This comprehensive overview of the historical milestones in cell culture underscores key breakthroughs that have shaped the field over time. It begins with Wilhelm Roux’s seminal experiments in the 1880s, followed by the pioneering efforts of Ross Granville Harrison, who initiated groundbreaking experiments that fundamentally shaped the landscape of cell culture in the early 20th century. Carrel’s influential contributions, notably the immortalization of chicken heart cells, have marked a significant advancement in cell culture techniques. Subsequently, Johannes Holtfreter, Aron Moscona, and Joseph Leighton introduced methodological innovations in three-dimensional (3D) cell culture, initiated by Alexis Carrel, laying the groundwork for future consolidation and expansion of the use of 3D cell culture in different areas of biomedical sciences. The advent of induced pluripotent stem cells by Takahashi and Yamanaka in 2006 was revolutionary, enabling the reprogramming of differentiated cells into a pluripotent state. Since then, recent innovations have included spheroids, organoids, and organ-on-a-chip technologies, aiming to mimic the structure and function of tissues and organs in vitro, pushing the boundaries of biological modeling and disease understanding. In this review, we overview the history of cell culture shedding light on the main discoveries, pitfalls and hurdles that were overcome during the transition from 2D to 3D cell culture techniques. Finally, we discussed the future directions for cell culture research that may accelerate the development of more effective and personalized treatments.

One of the biggest challenges of public health worldwide is reducing the number of events and deaths related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The angiotensinconverting enzyme 2 (ACE-2), a carboxypeptidase that degrades angiotensin II into angiotensin 1-7, has been identified as a potent receptor for SARS-CoV-2. In the last decades, ACE inhibition has assumed a central role in reducing cardiovascular and renal events. However, with the advent of COVID-19, attention has been turned to ACE-2 as a possible target to reduce virus binding to different human cells. This review aims to discuss recent developments related to the medicinal properties of natural compounds as ACE/ACE-2 inhibitors, which should be highlighted in the future development of studies looking for modulators in SARS-CoV-2 infection. Data show that bioactive compounds isolated from several natural products act by inhibiting ACE/ACE-2, which changes the entire axis of this system. Of the compounds addressed in this review, 7 phenolic compounds, including quercetin, curcumin, naringenin, luteolin, hesperidin, mangiferin, and gallic acid showed binding affinity with molecular ACE-2 target in silico, and 1, esculetin, decreased ACE-2 expression in vivo. Regarding terpenoids and alkaloids, nimbin, withaferin A, andrographolide, zingiberene and, berberine, piperine and thebaine, respectively, showed a binding affinity with molecular ACE-2 target in silico. These findings reinforce the need for future preclinical and clinical studies on these compounds and specific inhibitory effects on ACE-2 of all the other compounds described herein only as nonspecific ACE inhibitors. It is important to mention that some natural compounds such as magnolol, resveratrol, rosmarinic acid, tanshinone IIA, and nicotine have also demonstrated the potential to increase the activity or expression of ACE-2, and could therefore aggravate SARS-CoV-2 infection.