Background & Purpose: The constitutive androstane receptor (CAR) belongs to nuclear receptor superfamily. The administration of CAR agonist TCPOBOP to mice leads to hepatomegaly but the mechanism is unclear. Yes-associated protein (YAP) is a downstream factor of Hippo signaling pathway, which is a potent regulator of organ size and tissue homeostasis. This study examined the role of YAP in CAR-promoted hepatomegaly and liver regeneration. Experimental Approach: The effect of CAR on liver enlargement and liver regeneration was evaluated in wild-type (WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy (PHx) mice. KI67 and CTNNB1 staining were performed to evaluate the proliferation response and hepatocytes size. The protein levels of YAP and its downstream targets were measured and Co-IP was conducted to explore the protein-protein interaction between CAR and YAP. Key Results: The results suggested TCPOBOP increases the liver/body weight ratio in WT mice and PHx mice. Hepatocytes enlargement occurred around the central vein area, while the number of KI67+ cells increased around portal vein area. The translocation of YAP was induced and its downstream targets were upregulated after CAR activation via TCPOBOP. Co-IP results revealed a potential protein-protein interaction between CAR and YAP. However, CAR-induced hepatomegaly was still observed in Yap-/- mice. Conclusion and Implications: CAR activation promotes hepatomegaly and liver regeneration in part by inducing nuclear translocation of YAP and interaction with YAP pathway, which provides new insights for understanding the physiological functions of CAR, and suggests the potential for manipulation of liver size.
BACKGROUND AND PURPOSE Neutrophil overactivation is crucial in the pathogenesis of acute lung injury (ALI). Bletinib (3,3′-dihydroxy-2′,6′-bis(p-hydroxybenzyl)-5-methoxybibenzyl), a natural bibenzyl first extracted from Bletilla striata in 1983, has anti-inflammatory, antibacterial, and antimitotic potential. In this study, we evaluated the therapeutic effects of Bletinib in human neutrophilic inflammation and lipopolysaccharide (LPS)-mediated ALI. EXPERIMENTAL APPROACH We assessed integrin expression, superoxide anion production, degranulation, neutrophil extracellular trap (NET) formation, and adhesion in activated human neutrophils through flow cytometry, spectrophotometry, and immunofluorescence microscopy. Moreover, phosphorylation of Src family kinases (SFKs) and downstream proteins was evaluated through immunoblotting. Finally, a murine LPS-induced ALI model was used to investigate the potential therapeutic effects of Bletinib treatment. KEY RESULTS In activated human neutrophils, Bletinib reduced degranulation, respiratory burst, NET formation, adhesion, migration, and integrin expression; suppressed the enzymatic activity of SFKs, including Src, Lyn, Fgr, and Hck; and inhibited the phosphorylation of SFKs as well as Vav and Bruton’s tyrosine kinase (Btk). In our mice with ALI, the pulmonary sections demonstrated considerable amelioration of prominent inflammatory changes, such as haemorrhage, pulmonary oedema, and neutrophil infiltration, after Bletinib treatment. CONCLUSION AND IMPLICATIONS This is the first study to provide evidence that Bletinib regulates neutrophilic inflammation by inhibiting the SFKs–Btk–Vav pathway and that Bletinib ameliorates LPS-induced ALI in mice. Further biochemical optimisation of Bletinib may be a promising strategy for the development of novel therapeutics for inflammatory diseases.
Background The covid 19 positive patient who is subject to a hyperinflammatory condition associated with lung injury with the development of pneumonia is hospitalized in the intensive care unit. Before resolving and overcoming the “cytokine storm”, with overexpression of pro-inflammatory interleukins (IL-, Il-6), this patient will be intubated for more than 48 hours and therefore needs adequate nutrition. Experimental approach Malnutrition can lead to sarcopenia with a decrease in lean body mass and worsening of the inflammatory state underway. In addition, severe debilitation, if not corrected with adequate nutrition, can greatly lengthen rehabilitation times with prolonged hospitalization, increased costs and reduced turn over already in crisis due to the health emergency caused by coronavirus. Key Results The aim of this study is to focus attention on the nutritional importance that must be provided in case of covid 19 together with pharmacological treatments to lower the number of circulating proinflammatory cytokines. Conclusions Oral, enteral and parenteral nutrition should always be carried out according to the patient’s condition and, in the case of a hyperinflammatory patient, such as the one affected by covid 19, it has been shown that the supplementation of amino acids helps to lower the inflammatory state and promotes normal recovery physiological. Keywords: amino acids, nutrition, covid, glutamine, hyperinflammatory, sarcopenia, cytokine.
Background and purpose: Coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome- Coronavirus 2 (SARS-CoV2) is a highly contagious disease that has infected more than 200,000 patients and led to more than 10000 deaths in 166 countries in less than four months. New medications are needed to combat this disease. Since the process of discovery, development and approval of new drugs is long, old drugs can be repurposed for treatment of COVID-19. Oseltamivir is used for management of COVID-19 and Influenza A. Rimantadine is an alternative drug to oseltamivir for management of influenza A. Therefore, it is possible that rimantadine can be used for management of COVID-19 as an alternative to oseltamivir. The purpose of the study is to verify the potential of rimantadine as a drug for COVID-19 Methods: The SARS-CoV2 nucleocapsid was downloaded from the Protein databank and the chemical structure of rimantadine downloaded from Pubchem. Molecular docking of the nucleocapsid as the receptor and rimantadine as the ligand was done using avogadro and chimera software. Prediction of pharmacokinetic properties was done using SWISSADME website while the toxicity properties predicted using the ProTox server. Results: The interactions between rimantadine and the SARS-CoV2 nucleocapsid involved conventional hydrogen bonding with threonine & asparagine; attractive charge interaction with aspartate and Pi-alkyl interaction with tryptophan. Rimantadine has high gastrointestinal activity, very few drug-drug interactions and is relatively safe. Conclusion: Rimantadine binds to the SARS-CoV2 nucleocapsid and can thus be used for management of COVID-19. Keywords: Rimantadine, COVID-19, SARS-CoV2, Oseltamivir
Abstract Background and Purpose: The 2019 novel coronavirus (COVID-19) has been spread out since December 2019 from China to 29 countries. No effective treatment is currently available, although the combination regimen of the antiretroviral drugs– lopinavir/ritonavir (LPV/r), with other antiviral drugs have been using, but the evidences are limited. A recent in vitro study showed that chloroquine could inhibit COVID-19 to cells, and enhance antiviral efficacy. This study aimed to predict the optimal dose regimens of LPV/r, and chloroquine in combination as a potential treatment of COVID-19 infection, using the physiologically-based pharmacokinetic (PBPK) modelling. Experimental approach: The whole PBPK models were constructed. The predicted plasma drug concentrations were compared with the published clinical data. The validated models were used to predict optimal dosage regimens of LPV/r, and chloroquine co-administration. The optimal dose regimen was determined based on the efficacy, and toxicity reported in the published data. Key Results: The average errors of the predicted values were within 30% of the observed data. The proposed optimal dosage regimen is the once-daily dose of 800/200 mg LPV/r co-administered with chloroquine at a loading dose of 1,000 mg, followed by twice-daily dose of 500 mg for 8 doses on the second day, and the twice-daily dose of 400 mg for 18 doses. Conclusion and Implications: PBPK modelling successfully predicted pharmacokinetic profiles within an acceptable range of errors. The study provides a focus for clinical studies to confirm the efficacy of the proposed dosage regimen as a novel treatment for COVID-19 infection.
Background and Purpose: Minimal hepatic encephalopathy (MHE) is implicated in the impairment of memory function. Fibroblast growth factor-2 (FGF2) is involved in modulating synaptic and neuronal formation. Experimental Approach: The aim of this study is to examined the impacts of FGF2 on MHE pathology. Our study addressed whether FGF2 could trigger neuregulin 1 (NRG1) release to ameliorate synaptic impairment in MHE rats and in primary cultured neurons. Key Results: The results showed the decreased FGF2 expression in MHE brains. After treatment with FGF2, secreted neuregulin 1 (NRG1) and ErbB4 were increased, and the interaction of the 2 proteins was enhanced. Additionally, treatment with FGF2 or NRG1 induced synaptic formation, with increase in the activity of synapse and the density of dendritic spine, through Sirt1. NRG1 signaling was prevented by administration of FGF2, which acts through the FGFR1 in MHE rats. Finally, intracerebroventricular injection with FGF2 or NRG1 mitigated the impairment of synaptogenesis. Conclusions and Implications: The data suggest that FGF2 may be a promising latent therapeutic reagent for MHE pathogenesis.
There is not any medicine during the emergency of 2019-nCov has been an outbreak and we have already found antiviral phytomedicine Chinese elderberry will be inhibition of 2019-nCoV.This commentary used to be presented in June of 2013 at the first international symposium for the elderberry, the conference, held in the USA, many scientists were surprised to learn of the 9 native species of elderberry in China. This paper aims to publish our comment on the elderberry, as, since our initial presentation in 2013, no English literature references are present in China. Most Chinese horticulturists and farmers consider the elderberry a wild plant. It is regarded as a plant of little value due to its abundance and ease of harvest. This article contains details of the Sambucus species groups, including the botanical names, Chinese common names, geographic distributions, economic uses and full descriptions of the elderberry. In southwest China, where the climate is mildly warm, there are 2 species of elderberries; one, Sambucus adnata, is termed the “blood-red herb-elderberry” by local residents as the roots, rhizomes, and branches exude red-juice when broken. The second, named S. javanica or S. chinensis, is commonly called the “herb-elderberry”. In northeast China where the climate is cold, there are 7 species of elderberry, however, most scientists recognize only 2 main species: Sambucus. williamsii, commonly called the “woody-elderberry”, and Sambucus sibirica, commonly called the “Siberian woody-elderberry”. The other 5 species of elderberry in northern-east of China.