Pectins are complex polysaccharides and versatile hydrocolloids, vastly available in plant cell walls and the middle lamella of higher plants. These polysaccharides are major components for maintaining rigidity and integrity of the plant tissues, positively impacting plant growth and health [1]. Every source of pectin has a variable amount of sub-structures, such as homogalacturonans (HG), rhamnogalacturonans (RG-I and II), and xylogalacturonan [2]. The HG region is primarily composed of a homopolymer of partially esterified 1-4-α-d-galactopyranuronic acid (GalpA). RG-I regions are composed of repeated and intercalated α-d-GalpA with α-l-rhamnopyranose (Rhap) [→2)-α-l-Rhap-(1,4)-α-d-GalpA-(1→]. This region also has variable side chains of galactans (β-1,4-Galp residues with varying degree of polymerization), arabinans (α-1,5-l-Araf with 2- and 3- linked arabinose/arabinan branches), and arabinogalactans (Type I: β-1,4-d-galactans with O-3 linked l-arabinose or arabinan; Type II: β-1,3-linked d-galactans with β-O-6-linked galactans or arabinogalactan), attached to the Rhap residues (side chains are linked at Rhap O-4, as demonstrated in Figure 1 and Figure 2) ^[2][3][4][2,3,4]. In diverse fruits, these structures undergo a series of chemical and enzymatic alterations during the ripening process, resulting in a wide variety of intramolecular changes inside the pectic chain, as illustrated before for the papaya pulp, a fruit that rapidly undergoes the ripening process ^[5][6][7][8][5,6,7,8].

As part of the dietary fiber group, pectins are not digested by the human tract, although the fermentation process by the human microbiota is greatly important for the maintenance of the colonic and systemic health through local signaling. The fermentation products and molecular fragments can improve metabolic syndrome and attenuate hypercholesterolemia, hypertriglyceridemia, and hyperglycemia, markers related to heart disease risks in mice, rats, and humans ^{[10][11][12][13][14]}[10,11,12,13,14]. The pectic products and fragments after colonic fermentation also possess anti-oncogenic attributions in the colon for mitigating cancer-related risks in the colon and even in other types of neoplasia in humans [15].

Galectin-3 (Gal-3) is the chimeric representative member of the galectin protein family, located ubiquitously in the nucleus, cytoplasm, outer cell surface, and extracellular space in mammals. Gal-3 is classified as a β-galactoside binding protein, although—as it is discussed further ahead—its binding range cannot be restrained only to β-galactoside ligands. Gal-3 is composed of a flexible N-terminal domain, containing up to 150 amino acid residues with sequences rich in proline, tyrosine, glycine, and glutamine. This collagen-like region rich in proline, glycine, and tyrosine ends up in a C-terminal domain with a carbohydrate recognition domain (CRD) containing about 135 amino acids. The CRD region is responsible for the signature pattern of the galectins family ^[16][17][18][16,17,18]. Although the ubiquitous expression, the main biological source is derived from immunological and collagen-producing cells, where it helps to establish cell recognition and communication through protein–protein or glycan–protein interactions ^[19][20][19,20]. For example, one important and recently elucidated Gal-3 effect in physiological conditions is the recruitment of endosomal sorting complexes required for transport to damaged lysosomes (ESCRTs), so they can be effectively repaired [21]. However, alterations of Gal-3 expression are strongly related to tumor growth, cancer cell proliferation, cell-to-cell adhesion properties, fibrosis stimulation, T-lymphocytes apoptosis, macrophage differentiation into infiltrative forms that stabilize tumor environment, and other features ^{[22][23][24][25][26][27][28]}[22,23,24,25,26,27,28]. Those attributions are shown in Figure 3, where the intestinal model was chosen, as it is simple to explain the interface between endogenous and exogenous stimuli that differently activate Gal-3 functions. Moreover, pectin is considered a bioactive compound when ingested as a food component or as a dietary supplement, a topic that is explained in the next sections. It can be noted in Figure 3 the different Gal-3 forms available at biological environments, such as the monomeric unit (intra and extracellular) recently secreted present at initial interactions with natural ligands and pentameric (chimeric appearance) after associations of other monomeric units through their N-terminal domain due to ligand stimulus ^[18][29][18,29].

While there are extensive high-quality data regarding Gal-3 binding sites modeled to small glycoconjugates and an important level of binding/inhibition by those ^[30][31][30,31], the present review looks forward to establishing ways described in the literature regarding pectin and its fragments and different molecular interactions with Gal-3 protein, as it is highly controversial due to structural variability and reproducibility of experimental conditions. This re view also covers the Gal-3 independent pectin interactions. The gathering of these data is fundamental for a better understanding of the overall perspectives regarding this promising—but not yet fully understood—area to be explored. Likewise, all the structural parameters, such as distinct molecular sizes, a higher number of galactan/arabinan side chains or galacturonic acid contents, methyl esterification, and other properties important to pectin biological effects are also discussed by in vitro and in vivo perspectives ^[7][32][33][7,32,33].

Structurally, Gal-3 N-terminal tail (NT) transiently interacts with its CRD F-face and is linked to the glycine/proline-rich sequence, conferring its uniqueness in the galectin family, allowing self-oligomerization ^[74][75][76][74,75,76]. Gal-3 CRD is composed of 11 β-sheets, whereas five belong to the F-face and six belong to the conventional β-galactosides binding S-face, one opposed to the other, forming a β-sheet-sandwich (Figure 4A–C). In the S-face CRD, there is the NWGR conserved motif (Asparagine–Tryptophan–Glycine–Arginine), which is similarly encountered in the BH1 domain from B-cell Lymphoma-2 (Bcl-2) anti-apoptotic molecule, and suggested as the possible interaction that enables apoptosis evasion in tumoral cells (Figure 4B) ^[19][77][78][19,77,78]. Within the CRD, specifically the S-face, there are some subsites that can be named for easier comprehension of binding interactions. There are two conserved subsites (C and D), two non-conserved (A and B), and one not well-defined subsite (E) [30], where their interfaces are mainly constituted of hydrogen bonds. The CD-associated subsites are a target of natural ligands such as the N-acetyllactosamine (LacNAc) Gal-3 inhibitor or the β-d-galactopyranoside residue located in the Lactose molecule, where it remains tightly bonded mainly to C subsite amino acids (Figure 4D) [79].

However, there is extensive literature regarding other synthetic and sugar-derived molecules (especially tetrasaccharides and thiosaccharides) that utilize the whole ABCD region (also mentioned as Gal-3 binding groove, as its morphological 3D structure conformation due to the interactions between the groups AB/CD and each one of them individually) for a better affinity performance and inhibition potential ^{[30][49][74][82]}[30,49,74,82]. In addition to this, the interaction of pectic poly- and oligosaccharides with Gal-3 is suggested through N-tail epitope recognition by pectin side-chain residues (e.g., galactans). The F-face interacts with β-galactosides (but also other portions), disrupting the CRD F-face binding with NT. Additionally, the same pectic structure could show multiple interactions involving both the S face region (disturbance of amino acids residues from the canonical binding site, e.g., 154–176 sequence observed with Heteronuclear single quantum coherence spectroscopy (HSQC spectra)) and F-face region (amino acids residues of β-sheets 7, 8, and 9 mostly, e.g., 210–225 sequence) (Figure 5) ^[76][83][84][76,83,84].

Other Gal-3 inhibitors that have been thoroughly and increasingly studied are pectin and its fragments. Some of the possible Gal-3 inhibition effects by pectin and fragments might include protecting pancreatic β-cells against oxidative and inflammatory stress [85]. Xu et al. [86] observed modified citrus pectin (MCP) downregulated pathways involved in myocardial fibrosis, but the authors did not study the Gal-3 inhibition by MCP in vivo, although Gal-3 was downregulated in the treated group [86]. Some other biological effects from Gal-3 inhibition are related to cancer proliferation control ^[7][32][7,32], with a strong positive relationship between overexpression of Gal-3 and carcinogenic processes, such as apoptosis evasion, higher cell invasion, and metastatic progression, which are key signatures in tumor and metastatic types of cells [87]. The structural relationship between the pectic chain and Gal-3 binding sites is also very important for the expected positive functional effects ^[33][88][33,88]. Extracellular Gal-3 biological functions are exerted mostly by interacting with glycoconjugates in cell surfaces, such as laminin and adhesin, signaling and activating specific pathways. Some studies regarding binding interactions between pectin and its fragments with Gal-3 are listed below (Table 1).

The Gal-3 binding range is considerably wide, including oligolactosamines, sulfated and sialylated glycans, and α-binding glycans, such as Fucα1-2, Galα1-3, and Galα1-4 added to the core of LacNAc molecule (as terminations) ^{[89][90][93][94]}[89,90,93,94], which could indicate why non-β-Gal pectic fragments and other sources can still perform positively in some binding experiments. The β-1-4-galactan side chains inside the pectic RG-I domains have been highly attributed as the molecular factor involved in direct inhibition of Gal-3 (recombinant proteins and native proteins from cells), mainly discussed as a motif varying reaction, such as galactose residues in the middle or at terminal parts of those linear molecules. The longer galactan side chains in RG-I molecules identified in MCP and ginseng pectin were also associated with a stronger interaction with Gal-3 in vitro ^[40][95][40,95]. Similar positive binding affinity results with Gal-3, higher than observed with potato galactan, were obtained when isolating a 22.6 kDa RG-I polysaccharide from pumpkin [91]. Meanwhile, the RG-II enriched fractions extracted from Panax ginseng flower buds, with a high methyl-esterification and backbone substitution, as well as with lower content of galactose residues and low molecular weight, were associated with an absence of Gal-3 binding [3]. Highly esterified HG samples also did not inhibit Gal-3 [3]. However, other ginseng samples with an equivalent ratio between HG and RG-II regions had a positive binding affinity to Gal-3 in a similar way to the synergistic effect of HG and RG-I of citrus pectin ^[34][83][34,83]. In the latter case, the authors also suggested that the unesterified characteristic of pectin, alongside non-substituted GalA segments, were crucial structural elements for the observed biological effects [83]. Following this trend, commercial lemon pectin samples (from CP Kelco) with a low degree of methyl-esterification and low molecular weight were consistently and extremely potent in preventing negative outcomes in human islets with β-cell apoptosis (diabetes model) induced stress in vitro [85], in a dose–response manner. Gal-3 inflammatory stress induction was analyzed by evaluating oxygen consumption rate (OCR) in the presence and absence of a Gal-3 known inhibitor, α-lactose. After the previous incubation with α-lactose, the pectin sample effects that reversed OCR reduction induced by streptozocin and minimized inflammation induced by cytokine incubation were greatly compromised. The author’s suggestions were based on the observed effects derived from pectin binding to Gal-3 [85]. However, specific data regarding the connection between the in vitro effects and Gal-3 inhibition by pectins were not proposed.

As already mentioned before in this topic, Gal-3 does not have only one direct binding site toward polysaccharides, known as the canonical S-face (sugar-binding) region inside the CRD. This can help to explain the different results in distinct binding experiments based upon competitive inhibition and chain length [88]. Detailed data suggest that the Gal-3 N-terminal binds to a 60 kDa RG-I-rich pectin portion of ginseng through galactans located in RG-I ramifications [92]. This same molecule with removed ramifications (Rhap and GalpA intercalated residues only) did not bind with Gal-3 [92]. Another molecule rich in galactose—but not derived from pectin—is a galactomannan isolated from Cyamopsis tetragonoloba guar gum flour (1-4-β-d-mannopyranose backbone with 1-6-α-d-galactose ramifications) also did not bind with Gal-3 [92]. However, experiments performed with potato galactans oligosaccharides derived from pectin had similar results as observed for the ginseng RG-I regarding Gal-3 binding [92], demonstrating the probable uniqueness structural features of pectin-derived molecules that can result in Gal-3 binding.

Gal-3 F-face has shown strong binding signals with pectin molecules, mainly at lower polysaccharide concentrations, opening more space to conventional S-face binding in higher concentrations. Like S-face, the F-face non-orthodox site is enriched by hydrophilic and charged amino acids residues. In addition to not having the Trp key-residue, other hydrophobic side chains could have similar functionality, as well as similar concave shape conformation ^[84][92][84,92] (Figure 4A–D). It is specified that resonance broadening was attributed as the primary capability of binding between Gal-3 and the RG-I-4 (a ginseng-derived rhamnogalacturonan), but also that broadening would be directly correlated to higher noise and lower sensitivity in analytical techniques ^[84][92][84,92], a factor which has to be taken into account. The presence of those non-conventional sites was suggested when lactose (CRD S-face inhibitor) did not interfere in RG-I binding to Gal-3 [40]. Furthermore, the binding of a determined ligand to the F-face of Gal-3 CRD could allosterically modify S-face residues. These shifts influence the conformation of the opposing face affecting the affinity between ligand (peptide, glycoconjugate, or polysaccharide) and the Gal-3, improving or attenuating the inhibitory/activity effects [76]. Moreover, Gal-3 N-terminal tail phosphorylation, although having little impact in CRD F-face, may be related to allosterically influencing carbohydrate-binding to the canonical CRD S-face site [76]. This structure-related information and respective identification method improvement contributed to more profoundly describing how the synergistic effects between pectin fragments work, as will be thoroughly discussed below.

Unusual non-galactoside poly-oligomeric ligands could act through multivalence interaction with Gal-3. The synthesis or identification of molecules that represent potential inhibitors of multimeric (chimeric) Gal-3 to cell-membrane glycoconjugates could be critical for minimizing known observed effects, such as the glycoclustering of receptors resulting in apoptosis induction of T cells [96]. Chelation, subsite binding, and reassociation of the binding site towards different monomeric structures within a molecule are also candidates for multivalent interactions with Gal-3 [97]. Although pectins and other natural ligands are harder to validate in comparison to synthetic compounds, parameters such as molecular flexibility and occupation of binding sites can be less manipulated/predicted [98]; the study of monosaccharide and consequently substructures ratios influencing Gal-3 binding is a promising area of investigation.

A recent in vitro study analyzed Gal-3 inhibition and MCF cell viability after specific enzymatic modification of citrus water-soluble fraction (WSF) rich in pectin. It was demonstrated that although β-1,4-galactan side chains in RG-I are still considered the most accountable molecular part for the observed effects, the partial removal of the side chains composed of other monosaccharide residues, such as α-1,5-arabinan, also contributed to inferior results both at cancer cell proliferation and direct gal-3 binding [33]. Other complex structures, such as the pectic acidic fractions extracted from Camellia japonica pollen, described as an RG-I-like polysaccharide, had their branched α-1-3,5 arabinan and type II arabinogalactans attributed to their strong Gal-3 inhibition effects [53]. It is suggested that, despite not having a significant relationship to the ratio of RG-I/HG, pectin-rich WSF bioactivity was dependent on cooperation between RG-I and HG regions [33]. In addition to this pectin fragment ratio, the monosaccharide residue composition ratio had an impactful performance. The Galp amount is necessary for the best Gal-3 inhibitory results since pectic fragments with lower Galp/Araf ratio resulted in lower Gal-3 inhibition even with similar molecular sizes than other studies (50 to 60 kDa) [52].

There are also in vitro data for anti-proliferative characteristics for sugar-beet pectin, in which both the RGI/HG backbone and the galactans/arabinan side chains exhibited those positive effects in HT-29 (human colorectal adenocarcinoma) cell populations [99]. The alkali treatment not only increased the RG-I/HG ratio (which translates to more neutral sugar side chains) but also enhanced the anti-proliferative effects. The removal of almost all side chains in the sample did not completely abolish the effects, denoting the importance of the cooperative effects between different pectic structures ^[99][99]. Similar results were obtained in our lab, in which papaya uronic fraction, a GalpA fraction enriched with galactans, had the best in vitro results in inhibiting Gal-3 hemagglutination than neutral sugar-enriched fractions [7]. The difference of the samples was the degree of methylation, in which the former had low DM, and the latter had high DM.

Zhang and colleagues [83] indicated that a combination of RG and HG polysaccharides enhances the Gal-3 binding in vitro through HG interaction with RG, opening more Gal-3 binding epitopes in the RG molecule. At a particular RG/HG molar ratio, the interaction between polysaccharide and the F-face of Gal-3 could establish the new activated binding epitopes due to the higher prevalence of galactose residues, facilitating the S-face CRD interaction. This interaction between HG and RG could perform alterations in its conformation and increase or enhance the synergistic functional effects [83]. Each 130 kDa molecule of the isolated pectin fraction could bind up to 16 Gal-3 molecules. Overall, the combination of both structures showed biologically better activity than separated molecules [83]. Additional ginseng HG-rich fractions were responsible for inducing apoptotic process in vitro at higher doses and cell cycle arrest at lower doses in HT-29 cells, and these biological effects were increased after heat treatment of the polysaccharide fractions [100].

Another ginseng polysaccharide fraction had 91 kDa, an Araf/Rhap ratio of 2:1, and a Galp/Xylp ratio of 1:1 and was characterized as xylo/rhamnogalacturonan I with arabinan/galactan side chains. This fraction was evaluated for in vitro Gal-3 inhibition, anticancer effect, and in vivo gut microbiota modulation [101]. The authors indicated that the xylans were mostly responsible for the microbiota’s healthy recovery and protection. Meanwhile, arabinogalactan side chains can interact with Gal-3 down-regulating tyrosinase through its N-glycan binding site [101]. Overall, the polysaccharide was effective in restoring normal levels of the important interleukin for tumor rejection and T cell activation, such as IL-10. The polysaccharide also modulated IL-17, a mediating molecule over-produced by the tumor cell microenvironment, revealing a multi-targeted functionality of the ginseng polysaccharide [101]. Although studied for many years, this pectic polysaccharide immunomodulatory property is still a trending topic, especially when the structural differences influence the interaction between the pectin and immune receptors, such as the toll-like receptor family (TLR) and interleukins at the macrophage cell surface ^[73][102][73,102], and will be more profoundly discussed later.

After determining the direct inhibition potential by competing with Gal-3 ligands in ECM, it was demonstrated that MCP can also downregulate Gal-3 expression. The in vitro induction of cell cycle arrest at the G2/M phase, through Cyclin B1 decrease and cyclin-dependent kinase 1 (Cdc2) phosphorylation, disrupts the Gal-3 pathological function of maintaining cell cycle arrest at the late G1 phase that leads to evasion from apoptosis induction [103]. Gal-3 can also induce phosphorylation in the signal transducer and activator of transcription 3 (STAT-3) in ovarian cancer cell spheroids. Although demonstrating slight decreases in cell viability after treating with paclitaxel, a strong synergistic effect between this drug and MCP was observed. The IC50 values decreased when both compounds were together, alongside a 70% increase in caspase-3 activity and a 75% Cyclin D1 expression level decrease against the values obtained using only paclitaxel [104].

Regarding fibrosis induction, MCP alleviated liver fibrosis and stress-induced secretions, such as decreased malondialdehyde (MDA), TIMP metallopeptidase inhibitor 1 (TIMP-1), collagen-1 α-1 (Col1A1), and Gal-3 expressions, improving HSC apoptosis rate and the upregulation of glutathione and superoxide dismutase in vivo [105]. Renal fibrosis-related biomarkers in an adult male Wistar murine model were also attenuated by treatment with MCP in drinking water. Albuminuria, proinflammatory cytokines, such as small inducible cytokine A2, osteopontin, epithelial transforming growth factor-β1, and other epithelial to mesenchymal transition factors, were all controlled or restored to normal levels after treatment in normotensive experimental models of renal damage [106].

Gal-3 is up-regulated by aldosterone, mediating inflammatory and fibrotic response in vascular muscle cells in vitro and in vivo [107]. The mechanism was demonstrated as inducing Gal-3 secretion by macrophages via phosphatidylinositol 3-kinase inhibitor/AKT and nuclear factor κB transcription signaling pathways in vitro and in vivo [108]. Furthermore, in aldosterone-induced cardiac and renal injuries, MCP subcutaneous injection in mice—different from the major in vivo experiments when MCP was diluted in drinking water—downregulated Gal-3 at protein and mRNA levels while also minimizing cardiac adverse effects induced by aldosterone salt [109]. In addition, for the renal injuries, MCP inhibited Gal-3 at the tubular level but not in the glomeruli, which is highlighted by the authors since Gal-3 is not expressed at the glomerular level [109]. Nephrotoxicity is a major side-effect of cisplatin chemotherapy, which contributes to the number of acute kidney injury (AKI) hospitalizations. Mice that received 1% MCP in drinking water during the same period after cisplatin injection had better morphometric preservation and prognostic regarding renal fibrosis, such as lower serum creatinine levels, Gal-3, fibronectin, and collagen-1 expression, which could point to a protective effect of MCP in this treatment [110]. Specific mechanisms and routes of Gal-3 downregulation, however, were not successfully addressed by those studies. Therefore, those points should be considered for better knowledge of the possible link between treatment and the biological effect.

AKI-induced mice through the ischemia/reperfusion (IR) model led to Gal-3 expression, cardiac injury, and systemic inflammation. The authors indicate that the induction of inflammation alongside cardiac fibrosis was Gal-3 dependent, demonstrated through significant reduced deleterious outcomes in genetically Gal-3-KO mice that received orally MCP (100 mg/kg/day), which was also seen at WT-MCP-treated mice group [111], but the expression of other markers such as MCP-1 and ICAM-1 mRNA were also decreased by MCP treatment. Rats submitted to myocardial IR also had better prognostics when treated with MCP (in drinking water) one day before and eight days after the procedure, such as improved perfusion, serum brain natriuretic peptide normalization, IL-1b and C-reactive protein (CRP) reduction, lower Gal-3 expression levels at the ischemic tissue, and other parameters. The Gal-3 specific blockade suggested was measured by the authors through the expression of two proteins that are down-regulated by Gal-3, fumarase, and reticulocalbin-3, which were restored after MCP treatment [112]. Perindopril and MCP (in drinking water) were similarly effective as treatments for ischemic heart failures in rabbit models, lowering Collagen-I, III, and Gal-3 mRNA and protein expression, alongside slight reversion of histological remodeling (an important level of fibrosis was still maintained, visible by Masson staining of myocardial tissues). However, the exact mechanisms by which MCP or perindopril could exert their observed effects are still unclear and were not directly addressed [113]. Both the effects of Gal-3 and isoproterenol-induced left ventricular systolic dysfunction in the mice model with selective hyperaldosteronism, alongside myocardial fibrosis installation. Combined therapies with MCP in drinking water and canrenoate as an aldosterone blocker enhanced the anti-inflammatory and anti-fibrotic effects [114]. Rats in a pressure overload model that were treated with MCP in drinking water had lower Gal-3 mRNA expression and Gal-3 immunostaining-confirmed presence than control. Other fibrosis-related proteins such as α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), transforming growth factor (TGF)β-1 and fibronectin, and also inflammation factors such as IL-6, IL-1β, and TNF-α were at lower levels than control [115]. The studies described herein regarding oral MCP supplementation, either isolated or in combination with other molecules: (i) did not only show effects influencing Gal-3, but also other pathways, receptors, and protein expressions; (ii) authors did not explain, or at least brought up for the discussion, if orally consumed MCP could reach the target organs, such as kidney, heart or liver. These factors should be considered whenever reading these interesting but overly biased results, denoting not-so exclusive observations that are also promising but opening many questions regarding the systemic distribution of pectin’s pre- or post- colonic fermentation.

As mentioned before, there are physiological activation pathways that could involve Gal-3 action, important data to account for whenever testing new possible therapeutic agents that could selectively induce activation/apoptosis depending on the target [116]. This in vitro work has demonstrated that recombinant human Gal-3 initiates three distinct pathways, one for T cell activation (PIK3) and two hybrids (reactive oxygen species and protein kinase C—ROS and PKC, respectively). Furthermore, MCP and acidic fraction from ginseng roots inhibited T cell apoptosis in vitro by caspase-3 cleavage, and ginseng-derived fractions did not interfere in IL-2 secretion [116]. One of the Gal-3 connections established by the authors to the observed effects is proposed as upregulation of PI3K/Akt phosphorylation, in which the presence of an inhibitor for each molecule also inhibited IL-2 secretion. However, no similar effects regarding the effects of MCP in cardiac protection, fibrosis regulation, and normalized hypertension were observed in a recently published clinical trial from Lau et al. [117] in patients with high Gal-3 levels and established hypertension. The results raise many doubts and counterpoints regarding the MCP effects in in vitro and in vivo studies to be replicated in humans, which is discussed in the next chapter.

Recently, Gal-3 has been treated as a treatment target and prognostic marker for patients with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Higher serum levels of Gal-3 were related to a tendency of severe acute respiratory distress syndrome (ARDS) development, and alongside IL-6 and CRP, Gal-3 was demonstrated to be the best predictive power for mortality outcome [118]. There are also positive correlations between Gal-3 and other inflammatory markers such as PTX-3, ferritin, and the marker of endothelial dysfunction, sFlt-1 [119], which could be utilized for intensive care unit (ICU) admission biomarker. A phase 2a study, the first clinical trial using an inhalator treatment targeting Gal-3-GB0139—associated with the standard of care procedure (dexamethasone)—identified lower Gal-3 serum levels, higher mean downward of CRP levels (although higher CRP was identified at first in the treatment group) and other inflammatory agents and better fibrosis marker levels than the control group. However, there was no statistical difference between patient mortality rates between groups [120]. This enhances and augments the discussion to further explore alternative treatments regarding Gal-3 inhibition.