## 3 Vitamin A, Its Vitaminoids and Carotenoids' General Profile and Health Benefits
### Vitamin A-Related Bioactive Compounds: Provitamins (Carotenoids)
#### 4.1.3 Other Absorption Pathways of Vitamin A, Its Vitaminoids, and Carotenoids  
Vitamin A can be delivered intramuscularly (IM) as well, with a view to achieving rapid systemic effects, during a parenteral absorption (via injection) pathway [3,21]. IM injections bypass the GI tract, delivering vitamin A directly to the bloodstream, commonly in cases of a malabsorption syndrome or severe deficiency. Once in circulation, retinol binds to the RBP and transthyretin in order to be transported to the target tissues. Liquid formulations provide a convenient way of rapidly addressing vitamin A deficiency, especially when oral supplementation through water or parenteral administration is inefficient, via promoting bioavailability and micronutrient use [3,21]. Vitamin A in sublingual drops (sublingual absorption) bypasses the GI tract by direct absorption into systemic circulation through the sublingual mucosa. Sublingual absorption is remarkably effective for individuals with impaired digestive systems [3,107]. Furthermore, vitamin A suppositories or enemas deliver the nutrient via the rectal mucosa following the rectal absorption pathway, suitable for patients unable to take oral or injectable forms in cases of vitamin A deficiency [3,108]. Figure 8: The cellular pathway of topically administered vitamin A.  
Biochemical Mechanisms of Action of Vitamin A, Its Vitaminoids, and Carotenoids: Gene Regulation and Mediation in Thromboinflammatory Pathways  
Once metabolized, vitamin A, its vitaminoids, and carotenoids partake in several biochemical pathways and thrombo-inflammatory manifestations, crucial for cellular and physiological functions. Carotenoids and vitamin A derivatives scavenge excessive free radicals during oxidative stress cases and inflammatory manifestations from several genetic, epigenetic, age-, UV-, or dietary-related, photo-oxidative, or concomitant factors. Hence, they provide enhanced antioxidant and anti-inflammatory shielding by affecting the binding, inhibiting the associated signaling, or modulating the metabolism of thrombotic and inflammatory mediators (reduction), reducing inflammatory/oxidative, and increasing anti-inflammatory/antioxidant genes [3; 77; 88; 109]. ATRA, as the end product of the vitamin A, retinoids, and carotenoids' metabolism, acts as aforementioned, as a ligand via several co-activators and CRABPII binding for NRs, namely RARs that regulate gene expression involved in cell differentiation, proliferation, and apoptosis and RXRs that partner with other receptors (e.g., peroxisome proliferatorator-activated receptor (PPARs) and VDRs), modulating diverse pathways. Such a pathway of gene expression regulation is vital for embryonic development, immune function, and skin renewal [3; 77; 87; 100]. ATRA is involved in cellular differentiation and apoptosis in epithelial tissues, prevents keratinization disorders, aids in tissue regeneration, and induces apoptosis in aberrant cells, with implications for anti-cancer therapy [3; 77; 87; 100]. Furthermore, ATRA promotes immune homeostasis by regulating T-regulatory cells (T-regs), hence enhancing anti-inflammatory responses and type 1T helper/type 2 T helper (Th1/Th2) balance, by supporting adaptive immunity and affecting pro-inflammatory cytokine formation as well [110]. Lastly, ATRA, when retinol-bound protein 4 (holo-RBP4) is bound, triggers the retinoic acid 6 (STRA6) gene. Once STRA6 is boosted to relocate in the cell membrane, it catalyzes the transport of RBP4's retinol release. Thus, it sets off tyrosine phosphorylation on the C-terminal tail, which attracts signal transducer and activator of transcription 3 and 5 (STAT 3/5) and Janus kinase 2 (JAK2). Notably, STRA6 partakes in the intrinsic mechanism of p53-mediated apoptosis, occurring after cellular DNA damage or elevated intracellular ROS [111]. Concerning the visual cycle, retinal is a key molecule where it combines with opsin in the retina to form rhodopsin, essential for low-light vision.