Kannan Ramalingam

Breast cancer is a multi-stage disease that unfolds with the utmost complexity and heterogeneity of various cell types; thus, the unraveling of its molecular mechanisms is required to develop improved therapeutic strategies. This review tries to dissect the complex landscape related to changes in gene expression control dynamics in breast cancer. The large area of gene mutations is discussed, pointing out their important part in the pathogenesis of the disease. The article further explains the heterogeneity of tumors, unwinding the hormone receptor pathways responsible for the variability in disease presentation. We also conducted a thorough examination of the tumor microenvironment, uncovering the complex involvement of immune cells in both protecting against and promoting tumor growth. This analysis uncovered tactics employed by tumors to evade the immune system. All in all, this review has strong implications for the understanding of molecular mechanisms and subsequently provides a background for current improvements in targeted therapy. The use of illustrative figures aids in enhancing the understanding of the complex molecular mechanisms underlying breast cancer. Graphical Abstract

Chimeric antigen receptor (CAR) technology has revolutionized cancer therapy, yet its full potential remains untapped within the innate immune system. Beyond CAR-T cells, a growing cadre of MHC-independent effectors, including NK cells, macrophages, γδ T cells and the emerging innate-like T cells such as invariant NKT (iNKT) and mucosal-associated invariant T (MAIT) cells, offer complementary mechanisms for tumor recognition and elimination. These platforms combine facile, off-the-shelf manufacture from healthy donors with low graft-versus-host disease risk and a reduced propensity for severe cytokine release syndromes. Mechanistically, they span missing-self and antibody-dependent cytotoxicity (NK), phagocytosis and cross-presentation (macrophages), stress-ligand recognition (γδ T cells), and rapid, tissue-tropic, TCR-mediated responses to conserved lipid and metabolite antigens (iNKT via CD1d; MAIT via MR1). CAR engineering of these cells leverages their innate rapidity, innate/adaptive cross-talk, and distinctive homing to confront heterogeneous and immune-evasive tumors. Here, we synthesize recent advances in cell design, dual/split CARs, switchable control systems, armored payloads and synthetic-biology circuits, and evaluate translational progress, manufacturing bottlenecks, and regulatory considerations. We argue that integrating innate and innate-like programs with precision CAR architectures will yield a new generation of universal, resilient cellular therapeutics with broadened antigen reach, improved safety profiles, and enhanced capacity to overcome the suppressive tumor microenvironment.

Objective Though a number of bioavailable formulations of curcuminoids have been reported and available commercially as nutraceuticals for brain health, systematic informations on their blood-brain-barrier permeability and brain tissue distribution have not been reported. The present study was aimed to investigate the brain regional pharmacokinetics of curcuminoids following both single dose and repeated dose oral administration of a self-emulsifying food-grade formulation of curcuminoids using fenugreek galactomannan hydrogel scaffold as 'curcumagalactomannosides' (CGM), and its influence on cognitive functions in comparison with unformulated natural curcuminoids (NC) in Wistar rats. Methods CGM was given to animals in single dose (100 mg curcuminoids/kg b. wt.) and repeated dose (100 mg curcuminoids/kg b. wt. for 28 days) and the concentration of total curcuminoids at various parts of brain was evaluated at different time points using Ultra-performance liquid chromatography/electrospray ionization triple quadruple tandem mass spectroscopy (UPLC-ESI-MS/MS) system. Another set of animals were also fed with CGM at single dose (100 mg curcuminoids/kg b. wt.) and repeated dose (100 mg curcuminoids/kg b. wt. for 28 days) and the behavioural studies were conducted using open field test and radial arm maze. Results UPLC-ESI-MS/MS analyses of plasma revealed significant absorption of unconjugated (free) curcuminoids upon both single and repeated dose administration of CGM with maximum concentrations of 173.34 +/- 27.12 ng/mL and 223.22 +/- 32.73 ng/mL, respectively. Further analysis of brain tissues demonstrated significant blood-brain-barrier permeability. Brain regional pharmacokinetics (AUC, C (max) and t (1/2)) indicated a relative distribution order of hippocampus > striatum > cerebellum > cerebral cortex > brain stem. Supplementation of CGM for 28 days also offered significant (p < 0.05) improvement in locomotor activity and reduction in spatial memory errors as compared to NC. The NC treatment also improved the behaviour better than the vehicle-treated group. Conclusion CGM could distribute significant amount of free curcuminoids, in brain especially in the hippocampus at both single and repeated dose administration with an elimination half-life of 2.6 h. CGM also showed a positive impact in behaviour of animals in comparison with normal unformulated curcuminoids.