Cancer is a major cause of death, affecting human life in both developed and developing countries. Numerous antitumor agents exist but their toxicity and low efficacy limits their utility. Furthermore, the complex pathophysiological mechanisms of cancer, serious side effects and poor prognosis restrict the administration of available cancer therapies. Thus, developing novel therapeutic agents are required towards a simultaneous targeting of major dysregulated signaling mediators in cancer etiology, while possessing lower side effects. In this line, the plant kingdom is introduced as a rich source of active phytochemicals. The secondary metabolites produced by plants could potentially regulate several dysregulated pathways in cancer. Among the secondary metabolites, flavonoids are hopeful phytochemicals with established biological activities and minimal side effects. Flavonoids inhibit B-cell lymphoma 2 (Bcl-2) via the p53 signaling pathway, which is a significant apoptotic target in many cancer types, hence suppressing a major dysregulated pathway in cancer. To date, there have been no studies reported which extensively highlight the role of flavonoids and especially the different classes of flavonoids in the modulation of Bcl-2 in the P53 signaling pathway. Herein, we discuss the modulation of Bcl-2 in the p53 signaling pathway by different classes of flavonoids and highlight different mechanisms through which this modulation can occur. This study will provide a rationale for the use of flavonoids against different cancers paving a new mechanistic-based approach to cancer therapy.

Leishmania tropica is a vector-borne parasitic protozoa that is the leading cause of leishmaniasis throughout the global tropics and subtropics. L. tropica is a multidrug-resistant parasite with a diverse set of serological, biochemical, and genomic features. There are currently no particular vaccines available to combat leishmaniasis. The present study prioritized potential vaccine candidate proteins of L. tropica using subtractive proteomics and vaccinomics approaches. These vaccine candidate proteins were downstream analyzed to predict B- and T-cell epitopes based on high antigenicity, non-allergenic, and non-toxic characteristics. The top-ranked overlapping MHC-I, MHC-II, and linear B-cell epitopes were prioritized for model vaccine designing. The lead epitopes were linked together by suitable linker sequences to design multi-epitope constructs. Immunogenic adjuvant sequences were incorporated at the N-terminus of the model vaccine constructs to enhance their immunological potential. Among different combinations of constructs, four vaccine designs were selected based on their physicochemical and immunological features. The tertiary structure models of the designed vaccine constructs were predicted and verified. The molecular docking and molecular dynamic (MD) simulation analyses indicated that the vaccine design V1 demonstrated robust and stable molecular interactions with toll-like receptor 4 (TLR4). The top-ranked vaccine construct model-IV demonstrated significant expressive capability in the E. coli expression system during in-silico restriction cloning analysis. The results of the present study are intriguing; nevertheless, experimental bioassays are required to validate the efficacy of the predicted model chimeric vaccine.

Lumpy skin disease is a fatal emerging disease of cattle, which has started to gain extensive attention due to its rapid incursions across the globe. The disease epidemic causes economic loss and cattle morbidity. Currently, there are no specific treatments and safe vaccines against the lumpy skin disease virus (LSDV) to halt the spread of the disease. The current study uses genome-scan vaccinomics analyses to prioritize promiscuous vaccine candidate proteins of the LSDV. These proteins were subjected to top-ranked B- and T-cell epitope prediction based on their antigenicity, allergenicity, and toxicity values. The shortlisted epitopes were connected using appropriate linkers and adjuvant sequences to design multi-epitope vaccine constructs. Three vaccine constructs were prioritized based on their immunological and physicochemical properties. The model constructs were back-translated to nucleotide sequences and codons were optimized. The Kozak sequence with a start codon along with MITD, tPA, Goblin 5′, 3′ UTRs, and a poly(A) tail sequences were added to design a stable and highly immunogenic mRNA vaccine. Molecular docking followed by MD simulation analysis predicted significant binding affinity and stability of LSDV-V2 construct within bovine immune receptors and predicted it to be the top-ranked candidate to stimulate the humeral and cellular immunogenic responses. Furthermore, in silico restriction cloning predicted feasible gene expression of the LSDV-V2 construct in a bacterial expression vector. It could prove worthwhile to validate the predicted vaccine models experimentally and clinically against LSDV.