The Potential Pharmacological Effects of Natural Product Withaferin A in Cancer: Opportunities and Challenges for Clinical Translation.

Cancer is one of the biggest health concerns with a complex pathophysiology. Currently, available chemotherapeutic drugs are showing deleterious side effects, and tumors often show resistance to treatment. Hence, extensive research is required to develop new treatment strategies to fight against cancer. Natural resources from plants are at the forefront of hunting novel drugs to treat various types of cancers. Withaferin A (WA) is a naturally occurring withanolide, a biologically active component obtained from the plant Ashwagandha. Various in vitro and in vivo oncological studies have reported that Withaferin A (WA) has shown protection from cancer. WA shows its activity by inhibiting the growth and proliferation of malignant cells, apoptosis, and inhibiting angiogenesis, metastasis, and cancer stem cells (CSCs). In addition, WA also showed chemo- and radio-sensitizing properties. Besides the beneficiary pharmacological activities of WA, a few aspects like pharmacokinetic properties, safety, and toxicity studies are still lacking, hindering this potent natural product from entering clinical development. In this review, we have summarized the various pharmacological mechanisms shown by WA in in vitro and in vivo cancer studies and the challenges that must be overcome for this potential natural product's clinical translation to be effective.

Emerging In Vitro and In Vivo Models: Hope for the Better Understanding of Cancer Progression and Treatment.

Various cancer models have been developed to aid the understanding of the underlying mechanisms of tumor development and evaluate the effectiveness of various anticancer drugs in preclinical studies. These models accurately reproduce the critical stages of tumor initiation and development to mimic the tumor microenvironment better. Using these models for target validation, tumor response evaluation, resistance modeling, and toxicity comprehension can significantly enhance the drug development process. Herein, various in vivo or animal models are presented, typically consisting of several mice and in vitro models ranging in complexity from transwell models to spheroids and CRISPR-Cas9 technologies. While in vitro models have been used for decades and dominate the early stages of drug development, they are still limited primary to simplistic tests based on testing on a single cell type cultivated in Petri dishes. Recent advancements in developing new cancer therapies necessitate the generation of complicated animal models that accurately mimic the tumor's complexity and microenvironment. Mice make effective tumor models as they are affordable, have a short reproductive cycle, exhibit rapid tumor growth, and are simple to manipulate genetically. Human cancer mouse models are crucial to understanding the neoplastic process and basic and clinical research improvements. The following review summarizes different in vitro and in vivo metastasis models, their advantages and disadvantages, and their ability to serve as a model for cancer research.

DNase based therapeutic approaches for the treatment of NETosis related inflammatory diseases.

Neutrophils are the primary host innate immune cells defending against pathogens. One proposed mechanism by which neutrophils limit pathogen transmission is NETosis, which includes releasing the nuclear content into the cytosol by forming pores in the plasma membrane. The extrusion of cellular deoxyribonucleic acid (DNA) results in neutrophil extracellular traps (NETs) composed of nuclear DNA associated with histones and granule proteins. NETosis is driven by the enzyme PAD-4 (Peptidylarginine deiminase-4), which converts arginine into citrulline, leading to decondensation of chromatin, separation of DNA, and eventual extrusion. DNase is responsible for the breakdown of NETs. On the one hand, the release of DNase may interfere with the antibacterial effects of NETs; further, DNase may protect tissues from self-destruction caused by the increased release of NET under septic conditions. NETs in physiological quantities are expected to have a role in anti-infectious innate immune responses. In contrast, abnormally high concentrations of NETs in the body that are not adequately cleared by DNases can damage tissues and cause inflammation. Through several novel approaches, it is now possible to avoid the adverse effects caused by the continued release of NETs into the extracellular environment. In this review we have highlighted the basic mechanisms of NETosis, its significance in the pathogenesis of various inflammatory disorders, and the role of DNase enzyme with a focus on the possible function of nanotechnology in its management.