Editorial: Brief research reports in experimental pharmacology and drug discovery: 2022
Tahsin Hassan, Aamina Yousuf, Naseer A. Kutchy · Frontiers in Pharmacology · 2023
According to Brooks et al., article, the angiotensin-converting enzyme 2 (ACE2) is an established receptor and entry point for both SARSCoV-1 and the novel SARS-CoV-2 coronavirus. The spike proteins on the viral envelope bind the ACE2 receptor, and the virus replicates efficiently in cells expressing ACE2. Given the widespread abundance of ACE2 in tissue epithelial and endothelial cells like lungs, intestines, kidneys and brain, the role of ACE2 as the entry site for SARS-CoV-2, there has been much speculation regarding whether ACE inhibitors and/or angiotensin receptor blockers (ARBs) may alter ACE2 tissue abundance and thereby change the risk of transmission or development of severe complications. However, it is unclear whether ACE1 inhibitors (e.g., lisinopril) or angiotensin receptor blockers (e.g., losartan) alter tissue ACE2 expression. Brooks et al., sought to determine whether lisinopril or losartan, as monotherapies or in combination, changes tissue levels of ACE2 in healthy male and female mice. They used 8 weeks old, 40 male and 40 female mice treated for 21days with drinking water containing lisinopril, losartan, their combination or no drug (vehicle control). On day 21, 40 animals were euthanized for collection of plasma and tissues, while the others transitioned to standard drinking water for an additional 21 days to assess whether drug-induced changes in ACE2 resolve after drug cessation.Specimens collected underwent different procedures for measurement of ACE2 protein index, measurement of Ace2 gene expression, immunohistochemistry of tissue sections and measurement of plasma renin activity. It was intresting to see that the ACE2 protein index (which persisted 21 days after discontinuation of drug ) and the Ace2/Gapdh transcript differed significantly by tissue, it was highest in the small intestine, followed by the kidney (kidney ACE2 levels were higher in males vs females ), lung, and brain . Lisinopril treatment raised ACE2 protein index in tissues but the combination of lisinopril and losartan did not. Inturn lisinopril and losartan combination treatment suppressed Ace2 gene expression in tissue.The article of Roquini et al., described that helminthic infections affect huge portion of human population worlwide, majority being poor population living in economically suseptibel places. One among such parasitic diseases is human angiostrongyliasis, caused by nematode Angiostrongylus cantonensis . The Roquini et al., group designed a study aimed to evaluate the antiparasitic and molecular properties of the major available anthelmintic drugs against A. cantonensis in vitro. It was revealed that these drugs showed concentration and time dependent effect on the larvae which was measured by larval motility assay, currently the method of choice to evaluate drug sensitivity of different nematode species. The group found that Ivermectin caused larval immotility in first 2 hours and when concentration was increased, arrest was almost instantaneous. Salamectin, moxidectin, levamisole caused larval immotility in 6,12 and 2 hours respectively. However when parasites were exposed to pyrantel pamoate or albendazole, with a maximum loss of spontaneous movement within 2 and 24h, respectively. It was also noted that mebendazole and fenbendazole lacked activity against A. cantonensis. Their findings contribute to the existing knowledge on potential drug options and can aid in the development of targeted therapies for this parasitic disease.The research article by D'Ercole et al., described the serlexin a recombinant human H2 relaxin. Relaxin, a natural peptide hormone has been found having anti-fibrotic activity, hence analogues if developed successfully could be useful in catering different pathological conditions including cardiovascular diseases. In view of the above group tried to design some conformationaly variable peptides over receptor binding domain of human H1 relaxin. Peptides, some linear and some stapled by triazole bonds were created and their effects were studied in cells expressing relaxin receptors. Despite the favourable premises, none of the tested H1 peptides, either linear or stapled, revealed a substantial affinity to RXFP1 nor displayed any RLX-like biological effects. Group showed significant cAMP elevation and ERK1/2 phosphorylation in RXFP1-expressing cells however B7-33 a linear H2 relaxin analogue produced effects similar to serlexin suggesting difference in B chains of H1 and H2 relaxins. In addition, their study in turn revealed that triazole conformational changes have a negative impact on H1 relaxin activity. Overall, their findings provide valuable insights into the design of relaxin agonists and highlight the importance of preserving the unique properties of H1 relaxin when developing synthetic analogues. This knowledge can guide future research and aid in the development of more effective therapeutic agents targeting the relaxin system.In the research article of Zubkov et al., they detailed about the relationship between acute stressful situations to depression, anxiety disorders and post-traumatic stress disorder (PTSD) in humans. As, there is little data on possible treatment options to alleviate acute stress symptoms and prevent harmful long-term effects. This is why developing efficacious treatment is an urgent task. Group analyzed the effects of different substances like melatonin, neuropeptide Y (NPY), orexin, oxytocin, and clomipramine towards acute stressful situations. Acute stress was induced in rats after anhedonia test and forced swimming test. Control and tests groups were selected and effects of different substances were observed by serum corticosteroid measurements and sucrose preference index. It was noted that clomapramine, NPY and oxytocin had a positive effect on acute stressful behaviour as all of them decreased immobilisation time in experimental animals, however no such response was seen with melatonin amd orexin. It was very intresting to see that none other than single dose of NPY decreased the levels of corticosteroids post stress. This study further, highlighted the potential of intranasal NPY as a promising option for addressing specific aspects of acute stress, while emphasizing the need for additional investigations to validate its effectiveness and broaden our understanding of its therapeutic applications. This Wang et al., research investigated the immunomodulatory effects and underlying mechanisms of bioactive peptides derived from Xinjiang fermented camel milk. The study utilizes network pharmacology and molecular docking approaches to explore the potential interactions between the bioactive peptides and immune-related targets.The group showed that several bioactive peptides derived from Xinjiang fermented camel milk exhibit potential immunomodulatory effects, network pharmacology analysis revealed specific targets and pathways involved in immune regulation.In addition, molecular docking simulations confirmed the binding interactions between the bioactive peptides and immune-related targets having the potential to modulate the immune system through direct interactions with key immune molecules.Their findings contribute to our understanding of the potential therapeutic applications of these peptides in immune-related disorders and highlight their potential as natural immunomodulators. Further experimental studies are warranted to validate these predictions and explore the clinical implications of Xinjiang fermented camel milk-derived bioactive peptides.The Saran et al., study investigated the impact of mTOR (mammalian target of rapamycin) inhibitors on the function of a protein called sodium taurocholate cotransporting polypeptide (NTCP). NTCP is responsible for transporting bile acids into liver cells, and its proper functioning is crucial for maintaining liver health. The group used liver cell lines and exposed them to different mTOR inhibitors commonly used in clinical settings. They assessed the impact of these inhibitors on NTCP expression, function, and intracellular localization. The group showed that mTOR inhibitors could influence NTCP expression levels, leading to a decrease in its abundance. Furthermore, the inhibitors affected NTCP localization within the liver cells, potentially impairing its ability to transport bile acids effectively, suggesting mTOR inhibitors negative impact on NTCP function as therapeutic agents, particularly in liver -related conditions. Further research is needed to better understand the underlying mechanisms and assess the clinical implications of these findings. This editorial summarizes the various articles on the advancements in experimental pharmacology and drug discovery. We believe that the findings presented in the research topic would help in understaning the novel drug targets, innovative drug delivery systems, drug screening methods, pharmacological studies, and advancements in understanding disease mechanisms. We appreciate all contributors to this research article, including the authors, reviewers, and the editorial team, Frontiers in Pharamacology.