**2.3 Yeast MAPK cascades**

Five MAPK pathways have been well characterized in the budding yeast, *S. cerevisiae*. In vegetative cells, the four MAPKs Fus3, Kss1, Hog1, and Slt2/Mpk1 are involved in the mating-pheromone response, the filamentous-invasion pathway, the high osmolarity growth, and the cell integrity pathway, respectively. The fifth MAPK, Smk1, is believed to play a role in spore wall assembly [16, 17].

Haploid yeast cells sense the reciprocal mating pheromones (α-factor or a-factor) through Ste2 and Ste3 GPCRs. The signal is then transmitted by GTPases to the p21-activated kinase (PAK)-like kinase Ste20, the MAPK scaffold Ste5, Cdc42, a guanine-nucleotide exchange factor (GEF), and Far1. Ste5 signals and serves as a scaffold that links the MAP4K and the MAPK signalosome (Ste11 → Ste7 → Fus3; the latter is the ERK1 homolog) [18].

The high osmolarity glycerol (Hog1) MAPK, the yeast homolog of p38, is activated in response to osmotic stress as a consequence of signaling elicited from two upstream-independent mechanisms (Sln1/Sho1). The Sln1 sensor is the primary osmosensor and is a complex variation of the well-known bacterial two-component system. Upon osmostress, inactivation of the transmembrane histidine kinase Sln1 leads to the derepression and activation of the MAP3K (Ssk2/22) via Ypd1/Skk1. The Sho1 osmosensing branch is mediated by mucin-like proteins (Hkr1 and Msb2) and ultimately activates the MAP3K Ste11 through the integral transmembrane

protein Opy2, the GTPase Cdc42 and the MAP4K Ste20. These two osmosensing branches converge at the MAP2K (Pbs2) that acts as a scaffold protein for phosphorylation of the MAPK Hog1 [19].

The filamentous/invasive growth pathway leads to the activation of Kss1 (an ortholog of mammalian Erk2) under nutrient limiting conditions and, to a much lesser extent, to pheromone stimulation. Remarkably, it relies on proteins involved in the HOG pathway and the pheromone pathway (Mep2, Gpr1, Msb2, Sho1, Ste20, Ste11, and Ste7). In this case, specific activation of Kss1 is achieved by the absence of the Ste5 scaffold that liberates Ste7 allowing its interaction with Kss1 [20].

Cell wall instability is sensed through the cell wall integrity pathway (CWI) (Mpk1 MAPK) and is detected by five mechanosensors (Wsc1–3, Mid2, and Mtl1) that interact with the guanine nucleotide exchange factor (GED) Rom2 to activate Rho1 GTPase leading to protein kinase C (Pkc1) phosphorylation. Yeast Pkc1 serves as a MAP4K that phosphorylates the MAP3K Bck1, which leads to activation of Mpk1 through activation of the redundant MAP2K (Mkk1/2). Despite the absence of a cell wall in higher eukaryotes, mammalian ERK5 has been characterized as a functional ortholog of the CWI pathway [21].

Finally, the meiosis-specific MAPK Smk1 controls the postmeiotic program in diploid cells subjected to nutrient starvation. Activation of Smk1 differs from activation of MAPKs in the classical three-tiered MAPK cascade in which a CDK-activating kinase (CAK1) phosphorylates Smk1 and induces its auto-phosphorylation [22].

#### **2.4 Dynamics of signal transduction**

According to the nature of its input signal, MAPK activation can range from minutes (transient) to hours (sustained). The dynamics of MAPK activation results from the interplay between the extracellular environment and a myriad of intracellular feedforward/feedback regulators that give rise to cell fate decisions during cancer progression or development. For example, pulses of or continuous high EGF administration induce transient ERK activation and cell proliferation in rat adrenal cells, whereas repeated pulses of low EGF induce ERK-mediated differentiation into sympathetic-like neurons [23]. Similarly, different dynamics of JNK can generate opposing behaviors as persistent JNK activation has been shown to trigger apoptosis while its transient activation promotes cell survival [24]. Despite different signaling dynamics can determine cell fate, the underlying molecular mechanisms are not well understood.

#### **2.5 Output responses to MAPK activation**

The first response to extracellular insults is the immediate arrest of cell growth and hence a blockage of or a delay in cell cycle progression. Once activated, the different MAPKs phosphorylate a large number of substrates that distribute over many cellular compartments. In general terms, the ERK1/2 pathway is mainly associated with the promotion of growth in most cell types and is often linked with differentiation processes, although it can occasionally suppress cell survival [25]. Similarly, ERK5 also promotes proliferation during normal cell growth and differentiation [3]. On the other hand, JNK and p38 pathways have a well-established role in apoptosis, although they have also been shown to contribute to survival, immunity, development, and differentiation [4, 26–29]. One of the main mechanisms by which MAPKs modulate the abovementioned cellular processes is by controlling gene expression, mainly through regulation of the transcriptional machinery, chromatin structure, and post-transcriptional modifications.

**25**

**Figure 2.**

*Shaping the Transcriptional Landscape through MAPK Signaling*

**3. Nuclear localization and function of MAPKs**

In resting cells, MAPK components are usually located in the cytoplasm through their interaction with different anchor proteins, scaffolds, or phosphatases. Upon stimulation, MAPK signaling cascades rapidly transmit information into the nucleus to ensure the appropriate transcriptional response (**Figure 2A**). Across eukaryotes, this process is often initiated by transient accumulation of the MAPKs within the nucleus. The duration and the type of stimuli affect the nuclear localization of MAPK signaling proteins and play an important role in determination of the transcriptional output. Translocation of MAPK molecules requires specialized transport elements to travel through the nuclear pore complex (NPC).

*MAPK regulatory roles on gene expression: From transcription initiation to translation. (***A***) Activated MAPK is released from its cytoplasmic anchor and translocated to the nucleus. (***B***) From top and clockwise, MAPK regulation on different targets is represented by a black arrow; MAPKs are known to activate transcription factors (TFs) through phosphorylation and to recruit PolII to initiate transcription. Moreover, MAPKs also target several chromatin remodelers (Ch Rem) and histone modifiers (Hist mod) to regulate chromatin structure and histone eviction. MAPK interacts with transcription elongating (TEF) and termination factors to enhance transcription rate. mRNA is shown as a green line with a 5*′ *cap (green dot) and the polyA at the 3*′ *end. MAPKs also regulate several stabilizing RNA-binding proteins (RBPs), target miRNA processing through the microprocessor complex (MC), nuclear exporters, and splicing factors. Finally, MAPKs are also known to regulate translation elongation initiation factors (eIFs) to stimulate rapid mRNA translation. Overall, all these*

*mechanisms aim to promote a rapid and efficient response for maximal cell adaptation.*

*DOI: http://dx.doi.org/10.5772/intechopen.80634*

*Gene Expression and Control*

Kss1 [20].

phorylation of the MAPK Hog1 [19].

functional ortholog of the CWI pathway [21].

**2.4 Dynamics of signal transduction**

**2.5 Output responses to MAPK activation**

structure, and post-transcriptional modifications.

protein Opy2, the GTPase Cdc42 and the MAP4K Ste20. These two osmosensing branches converge at the MAP2K (Pbs2) that acts as a scaffold protein for phos-

The filamentous/invasive growth pathway leads to the activation of Kss1 (an ortholog of mammalian Erk2) under nutrient limiting conditions and, to a much lesser extent, to pheromone stimulation. Remarkably, it relies on proteins involved in the HOG pathway and the pheromone pathway (Mep2, Gpr1, Msb2, Sho1, Ste20, Ste11, and Ste7). In this case, specific activation of Kss1 is achieved by the absence of the Ste5 scaffold that liberates Ste7 allowing its interaction with

Cell wall instability is sensed through the cell wall integrity pathway (CWI) (Mpk1 MAPK) and is detected by five mechanosensors (Wsc1–3, Mid2, and Mtl1) that interact with the guanine nucleotide exchange factor (GED) Rom2 to activate Rho1 GTPase leading to protein kinase C (Pkc1) phosphorylation. Yeast Pkc1 serves as a MAP4K that phosphorylates the MAP3K Bck1, which leads to activation of Mpk1 through activation of the redundant MAP2K (Mkk1/2). Despite the absence of a cell wall in higher eukaryotes, mammalian ERK5 has been characterized as a

Finally, the meiosis-specific MAPK Smk1 controls the postmeiotic program in diploid cells subjected to nutrient starvation. Activation of Smk1 differs from activation of MAPKs in the classical three-tiered MAPK cascade in which a CDK-activating kinase (CAK1) phosphorylates Smk1 and induces its auto-phosphorylation [22].

According to the nature of its input signal, MAPK activation can range from minutes (transient) to hours (sustained). The dynamics of MAPK activation results from the interplay between the extracellular environment and a myriad of intracellular feedforward/feedback regulators that give rise to cell fate decisions during cancer progression or development. For example, pulses of or continuous high EGF administration induce transient ERK activation and cell proliferation in rat adrenal cells, whereas repeated pulses of low EGF induce ERK-mediated differentiation into sympathetic-like neurons [23]. Similarly, different dynamics of JNK can generate opposing behaviors as persistent JNK activation has been shown to trigger apoptosis while its transient activation promotes cell survival [24]. Despite different signaling dynamics can determine cell fate, the underlying molecular mechanisms are not

The first response to extracellular insults is the immediate arrest of cell growth and hence a blockage of or a delay in cell cycle progression. Once activated, the different MAPKs phosphorylate a large number of substrates that distribute over many cellular compartments. In general terms, the ERK1/2 pathway is mainly associated with the promotion of growth in most cell types and is often linked with differentiation processes, although it can occasionally suppress cell survival [25]. Similarly, ERK5 also promotes proliferation during normal cell growth and differentiation [3]. On the other hand, JNK and p38 pathways have a well-established role in apoptosis, although they have also been shown to contribute to survival, immunity, development, and differentiation [4, 26–29]. One of the main mechanisms by which MAPKs modulate the abovementioned cellular processes is by controlling gene expression, mainly through regulation of the transcriptional machinery, chromatin

**24**

well understood.


**3. Industrial applications**

Alginate has various applications in industries, such as thickener, emulsifier, and stabilizer, increasing the viscosity of gels, water preservation, transfer of drugs and biomolecules, and edible films and coatings. A variety of alginates are accessible in the market according to the distribution of M and G blocks, molecular weight, purity, and composition. The Food Standards Agency has approved the "E numbers" to alginates for usage as food additives, and has allowed a variety of sodium, ammonium, potassium, and calcium salts as well as alginic acid esters and propylene glycol alginate. These compounds are used in the food industry depending on different degrees of concentration and viscosity. Sodium alginate is the most common alginate extracted from seaweed. In various countries and on diverse scales, sodium alginate is used in the biotechnology industry as a gelling agent and colloidal stabilizer. Alginate has low solubility in liquids and high viscosity, and it has attracted the attention of some industries (**Table 2**) [30].

Today, environmental pollution caused by the disposal of waste packaging materials, specifically artificial synthetic polymers with a long-life cycle in nature, is regarded as one of the most important concerns at the global level. One of the ways to decrease the volume of packaging waste is to use bio-polymers in packaging. In recent decades, special and increasing attention has been paid to edible films and coatings that have the feature of biodegradability as appropriate and promising alternatives to synthetic polymers. The use of edible biopolymers for preparing films and coatings for food protection has a long history in the packaging industry and has attracted many researchers' attention [31–33].

Among the significant benefits of edible films are antimicrobial and antioxidant properties. The cheapness of alginate, water-binding capacity, thickening, and emulsifying properties have made it essential in various industries for food and pharmaceutical packaging. Alginate films or nanocapsules gained from them also help to create natural products more attractive, such as additives, colors, and preservatives. Alginate edible coatings consist of a thin layer on the product's surface, and their commercial applications face limitations. Of course, many experimental studies have been performed on food coating applications. In industrial dimensions, by spraying on irregular surfaces and vacuum tanks, it is possible to prevent microbial pollution and loss of food taste. The alginate-based edible film is constituted on the surface of food products by methods, such as dipping, coating, extrusion, casting, spraying, and brushing and can be used. The most common production method for food films is the casting method. For this purpose, a mixture of alginates with deionized water, softener, and other ingredients is used, and then it is stirred on a hot plate and poured on the surface. Silicone foils are used because of their ability to form thin layers and low adhesion, and Teflon sheets are used due to their high adhesion. Alginate is commonly used to extend the shelf life of food. Some compounds, such as essential oils, pureed fruits, natural extracts, and vegetables, are combined with alginate. Alginate films decrease spoilage and food waste and reduce foodborne illnesses. To expand the storage time and dissuade spoilage of food, such as mushrooms, tomatoes, turkey fillets, shrimp, meat, chicken thighs, cheese, etc., alginate compounds and coatings are used too. In the meat packaging industry, structures, such as calcium alginate are utilized as a replacement for natural coatings, such as the coating of fermented sausages. Techniques, such as immersion, spraying, or brushing are used for direct coatings on the surface of food, such as vegetables, meat, and fruits, but indirect coatings are for the surface of packaging materials [5, 34–37].

Properties, such as gelling and thickening of alginate are used in food, such as animal food, sauce, ice cream topping, syrup, etc. The use of propylene glycol alginate in a very small portion creates a soft texture as well as the production of frozen crystals and furnishes a favorable feeling in the ice cream production process. Another use of alginate in the food industry is to stabilize fruit drinks. The use of alginate in all kinds of sauces is also common [30, 38].

Studies showed that iron-rich foods in combination with Alginate are very beneficial. Combining these foods with Alginate increases iron absorption. Modified starch

#### **Table 2.**

*Applications of alginate in the fields of industry.*

is considered an essential ingredient in food industry applications. Studies show that some physicochemical properties of ordinary corn starch increase in the presence of Alginate [39, 40].

Alginate ratio and monomer composition is effective in some of its physiological and rheological properties. These properties also affect the applications of Alginate, such as thickening, stabilizing, and gelling. Because of its antioxidant properties, such as suitable molecular weight, monomer composition, and branching, Alginate prevents the generation of some harmful substances, such as oxidative compounds and free radicals, in foods and improves the quality of foods. Sodium Alginate extracted from some seaweeds is not sensitive to high temperatures due to the G/M monomer composition ratio, is stable in acidic conditions and has good antioxidant properties and has been used in the food industry [41–43].

For some probiotic food products, Alginate can be used to encapsulate the species and valuable substances in the digestive system. These tiny coatings protect helpful substances and bacteria during the digestive system and are very useful for delivery. In some chocolates and probiotic products, Alginate is used as a stabilizer, thickener, etc. [23, 44].

Alginate is used in polyelectrolyte membrane fuel cells, such as methanol and biological fuel cells, as well as alkaline-polymer fuel cells. Alginate compounds can also improve methanol permeability and proton conduction in some membranes [45–47]. The weak stability of antimony during the repeated insertion and unloading process of sodium ions leads to an unwanted application as an anode material in sodium-ion batteries. To solve this problem, Studies have shown that the electrochemical stability of the antimony nanoparticle coating can be enhanced with a carbon layer of sodium Alginate [48].

The limited water resources and the increasing expansion of industrial units, the growth in the production of industrial wastewater, and the pollution of water resources are among the social and economic problems. Wastewater from factories and production centers, such as textile, paper, pharmaceutical, and leather industries problematizes the process of wastewater purification due to the consumption of various chemicals and dyes. Alginate is also used in the purification of industrial wastewater pollution. Heavy metals and other microbial factors from the production and processing of industrial materials enter water and soil environments and cause environmental pollution. Numerous studies have been carried out to treat polluted wastewater using absorption technology and thus remove them. Combinations with Alginates, such as gels, nanoparticles, and microorganisms, can easily absorb and purify heavy metals, toxic compounds, and other industrial pollutants at a meager cost. Microorganisms that can produce Alginate among their compounds can absorb heavy metal ions. Likewise, by using Alginate, they can purify polluted water by changing and transforming polluting compounds. The composition of constructive monomers, as well as branches in the composition of Alginate, boost the removal property of ions and heavy metals. Alginate hydrogel absorption feature can also be used to absorb metals and

industrial waste pollution [7, 49, 50]. Features of Alginate gel, like the thickening and stabilizing, is used in some papermaking and textile industries [8, 51].

The Stabilizing and stability properties of alginate can also be used in the production of biotechnology compounds. To perform some production and conversion processes, enzymes and microorganisms are used, which requires their stabilization and stability during the process. Enzymes can be immobilized on alginate as a stable substrate to carry out their process properly and prosper its efficiency. An example of this procedure is the conversion of agricultural trash, such as cellulose into hemicellulose, which stabilizes the cellulase enzyme on the alginate substrate and makes it more efficacious and stable. An example of this procedure is the conversion of agricultural trash, such as cellulose available in hemicellulose. Cellulase enzyme stabilized on the alginate substrate and become more efficacious and stable [52, 53]. Another case is to make capsules and porous enclosures from alginate for the accumulation of producing microorganisms. This feature prevents the distance of microorganisms and causes them to be closely related for better efficiency. Alginate is also employed as an enclosing matrix for drug delivery or some materials in the pharmaceutical and biotechnology industry (**Figure 3**) [3, 54].

Synthetic silver and gold nanoparticles (AuNPs) are widely used due to their colloidal stability and some unique chemical, physical, and biological properties. Gold nanoparticles (AuNPs) can be stabilized with sodium alginate (SA)/chitosan (GC) compounds in aqueous solutions at room temperature. Also, the distribution of different sizes of AuNP gold nanoparticles is obtained according to sodium alginate/ chitosan polymer stabilizers [55, 56].

One of the ways to enhance the biodegradability of alginate is to oxidation the adjacent DL groups in the structure of uronic acid rings to aldehyde groups. Alginate oxide (alginate dialdehyde) is used to make biodegradable hydrogels. Also, due to the quick chemical reaction between amine and aldehyde groups, aldehyde alginate is used in the manufacture of chemical hydrogels with Schiff reaction and as biological ink [57, 58].

The water transmission pipeline system, including the drinking water network, sewage water network and circulating water system, is closely related to the safety of the water environment and human health. However, the corrosion of water transmission pipelines has become a great problem in practical applications, which affects both the lifetime of the pipeline and the quality of the water environment. Studies have shown that making a sustainable and environmentally friendly coating using sodium polycarbonate polyethylene/alginate coating is effective for corrosion protection of water transmission lines [59, 60]. There is also a notable concern for membrane fouling in membrane-based desalination technologies, especially in reverse osmosis (RO) membranes for implementing, such technologies. Some studies have

### *Applications of Alginate in the Fields of Research Medicine, Industry and Agriculture DOI: http://dx.doi.org/10.5772/intechopen.110209*

found sedimentation using a silica/sodium alginate combination of reverse osmosis membranes to be helpful for seawater desalination [61, 62].

Flotation in the term means buoyancy and is one of the ways of concentration in the industry or increasing the grade of minerals (material enrichment). Today, flotation is undoubtedly the most important and comprehensive approach to mineral separation. Scheelite (CaWO4) is a common mineral and generally occurs in sediments with other minerals, such as calcite (CaCO3) and fluorite (CaF2). Currently, flotation is the most common technique used to isolate scheelite from calcite and fluorite. Research has shown that sodium alginate is effective in the flotation separation of scheelite from calcite and fluorite using sodium oleate as a collector. Sodium alginate has the potential to chelate calcium minerals and then hydrophilic their surface in solution [63, 64].