Abstract GLP1 receptor agonist liraglutide has been shown to upregulate ACE2 expressions in several animal studies and thereby mediate strong positive stress response 1 . On the other hand, two in silico studies suggest that valproate downregulates ACE2 and AGTR2 gene expressions 2,3 . In this study, we have evaluated how these two widely used drugs, liraglutide and valproate, change the expression pattern of RAS system genes in the rat lungs. Our results indicate that eight-day treatment with valproate significantly downregulates the gene expression of Agtr2, Mas1 and Agrt1b in the rat lungs. These effects are reversed by co-administration of liraglutide.
Abstract Wolfram syndrome (WS) is a monogenic progressive neurodegenerative disease and is characterized by various neurological symptoms, such as optic nerve atrophy, loss of vision, cognitive decline, memory impairment, and learning difficulties. GLP1 receptor agonist liraglutide and BDNF mimetic 7,8-dihydroxyflavone (7,8-DHF) have had protective effect to visual pathway and to learning and memory in different rat models of neurodegenerative disorders. Although synergistic co-treatment effect has not been reported before and therefore the aim of the current study was to investigate liraglutide, 7,8-DHF and most importantly for the first time their co-treatment effect on degenerative processes in WS rat model. We took 9 months old WS rats and their wild-type (WT) control animals and treated them daily with liraglutide, 7,8-DHF or with the combination of liraglutide and 7,8-DHF up to the age of 12.5 months (n = 47, 5–8 per group). We found that liraglutide, 7,8-DHF and their co-treatment all prevented lateral ventricle enlargement, improved learning in Morris Water maze, reduced neuronal inflammation, delayed the progression of optic nerve atrophy, had remyelinating effect on optic nerve and thereby improved visual acuity in WS rats compared to WT controls. Thus, the use of the liraglutide, 7,8-DHF and their co-treatment could potentially be used as a therapeutic intervention to induce neuroprotection or even neuronal regeneration.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to impose a serious burden on health systems globally. Despite worldwide vaccination, social distancing and wearing masks, the spread of the virus is ongoing. One of the mechanisms by which neutralizing antibodies (NAbs) block virus entry into cells encompasses interaction inhibition between the cell surface receptor angiotensin-converting enzyme 2 (ACE2) and the spike (S) protein of SARS-CoV-2. SARS-CoV-2-specific NAb development can be induced in the blood of cattle. Pregnant cows produce NAbs upon immunization, and antibodies move into the colostrum immediately before calving. Here, we immunized cows with SARS-CoV-2 S1 receptor binding domain (RBD) protein in proper adjuvant solutions, followed by one boost with SARS-CoV-2 trimeric S protein and purified immunoglobulins from colostrum. We demonstrate that this preparation indeed blocks the interaction between the trimeric S protein and ACE2 in different in vitro assays. Moreover, we describe the formulation of purified immunoglobulin preparation into a nasal spray. When administered to human subjects, the formulation persisted on the nasal mucosa for at least 4 hours, as determined by a clinical study. Therefore, we are presenting a solution that shows great potential to serve as a prophylactic agent against SARS-CoV-2 infection as an additional measure to vaccination and wearing masks. Moreover, our technology allows for rapid and versatile adaptation for preparing prophylactic treatments against other diseases using the defined characteristics of antibody movement into the colostrum.
Mutations in WFS1 gene cause autosomal recessive disorder Wolfram syndrome (WS). One of the first hallmarks of WS is diabetes mellitus. Impairment of glucose metabolism is also present in Wfs1‐deficient mice. While homozygous mutations in Wfs1 cause WS, GWAS studies have shown that heterozygous Wfs1 mutation carriers have increased risk for development of type 2 diabetes. Therefore, in this study, first and second phase insulin secretion was investigated, using glucose tolerance test, muscarinic receptor agonist carbachol and ELISA. Intracellular calcium measurements in single beta‐cells were performed, using cell permeant calcium indicator Fluo‐4 AM. Results of study show that impaired insulin secretion can be managed by evoking insulin release via muscarinic pathway, using carbachol. Although there seems not to be notable differences in the second phase insulin secretion between wild‐type and heterozygous littermates, first phase secretion in heterozygous animals is delayed and this deficit is possibly related to the delayed calcium response in beta‐cells. Altogether, these results show that Wfs1 mutations cause impairment of insulin release in heterozygous animals, the first definite hallmark of type 2 diabetes.
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In the large GWAS studies, NEGR1 gene has been one of the most significant gene loci for body mass phenotype. The purpose of the current study was to clarify the role of NEGR1 in the maintenance of systemic metabolism, including glucose homeostasis, by using both male and female Negr1−/− mice receiving a standard or high fat diet (HFD). We found that 6 weeks of HFD leads to higher levels of blood glucose in Negr1−/− mice. In the glucose tolerance test, HFD induced phenotype difference only in male mice; Negr1−/− male mice displayed altered glucose tolerance, accompanied with upregulation of circulatory branched-chain amino acids (BCAA). The general metabolomic profile indicates that Negr1−/− mice are biased towards glyconeogenesis, fatty acid synthesis, and higher protein catabolism, all of which are amplified by HFD. Negr1 deficiency appears to induce alterations in the efficiency of energy storage; reduced food intake could be an attempt to compensate for the metabolic challenge present in the Negr1−/− males, particularly during the HFD exposure. Our results suggest that the presence of functional Negr1 allows male mice to consume more HFD and prevents the development of glucose intolerance, liver steatosis, and excessive weight gain.
