Table 1.

The main biomolecular effects of the YPs.

	Heme	HMOX	Fe2+	BV	BLVR	UCB
Changes During Disease	Accumulating in the site of lesion	Usually induced (chemical induction, inhibition, and Ko models frequently used to assess its biologic and pathologic functions)	Increased as part of BBB breakdown, hemorrhage and HMXO1 induction.	Rarely quantified. Suddenly added to model of diseases to assess its functions.	Usually induced (with possible induction of defects in its enzymatic activity in high redox stress environment). Fewer chemical inducers/inhibitors are available to assess its functions. KO models are seldom used for this purpose.	TSB: both increased and decreased. Supposed to be increased if HMXO and BLVR induced Seldom added to models of diseases to assess its functions.
Target and Effect	Protective Reducing apoptosis and inducing SOD and HMOX1, mitochondrial functions and cytochrome C release, and ferritin production [30,31,137]. Enhancing redox stress and heme release, protein and lipid oxidation, metalloproteinases release and tissue damage, inhibiting the antioxidant response through NRF2, and impairing the proteasome and unfolded protein response, inducing mitochondrial dysfunctions and mitophagy and apoptosis (Frederic ataxia, posterior column ataxia, neurodegenerative diseases) [32,37].	Protective Reducing redox stress, increasing survival, inducing the transcription of the stress response genes, reducing lipid peroxidation [89] and inducing the synthesis and release of GSH [137]. Promoting proliferation and neuronal survival via PI3K/Akt/BDNF signaling, even migrating into the nuclei and acting as a transcription factor [9,11] (AD, PD, ischemia, HD [38]). Improving glutamate neurotoxicity, mitochondrial damage [137]. Antioxidant (by producing BV, UCB, and acting as a transcriptional factor [9,11]). Potentially dangerous if excessively induced (AD, PD, SCZ, Stroke, trauma [3,60]). Increasing cholesterol and products of cholesterol oxidation [99]. Increasing Fe2+ production in turn enhancing DNA damage, cell bioenergetic failure, mitophagy and autophagy, oxidizing catecholamine [3,60].	Damaging Worsening redox stress, enhancing protein and lipid oxidation, and DNA damage. Reducing SOD activity, inducing a cell bioenergetic failure, apoptosis, neuronal autophagy, damaging the BBB (via NFkβ, AP1) [32,89].	Protective Levering DNA damage (possibly by scavenging ROS directly or after conversion into UCB [27]), inducing BLVR translocation into nucleus [9,11], with multiple anti-inflammatory actions [9,11].	Protective Protective in meningioma and glioma [220], and EAE [98]. Modulating Tau deposition [43]; enhancing neuronal and synaptic plasticity (MAPK/PI3k) [60], Reducing apoptosis (MAPK/Akt [9,11]) Activating the stress responses gene (including HMOX) [29], ameliorating insulin brain resistance [70]. Inducing chemoresistance [211]. Missed Protection Missed protection in AD (gene up, activity down [60,68,73]).	Protective Protective (EAE, PD, stroke, ischemia, traumatic brain injury, cerebral atherosclerosis, glioma, etc. [11,51,86,99]). Activating the antioxidant response (NRF2 [29]); boosting survival and repair (AKT/CREB/BDNF [9,11]); increasing mitochondrial respiration, AMPA and Ca channels [11]; enhancing the transcription of the detoxification system (CYPs, UGT, by MAPK/NRF2) [11,156], inhibiting NMDA excitotoxicity and related neuronal death [28] Damaging Responsible for acute and chronic bilirubin encephalopathy (kernicterus), and suggested increasing the risk of ADHD, SCZ, autism [194], by inducing a plethora of mechanism (among them oxidative stress, apoptosis, glutamate neurotoxicity, inflammation, epigenetic alterations of brain development, reduced myelinating, cell death, ca imbalance, etc. [49,194]).