ABSTRACT
Tuberculosis (TB) is a leading cause of death from a single infectious agent, Mycobacterium tuberculosis (Mtb). Although progress has been made in TB control, still about 10 million people worldwide develop TB annually and 1.5 million die of the disease. The rapid emergence of aggressive, drug-resistant strains and latent infections have caused TB to remain a global health challenge. TB treatments are lengthy and their side effects lead to poor patient compliance, which in turn has contributed to the drug resistance and exacerbated the TB epidemic. The relatively low output of newly approved antibiotics has spurred research interest toward alternative antibacterial molecules such as silver nanoparticles (AgNPs). In the present study, we use the natural biopolymer alginate to serve as a stabilizer and/or reductant to green synthesize AgNPs, which improves their biocompatibility and avoids the use of toxic chemicals. The average size of the alginate-capped AgNPs (ALG-AgNPs) was characterized as nanoscale, and the particles were round in shape. Drug susceptibility tests showed that these ALG-AgNPs are effective against both drug-resistant Mtb strains and dormant Mtb. A bacterial cell-wall permeability assay showed that the anti-mycobacterial action of ALG-AgNPs is mediated through an increase in cell-wall permeability. Notably, the anti-mycobacterial potential of ALG-AgNPs was effective in both zebrafish and mouse TB animal models in vivo. These results suggest that ALG-AgNPs could provide a new therapeutic option to overcome the difficulties of current TB treatments.
ABSTRACT
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus which caused a global respiratory disease pandemic beginning in December 2019. Understanding the pathogenesis of infection and the immune responses in a SARS-CoV-2-infected animal model is urgently needed for vaccine development. METHODS: Syrian hamsters (Mesocricetus auratus) were intranasally inoculated with 105, 5×105, and 106 TCID50 of SARS-CoV-2 per animal and studied for up to 14 days. Body weight, viral load and real-time PCR amplification of the SARS-CoV-2 N gene were measured. On days 3, 6 and 9, lung, blood, liver, pancreas, heart, kidney, and bone marrow were harvested and processed for pathology, viral load, and cytokine expression. RESULTS: Body weight loss, increased viral load, immune cell infiltration, upregulated cytokine expression, viral RNA, SARS-CoV-2 nucleoprotein, and mucus were detected in the lungs, particularly on day 3 post-infection. Extremely high expression of the pro-inflammatory cytokines MIP-1 and RANTES was detected in lung tissue, as was high expression of IL-1ß, IL-6, IL-12, and PD-L1. The glutamic oxalacetic transaminase/glutamic pyruvic transaminase (GOT/GPT) ratio in blood was significantly increased at 6 days post-infection, and plasma amylase and lipase levels were also elevated in infected hamsters. CONCLUSION: Our results provide new information on immunological cytokines and biological parameters related to the pathogenesis and immune response profile in the Syrian hamster model of SARS-CoV-2 infection.
ABSTRACT
Sorbic acid (SA) is one of the most commonly used food preservatives worldwide. Despite SA having no hepatotoxicity at legal dosages, its effect on hepatic lipid metabolism is still unclear. We investigated the effect of SA on hepatic lipid metabolism and its mechanism of action in C57BL/6 mice. Daily treatment with SA (1 g/kg in diet) for 4 weeks did not alter the body weight, organ weight, and blood lipids in mice. However, hepatic lipid accumulation, particularly that of triglycerides, fatty acids, and glycerol, but not cholesteryl ester and free cholesterol, was increased with SA treatment. Mechanistically, SA decreased the expression of proteins related to de novo fatty acid lipogenesis, fatty acid internalization, and very low-density lipoprotein (VLDL) secretion-related pathways, including sterol regulatory element-binding proteins, acetyl-coA carboxylase, fatty acid synthase, liver fatty acid-binding protein, CD36, and apolipoprotein E. In contrast, SA increased the expression of diacylglycerol O-acyltransferase 2, the key enzyme for triacylglycerol synthesis. Moreover, SA downregulated the protein expression of autophagy-related and ß-oxidation-related pathways, the two major metabolic pathways for lipid metabolism, including LC-3, beclin-1, autophagy related protein 5 (ATG-5) and ATG-7, acyl-CoA synthetase long chain family member 1, carnitine palmitoyltransferase Iα, peroxisome proliferator-activated receptor α (PPARα), PPARγ, and PPARγ coactivator-1. Collectively, SA deregulates de novo lipogenesis and fatty acid internalization, VLDL secretion, autophagy, and ß-oxidation in the liver, leading to impaired lipid clearance and ultimately, resulting in lipid accumulation in the liver.
