Albumin: Bountiful Arrow in the Quiver of Liver and Its Significance in Physiology

Abstract

Albumin is the most abundant protein synthesized exclusively by the hepatocytes in the liver. Once secreted into plasma, it helps in the maintenance of osmotic pressure, as well as the exertion of defensive roles such as anti-oxidative and anti-inflammatory functions. Dysregulation in the synthesis and clearance of albumin is observed in various hepatic and extra-hepatic diseases. Abnormal levels of albumin could be either a cause or an effect of various pathological ailments, including hepatic, cardiac, renal, neurological, etc. Owing to its long half-life and multiple binding sites in its heart-shaped structure, it interacts with various internal agents, such as hormones, or external substances like drugs, which is why transportation can be one of its many functions. Additionally, albumin’s drug interactions, as well as displacement of albumin–drug binding, could have serious clinical consequences, and careful considerations should be made in determining an appropriate drug regimen to achieve a desired therapeutic outcome with minimal side effects. Moreover, albumin also undergoes several post-translational modifications that can influence its physiological roles, including drug binding and antioxidant functions. Furthermore, it has a complicated role in physiology, where it can help in maintaining plasma oncotic pressure and prevent endothelial cell apoptosis but can have adverse effects on the lungs and kidneys. These adverse effects are mainly attributed to ER stress and inflammasome activation. This narrative review provides an overview of the general biology of albumin and its effects in physiology, with a focus on its beneficial and adverse effects and the underlying molecular mechanisms.

1. Introduction

The liver is an important secretory organ, and it influences physiology via the secretion of a large number of proteins, such as prothrombin, fibrinogen, α1-antitrypsin, RBP, DBP etc. These proteins act on different organs to maintain physiological homeostasis. Among these diverse proteins secreted by the liver, albumin is the most abundant plasma protein. It is synthesized predominantly by the hepatocytes. Several liver-dependent transcription factors (such as HNF1/LFB1, HNF4α, c/EBPα, FOXA2, etc.) induce its gene expression [1,2,3,4,5], while others (such as p53 and c/EBPβ) are implicated in the negative regulation of its gene expression [6,7]. An interesting aspect associated with its synthesis is that it can occur in developing embryos, where liver cells are also at a phase of development, which highlights an intricate association between albumin production and the genesis and development of hepatocytes themselves [8]. Initially synthesized as a pre-pro form in ribosomes, this pre-pro protein undergoes several transformations before converting into mature albumin found in plasma, such as cleavages in the ER and Golgi. Specifically in the ER, the 24-amino-acid-long N-terminal extension present in the pre-pro form has 18 of its amino acids removed and transported into the Golgi, where furin-dependent action further removes 6 other amino acids, thereby transforming it into a mature protein with 585 amino acids [9], which is subsequently packed into vesicles destined for secretion, as indicated in Figure 1.

Serum levels of albumin seem to be influenced by the rates of its synthesis and degradation. These steps are further governed by various factors, including insulin, the type of amino acid, and nutritional status, which is directly proportional to albumin synthesis, while pro-inflammatory cytokines [10,11] and starvation downregulate albumin synthesis [12]. Albumin synthesis has a complicated relationship with amino acids, some of which enhance albumin synthesis, while others do not show such an effect. Particularly, the amino acids alanine, arginine, glutamine, lysine, ornithine, phenylalanine, proline, threonine, and tryptophan stimulate albumin production, while histidine, leucine, methionine, and valine fail to cause any increment in albumin production [13,14,15]. Another factor that influences albumin synthesis is the urea cycle, which can modulate albumin synthesis via the production of amino acids such as ornithine from arginine, where the production of polyamines plays an important role in the aggregation of polysomes and the subsequent process of albumin synthesis [16]. Additionally, arginine and spermine have also been observed to prevent the inhibitory effects of alcohol in albumin synthesis, and they even synergize to replenish albumin synthesis [17]. Albumin levels are also regulated by post-transcriptional processes such as mRNA stability, and it has been observed that both insulin and growth hormone enhance albumin synthesis, but growth hormone is less effective in sustaining mRNA stability than insulin [18].

Oncotic pressure is also known to influence albumin synthesis, while viscosity has no significant effect. In a classical study, modulation of oncotic pressure was achieved by using a varying dose of dextran—which exerts high osmotic pressure at low molecular weight, and vice versa [19]—and it was observed that a decrease in mRNA levels of albumin correlated with an increase in oncotic pressure by low-molecular-weight dextran, while this negative effect on albumin synthesis was suppressed by reducing oncotic pressure with the use of high-molecular-weight dextran. Furthermore, despite being more viscous than dextran, γ-globulin did not significantly affect the mRNA levels of albumin. The authors further confirmed that this effect occurs at transcriptional levels using cycloheximide, which acts as translation inhibitor. Herein, cycloheximide restored dextran-suppressed albumin mRNA to basal levels, hinting at the possible role of a limiting transcription factor or the requirement for oncotic pressure to suppress mRNA levels of albumin via synthesis of some labile protein [20].

ATP and GTP are also important requisites for albumin synthesis, because a significant deficiency of ATP and GTP is known to cause disaggregation of polysomes, which can then negatively impact the overall process of protein synthesis [21]. This generalized effect on protein synthesis can ultimately impact albumin synthesis too, but here a noteworthy factor is that not all agents that are implicated in reduced albumin synthesis necessarily promote polysome disaggregation [22], so the role of polysome disaggregation in albumin synthesis might have to be deduced on a case-by-case basis, with consideration of nutritional status. Furthermore, optimal concentrations of MgCl₂ and KCl are also an important prerequisite that governs albumin synthesis [23]. Interestingly, these ions modulate albumin synthesis in extracellular environments too, where the translation of albumin from albumin mRNA can also occur in a cell-free system derived from wheat germ. In the course of this, the concentrations of K⁺ and Mg²⁺ determine the formation of intact albumin or some fragmented forms, wherein higher concentrations of these ions favor the intact form, while lower concentrations of these ions lead to the formation of fragments [24]. In addition to these ions, calcium also seems to be important from multiple perspectives with regard to albumin production. For instance, Ca²⁺-dependent proteases are involved in the transformation of proalbumin to albumin, and Ca²⁺-dependent vesicle fusion also plays a crucial role in its secretion [25].

Site-specific mutagenesis has strengthened the requirement for cleavage at Arg-Arg dibasic sites for the conversion of proalbumin into albumin [26]. In addition to this factor, substitution assays have demonstrated that residue adjacent to this Arg-Arg dibasic pair is also important in promoting the conversion into mature albumin, because the replacement of Asp and Glu—which are the adjacent amino acids to the dibasic Arg-Arg pair in humans and mice, respectively—with hydrophobic amino acids such as Val, Leu, or Ile did not result in the production of mature albumin from proalbumin [26,27]. Additionally, pH seems to be an important determinant in this conversion of proalbumin into albumin, because various weakly basic amines have been observed to inhibit the process of proalbumin conversion [28]. Furthermore, an important aspect to consider in this topic is that these weakly basic amines, such as chloroquine and NH₄Cl, are also known for their ability to inhibit autophagy, which is essentially a cellular mechanism that engulfs various intracellular materials into double-membraned vesicles called autophagosomes and merges them with lysosomes to degrade their contents. Therefore, this correlation between the requirement of optimal pH, the ability to disturb Golgi function in order to dampen proalbumin conversion by weakly basic amines, and their effect in suppressing autophagy is quite thought-provoking in the assessment of a potential role of autophagy in the corresponding process of proalbumin conversion by these weakly basic amines.

Degradation of albumin occurs via uptake into endocytic vesicles with the help of membrane-bound receptors, including gp18 and gp30, and occurs predominantly in organs such as the muscles and skin, while the rest of the degradation process occurs in the liver and kidneys [29,30,31]. Although renal cells primarily utilize the lysosome-mediated pathway for the degradation of albumin [31,32], non-lysosome-mediated degradation by pathways involving proteasomes has also been reported in hepatoma cells [33]. Lysosomal acidification accounts for major activity of lysosomes, and inhibition of this process or a rise in pH caused by chloroquine (CQ) can prevent the degradation of albumin. This is further supported by the discovery that the proteasome inhibitor MG-132 did not prevent the degradation of albumin; however, CQ blocked this effect [32], thus highlighting a major role of lysosomes rather than proteasomes in degrading albumin. Interestingly, this endolysis of albumin into podocytes can also reduce the activity of cathepsin B, a protease responsible for albumin turnover and degradation. This can actually have varying consequences because, from one perspective, inhibition of cathepsin B activity is also likely to minimize the conversion of proalbumin, while at the same time, since the inhibition of cathepsin B activity prevents albumin degradation, the concentration of mature albumin may be enhanced. In this way, the net levels of mature albumin can be modulated in diverse ways, depending on the situation, such as an encounter with proteases by the particular form of albumin. Additionally, this also signifies a self-protecting mechanism of albumin, at least in part via the inhibition of cathepsin B-dependent degradation.

Despite being the exclusive site of synthesis, its residency in the liver is quite limited owing to its rapid secretion via Golgi-derived secretory vesicles that can bypass cisternae [34]. This secreted protein of about 66 kDa has a net negative charge and multiple binding sites, because of which it can interact with diverse molecules of varying structures, such as vitamins, hormones, fatty acids, and multiple drugs. Serum albumin levels can be a valuable tool to deduce the nutritional status of individuals, although it is debatable whether pre-albumin would be a better choice to confirm nutritional status because of its shorter half-life in comparison to that of albumin [35].

Impermeant charged ions lead to a difference in potential across a semi-permeable membrane, which is elucidated by the Gibbs–Donnan effect. The fundamental principles of the Gibbs–Donnan effect are utilized by albumin to maintain colloid osmotic pressure. Transport of albumin into and from the capillaries is a continuous process, and it can translocate into interstitial space by the action of the albumin transporter protein known as albondin, while its replacement in the plasma occurs via the lymphatic system, albeit to a smaller extent [36,37]. Because of its high molecular weight and net negative charge, it attracts positively charged ions such as Na⁺ and K⁺ into the plasma, while also repelling negatively charged ions such as Cl⁻. This helps to sustain the capillary membrane pressure by allowing the well-controlled inlet of fluid into the interstitial space and capillaries, as shown in Figure 2. Conversely, low albumin levels can limit this effect and, as a consequence, enhance the leakage of fluid into the interstitial space, resulting in edema [38].

2. Mutations and Post-Translational Modifications of Albumin and Their Physiological Consequences

While furin has been known to convert proalbumin into albumin, some conflicting information surrounds whether furin is in fact the major protease responsible for proalbumin conversion, because the absence of furin has also resulted in the conversion of proalbumin into albumin [39]. Therefore, this led to the understanding that proteases other than furin are also responsible for proalbumin cleavage [40]. Indeed, this is true for different variants of albumin, where various proteases such as trypsin and cathepsin B have been observed to transform proalbumin into serum albumin [41]; herein, cathepsin B converted albumin Tokushima into serum albumin, while another variant referred to as the Pittsburgh variant was observed to be resistant to various proteases (except trypsin) [41]. In this Pittsburgh variant, despite the normal sequence of amino acids required for cleavage (Arg-Arg), the proteases failed to cleave, which was attributed mainly to the abnormal activity of proteases rather than the lack of a proper cleavage site, as opposed to other variants such as proalbumin Christchurch and proalbumin Lille, where Arg is replaced by His in Lille and by Gln in Christchurch [42]. A noteworthy factor here is that, despite a lack of in vivo processing, in vitro transformation into mature albumin does occur by trypsin activity. These studies insinuate the requirement of optimal activation of many cellular systems for a proper conversion of proalbumin into albumin under various conditions. Subsequently, several variants of proalbumin have been discovered, with some differences in processing and properties [43]. For instance, the Zn²⁺-binding constant is higher for a variant known as proAlb Varese, while that of the Christchurch variant is lower, and no significant difference was observed for proAlb Blenheim [44].

The stability and structural integrity of albumin are provided by 17 disulfide bonds between two α-helices, while a free cysteine residue present in domain I provides important anti-oxidative functions [45,46]. Albumin has a tendency to undergo several PTMs, including acetylation, glycation, carbonylation, phosphorylation, dimerization, etc. [47]. Some of these PTMs are reported to be physiologically relevant, while others—such as phosphorylation, which has been observed in vitro but not in vivo—are supposed to have no drastic effect on physiology [48]. Nonetheless, because of the possibility of forming harmful substances, PTMs of albumin might need to be seriously considered and filtered out of any sources used in research and clinical practice. This could still need some assessment for the supposedly non-effective modifications, such as phosphorylation, because of the ability of albumin to bind multiple agents and transform in structure, so any effect on its native structure is likely to impact drug binding and needs further research to delineate such effects.

The potential to use albumin as a biomarker in diabetes has shifted considerable attention toward glycation and glycated HSA, which occur mainly at lysine residues because of high glucose due to oxidation or dehydrogenation by methylglyoxal, which is produced as a byproduct of the glycolytic pathway [49]. Glycation can be a sensitive issue for albumin, because it stays in the blood for a long period of time and essentially provides enough opportunity for glucose molecules to act on it and cause its glycation [50]. Furthermore, glycated albumin has been demonstrated to inhibit insulin secretion [51]. Therefore, there seems to be a vicious cycle between albumin glycation and loss of blood glucose control.

Although mild oxidation has no significant effect on drug binding, excess oxidation decreases the stability of albumin, alters the ligand binding at site II [52], and compromises the binding ability between agents that interact with albumin at this site, such as L-Trp [53]. Furthermore, in another study, while mild oxidation did not change the structure of albumin drastically, it had a disproportionate effect on drug binding [54]. Similarly, S-nitrosylation, which can occur due to excess production of NO in cases such as cirrhosis, can lead to the formation of S-nitrosoalbumin, which reduces binding capabilities with ligands such as palmitate, leading to an increase in unbound fraction [55].

Dimerization of albumin, which is a reversible process where the α-helical structure is unaffected, can also influence drug binding and affect the transport and concentration of myristic acid. Interestingly, because of the interchangeable nature of albumin dimerization and momomerization themselves, myristic acid binding is affected, where dimerization induces an increase in free myristic acid and momomerization enhances the interaction [56].

3. Association of Albumin with Cellular Physiology and Adverse Effects

While various antioxidants (including thioredoxin, selenoprotein, etc.) can be present in plasma in any state, their concentration lies far lower than that of albumin, which consists of a free thiol group at cysteine 34, because of which albumin can exert its antioxidant activity [57]. In a normal state, the thiol group lies mainly in a reduced state; however, encounter with free radicals promotes its oxidation, leading to the formation of a cysteinylated form [58]. In this process, albumin can act as an antioxidant by limiting the cellular damage due to free radicals. This property of albumin can impart vital information about the health condition of an individual, because its levels can vary in various pathologies [59,60,61].

Albumin has also been reported as an inhibitor of apoptosis in human endothelial cells, in an adhesion-dependent manner. Since the lack of adhesion did not support the anti-apoptotic effect of albumin, we can infer an important role of cell–cell communication and signaling in the protective effects of albumin [62]. In a study, the authors employed FACS-dependent analysis of a sub-G1 population, which represents the dead cell population, and based on the position and/or number of fragments a general idea of apoptosis can be deduced. Here, the authors observed a significant increase in the population of cells at the sub-G1 phase, with a clear single peak insinuating induction of apoptosis by serum deprivation. Furthermore, this effect was suppressed upon administration of HSA, thus reinforcing its anti-apoptotic property. Finally, the authors also determined an involvement of the AGE-RAGE axis in the corresponding anti-apoptotic effect of HSA by developing AGE-conjugated HSA, which displayed a reduction in protective effects. However, a CNBr fragmentation of HSA-BSA was found to replenish the anti-apoptotic effects [63], essentially strengthening the negative role of glycation in the anti-apoptotic effects of albumin. Likewise, other reports also suggest it to play a beneficial role in enhancing the vasodilatory effect via NO-dependent signaling. Herein, a sustained vasodilatory effect was achieved due to the formation of S-nitroso-BSA because of reactions between BSA and oxides of nitrogen [64]. This is in line with a previous report by Keaney et al. [65], which also reinforces a similar hypothesis: that the reaction between BSA and NO leads to the formation of S-nitrosothiol, which has remarkably similar properties to those of endothelium-derived relaxing factors.

Although albumin has an ability to exert protective effects, such as anti-oxidative functions in plasma and anti-apoptotic effects in endothelial cells, it can also exert adverse effects on certain organs, such as the kidneys. This aspect is often associated with its effects on the modulation of cellular mechanisms, including autophagy, ROS, ER stress, and inflammasome activation. The complexity lies in the double-edged role of these pathways in health and disease. Depending on the specific circumstance, experimental conditions, and inducers, they can display either a cytoprotective or a cytotoxic effect. For instance, the autophagy machinery, which has been reported to generate new amino acids from damaged cell organelles with the aid of lysosomes, has been shown to exert cytoprotective effects in several reports [66]. Conversely, autophagy can also elicit a cytotoxic effect, either via the promotion of cell death pathways, such as apoptosis, or directly, in a manner referred to as autophagic cell death [67,68,69,70,71]. Specifically, these matters could account for autophagy-dependent adverse effects on CHD at low albumin levels in serum [72,73]. Furthermore, the role of autophagy itself in albumin production is not well understood. Although de novo protein synthesis does not generate essential amino acids, a catalytic breakdown by processes such as autophagy can enhance the pool of some amino acids [74,75]; hence, the ultimate effect might be associated with the generation of specific amino acids that induce either an upregulation or a null effect in albumin synthesis. It has been observed over 55 years ago that a rapid decline in albumin synthesis takes place during fasting [12]. Furthermore, fasting is also a well-known condition that induces autophagy. As mentioned previously, the role of autophagy itself is complicated with regard to cell death and survival [66]; therefore, an interesting direction of research would be to investigate whether the reduction in albumin synthesis during starvation has any direct physiological consequences in healthy individuals or those with certain pathological ailments. Such a study might be even more complicated because of albumin’s interaction with multiple drugs in people with various pathologies. However, the findings would be monumental considering the transcendence of fasting across multiple cultural and lifestyle choices. Also, would patients with hyperalbuminemia-dependent diseases such as renal disorders benefit from such a strategy of reducing albumin production by fasting? This is difficult to assess, and only future research can clarify it better.

When in excess, ROS production, which is a byproduct of cellular metabolism or an adverse outcome of exogenous agents, can elicit damage to membrane proteins and promote various cell death pathways in multiple cell types [76,77]. Although the antioxidant role of albumin due to cysteine 34 is well established, albumin can also provoke oxidative stress by modulating calcium-dependent pathways, leading to renal cell death via apoptosis [78]. ER stress, which is a cellular response generated due to the accumulation of misfolded proteins, has been observed to be involved in the death of multiple cell types [79,80,81,82]. In line with this, many reports have uncovered a crucial role of ER stress in contributing to renal injuries, and the effect of albumin in causing renal injury via induction of ER stress has been very well documented [83]. Perhaps one of the most widely studied and concerning aspect of albumin toxicity would be albuminuria, as observed in renal diseases, and excess albumin has been noted to be a responsible factor in renal diseases via the induction of renal atrophy and progression to renal fibrosis [84]. In a report, Klotho downregulation by albumin in an ER stress-dependent manner led to cytotoxic effects in tubular cells [85]. Additionally, another study uncovered the role of ROS production and ER stress in renal injury via the downregulation of E-cadherin and induction of EMT by albumin administration at a dosage of 5 mg/mL. As downregulation of E-cadherin and EMT induction are consequential mechanisms in the development of renal fibrosis, this study underscores a detrimental effect of albumin in inducing renal fibrosis, with a critical role of ROS production and ER stress in the corresponding adverse process [86]. In yet another study, albumin-induced ER stress caused an activation of the PKC-δ/MAPK pathway that further led to the activation of caspase-12 and culminated in apoptosis of podocytes [87].

Another emerging physiological response that modulates renal physiology is the activation of inflammasomes, which is mainly induced after the sensing of various PAMPs and DAMPs, resulting in the formation of a multi-protein complex that subsequently generates mature forms of the pro-inflammatory cytokines IL-18 and IL-1β and has been reported to cause cell death in different cell types, including renal cells [88,89,90]. In this scenario, albumin induced the activation of NLRP3 inflammasomes via mitochondrial dysfunction, as assessed based on damage to the morphology of mitochondria and enhanced levels of cytochrome c in cytosol [91]. The authors further confirmed the role of mitochondrial dysfunction in NLRP3-induced renal injury by employing an SOD2 mimetic and inhibitor of mitochondrial permeability (MnTBAP). This inhibitor significantly suppressed the activation of inflammasomes and renal injury even in the presence of albumin, thus elucidating the simultaneous correlation between NLRP3 activation and dysfunction of renal cells. While the study did not explicitly demonstrate the role of inflammasomes because of an absence in the use of inhibitors such as MCC950, Ac-YVAD, or IL-1Ra, the study clearly hinted at the existence of inflammasome activation and renal injury upon albumin administration. Nonetheless, a previous study has already demonstrated that NLRP3 inflammasomes substantially contribute to renal fibrosis [92]. Furthermore, a subsequent study also demonstrated that gene silencing of NLRP3 can prevent apoptosis of proximal tubule cells [93] and collectively establish an adverse role of dysfunction in mitochondrial function that compromises its ability as one of the well-known mechanisms of inflammasome-induced renal injury [85,94]. Moreover, recent studies have further elaborated that the inhibition of NLRP3 inflammasomes by MCC950 can provide substantial relief in kidney disease [95,96].

Hence, this axis of ROS/ER stress and inflammasome activation seems to be quite crucial in generating adverse consequences to renal cells. Therefore, due attention must be given to whether it would be possible to achieve a beneficial effect by inhibiting these pathways in hyperalbuminemia-induced renal damage, and special note must be taken from studies that found an amplification of damage upon inhibition of inflammasomes [97]. Together, these studies indicate the cell-type-dependent effects of albumin in determining cell fate and underscore the complexity of albumin in biology, with beneficial effects in certain cells (such as endothelial cells) and an adverse effect in renal cells.

4. Role of Albumin Levels in Various Pathologies

The liver cross-talks with various organ systems via albumin secretion, and low albumin levels are known risk factors for different diseases (including hepatic, cardiac, pancreatic, etc.), as shown in Figure 3.

4.1. Role in Hepatic Diseases

Albumin levels in the plasma are determined by the rate of its synthesis, distribution to intravascular sites, and clearance via degradation in organs such as the muscles, skin, liver, and kidneys [37]. Plasma albumin decreases in liver hepatectomy, which could be due to either a reduction in synthesis or a failure to compensate for its degradation [98]. Additionally, low levels of albumin also predict the mortality outcomes in liver cirrhosis, where the effective albumin concentration seems to be a more important factor than total albumin levels. This could be because effective albumin would mean that its native structure and properties have not been altered and, thus, it can effectively counter against detrimental stimuli; however, total albumin levels do not necessarily indicate the status of albumin in terms of its optimal function, and they may include varyingly modified albumin, thereby giving a false impression [99]. The initial accounts of individual differences in albumin synthesis from MA Rothschild suggest that, although serum albumin levels decreased unanimously among all patients, the synthesis rate varied, with some patients displaying slight elevation, some displaying decreased production, and few of them showing no change. This suggests that reductions in serum albumin levels during cirrhosis may not necessarily be due to reductions in synthesis, but factors such as albumin leakage or degradation can also account for net albumin levels in cirrhosis. Nonetheless, the effect on drug binding in liver disease due to low albumin levels would persist almost similarly, irrespective of the reason for the decrease in albumin levels [100]. Hypoalbuminemia, which can occur in advanced liver disease such as cirrhosis, has been found to be responsible for edema, and even though factors other than low albumin levels can also contribute to edema in many cases, which may in some ways minimize the general role of albumin levels in edema [101], we cannot completely discount the importance of albumin levels to any extent. So at the very least, this suggests either an indirect role of hypoalbuminemia in the development of edema or a secondary role in the process. This would be even more important considering the recent discovery that hypoalbuminemia caused sodium and water retention and led to ascites [102]. In a varying scenario, inhibitors of albumin synthesis, such as retinoic acid, have also been reported to induce apoptosis of hepatocytes [103]. Since hepatocyte death is the most important determining factor in all forms of liver failure, this information together reinforces the possible role of albumin in protecting hepatocytes and liver function, along with an opposing effect due to hypoalbuminemia, although confirming this in relation to all inhibitors of albumin synthesis would require some additional research.

Oxidation of albumin has been observed to contribute substantially to the generation of oxidative stress and play an important role in alcoholic hepatitis [104]. Alternatively, subsidization of inflammation by albumin provided a significantly beneficial effect in decompensated cirrhosis, which was accompanied by the suppression of pro-inflammatory cytokines such as IL-6 and GMCSF, as per the cumulative assessment of the PRECIOSA and INFECIR-2 trials. [105]. On the one hand, TNFα has been reported to inhibit albumin synthesis [11], and on the other hand, TNFα-induced hepatic damage has been prevented by albumin, thus insinuating an interesting aspect in the vicinity of a mutual negative regulation in the determination of hepatocytes’ fate by the figurative battle of these two proteins [106]. It can also restore the oxidative phosphorylation capacity of the liver and prevent damage by various agents, such as pentachlorphenol, via a mechanism dependent on its property of physically interacting with different molecules [107]. Improvements in the immune functions of B cells and neutrophils by albumin displayed a protective effect in decompensated cirrhosis [108]. In the case of NAFLD/MASLD, albumin conferred significant hepatoprotection by preserving mitochondrial function. The study insinuated a crucial role of pre-albumin rather than mature albumin in the corresponding process via interaction with CPT2 to downregulate hepatic steatosis [109], and despite the different forms of albumin involved, the hepatoprotective effect of albumin is certainly undeniable. CCl₄, which is widely used in experimental models of hepatic fibrosis, has also been known to downregulate albumin transcription [110]. Although this correlation might provoke the thought that albumin downregulation may be responsible for the fibrotic effects of CCl₄ and, conversely, insinuate that albumin provides some therapeutic effect against fibrosis, a factor to consider here is that BSA itself has been known to contribute to hepatic fibrosis [111], so the downregulation in the albumin gene might be just an unrelated offshoot of CCl₄-induced hepatic fibrosis, and whether it has a causative role needs further exploration from these perspectives. Also, whether the exogenous administration of BSA can substantially correspond to the albumin synthesized in situ (in terms of pharmacological effects) also needs to be determined.

4.2. Effects of Albumin in Neurological Diseases

Accumulation of amyloid beta plaques in the brain accounts for the development of Alzheimer’s disease. Albumin can bind to these amyloid beta plaques and reduce their neurotoxicity by clearing them off the brain [112], and a noteworthy fact is that this protective effect of albumin is dampened by known interactors such as warfarin, fatty acids, and cholesterol [113]. Experiments performed on laboratory animals in various models of neuronal apoptosis [114] and SAH [115] have displayed significant protective effects of albumin, as observed from improvements in memory and learning abilities. Meanwhile, in human subjects, although albumin was found to be effective against Alzheimer’s disease in clinical trials, where it aided in the removal of Aβ plaques by plasma exchange technique [116], no significant improvement in stroke patients was observed from albumin therapy in a large, multicenter, double-blind trial known as the ALIAS trial; in fact, the researchers reported a worsening of certain parameters, such as cerebral hemorrhage and pulmonary edema [117]. These seemingly discrepant effects observed between the clearance of Aβ plaques and neural injuries is not yet clear; however, it might be associated with the fact that albumin might not have a high potential for neuroregeneration, as suggested by one study [118], so while it may be a good agent to prevent certain abnormalities in the brain, such as clearing Aβ plaques via physical interaction or inhibition of apoptosis by antioxidant properties, it cannot effectively promote the genesis of neurons. Additionally, although reported to improve blood flow in ischemic stroke [119], its property of increasing blood pressure at high doses [120] may even be counterproductive for hemorrhagic stroke; hence, the discrepancies could have persisted, although further research is required to delineate this hypothesis. Parkinson’s disease (PD) is another widely studied neurological disorder, characterized by a progressive loss of dopaminergic neurons. While serum albumin was reported to be lower in PD patients [121], it has also been observed that a loss in integrity of the BBB can result in the leakage of albumin in the brain; hence, significantly high ratios of albumin were detected in PD, as well as an increase in oxidation of albumin in Alzheimer’s disease patients [122,123]. In slightly differing circumstances, albumin can also provide therapeutic advantages in PD in the form of a carrier system. For instance, albumin nanoparticles containing curcumin [124] and selenium [125] have been found to prevent the progression of PD, as observed by improvements in DA-regulated behavior in the case of C. elegans and an MPP⁺-induced neuronal damage model of PD. Microglial activation, which can enhance the inflammatory environment in the brain [126], can also secrete AGE-albumin [127] and modulate PD in an adverse way by inducing the death of dopaminergic neurons. Hence, it is likely that the PTMs of albumin can also be a crucial factor in determining the outcomes of albumin-based therapy in PD.

4.3. Effects of Albumin in the Immune System

Albumin can modulate immune responses in diverse ways. The suppression of immune responses by PGE2 has been found to recover upon the administration of albumin [128]. Albumin has also been reported to improve the survival of tumor patients via the improvement of radiographic responses, as assessed by an improvement in anti-tumor response in patients with higher albumin levels compared to those with low albumin levels [129]. This response was corroborated across various cancers, suggesting a generalized effect of albumin in cancer therapy. In addition, high albumin levels favorably predict the therapeutic responses in autoimmune encephalitis as well [130]. Interestingly, while albumin has been observed to suppress IL1β and other cytokines, it simultaneously does not impair important defensive responses of leukocytes [131]. In an experimental model of sub-arachnoid hemorrhage, albumin prevented macrophage polarization towards the pro-inflammatory M1 phenotype, accompanied by a reduction in cytokines such as IL-1β, which was attributed to an inhibitory effect of albumin on the Mincle receptor in the microglia [115]. Consequently, this prevention of the aberrant activation of immune responses by albumin resulted in an improvement in sub-arachnoid hemorrhage. LPS, which is an endotoxin, is well known to enhance pro-inflammatory activity, resulting in various forms of tissue damage [126], but in a study, pretreatment of endothelial cells with albumin prevented the inflammatory effect of LPS, leading to downregulation of ROS and a reduction in cellular stress [132]. Additionally, the study also reported that a lack of albumin due to genetic defects was responsible for the decrease in the phagocytic capacity of CD11b and CD68 double-positive cells following BDL, which could worsen the prognosis because of the absence of an adequate immune response.

4.4. Effects of Albumin in Sepsis

The use of albumin in sepsis is one of the most controversial and heavily debated topics. Sepsis is a life-threatening condition caused primarily by endotoxins derived from Gram-negative bacteria. A hyper-activation of immune response follows the leakage of bacterial endotoxins in the blood. The final consequence of sepsis is observed in the form of multiple organ failure, resulting in death. There is an alarming loss of albumin levels in sepsis, by about 300% [133]. While antimicrobial therapy is required to counter the activity of bacterial endotoxins, the use of albumin could be advantageous in replenishing a decrease in mean arterial pressure that could lead to septic shock. In this regard, an international guideline recommends the use of albumin plus crystalloids during initial resuscitation in patients with sepsis and septic shock, rather than crystalloids alone at higher quantities [134]. On a different note, the combination of albumin and crystalloids did not improve survival for a period between 28 and 90 days in patients with severe sepsis [135]. However, it might offer advantages over saline according to a recent study [136]. Furthermore, no improvement in cardiovascular mortality was observed as per another study [137]. A randomized trial discovered its superior efficacy in comparison to plasmalyte in reversing hypotension associated with sepsis; however, it generated more pulmonary complications and no added benefit for mortality [138]. Although the effect of albumin in countering septic shock is well acknowledged, these studies suggest a limited application of albumin in septic shock from a broad perspective of health and wellness. More detailed information on these matters can probably be uncovered after the complete results of the ARISS multicenter trial are released [139].

4.5. Effects of Albumin in CVD

Hypoalbuminemia independently predicts the risk of CVD, especially in cigarette smokers, which was insinuated to occur probably as a result of arterial injuries due to a lack of antioxidant effects, as well as possible enhancements in the levels of fibrinogen, which can act as a clotting factor. While the Framingham offspring study has recognized some of its limitations, such as the lack of nutritional data and limited time points of albumin measurements, the study nonetheless uncovered that hypoalbuminemia is an independent risk factor for MI, and additionally, the association is more pronounced in hypertensive individuals, with increased mortality in women [140]. Although lower albumin levels have been reported in CVD, a study showed that albumin infusion did not demonstrate a significant improvement in CVD. However, as per one study, it turns out that a crucial factor in determining the effectiveness of albumin therapy in heart diseases is the level of albumin in serum, and there is a significant improvement in heart failure cases if it reaches a value greater than 3 g/dL [141]. LPC is an agent that can cause vasoconstriction by a variety of mechanisms, including suppression of nitric oxide-dependent vasodilation in endothelial cells and decreases in red cells’ deformability [142]. Hypoalbuminemia has also been reported to cause an increase in whole-blood viscosity because of a shift in LPC from plasma to RBC membranes, causing reductions in red cells’ deformability [143], which can ultimately aggravate CVD. However, albumin supplementation rescued this effect by directing LPC to plasma [144].

4.6. Effects of Albumin in Blood Coagulation

Another important function of albumin could be the prevention of thrombotic events, which can also provide cardioprotection. A large meta-analysis has uncovered low albumin levels as an independent risk factor for venous thromboembolism [145], and this correlation also persisted with cases of acute MI and stroke. Additionally, hypoalbuminemia observed during cirrhosis has also been found to be implicated in thrombosis [146]. Likewise, studies from platelet aggregation assays [147], surgical cases [148], and in vitro and in vivo [146] studies have elucidated that albumin has anti-coagulant functions. Mechanistically, these anti-coagulant effects of albumin have been attributed to its ability to inhibit fibrin polymerization and promotion of anti-thrombin activity [149,150], as well as antioxidant-property-dependent downregulation of the Nox2 gene [146], which plays a critical role in the process of platelet activation. Albumin can also behave as an anti-coagulant by exerting an inhibitory effect on histones [151], which are responsible for platelet aggregation during inflammation.

4.7. Effects of Albumin in Pancreatitis

Hypoalbuminemia has been observed to be an important indicator of mortality in acute pancreatitis, and the therapeutic advantage of albumin administration has been observed over 70 years ago in a canine model of surgically induced pancreatitis [152]. This is supported by several recent studies as well, where albumin provided a beneficial effect against pancreatitis in humans, especially when albumin therapy was initiated promptly in hypoalbuminemic patients [153]. However, a factor to be considered with regard to albumin therapy in pancreatitis is potential lung damage. Fortunately, it has also been discovered from studies with experimental animals that this unwanted effect can be minimized by inhibiting iNOS signaling. Therefore, suppression of iNOS during the administration of albumin to counter pancreatitis could be a good strategy, at least from a theoretical perspective [154]. In addition, in an in vitro model of pancreatic β-cell death induced by cytokines, cell death was prevented upon administration of albumin via activation of the survival kinase AKT and suppression of ROS production [155], as observed from a restoration in cell viability that was decreased by a combination of cytokines, including IL-1β, IFNγ, and TNFα.

4.8. Effects of Albumin in Colitis

Colitis, which is an inflammatory intestinal disorder, occurs due to aberrant activation of innate and adaptive immune responses by T cells such as Th17 and Th1, and it is marked by a high ratio of CRPs and albumin [156,157]. Additionally, in a Japanese population, the outcome of colitis was determined by the ratio between albumin and globulin, where high ratios of albumin to globulin promoted better clinical remission [158]. Sometimes hypoalbuminemia is co-diagnosed with colitis and has been attributed to enhanced degradation of albumin [159]. The activation of NFκB, which acts as a master transcription factor for pro-inflammatory cytokines such as TNFα and IL1β, can be suppressed by albumin to ameliorate colitis [160]. Furthermore, in an experimental model of DSS-induced colitis, reductively modified albumin conferred significant protection by maintaining a balance in the redox status, courtesy of its thiol group [161]. Cumulatively, these studies suggest a substantial effect of albumin in ameliorating colitis via the suppression of inflammatory activity. The diverse roles of albumin in physiology are indicated below in

Table 1. Effects of albumin in various pathologies, and underlying mechanisms.

Pathology	Albumin Administration	Mechanisms Involved	Refs.
Ascites	Improves	Albumin prevents the abnormal leakage of ions and fluids by sustaining the colloidal osmotic pressure and also reduces systemic inflammation	[102,105]
CVD	Improves	Due to the antioxidant properties of albumin, it prevents endothelial injury and also suppresses histones and fibrinogen-dependent blood clotting to prevent CVD	[132,149,151]
Pancreatitis	Improves	Studies indicate that albumin can activate survival kinase pathways in pancreatic cells to prevent inflammatory cell death and preserve pancreatic function	[155]
Alzheimer	Improves	Clearance of amyloid-β plaques off the brain via direct interaction, and also preventing hyperphosphorylation of Tau in order to prevent neuronal apoptosis	[112,114]
SHA	Improves	Experimental evidence suggests that the suppression of inflammatory pathways such as IL-1β by albumin exerts neuroprotective effects during SHA	[115]
NAFLD/ MASLD	Unsure but may improve	Mitochondrial protection by albumosomes formed by pre-albumin’s interaction with CPT2 to prevent fat accumulation in the liver	[109]
Sepsis	Controversial	Mainly due to the restoration in osmotic pressure, it can improve hypovolemic shock and lactate clearance in sepsis, but on the other hand can result in adverse effects in the lungs	[138]
Renal disease	Worsens	Activation of the NLRP3 inflammasome pathway causes renal damage by albumin	[94]
IHC	Worsens	By a yet-unclear mechanism, a large multicenter study involving 1275 subjects concluded albumin as an infective agent for the management of stroke and worsened IHC in some patients	[117]
Pulmonary edema	Worsens	Activation of iNOS has been reported to be involved in certain cases of adverse pulmonary pathologies such as fibrosis, and in a study, albumin-activated iNOS was found to cause pulmonary edema	[154]

.

5. Albumin’s Drug Interactions and Physiological Consequences

Since liver disease can reduce plasma levels of albumin, it may not be an unexpected thing for liver diseases to affect the plasma concentration of albumin-binding drugs such as tiagibine; therefore, close monitoring and dose tailoring are required in order to prevent potential adverse effects [162]. It can also be decreased in patients with trauma and has been attributed to leakage because of endothelial injury dependent on IL-1 activity [163]. In addition to hepatic diseases, other diseases such as diabetes can also influence albumin levels and structure, thus impacting albumin–drug binding [164,165].

A product of furin-mediated cleavage, plasma albumin has a well-characterized structure. X-ray crystallography has revealed albumin to appear as a heart-shaped structure, but its structure can vary owing to several factors, such as presence in solution, which can result in an elliptical shape, or pH changes that can alter ellipticity itself, with a gradual decline in the α-helix content at low pH [166]. Temperature can also lead to alterations in its structure by the formation of β-structures, which are reversible below 45 °C [167]. Nonetheless, albumin has been observed to possess three main domains—namely, I, II, and III—which are further categorized into subdomains denoted as A and B. Additionally, the sites IIA and IIIA are commonly referred to as Sudlow sites I and II named after their discoverer. These domains promote the interaction of albumin with different molecules. For instance, bulky heterocyclic anions such as warfarin bind to Sudlow site I, while others (such as aromatic carboxylic compounds, including ibuprofen and diazepam) bind to Sudlow site II [168]. Various drugs and their interaction sites in albumin have been well reported previously and can be found in an interesting article elsewhere [169]. Albumin is abundant in both positively and negatively charged amino acids; however, it is predominantly found in negatively charged amino acids, which gives it a net negative charge [170]. While the presence of negative charge facilitates interactions with albumin, it has been suggested that it may not be an absolute requirement, and as long as a strong electronegative center is present, binding can occur. This has been observed with diazepam, which is a basic drug and can interact with albumin at Sudlow site II in an un-ionized form [171].

The structure of albumin can vary subject to pH, in a phenomenon referred to as neutral-to-base transition, which mainly occurs between pH 6 and 9. Additionally, in silico molecular dynamics has uncovered a characteristic transformation of albumin to an F-isoform from an N-isoform under low pH, due to the development of electrostatic repulsions, which promote the exposure of its hydrophobic core [172]. These transitions in albumin can also affect drug binding, with an enhanced interaction found for the more basic form compared to the neutral form [173]. In addition, this interaction is also influenced by certain ions; for instance, Cl⁻ has been reported to displace warfarin from albumin binding by competitive displacement and reduction in the ellipsoid form, while Ca²⁺ and Mg²⁺ were not observed to affect albumin–warfarin interactions significantly in one study [174], although a different report indicated that Ca²⁺ enhances the high affinity constant between albumin and warfarin, leading to a stronger drug interaction [173]. An interesting thought from this perspective is that, although low Ca²⁺ levels are independently associated with bleeding [175], it is not well known whether low Ca²⁺ contributes to increased bleeding upon warfarin therapy due to the supposedly low albumin–warfarin interaction and the resulting increase in the concentration of free warfarin.

An allosteric modification in the structure of albumin can also occur, which can accommodate further binding of a different drug moiety that would otherwise compete for albumin binding. This is precisely seen in the case of fatty acids and thyroxine, where allosteric modification via FA binding leads to the opening of a different binding site for thyroxine [176]. In this way, albumin has remarkable capabilities to bind several molecules of similar or differing structures and modulate plasma concentrations (as well as their transportation) accordingly. Several reports have uncovered that binding of albumin with various mycotoxins can also help to minimize their toxicity [177]. Candidalysin, produced by Candida albicans, which can elicit systemic infection in high-risk individuals, can induce significant damage to various cells, including hepatocytes [178]. However, albumin, via hydrophobic interaction with candidalysin, averts this potentially adverse effect of candidalysin, resulting in the protection of kidney cells [179]. Additionally, removal of ammonia by albumin prevents adverse effects such as encephalopathy, which can arise due to ammonia overload in the brain [180]. Methemoglobin, developed using a combination of auto-oxidized ferric Hb and albumin, displayed a significant detoxifying property against a lethal dose of H₂S, essentially establishing a critical role of albumin’s interactions with toxins in various forms to remedy against potential pathological effects [181]. Conversely, as several drugs compete for albumin binding, they can also displace each other from interaction with albumin. This can be catastrophic for drugs such as warfarin, which have a narrow therapeutic window and can be displaced by drugs such as phenylbutazone [182]. Additionally, ibuprofen can displace bilirubin from albumin binding and can be consequential in hyperbilirubinemia [183]. Multiple parameters that influence drug binding can be involved in renal diseases, which ultimately affect albumin–drug binding and the resultant free concentration of drugs. These parameters include the accumulation of uremic toxins such as indole sulfate, hippuric acids, and CMPF, which can result in low clearance of diuretics such as furosemide, causing enhanced plasma levels and potential toxicity [184,185]. While the high specificity of uremic toxins for albumin can be of importance in limiting the toxicity of these toxins, their effect on the displacement of drugs bound with albumin can also be a critical factor to be considered in assessing the final outcomes related to albumin–drug interactions, which are even more crucial for drugs with a low therapeutic window. Additionally, this binding and detoxification ability of albumin reduces following hemodialysis [186], which can also be a determining factor in considering the potential application of albumin in detoxification in patients with renal dysfunction.

Natural-product-based drug or functional food discoveries have drawn remarkable attention in research to tackle different pathologies [187]. Additionally, in current times, computer-aided technologies have been quite helpful in discovering new agents or repurposing previously discovered drugs to ameliorate various pathological conditions [188,189]. However, seemingly conflicting reports have been observed between computational and empirical studies with regard to the binding site and displacement of warfarin by flavonoids, which are natural-product-derived compounds with potential application as drugs or functional foods. In this regard, computational analysis identified a different binding site in albumin between flavonoids and warfarin [190], while fluorescence studies have discovered a reduction in the fluorescence intensity of the warfarin–albumin complex upon the addition of flavonoids, thus suggesting drug displacement [191]. The consequence of drug displacement from albumin can be advantageous in certain cases, from an efficacy point of view. For instance, competitive binding of diclofenac from albumin bound by 6-MNA, a metabolite of nabumetone, enhanced the analgesic effect of diclofenac [192]. Similarly, a strategic displacement of drugs from albumin binding can be also be beneficial in cases such as nephrotic syndrome accompanied by diuretic resistance. In this case, displacement of furosemide from albumin interaction by bucolone provided significant therapeutic benefits [193].

6. Albumin in Therapeutics

Recent studies have uncovered wide applications of albumin in a variety of pharmaceuticals, such as in infusion therapy, as a carrier in nanoparticle-based drug delivery systems, chelation therapy, etc.

6.1. Infusion Therapy

Albumin has found very significant applications in the field of infusion therapy in the past 80 years. However, the effects can vary depending on the cause of ascites. Particularly, alcohol- and nutrition-related short-term ascites responded very well to low doses of albumin, and long-standing ascites responded less to albumin therapy [194]. Essentially similar effectiveness of albumin infusion in mitigating ascites was demonstrated by subsequent studies in patients who were unresponsive to diuretics and sodium restriction [195,196]. Interestingly, it has also been observed that, although the underlying cause of hyponatremia still persists with albumin infusion, this strategy may be beneficial to prevent subsequent neurological complications that arise due to hyponatremia [197]. Later, an unblinded study also discovered a remarkable improvement in patients with ascites put on albumin therapy [198]. In a landmark study performed over a period of 4 years in patients with decompensated cirrhosis, popularly known as the ANSWER trial, albumin supplementation to standard therapy was found to improve survival in comparison to the standard therapy of anti-aldosterone drugs and furosemide [199]. This is further supported by a recent study by Lombardo A et al., where the researchers also found albumin to be well tolerated and efficacious in improving the prognosis and reduction in mortality in Italian patients with refractory ascites [200]. Furthermore, another landmark study in a population of 410 patients with decompensated cirrhosis, known as the PRECIOSA trial, has recently released some reports indicating that there is an improvement in patient survival upon administering albumin in the long term [201]. This protective effect of albumin has been attributed to its antioxidant and anti-inflammatory properties. Additionally, although carried out in a small number of pediatric patients, another study has also discovered that albumin infusion is safe and can improve outcomes in patients with congenital nephrotic syndrome [202]. In the short term, however, no extra benefits of albumin infusion have been observed, despite the serum levels reaching a target of 30 g/l; on the contrary, the researchers reported an increase in critical complications in patients treated with albumin as opposed to the standard care [203].

Although suggested for a few medical conditions, as described above, albumin is not recommended in several cases, including some critically ill patients and neonates with respiratory distress, among others. A detailed summary has been put forth by the International Collaboration for Transfusion Medicine Guidelines, which can be found in an excellent article elsewhere [204]. Additionally, an important factor to consider in choosing one therapy over the other for long-term conditions would be the resulting economic burden of a particular therapeutic regimen. Multiple comparative studies have discovered albumin therapy to be a more economical option than other therapies for similar objectives, such as in patients with uncomplicated ascites [205] and septic shock [206].

6.2. Albumin as a Drug Itself, and Also as a Drug Delivery Agent

Supplementation of albumin to a standard medical treatment prolonged the survival of patients with decompensated cirrhosis, accompanied by an overall reduction in mortality by about 40%, which was suggested to be a possible modification of the disease process [199]. Here, the diuretics, anti-aldosteronic drugs, and furosemide were administered as standard medical treatment, and the supplementation of albumin enhanced the efficacy of the therapy in comparison to the standard regimen alone. In another study, a loading dose of 1 g/kg albumin for a day, followed by a maintenance dose of 20–40 g/day until the study period, uncovered a crucial effect of albumin in acting as a good adjunct for the management of hepatorenal syndrome [207]. Disruption in intestinal barrier function promotes the translocation of bacteria from the GIT to the peritoneal cavity, as observed in SBP, which is further worsened during ascites due to low levels of albumin [208]. Subsequently, these circumstances create a favorable environment for the production of nitric oxide by bacteria, which can lead to vasodilation and cause hypoperfusion of the kidneys, ultimately resulting in kidney failure, which is observed in case of HRS [209]. Multiple mechanisms could be at play by which albumin mitigates HRS. These could range from its antioxidant properties to suppress inflammation, to the enhancement of cardiac function, leading to proper blood flow and plasma expansion [210]. Despite all of these mechanisms, albumin alone is not very effective, but it can act as a great adjunct with vasoconstrictors such as terlipressin for HRS [211], and with antibiotics for SBP [212].

A change in the conformation of BSA conjugated with remimazolam has found application as a drug delivery system in the field of nanoparticle-based drug delivery, which promotes well-controlled drug release and, thus, can enhance drug efficacy, with a reduction in toxic effects at the same time [213]. Additionally, a BSA-based nanoparticle was conjugated with an MMP-3-responsive peptide, which effectively remedied C. neoformans in vivo [214]. In another report, a conjugate of BSA-PCLA sustained good adhesive properties and promoted angiogenesis and collagen deposition, which acts as a crucial response in wound healing. Additionally, this effect coincided with reduced toxicity as well as an enhanced therapeutic response due to albumin conjugation, in comparison to PCLA gel alone or PBS controls [215], thus signifying an application of BSA in therapeutics associated with wound healing. A more targeted delivery of AMPT due to conjugation with BSA greatly minimized the systemic adverse effects of AMPT, while sustaining its anti-cancer effect, as evidenced by a reduction in tumor volume [216]. Furthermore, in another study, the authors developed nanoparticles conjugated with BSA and PMMA using a non-covalent method. This strategy of conjugation with BSA was found to enhance the uptake of PMMA, resulting in a more efficacious drug delivery system and a potential reduction in side effects [217].

6.3. Aid in Chelation Therapy

Nanoparticles loaded with EDTA and albumin displayed a reduction in side effects and minimized renal toxicity in comparison to EDTA alone, and they aided in chelation therapy to demineralize calcified tissue [218]. Additionally, in another report, an albumin-based nanoparticle system loaded with EDTA reversed arterial calcification in a model of kidney disease. Interestingly, this study also reported diminished side effects such as hypocalcemia, which can arise due to systemic administration of EDTA, in the case of a BSA-based nanoparticle system in comparison to EDTA alone [219]. Furthermore, albumin binding with Zn²⁺-bound insulin led to a correct determination of insulin and also possibly improved insulin’s pharmacokinetics following islet transplantation, as evidenced by an expected reduction in plasma glucose levels by the BSA-conjugated Zn²⁺ insulin in comparison to the unconjugated form [220]. Although effective in various chelation therapies, albumin’s interaction with calcium enhances the total calcium levels and causes a disruption in calcium dynamics, which ultimately contributes to heart failure during albumin resuscitation [221], so this point should also be considered in determining its clinical application.

6.4. Use of Albumin in Various Forms in Research and Cell Culture

It is widely known that albumin is one of the major components of FBS, which is used in the field of cell culture to support cell growth. Emerging opinions in recent days in the field of cultured meat production have suggested that it might be a good alternative to FBS for supporting the growth and differentiation of MuSCs. It is also used as a conjugate for FAs to study the effects of fatty acids in different experimental systems [222,223]. Also, some researchers prefer it as a blocking agent in Western blotting, mainly to detect phosphorylated proteins [224].

7. Conclusions

While the liver is the predominant source of albumin, it plays a critical role in the maintenance of general physiological homeostasis, and most importantly as a balancer of colloidal osmotic pressure by employing the principle of the Gibbs–Donnan effect. It also acts as a primary antioxidant source in the plasma, among other things. This is why it has found good utility in the management of various pathological conditions, such as edema and septic shock, to balance fluid levels in various body compartments and sustain arterial pressure. These properties accentuate the crucial importance of albumin and necessitate its intact nature, which when compromised by PTMs such as glycation can affect its properties adversely. Additionally, it also has a major function in the binding and/or transportation of various drugs, and it can also contribute to reductions in side effects via targeted delivery. Despite these beneficial effects, it can also lead to adverse consequences in certain conditions, such as renal dysfunction, thus limiting its application. Its adverse effects are mainly associated with the activation of the axis of ROS/ER stress and inflammasomes. Therefore, a well-thought and -designed regimen by carefully considering the albumin levels, dose–response and duration of treatment, replacement with fresh albumin considering its potential to undergo oxidation and glycation, patient conditions, and respective pathology, as suggested by several related studies, might be crucial to determine the useful effects of albumin, while simultaneously limiting the adverse consequences.