Glycyrrhizin: An alternative drug for the treatment of COVID-19 infection and the associated respiratory syndrome?

With unknown etiology and limited treatment options, neonatal hypoxic-ischemic brain damage (HIBD) remains a major cause of mortality in newborns. Ferroptosis, a recently discovered type of cell death triggered by lipid peroxidation, is closely associated with HIBD. High-mobility group box 1 (HMGB1), a molecule associated with inflammation damage, can induce neuronal death in HIBD. However, it remains unknown whether HMGB1 contributes to neuronal ferroptosis in patients with HIBD. Herein, glycyrrhizin (GL), an HMGB1 inhibitor, was used to investigate the relationship between ferroptosis and HMGB1. RAS-selective lethal 3(RSL3), a ferroptosis agonist, was administered to further confirm the changes in the signaling pathway between HMGB1 and ferroptosis. Western blot analysis revealed that GL markedly suppressed the expression of HMGB1 and increased the level of GPX4 in the context of HIBD. We observed changes in neuronal ultrastructure via transmission electron microscopy to further confirm the occurrence of ferroptosis. Real-time PCR indicated that GL inhibited the expression of ferroptosis-related genes and inflammatory factors. Immunofluorescence and immunohistochemistry staining confirmed GL inhibition of neuronal damage and ferroptosis in HIBD associated with GPX4 and ROS. GL not only inhibited ferroptosis induced by RSL3 and oxygen-glucose deprivation in vitro but also inhibited ferroptosis induced by HIBD in vivo. More importantly, GL may improve oxidative stress imbalance and mitochondrial damage, alleviate the downstream production of inflammatory factors, and ultimately reduce ferroptosis and damage to cortical neurons following HIBD via the HMGB1/GPX4 pathway. In conclusion, we showed for the first time that GL could suppress the occurrence of neuronal ferroptosis and reduce neuronal loss in HIBD via the HMGB1/GPX4 pathway. These findings highlight the potential of HMGB1 signaling antagonists to treat neuronal damage by suppressing ferroptosis, provide new and unique insights into GL as a neuroprotective agent, and suggest new prevention and treatment strategies for HIBD.

https://downloads.hindawi.com/journals/omcl/2022/8438528.pdf

Glycyrrhizin Attenuates Hypoxic-Ischemic Brain Damage by Inhibiting Ferroptosis and Neuroinflammation in Neonatal Rats via the HMGB1/GPX4 Pathway

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a fatal and fast-spreading viral infection. To date, the number of COVID-19 patients worldwide has crossed over six million with over three hundred and seventy thousand deaths (according to the data from World Health Organization; updated on 2 June 2020). Although COVID-19 can be rapidly diagnosed, efficient clinical treatment of COVID-19 remains unavailable, resulting in high fatality. Some clinical trials have identified vitamin C (VC) as a potent compound pneumonia management. In addition, glycyrrhizic acid (GA) is clinically as an anti-inflammatory medicine against pneumonia-induced inflammatory stress. We hypothesized that the combination of VC and GA is a potential option for treating COVID-19. METHODS: The aim of this study was to determine pharmacological targets and molecular mechanisms of VC + GA treatment for COVID-19, using bioinformational network pharmacology. RESULTS: We uncovered optimal targets, biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of VC + GA against COVID-19. Our findings suggested that combinatorial VC and GA treatment for COVID-19 was associated with elevation of immunity and suppression of inflammatory stress, including activation of the T cell receptor signaling pathway, regulation of Fc gamma R-mediated phagocytosis, ErbB signaling pathway and vascular endothelial growth factor signaling pathway. We also identified 17 core targets of VC + GA, which suggest as antimicrobial function. CONCLUSIONS: For the first time, our study uncovered the pharmacological mechanism underlying combined VC and GA treatment for COVID-19. These results should benefit efforts to address the most pressing problem currently facing the world.

/pdf/integrative-pharmacological-mechanism-of-vitamin-c-combined-2m14sk1g81.pdf

Integrative pharmacological mechanism of vitamin C combined with glycyrrhizic acid against COVID-19: findings of bioinformatics analyses.

Background Bacillus coagulans has been widely used in food and feed additives, which can effectively inhibit the growth of harmful bacteria, improve intestinal microecological environment, promote intestinal development, and enhance intestinal function, but its probiotic mechanism is not completely clear. Aim The aim of this study is to discuss the effect and mechanism of Bacillus coagulans TL3 on oxidative stress and inflammatory injury of cecum induced by LPS. Method The Wistar rats were randomly divided into four groups, each containing 7 animals. Two groups were fed with basic diet (the LPS and control, or CON, groups). The remaining groups were fed with basic diet and either a intragastric administration high or low dose of B. coagulans, forming the HBC and LBC groups, respectively. The rats were fed normally for two weeks. On the 15th day, those in the LPS, HBC, and LBC groups were injected intraperitoneally with LPS—the rats in the CON group were injected intraperitoneally with physiological saline. After 4 hours, all the rats were anesthetized and sacrificed by cervical dislocation, allowing samples to be collected and labeled. The inflammatory and antioxidant cytokine changes of the cecum were measured, and the pathological changes of the cecum were observed, determining the cecal antioxidant, inflammation, and changes in tight junction proteins and analysis of intestinal flora. Result The results show that LPS induces oxidative damage in the cecal tissues of rats and the occurrence of inflammation could also be detected in the serum. The Western blot results detected changes in the NF-κB- and Nrf2-related signaling pathways and TJ-related protein levels. Compared with the LPS group, the HBC group showed significantly downregulated levels of expression of Nrf2, NQO1, HO-1, GPX, and GCLC. The expression of TLR4, MYD88, NF-κB, IL-6, TNFα, and IL-1β was also significantly downregulated, while the expression of other proteins (ZO-1, occludin, and claudin-1) increased significantly. Bacillus coagulans TL3 was also found to increase the relative abundance of the beneficial bacterium Akkermansia muciniphila in the intestines. There is also a significant reduction in the number of harmful bacteria Escherichia coli and Shigella (Enterobacteriaceae). Conclusion Bacillus coagulans TL3 regulates the TLR4/MyD88/NF-κB and Nrf2 signaling pathways in the cecal tissue of rats, protects the intestine from inflammation and oxidative damage caused by LPS, and inhibits the reproduction of harmful bacteria and promotes beneficial effects by regulating the intestinal flora bacteria grow, thereby enhancing intestinal immunity.

https://downloads.hindawi.com/journals/omcl/2022/5463290.pdf

Bacillus coagulans TL3 Inhibits LPS-Induced Caecum Damage in Rat by Regulating the TLR4/MyD88/NF-κB and Nrf2 Signal Pathways and Modulating Intestinal Microflora

Florfenicol, as a replacement for chloramphenicol, can tightly bind to the A site of the 23S rRNA in the 50S subunit of the 70S ribosome, thereby inhibiting protein synthesis and bacterial proliferation. Due to the widespread use in aquaculture and veterinary medicine, florfenicol has been detected in the aquatic environment worldwide. Concerns over the effects and health risks of florfenicol on target and non-target organisms have been raised in recent years. Although the ecotoxicity of florfenicol has been widely reported in different species, no attempt has been made to review the current research progress of florfenicol toxicity, hormesis, and its health risks posed to biota. In this study, a comprehensive literature review was conducted to summarize the effects of florfenicol on various organisms including bacteria, algae, invertebrates, fishes, birds, and mammals. The generation of antibiotic resistant bacteria and spread antibiotic resistant genes, closely associated with hormesis, are pressing environmental health issues stemming from overuse or misuse of antibiotics including florfenicol. Exposure to florfenicol at μg/L–mg/L induced hormetic effects in several algal species, and chromoplasts might serve as a target for florfenicol-induced effects; however, the underlying molecular mechanisms are completely lacking. Exposure to high levels (mg/L) of florfenicol modified the xenobiotic metabolism, antioxidant systems, and energy metabolism, resulting in hepatotoxicity, renal toxicity, immunotoxicity, developmental toxicity, reproductive toxicity, obesogenic effects, and hormesis in different animal species. Mitochondria and the associated energy metabolism are suggested to be the primary targets for florfenicol toxicity in animals, albeit further in-depth investigations are warranted for revealing the long-term effects (e.g., whole-life-cycle impacts, multigenerational effects) of florfenicol, especially at environmental levels, and the underlying mechanisms. This will facilitate the evaluation of potential hormetic effects and construction of adverse outcome pathways for environmental risk assessment and regulation of florfenicol. 

A review on the antibiotic florfenicol: Occurrence, environmental fate, effects, and health risks.

Florfenicol (FFC), a widely used drug for chicken diseases, can aggravate lipopolysaccharide (LPS) damage to the liver For this condition, natural or synthetic products displaying strong antioxidant capacity are expected to prevent LPS/FFC from inducing liver injury, so in our study, the compound ammonium glycyrrhizin (CAG) is used as the protective drug to decrease the injury to liver The research aims to illustrate the underlying mechanism of combining LPS with FFC-induced liver injury and the protective role of CAG by using primary chicken hepatocytes as an in vitro model The results show that LPS/FFC induced cell apoptosis and CAG protected hepatocytes from injury The permeability of the cell membrane is elevated by LPS/FFC, leading to the efflux of enzymes (ALT, AST) Flow cytometry analysis indicates that LPS/FFC treatment increased the apoptosis rate significantly Furthermore, with the up-regulation of apoptosis genes bax, cytochrome c and the down-regulation of bcl-2, caspase-3 and caspase-9 are activated at the gene level LPS/FFC-induced mitochondrial damage is accompanied by a significant decrease in mitochondrial membrane potential (MMP) and severe mitochondrial damage However, CAG improves the situation for the purpose of protecting the liver In conclusion, it is speculated that LPS/FFC induces severe liver injury through apoptosis and the CAG protects hepatocytes from injury via the mitochondria-mediated apoptosis pathway

https://www.mdpi.com/1420-3049/23/9/2378/pdf

Compound Ammonium Glycyrrhizin Protects Hepatocytes from Injury Induced by Lipopolysaccharide/Florfenicol through a Mitochondrial Pathway.

Compound ammonium glycyrrhizin (CAG) protects hepatocytes from injury induced by lipopolysaccharide (LPS)/florfenicol (FFC) through a mitochondrial pathway. On this basis, the research was aimed to investigate whether CAG protects hepatocytes from injury induced by LPS/FFC through oxidative stress and the MAPK pathway. For liver injury induced by LPS/FFC, not only CAG can protect hepatocytes and prevent membrane permeability from being increased, but also the activities of ALT and AST were decreased significantly by CAG. Flow cytometry analysis indicated that the apoptosis rate (35.65 ± 2.48%) of LPS/FFC group was significantly higher than that of the control group (8.60 ± 0.32%). CAG (concentration of 0.01 μg/mL, 0.1 μg/mL, 1 μg/mL) significantly decreased the apoptosis rate (23.69 ± 0.54%, 14.92 ± 2.45% and 9.47 ± 1.28%) for the liver injury induced by LPS/FFC. The activities of SOD and GSH were increased with the increased concentration of CAG, and the activity of MDA was decreased with the increased concentration of CAG. All the mRNA and proteins expression levels were increased by LPS/FFC-induced liver injury which associated with the MAPK pathway, and those of the CAG group were decreased with the increased concentration of CAG. And the change of caspase-3 activity was consistent with that of proteins and mRNA. It is suggested that LPS/FFC can induce liver injury through apoptosis and the CAG can protect hepatocytes from injury through the MAPK pathway and oxidative stress.

Compound ammonium glycyrrhizin protects hepatocytes from injury induced by lipopolysaccharide/florfenicol through oxidative stress and a MAPK pathway.

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Compound Ammonium Glycyrrhizin Protects Hepatocytes from Injury Induced by Lipopolysaccharide/Florfenicol through a Mitochondrial Pathway.

Compound ammonium glycyrrhizin protects hepatocytes from injury induced by lipopolysaccharide/florfenicol through oxidative stress and a MAPK pathway.