sepsis. The precise molecular pathophysiology of mitochondrial calcium uptake 1 (MICU1) and mitochondrial calcium uniporter (MCU) in ICUAW has not been fully elucidated. Here, we speculate that ICUAW is associated with MICU1:MCU protein ratio-mediated mitochondrial calcium ([Ca 2+ ] m ) uptake dysfunction. Methods: Cecal ligation and perforation (CLP) was performed on C57BL/6J mice to induce sepsis. Sham-operated animals were used as controls. Lipopolysaccharide (LPS) (5 µg/mL) was used to induce inflammation in differentiated C2C12 myoblasts. Compound muscle action potential (CMAP) was detected using a biological signal acquisition system. Grip strength was measured using a grip-strength meter. Skeletal muscle inflammatory factors were detected using ELISA kits. The cross-sectional area (CSA) of the tibialis anterior (TA) muscle was detected by hematoxylin and eosin staining. Cytosolic calcium ([Ca 2+ ] c ) levels were measured using Fluo-4 AM. Adeno-associated virus (AAV) was injected into TA muscles for 4 weeks to overexpress MICU1 prophylactically. A lentivirus was used to infect C2C12 cells to increase MICU1 expression prophylactically. Findings: The results suggest that sepsis induces [Ca 2+ ] m uptake disorder by reducing the MICU1:MCU protein ratio, resulting in skeletal muscle weakness and muscle fiber atrophy. However, MICU1 prophylactic overexpression reversed these effects by increasing the MICU1:MCU protein ratio. Conclusions: ICUAW is associated with impaired [Ca 2+ ] m uptake caused by a decreased MICU1:MCU protein ratio. MICU1 overexpression improves sepsis-induced skeletal muscle weakness and atrophy by ameliorating the [Ca 2+ ] m uptake disorder.

Research progress on perioperative blood-brain barrier damage and its potential mechanism.

The blood-brain barrier (BBB) is an important barrier separating the central nervous system from the periphery. The composition includes endothelial cells, pericytes, astrocytes, synapses and tight junction proteins. During the perioperative period, anesthesia and surgical operations are also a kind of stress to the body, which may be accompanied by blood-brain barrier damage and brain metabolism dysfunction. Perioperative blood-brain barrier destruction is closely associated with cognitive impairment and may increase the risk of postoperative mortality, which is not conducive to enhanced recovery after surgery. However, the potential pathophysiological process and specific mechanism of blood-brain barrier damage during the perioperative period have not been fully elucidated. Changes in blood-brain barrier permeability, inflammation and neuroinflammation, oxidative stress, ferroptosis, and intestinal dysbiosis may be involved in blood-brain barrier damage. We aim to review the research progress of perioperative blood-brain barrier damage and its potential adverse effects and potential molecular mechanisms, and provide ideas for the study of homeostasis maintenance of brain function and precision anesthesia.

PINK1/Parkin-mediated mitophagy in mechanical ventilation-induced diaphragmatic dysfunction.

BACKGROUND: Mechanical ventilation (MV) often leads to ventilation-induced diaphragm dysfunction (VIDD). Although the development of this disorder had been linked to oxidative stress, mitochondrial energy deficiency, autophagy activation, and apoptosis in the diaphragm, it remains unclear whether the activation of mitophagy can induce VIDD. With our research, our endeavor is to uncover whether PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy affects the MV-caused diaphragmatic dysfunction. METHODS: Sprague-Dawley rats were subjected to MV treatment for 6 h (MV-6h), 12 h (MV-12h), or 24 h (MV-24h). Post MV, the diaphragm muscle compound action potential (CMAP) and cross-sectional areas (CSAs) of the diaphragm of these rats were measured. The levels of proteins of interest were examined to assess muscle health, mitochondrial dynamics, and mitophagy in the diaphragm. The co-localization of PINK1 with the mitochondrial protein marker tom20 was examined, as well as transmission electron microscopy analysis to detect changes in diaphragm mitochondrial ultrastructure. RESULTS: MV-12h and MV-24h treatments resulted in a decrease in CSA of diaphragm and CMAP amplitude. In addition, the expressions of F-box (MFAbx), muscle-specific ring finger 1 (MURF1), PINK1, and p62 were elevated in rats treated with MV for 12 h and 24 h, while mfn2 expression was reduced. Rats following MV-24h treatment displayed an increase in mitochondrial dynamic protein (Drp1) and Parkin expression and microtubule-associated protein 1 light chain 3/1 (LC3II/I) ratio. Moreover, decreased SOD and GSH activity and membrane potential were observed after MV-12h and MV-24h treatment, while H2O2 activity increased after MV-24h treatment. In addition, a strong co-localization between PINK1 and tom20 was identified. CONCLUSION: These results reveal that MV leads to various changes in mitochondrial dynamics and significantly increases the mitophagy levels, which subsequently cause the variation in diaphragmatic function and muscle atrophy, indicating that mitophagy could be one of the possible mechanisms by which MV induces diaphragmatic dysfunction.The reviews of this paper are available via the supplemental material section.

Exposure to isomers of per- and polyfluoroalkyl substances increases the risk of diabetes and impairs glucose-homeostasis in Chinese adults: Isomers of C8 health project.

Per- and polyfluoroalkyl substances (PFAS) exposure has been linked to diabetes, but evidence on the association of isomers of PFAS with type 2 diabetes (T2D) remains scant. This population based cross-sectional study aimed to investigate associations between serum PFAS isomers, glucose-homeostasis markers and T2D, adjusted for multiple potential confounders. We used data from "Isomers of C8 Health Project in China" from July 2015 to October 2016. A total of 10 PFAS including isomers of PFOS and PFOA were measured in serum of 1045 Chinese adults. Fasting blood glucose, fasting insulin, homeostasis model of insulin (HOMA-IR) and beta cell function (HOMA-ß) were considered as markers of glucose-homeostasis. We found significant positive associations between serum PFAS isomers and glucose-homeostasis markers, namely, fasting blood glucose, fasting insulin and HOMA-IR. Per log-unit increase in branched (br)-PFOS concentration was associated with increased fasting blood glucose (ß = 0.25, 95% CI: 0.18, 0.33), fasting insulin (ß = 2.19, 95% CI: 1.44, 2.93) and HOMA-IR (ß = 0.69, 95% CI: 0.50, 0.89). As compared to br-PFOS, linear (n)-PFOS and -PFOA showed lesser significant associations with glucose-homeostasis makers. Further, exposure to all PFAS including isomeric PFOS, PFOA and PFHxS increased the risk of T2D with br-PFOS exhibiting the highest risk (OR = 5.41, 95% CI: 3.68-7.96). The associations were stronger among women than men. In conclusion, chronic exposure to PFAS isomers was associated with impaired glucose-homeostasis and may increase the prevalence of T2D in Chinese adults. Given the ubiquity of PFAS in the environment and the public health burden of T2D, future studies are warranted to corroborate the findings.

Sepsis Activates the TLR4/MyD88 Pathway in Schwann Cells to Promote Infiltration of Macrophages, Thereby Impeding Neuromuscular Function.

INTRODUCTION: Sepsis is a kind of maladjustment response to bacterial infection and activation of coagulation, which can induce neuromuscular dysfunction. However, there is scarce of experimental evidence about the relationship between Schwann cells (SCs) and sepsis in neuromuscular dysfunction. We therefore set out to identify the potential role of SCs in sepsis-induced neuromuscular dysfunction and to explore the underlying molecular mechanism. METHODS: Primary SCs were isolated from the left hind limb sciatic nerve of sepsis mice, which was constructed by cecal ligation and puncture. Then, the SCs were infected with adenovirus encoding toll-like receptor 4 (TLR4), MyD88, or IL-1R (with lipopolysaccharide stimulation), and the Raw 264.7 macrophages were injected with adenovirus with CCR2 silencing (with mMCP-1 stimulation). Further investigation of the interleukin 1 beta (IL-1ß) and macrophage cationic peptide 1 (MCP-1) expressions, we followed reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay techniques, the F4/80 and Ki67 expressions was observed by immunofluorescence staining, while the expressions of CCR2, FAK/p-FAK, nuclear factor-κB (NFκB)/p-NFκB, and ERK1/2/p-ERK1/2 were determined by Western blot analysis. Last, but not the least, the cell migration ability and cell proliferation ability were detected by Transwell assay and Flow cytometry respectively. RESULTS: Our results showed that in sepsis mice, the TLR4/MyD88/ERK pathway was activated in SCs, which triggered the cells to secrete IL-1ß and MCP-1. The secreted IL-1ß bound with IL-1ß receptor on the surface of SCs, thereby activating the IL-1ß/IL-1R/MyD88/ERK pathway and further promoting the secretion of MCP-1 by SCs. MCP-1 was found to bind to CCR2 on the surface of Raw264.7 macrophages to activate the TLR4/MyD88/ERK pathway which caused the inhibition of neuromuscular function. CONCLUSION: Sepsis significantly promotes the infiltration of macrophages by activating the TLR4/MyD88 pathway in SCs, thereby impeding neuromuscular function. Consistently, our study provides a novel concept in the area of neuromuscular dysfunction therapeutics following sepsis.

Associations between serum isomers of perfluoroalkyl acids and metabolic syndrome in adults: Isomers of C8 Health Project in China.

BACKGROUND: Exposure to perfluoroalkyl acids (PFAAs) is known to be associated with metabolic disorders. However, whether PFAAs isomers are associated with metabolic syndrome (MetS) still remains unknown. OBJECTIVES: To explore the associations between serum PFAAs isomers and MetS. METHODS: We recruited 1,501 adults from a cross-sectional study, the "Isomers of C8 Health Project in China" to investigate the associations between PFAAs isomers and MetS. A total of 20 PFAAs including the isomers of PFOS and PFOA were detected. Logistic regression models and restricted cubic spline models were used to evaluate the relationship of serum PFAAs isomers exposure with MetS and its components as well after adjusting for covariates. RESULTS: The MetS prevalence in our study was 43.0%. The serum levels of both PFOS and PFOA isomers were higher in participants with MetS than that with non-MetS (p < 0.05). We found positive associations for per natural log-transformed ng/mL of branched perfluorooctane sulfonate (br-PFOS) (odds ratio (OR) = 1.18, 95% confidence interval (CI): 1.01, 1.38)) linear perfluoronanoic acid (n-PFOA) (OR = 1.35, 95% CI: 1.16, 1.58) and perfluoro-6-methylpheptanoic acid (6 m-PFOA) (OR = 1.32, 95% CI: 1.11, 1.57) with higher odds of MetS after covariates adjustment, while null association was observed for linear isomers of PFOS (OR = 1.09, 95% CI: 0.94, 1.25). We found a nonlinear dose-response relationship with a "threshold" effect in serum br-PFOS isomers with MetS, in which the odds of MetS increased quickly with increasing serum br-PFOS isomers under low exposure (p for nonlinearity = 0.030). CONCLUSION: We report new evidence of associations between PFAAs isomers and MetS and the nonlinearity of dose-response relationship with br-PFOS isomers. Our findings indicate that more attention is needed to pay on the nonlinearity of dose-response relationship when investigate the association of PFAAs isomers with human health.

Correlation Between Plasma CircRNA-089763 and Postoperative Cognitive Dysfunction in Elderly Patients Undergoing Non-cardiac Surgery.

In our previous experiment, we found that there were abnormal levels of circRNA-089763 in the plasma exosomes of patients with postoperative cognitive dysfunction (POCD) after cardiac surgery. Therefore, the aim of this study was to further investigate the relationship between plasma circRNA-089763 level and POCD in elderly patients after non-cardiac surgery. A prospective cohort study was conducted to select elderly patients undergoing elective non-cardiac surgery. A total of 72 patients were enrolled in this study, and cognitive functions were assessed 1 day before and 3 days after surgery by a series of neuropsychological measurements. Next, patients were divided into POCD and non-POCD (NPOCD) groups according to the Z score method. Blood was collected the day before and 3 days after surgery, and the plasma circRNA-089763 level was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Then, the difference and correlation in plasma circRNA-089763 levels between the POCD and NPOCD groups were analyzed. On the third day after surgery, the incidence of POCD was 30.56%. The relative level of circRNA-089763 in the POCD group was 2.41 times higher than that in the NPOCD group (t = 4.711, p < 0.001), patients in POCD group had higher age (t = 5.971, p < 0.001), higher American Society of Anesthesiologists classification (χ2 = 14.726, p < 0.001), less years of education (t = 2.449, p = 0.017), more intraoperative blood loss (t = 3.196, p = 0.002), and higher visual analog scale (VAS) scores (t = 10.45, p < 0.001). The binary logistic regression analysis showed that the circRNA-089763 level, age, and intraoperative blood loss were independently associated with POCD (OR: 2.75, 95% CI: 1.261-5.999, p = 0.011; OR: 1.32, 95% CI: 1.114-1.565, p = 0.001; OR: 1.017, 95% CI: 1.004-1.03, p = 0.011). These results demonstrated that the circRNA-089763 plasma level was related to POCD after non-cardiac surgery in elderly patients.

Alternatives of perfluoroalkyl acids and hepatitis B virus surface antibody in adults: Isomers of C8 Health Project in China.

Previous epidemiological and experimental studies have shown that legacy perfluoroalkyl acids (PFAAs) are immunotoxic. However, whether the immunosuppressive effects in PFAA alternatives which recently have been widely detected in the environment are unknown. To address this knowledge gap, we investigated the relationship of serum legacy PFAAs and PFAA alternatives with the antibody of hepatitis B virus in adults. We recruited 605 participants from a cross-sectional study, the Isomer of C8 Health Project in China. We measured two representative legacy PFAAs (perfluorooctane sulfonate, PFOS and perfluorooctanoic acid, PFOA), and three PFAA alternatives (two chlorinated polyfluorinated ether sulfonic acids, Cl-PFESAs and perfluorobutanoic acid, PFBA) in serum using ultra-performance liquid chromatograph-tandem mass spectrometry (UPLC-MS/MS). We applied linear and logistic regression models to analyze associations between serum PFAAs and hepatitis B surface antibody (HBsAb) with multivariable adjustments. We found negative associations between serum PFAAs concentrations and HBsAb. Lower serum HBsAb levels (log mIU/mL) were observed for each log-unit increase in linear PFOS (ß = -0.31, 95% confidential interval: 0.84, -0.18), 6:2 PFESA (ß = -0.81, 95% CI: 1.20, -0.42), 8:2 PFESA (ß = -0.29, 95% CI: 0.43, -0.14) and PFBA (ß = -0.18, 95% CI: 0.28, -0.08). The association between PFAAs and HBsAb seronegative seemed to be higher for 6:2 PFESA (odds ratio = 3.32, 95% CI: 2.16, 5.10) than its predecessors, linear PFOS (OR = 1.96, 95% CI: 1.37, 2.81) and branched PFOS isomers (OR = 1.64, 95% CI: 1.05, 2.56). We report new evidence that exposure to PFAA alternatives are associated with lower HBsAb in adults. This association seems to be stronger in 6:2 PFESA than PFOS. Our results suggest that more studies are needed to clarify the potential toxicity of PFAA alternatives in human which will facilitate better chemical regulations for PFAAs.