Introduction

The escalating prevalence of disease and fatalities among humans, due to a variety of factors such as pollution and contemporary lifestyle habits, not only presents a significant threat to public health but also emphasisess a pressing societal concern. This concerning state of affairs extends to the context of marine ecosystems, especially when considering  their vital role in providing sustenance (both food and water) as well as having a positive effect on our well-being through activities both near and in the water. Adopting a holistic approach is imperative in addressing these interconnected challenges in order to safeguard both human health and the well-being of marine ecosystems. In this context, broad approaches to the health and well-being of communities have been developed to improve the quality of life for humans, animals as well as other organisms within their environment in a one-health ethos (Zinsstag et al. 2011). This aim can be realized through an enhanced collaboration between  disciplines looking at different aspects of human health, animal health, eco-system viability etc.. Integrated approaches have also been applied to save water and  protect aquatic environments to improve public health (Zinsstag et al. 2018).

Water is a remarkable molecule whose dynamics are essential for many biological processes, including protein folding and proton transport (Fayer 2011). Water is also an active matrix of life itself being at the basis of  most lifeforms on our planet; being a key component of cells, organisms and  indeed the global biosphere (Ball 2017). Taking into account these fundamental principles, people derive various benefits from water sources, such as water-based therapies, which have a longstanding history and continue to play a significant role in alternative and complementary healthcare practices (Fig. 1). Some of these, for example, utilize the benefits of subjecting the body to different temperatures;, cold water is used to enable analgesic and antiphlogistic effects allowing temporary peripheral vasoconstriction; whereas, warm water activates opposite effects, i.e., muscle relaxation, through dilatation of blood vessels (Reger et al. 2022).

Fig. 1
figure 1

Oceans provide numerous advantages for human health and sustenance. However, a concerted effort is imperative to protect marine ecosystems, including riparian vegetation, through a comprehensive ‘One-Health’ approach. The photograph used in the background was taken by Giovanni N. Roviello on the Domitian coast, south Italy in winter 2023

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The beneficial effects experienced through water therapies in healthy or diseased individuals definitely depend on the external or internal use of water in any of its forms (water, ice, steam) with diverse effects on various body parameters, including metabolic rate, systolic and diastolic blood pressure, and heart rate (Mooventhan and Nivethitha 2014). Natural water sources such as our oceans and waterways, which are commonly used for the practice of common or therapeutic activities, are damaged by pollution affecting both aquatic and coastal ecosystems (Roviello et al. 2022a, b; Crini and Lichtfouse 2018). Humanity is currently facing unprecedented challenges with significant consequences on the environment and our health, aspects which are strongly interrelated. Oceans and their delicate ecosystems are heavily under attack, facing huge threats from the effect of various human activities (Yang et al. 2022; Osman et al. 2023; Pontoni et al. 2022; Khristoforova et al. 2018; Morin-Crini et al. 2022; Padervand et al. 2020; Sharma et al. 2023) that alter the chemico-physical properties of seawater. These, in turn, cause serious damage to the surrounding ecosystems such as coastal forests, whose degradation further impacts sea health (Martin et al. 2019; John et al. 2022). The connection between ecosystems is indeed far deeper than we yet understand with, as an example, the cutting down of forests creating underwater deserts in nearby bodies of water (Matsunaga et al 1982). Famously, oceans harbor an enormous biological diversity (Bouchet 2006) and are a crucial source of secondary metabolites endowed with medicinal properties.

Marine-derived drugs (Papon et al. 2022) continue to be  discovered which contributes to the development of  novel therapeutic approaches for many socially relevant diseases such as cancer and neuropathies. Oceans offer numerous potential benefits crucial for strengthening the immune system and preventing disease which can be harnessed through ancient therapeutic practices such as balneotherapy and thalassotherapy (Kron 2007). We will touch on these further in a dedicated section of this work. The scientific literature contains many examples that present oceans as a source of natural drugs isolated from numerous marine life forms. Inorganic salts and organic compounds (Dittmar and Paeng 2009) are among the most relevant chemical components found in seawater or extractable from algae and other marine organisms, which are hypothesized to exert positive effects on human health. Moreover, oceans are positively correlated to our mental wellness, offering recreational relief from the stresses of modern life (Lim et al. 2021; Wiwatwongwana et al. 2016; Roviello et al. 2022a).

Alongside the positive effects provided by waterways, this review also focuses on the damage being caused to these and their related ecosystems, in an effort to point to the need for greater protection of our oceans and a holistic approach to planetary health  (Maharja et al. 2023; Fleming et al. 2023; Baker et al. 2022). Thus, in this work, we review the health benefits related to the sea while also corroborating the concept that oceans can provide a more holistic approach to healing, through water-based and marine-derived compound applications. As opposed to other published articles which limit their focus on certain sea based therapies or a select few marine compounds, we widen our view through the integration of the possible chemical and molecular mechanisms on health possibly associated to water and related organisms, also providing cutting-edge and omics perspectives on these topics.

Marine ecosystems and the threats they face

The threats faced by oceans today, including pollution from urban areas and coastal ecosystem deterioration, jeopardize marine life and human well-being. cAtivities such as logging in coastal forests are, for example, intricately linked to ocean ecosystem impoverishment and instances of ‘sea desertification’ due to iron decline (Fujimoto et al. 2012). Plastic, a significant cause of biotic impoverishment (Lucia et al. 2023; Loizidou et al. 2018; Wright et al. 2015), represents a major environmental concern, while microplastics, with their potential to carry other contaminants (Razeghi et al. 2021), exacerbate the problem. In fact, when ingested, microplastics and other hazardous chemical compounds are responsible for the long-term mortality of marine organisms (Egbeocha et al. 2018; Miller et al. 2020). Now firmly established in the food chain, microplastics are not only an issue for marine life but also for human health, with the most common effects being observed in foetus development, genetic changes, and respiration rates (Blackburn and Green 2021). Petrol and other hazardous liquids from factories, pharmaceutical waste and sunscreen, runoffs from megacities, as well as pesticides and fertilizers from agriculture, all contribute to the poisoning of marine life. The resulting effects include reduced fertility, weakened immune responses, and developmental abnormalities (Lewis and Ford 2012; Sharifinia et al. 2020). Reviewing the existing literature, it is clear that oceans face multiple threats, including pollution from urban areas and degradation of coastal ecosystems, which not only endanger marine life but also have significant implications for human health and well-being.

Challenges to ocean health

Overfishing is also a major threat as it destabilizes aquatic ecosystems and depletes resources, having a  negative impact on marine fauna and the seabed due to trawling activities as well as to our economy (Schartup et al. 2019; Scheffer et al. 2005). Additionally, the compounding effect of global warming on marine ecosystems is particularly worrying as it diminishes the ocean'sability to adsorb human-related CO2 emissions which leads to a drop in seawater pH and the creation of marine "dead zones" where marine life suffers from suffocation; this highlightsg the urgent need for mitigative actions (Knowlton and Di Lorenzo 2022). Both pollution and global warming contribute to the increase in harmful algae and the spread of pathogens such as bacteria and viruses, such as the spread of SARS-CoV-2 in municipal wastewater (Singh et al. 2021). These factors pose significant challenges not only to marine fauna but also to human communities where bathing restriction warnings are increasing. Human activities related to mining, fuel extraction and energy production also have a negative impact on our marine ecosystems (Brynolf et al. 2014; Deka et al. 2022). Thus, understanding the interplay between ecosystem changes and human influencs is of significant importance, especially when considering all the potential benefits of oceans and seas on human health. Overall, the subsection emphasizes the contemporary threats to oceans, highlighting the interconnected challenges of seawater pollution, coastal ecosystem deterioration, and human activities such as logging, underscoring their detrimental impact on marine and human life, and stressing the urgency of understanding the complex interplay between ecosystem changes and human influence for ocean preservation and human health.

Water therapies in medicinal chemistry

Oceans, with their vast biological diversity, serve as reservoirs of marine compounds possessing pharmaceutical properties;These have been utilised through traditional practices dating back to ancient times when marine invertebrates were harvested for their therapeutic benefits, particularly during the Ancient Greek and early Byzantine periods, forming the basis of various medical preparations (Voultsiadou 2010). Throughout history, the presence of salts in seawater has been associated with therapeutic and cosmetic benefits, spanning from ancient Greece where Hippocrates employed marine water for healing purposes, to later instances such as King Henry IV’s use of Normandy coast seawater to treat scabies in France in 1578, and the establishment of a research center by the Medical Faculty of the University of Paris in 1661 to explore the potential of marine therapy in treating rabies (Gotoh et al. 2008). The impact of human activities on marine environments not only compromises marine health but also heightens our vulnerability to disease, such as cancer and respiratory illnesses, by weakening our immune system, indicating a correlation between the degradation of marine ecosystems and increased susceptibility to respiratory diseases. Using the recent pandemic as an example, it has been observed that patients affected by COVID-19 residing at high altitudes exhibit higher levels of inflammatory cytokines compared to patients residing at sea level (del Valle-Mendoza et al. 2022). This heightened susceptibility could predispose individuals to the onset of such diseases as cancer (Costanzo et al. 2023). Overall, the key lies in re-establishing connections with the marine ecosystem, prioritizing its health to enhance our own immune systems, as evidenced by the growing global recognition of water-based therapies in medicinal chemistry, notably balneotherapy and thalassotherapy.

Balneotherapy

Balneotherapy, a widely used non-pharmacological treatment for conditions such as rheumatic and skin-related diseases, involves therapeutic activities such as bathing, physiotherapy in thermal water, medicinal drinks, and water jet massages which utilize natural hot springs, mud, mineral water, or seawater for recreation and relaxation (Matsumoto 2018). The successful management of low-grade inflammation as well as degenerative and stress-related diseases are connected with the mounting evidence of the beneficial effects of thermal water, including antioxidant, anti-inflammatory, anti-allergic, UV-protective and anti-angiogenic effects (Gerencsér et al. 2019). These properties, which most likely derive from a combination of mechanical, thermal, and chemical effects, have been proven to impact on different mediators of inflammation such as oxidative stress, cartilage metabolism, and humoral and cellular immune responses in individuals suffering from musculoskeletal disorders (Cheleschi et al. 2022). Moreover, studies on murine models of rheumatic diseases disclosed the beneficial properties of balneotherapy including the mitigation of pain and inflammation, ameliorating mobility and lowering the expression of matrix-degrading enzymes and oxidative stress mediators (Cheleschi et al. 2022). Thus, balneotherapeutic interventions have demonstrated efficacy in addressing diverse conditions through the rehabilitation from dermatological and immuno-inflammatory disorders, or cardiac, metabolic, and neurological disturbances. They have also been found beneficial for rehabilitating individuals with psychiatric disorders, proving to be effective for enhancing quality of life, general well-being, and physical conditioning (Matsumoto 2018). Overall, reviewing the literature, we found that balneotherapy offers a multifaceted approach to treating various conditions, including rheumatic and skin-related diseases, by leveraging the therapeutic properties of natural thermal water, mud, mineral water, and seawater to enhance inflammation management and overall well-being.

Healing power of thermal mineral waters

The positive effects of mineral waters are attributed to their physical and chemical characteristics, encompassing temperature, saline composition, osmotic pressure, and electric conductivity, underscoring the importance of understanding the mechanisms in balneotherapy and the potential functions of the diverse components comprising mineral water (Fioravanti et al. 2011; Morer et al. 2017). Indeed, researchers have employed tissues (primary or immortalized cells) to understand the basis of these beneficial effects, attributing several properties to inorganic compounds (Carbajo and Maraver 2017; Viegas et al. 2019; Wallace and Wang 2015) or organic molecules (Gerencsér et al. 2019) contained in thermal water, or the mineral water as a whole (Cheleschi et al. 2020; Fioravanti et al. 2011; Gálvez et al. 2018). As an inorganic element typically present in mineral water, sulfur has gained recognition as a key element with diverse functions, particularly when present in form of hydrogen sulfide (H2S), which serves as a principal bioactive molecule in sulfurous thermal waters. Despite originally being considered as a toxic gas, the scientific perspective has evolved in recent years with the publication of numerous reports highlighting hydrogen sulfide as biologically active compound (Carbajo and Maraver 2017; Viegas et al. 2019; Wallace and Wang 2015). Indeed, endogenous H2S has been associated with crucial physiological functions involving the brain, vascular system and other organs; whereas, the exogenous administration of H2S (e.g., in the medicinal waters) could offer a promising therapeutic alternative for inflammatory joint disease, given that numerous studies have demonstrated its anti-inflammatory, anti-catabolic, and antioxidant effects (Burguera et al. 2017; Vela-Anero et al. 2017; Zhao et al. 2015). Overall, understanding the mechanisms and potential functions of the diverse components comprising mineral water highlights their positive effects in balneotherapy which is supported by research on inorganic and organic compounds (particularly hydrogen sulfide as a biologically active compound). These then offer promising therapeutic alternatives for various inflammatory joint diseases.

Biological effects of organic components in thermal waters

The biological effects of the organic components found in thermal water have also been proven to contribute to healing mechanisms, even though the mechanisms that explain the therapeutic effectiveness , as well as those to establish the safety, standard procedures, and hypothetical side effects of balneotherapy are still unclear (Varga 2012a; Matsumoto 2018). Accordingly, the therapeutic impact of Szigetvár thermal mineral water was explored to understand whether its healing effects in individuals experiencing osteoarthritis in the hips and knees could be associated with the organic matter, suggesting that the organic fraction isolated from the medicinal water resulted in significantly improved clinical outcomes when compared with the use of tap water alone (Hanzel et al. 2019). Nevertheless, given the increased quantity and diversity of organic compounds, the sole approach to examining these organic mixtures, along with potential interactions, involves the identification of their biological activities through various tests, with the most informative results being observed with the Comet Assay (single-cell microgel electrophoresis for DNA damage) and Salmonella mutagenicity test (i.e., Ames test) conducted with the separated chemical fractions of waters and peloids. Recently, Varga et al. introduced a novel utilization of the Salmonella typhimurium TA strains, initially designed for the Ames mutagenicity test, and differing from the wild-type S. typhimurium in their UV sensitivity (Varga et al. 2015). Following the isolation of organic extracts from the water of five Hungarian thermal spas, the authors observed a marked UV-protective effect for Salmonella TA bacteria imputable to four out of five water samples showcasing the UV-protective characteristics of organic matter present in thermal water employed in balneotherapy (Varga et al. 2015). These discoveries elucidate and corroborate the “organic hypothesis” proposed by Varga, suggesting that the biological properties of thermal wates are more likely attributed to bioactive organic compounds rather than inorganic salts (Varga 2010, 2012b). Overall, by reviewing the literature, we found that the biological effects of organic components in thermal water, and potentially in seawaters, contribute significantly to healing mechanisms, despite uncertainties surrounding their therapeutic mechanisms and safety, indicating a promising avenue for further research and exploration in balneotherapy.

Mineral penetration and osmotic mechanisms

The chemical effects of balneotherapy could also be attributed to the uptake of minerals present in the water, even in trace amounts, through the skin, as demonstrated by increased serum concentrations of electrolytes (such as Br, Rb, Ca, and Zn) found in psoriatic patients who bathed in the Dead Sea (Shani et al. 1985). This data confirmed that there is a certain penetration of salts through the epidermis, suggesting that the improvement of psoriatic conditions is partly due to the properties of minerals (Shani et al. 1985). The infiltration of solutes through human barriers is surely affected by factors such as the duration of bathing, the temperature of medicinal waters, their composition, and other variables some of which are presumably still undiscovered (Fioravanti and Cheleschi 2015). In addition, it was found that the topical administration of saline waters rich in sodium and chloride modifies the local osmotic pressure stimulating skin nerve receptors through cell membrane ion channels identified as Piezo proteins (Carbajo and Maraver 2018). The effects of salt mineral water operate through various mechanisms influenced by the concentration and quality of their salts, which entails cellular osmosis that subsequently activates or inhibits apoptosis or necrosis within the cells, while also regulating mechanosensitive piezoelectric channels essential for converting mechanical forces into biological signals crucial for somatosensation and blood cell and vessel physiology (Carbajo and Maraver 2018). Nevertheless, despite certain authors’ efforts to focus on one component or the other, it is reasonable to assume that the effectiveness of medicinal water is likely associated with an intricate interplay among the various chemical components (Fioravanti et al. 2011; Morer et al. 2017). Overall, through literature review, we conclude that balneotherapy’s chemical effects involve mineral uptake via the skin, demonstrated by increased serum electrolyte concentrations in psoriatic patients bathing in the Dead Sea, suggesting a partial improvement of psoriatic conditions due to mineral properties, while the topical administration of saline waters rich in sodium and chloride stimulates skin nerve receptors through cell membrane ion channels identified as Piezo proteins, indicating a complex interplay among various chemical components for the therapeutic efficacy of medicinal water.

Microbial interactions in balneotherapy

The above considerations push the community to consider the most appropriate preclinical models to use for a more comprehensive investigation of the acting mechanisms of mineral water as a whole (Cheleschi et al. 2020). During balneotherapy treatments such as bathing, physiotherapy in thermal water, and mud application, individuals interact with microorganisms present in natural thermal waters, highlighting an intriguing relationship within balneotherapy. These microorganisms, comprising of bacteria, algae, and marine microflora, were shown to have anti-inflammatory, antioxidant, and wound healing properties (Foo et al. 2023; Halary et al. 2022; Tabarzad et al. 2020; Nabil-Adam et al. 2020). Various metabolites possessing recognized antioxidant or anti-inflammatory properties, including carotenoids, phycobilins, mycosporine-like amino acids, as well as bioactive metabolites such as microginins, microviridins, and anabaenolysins, were detected in populations of cyanobacteria composing the microbial biofilm observed on mud surfaces (Demay et al. 2020). Considering the impact of balneotherapy on the human microbiome is crucial, as certain endogenous microorganisms may shape the skin’s microbial signature, impacting the immune system and potentially contributing to the therapy’s overall benefits; thus, exploring the influence of commonly used mud in therapies on the skin microbiome is essential for comprehending its features (Antonelli and Donelli 2018). In fact, it was demonstrated that treatments with thermal water on the skin of individuals affected by psoriasis was efficient in changing microbiome composition, reducing the severity of the disease (Manara et al. 2023); while, the impact of drinking thermal water on the gut microbiome highlighted potential favorable effects such as a a reduced abundance of taxa previously associated with bad metabolic health, and an increase in bacteria associated with favorable metabolic health (Manara et al. 2023). Overall, this section highlights the urgent need for further research on the intricate interactions between balneotherapy and microorganisms, while emphasising its efficacy in addressing diverse conditions linked to the physical and chemical properties of mineral waters, particularly sulfur and organic compounds. It also  emphasises the potential therapeutic role of organic matter; while attributing the chemical effects of balneotherapy to mineral penetration through the skin, leading to changes in serum electrolyte concentrations, with osmotic mechanisms and microbial interactions, particularly with microorganisms in natural thermal waters, explored as contributing factors to the therapeutic effects.

Thalassotherapy

Thalassotherapy, derived from the Greek terms "thalasso" (i.e., sea) and "therapia" (i.e., cure), specifically refers to treatments employing seawater, contrasting with the broader term balneotherapy which encompasses various water-related therapies; however, due to its rising success, the term has been misappropriated to describe what are commonly known as "spa" treatments, raising concerns about the classification of treatments branded as thalassotherapy (Pereira 2018). As a main differentiating factor from balneotherapy, the term thalassotherapy might need to be restricted to treatments involving seawater and marine elements such as sand, algae, and mud, performed in a marine environment for healing and general well-being. Additionally, facilities offering thalassotherapy must be seaside-based, possess suitable amenities, and employ appropriately qualified medical and technical staff (Charlier and Chaineux 2009; Lucchetta et al. 2007), contrasting with the diverse settings where balneotherapy, including natural springs, spas, or wellness centers, is offered. Seawater maintains a consistent chemical composition across all oceans and seas, although the concentrations of its constituents, such as ions, vary globally; for instance, chloride and sodium are the most abundant ions in seawater with an average concentration of 18.980 and 10.556 mg/L, respectively (Mourelle et al. 2023; Samidah et al. 2021). Seawater is renowned for its therapeutic effects in treating various skin conditions such as eczema, dermatoses, and psoriasis, as well as respiratory issues such as nasopharyngeal inflammations, and managing gynecological diseases such as vaginitis and other infections of the external genitalia. Moreover, it improves overall functional activities in humans through the regulation of organic function via the neuro-endocrine system, activation of cutaneous metabolism, and muscle relaxation, through its crucial role in containing dissolved saline and metallic ions (Table 1) facilitating the excretion of toxic compounds and promoting tissue oxygenation (Pereira 2018).

Table 1 Main elements and properties characterizing the water sources employed in water therapies. This schematic table reports the principal sources from where the elements originate, with some associated biological properties and effects on cells and tissues as reported by literature reference
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The notable effects of seawater in thalassotherapy include skin hydration, tissue regeneration, and disease management, potentially attributed to algae’s richness in beneficial biomolecules such as proteins, vitamins, and minerals, which hold significant pharmacological and cosmetic potential, possibly contributing to reducing cholesterol levels and preventing hypertension (Pereira 2018). In addition, other researchers suggest that seawater would mediate the protection of the skin barrier through NaCl and KCl, with NaCl showing an emollient action (Yoshizawa et al. 2001). They also propose that mineral water with specific concentrations of NaCl (250 mM) plus KCl (50 mM) might be effective in preventing disruptions of the skin barrier as supplementary therapy in the treatment of atopic dermatitis of other chronic dermatitis (Yoshizawa et al. 2003) while research on concentrated deep-sea water, abundant in Ca, Mg, Na, K, and Fe, reveals its potential in inhibiting the formation of atopic dermatitis-like lesions in mice (Bak et al. 2012.; Furthermore, the application of concentrated deep-sea water with high levels of Mg and Ca also determined the suppression of the lipopolysaccharide-induced inflammatory responses via enzymatic signaling pathways in macrophage cells (Chun et al. 2017). Overall, this section underscores the necessity for clarity in defining thalassotherapy and differentiating  it from balneotherapy, emphasizing the importance of marine environments and the specific treatment components employed while also highlighting the diverse therapeutic effects of seawater, particularly its influence on skin health and its potential in managing various conditions, supported by emerging research on its biological properties and effects on cells and tissues.

Healing and metabolic benefits of seawater and thalassotherapy

Other interesting features of seawater and thalassotherapy effects regard the process of wound healing as sea salt accelerates the wound healing process in gingival fibroblasts in vitro and in patients undergoing oral surgery, which also suggests that mouth rinse with saline water improves oral hygiene (Cantore et al. 2020; Ballini et al. 2021; Huynh et al. 2016). The putative mechanisms of such improvement in wound healing would be based on the effects connected with NaCl or established saline concentrations that would increase the expression of collagen and extracellular matrix as well as cytoskeletal proteins (Mourelle et al. 2023; Samidah et al. 2021); while, the historical employment of thalassotherapy can be attributed to the presence of iodine in seawater, with iodide concentrations varying from the nanomolar range to nearly zero, being higher near the surface and gradually decreasing with depth (Chance et al. 2014). Due to the challenges provided by the complexity of seawater as matrix and the importance of determining seawater and atmospheric iodine, instrumental methods that allow the fast and direct quantification of inorganic iodine, e.g., liquid chromatography–mass spectrometry (LC–MS), are required (Hernáiz-Izquierdo et al. 2019). Iodine is absorbed in the form of iodide by the thyroid gland, gastric mucosa, salivary and mammary glands, and is then transported to the thyroid gland by specific enzymes and apical iodine transporters. In thyrocytes, the synthesis of thyroid hormones occurs through the iodination of tyrosine to form T3 and T4, whose secretion is regulated enzymatically (Zbigniew 2016), playing a crucial role in regulating thyroid function and metabolism and influencing essential activities such as heart rate, neural development, and cardiovascular, renal, and brain functions (Mondal et al. 2016). In addition, thyroid hormones were proven to differentially modulate the expression of genes involved in glucose metabolism and regulate mitochondrial fatty acid uptake and oxidation (Giacco et al. 2019), with environmental iodine exposure, dietary iodine, and seaweed consumption positively impacting metabolic control in patients with metabolic syndrome, influencing circulating levels of glucose, blood pressure, and lipids (Park et al. 2021). In fact, the absence of iodine from water obtained through desalination of seawater could drastically increase the risk of iodine-deficiency disorders, with impact on thyroid function and metabolism (Ovadia et al. 2016). Overall, the therapeutic efficacy of thalassotherapy stems from the combined effects of seawater’s chemical and physical properties, distinct from general balneotherapy, specifically utilizing marine elements for therapeutic purposes and demonstrating benefits on various skin and respiratory conditions, along with wound healing and metabolic regulation, highlighting the importance of a marine environment and qualified staff for its proper application.

Marine bioactive chemical species

Entire ecosystems exist in the shallows and the depths of oceans, holding inestimable potential for humans. Natural reservoirs like oceans and mineral waters, living or dead organisms, surrounding environments and plants represent a limitless supply of natural molecules with significant potential for the development of pharmaceuticals or biologically active compounds (Autiero and Roviello 2023; Ricci and Roviello 2023; Palumbo et al. 2023; Vicidomini and Roviello 2023a, b). This potential is intricately linked to the chemical nature of such compounds, which is amplified by the vast biological diversity found in oceans (Leychenko 2022). However, over 99% of the molecules of marine origin are novel, lacking counterparts among terrestrial plants and animals. These metabolites from marine origin display an extensive range of biological activities, showcasing antitumor, cancer-preventive, analgesic, antimicrobial, neuroprotective, and other properties (Leychenko 2022). There is an urgent need to discover new, highly effective substances from marine organisms (Table 2), forming the basis for the creation of drugs in human and veterinary medicine.

Table 2 Selected marine-derived compounds in biomedicine and their sources. This table provides a concise overview of some marine compounds, their biomedical applications, and the respective marine sources from which they are derived. Note how some of the molecules mentioned in the table are not directly sourced from marine organisms but rather are synthetic modifications of compounds extracted from sea
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Molecules derived from the sea, which can be extracted and employed as drugs for human health, can be copiously found in microorganisms, algae and invertebrates; while, they are scarce in vertebrates, with sponges, coelenterates and microorganisms being the major sources of biomedical compounds, but algae, echinoderms, molluscs and other organisms can also produce potentially active molecules (Jha and Zi-Rong 2004; Santorelli et al. 2023). Interestingly, endophytes constitute an intricate community of microorganisms that colonize the internal tissues of higher plants, including seaweeds, without causing visible symptoms (Ancheeva et al. 2020) but constituting a reservoir of bioactive compounds. Overall, the vast and diverse ecosystems within oceans harbor immense potential for humanity, offering a plethora of natural molecules sourced from oceans, mineral waters, organisms, and surrounding environments, which serve as promising candidates for pharmaceuticals or biologically active compounds, necessitating urgent exploration and discovery to advance drug development in human and veterinary medicine.

Marine endophytes as a biodiversity reservoir for bioactive compounds

Remarkably, marine endophytes inhabit both the inside and outer parts of cells of marine organisms such as plants (e.g., algae and seagrasses), vertebrates (e.g., fishes), and invertebrates (e.g., sponges and corals), and have co-evolved with their hosts owing to specific interaction mechanisms that regulate homeostasis, cell cycle and chemical signaling thus permitting the endophytic life (El-Bondkly et al. 2021), contributing to the host’s well-being by producing bioactive secondary metabolites that safeguard against herbivores and pathogenic microbes (Ancheeva et al. 2020). Endophytes are increasingly recognized for their capacity to produce valuable phytochemicals, representing a vast and largely untapped reservoir of biodiversity with potential applications in biomedicine, agriculture, and industry; their metabolites demonstrating diverse properties such as anticancer, antiviral, insulin-mimetic, anti-neurodegenerative, antibacterial, antioxidant, and immunosuppressive activities (El-Bondkly et al. 2021). The fast discovery of marine bioactive molecules with biological properties has been made possible thanks to the enhancement and optimization in chemical analytical methods, which include the application of sensitive and accurate mass spectrometry- or nuclear magnetic resonance-based techniques, in conjugation with chromatographic separative systems, for the identification and quantification of molecules (Roviello et al. 2014; Costanzo et al. 2020), while in the context of proteome, metabolome and lipidome analyses, these approaches can work in an untargeted fashion for the purpose of unbiased discovery (Costanzo et al. 2022b; Manganelli et al. 2021), can be set for the targeted detection of selected compounds (Costanzo and Caterino 2023; Costanzo et al. 2022a), or used for interaction studies between molecules (Santorelli et al. 2022; Melo et al. 2021). Furthermore, the omics approaches are also employed for the prediction of molecular targets and biological mechanisms of natural compounds, as illustrated by several marine anticancer compounds, such as the rhizochalinin (Zuo and Kwok 2021; Dyshlovoy et al. 2017). Within the large spectrum of molecules of marine origin, polyunsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are regularly ingested as dietary supplements (Fig. 2), primarily sourced from fish, whose concentrations vary depending on environmental factors and fat content, typically showing higher levels in fish from colder climates (Abedi and Sahari 2014).

Fig. 2
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EPA and DHA carboxylic acids and an oligomer of the marine polysaccharide chitosan from marine sources. IUPAC names for EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoic acid and (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid, respectively. Note how chitosan nanoparticles incorporating heavy metals, such as silver and gold, demonstrated promise in anticancer therapy

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Notably, there is a growing trend in the therapeutic use of marine PUFA for cancer patients, with literature suggesting their efficacy as chemotherapy adjuvants, showcasing direct anticancer effects, potentially alleviating certain secondary complications linked to cancer, and yielding overall positive clinical outcomes contingent upon dietary supplementation with fish oil or EPA and DHA (Murphy et al. 2011; Baracos et al. 2004; Vaughan et al. 2013; Van der Meij et al. 2012). Overall, this section underscores the multifaceted role of marine endophytes, which not only co-evolve with their hosts to regulate homeostasis but also contribute significantly to host well-being through the production of bioactive metabolites, representing a vast reservoir of biodiversity with applications across biomedicine, agriculture, and industry, facilitated by advancements in chemical analytical methods, particularly mass spectrometry and nuclear magnetic resonance, which have expedited the discovery and characterization of marine bioactive molecules, including polyunsaturated fatty acids, heralding a promising era in cancer therapy.

Therapeutic potential and biomedical applications of marine polysaccharides

The vast biodiversity of oceans hosts primitive polysaccharides, exhibiting significant chemical diversity and often species-specific traits, sourced primarily from marine organisms like algae, animals, and plants, particularly glycosaminoglycans, whose advancements in synthesis, structure, and function underscore their pivotal role in modulating physiological activities and disease processes, emphasizing the necessity for a profound understanding of structure–activity relationships to unlock their potential as efficient natural active factors for therapeutic applications (Senni et al. 2011). Marine polysaccharides, including fucoidan, carrageenan, alginic acid, and chitosan (Fig. 2), have revealed diverse therapeutic effects such as tumor suppression, anti-inflammatory actions, and combating viral infections, prompting extensive investigation in the pharmaceutical and biomedical fields due to their favorable attributes like biocompatibility, biodegradability, and bioactivity (Lee et al. 2017). Furthermore, marine polysaccharides demonstrate applications in tissue engineering, biomolecule immobilization, and stent coating, with their ability to respond to external stimuli such as pH, temperature, and electric fields, enabling the development of innovative drug delivery systems (Lee et al. 2017). Particularly, the role of fucoidan in modulating acute and chronic inflammation entails the blockage of selectins, enzyme inhibition, and inhibition of the complement cascade (Fitton 2011). Potential therapeutics based on the polysaccharides extracted from algae together with other algal compounds have been proposed for the development of novel drugs for the prevention/treatment of inflammatory bowel disease due to their anti-inflammatory properties (Besednova et al. 2020), wherein their mechanism of action, depending on their chemical and structural features, would enable interactions with inflammatory bowel disease therapeutic targets, including pro-inflammatory cytokines, chemokines, adhesion molecules, etc., as well as immune cells, epithelial cells, and intestinal microbiota (Besednova et al. 2020). A marine-derived oligosaccharide, sodium oligomannate (GV-971) passed phase 3 clinical trials showing promising results in the therapeutic approaches against Alzheimer’s disease (Xiao et al. 2021) with this compound demonstrating to attenuate the accumulation and aggregation of α-synuclein in mice and related pathology, contributing to neuronal protection when administered in the early stages of the disease (Yu et al. 2023). In addition, GV-971 was able to therapeutically remodel gut microbiota and destroy gut bacterial amino acids-shaped neuroinflammation in order to prevent Alzheimer’s disease progression (Wang et al. 2019), suggesting that these findings, in conjunction with other approaches such as combination therapy and multitargeting ligand therapy, may have potential applications in the treatment of Parkinson’s disease (PD), other synucleinopathies, and neurodegenerative diseases (Martins et al. 2020). Overall, the main conclusion of this section highlights the diverse therapeutic effects and biomedical applications of marine polysaccharides, emphasizing their potential as valuable natural compounds across various medical fields.

Marine compounds in cancer treatment

Remarkably, the majority of marine compounds are also tested for curative attempts against cancer, as despite the effectiveness of conventional treatments such as surgery, radiotherapy, chemotherapy, immunotherapy, targeted therapy, and gene therapy in sustaining and sometimes curing patients, many still succumb to cancer due to recurrence, pharmacological resistance, or treatment side effects, underscoring the urgent need for novel, efficient, and more specific compounds that target cancer cells and eradicate them (Zuo and Kwok 2021). Numerous compounds of marine origin exhibit diverse biological functions that apart from antibacterial, antifungal, antiviral, antiprotozoal, antimalarial, anticoagulant, antioxidant, anti-angiogenic include anticancer properties (Wang and Miao 2013; Wei et al. 2021; Casertano et al. 2020). Mechanisms from marine drugs that inhibit cellular proliferation and viability, induce reactive oxygen species accumulation, mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis, might show cytotoxic activity against several cancers (Yun et al. 2019). Cytarabine, originally obtained synthetically by modifying a compound extracted from a marine sponge, is now recognized for its ability to eliminate cancer cells by inhibiting the activity of DNA polymerase (Stonik 2009), having been tested and approved in 1969 for the treatment of acute myeloid leukemia, with the combined treatment of cytarabine as a continuous infusion for seven days and daunorubicin for three days still representing the backbone of treatment for this particular neoplasia (Murphy and Yee 2017). After the introduction of cytarabine, numerous marine-derived molecules have emerged as promising options for cancer treatment, including antibody–marine drug conjugates like brentuximab vedotin and polatuzumab vedotin, representing a groundbreaking advancement in targeted therapy (Zuo and Kwok 2021), as they link cytotoxic drugs to monoclonal antibodies that selectively target cancer cells’ antigens, thereby inducing apoptosis without harming normal cells (Akaiwa et al. 2020). A list of six marine-derived drugs approved as cancer drugs at the end of 2019 included the following: spongian cytarabine, spongian eribulin mesylate, ascidian trabectidine, ascidian plitidepsin, brentuximab vedotin, and polatuzumab vedotin (Dyshlovoy and Honecker 2019). Overall, the vast potential of marine compounds in cancer therapy highlights the necessity for novel, precise agents to combat the disease, as evidenced by the diverse biological functions exhibited by numerous marine-derived molecules, including their cytotoxic mechanisms, exemplified by the case of cytarabine originally derived from a marine sponge and subsequently approved for acute myeloid leukemia treatment, alongside the groundbreaking advancements in targeted therapy exemplified by antibody–marine drug conjugates, emphasizing the urgent need for further exploration and development of marine-derived compounds as effective cancer treatments.

Marine biomolecules in drug delivery and cancer therapy

Great opportunities can be found within the marine domain for novel drug applications including marine biopolymer chitosan (Fig. 2), holding great potential in cancer treatment, drug delivery nanoparticles, and vectors, as evidenced by formulations that amplify the drug delivery efficacy of chitosan nanoparticles by incorporating selected heavy metals, such as silver and gold nanoparticles, to enhance their anticancer potential (Saeed et al. 2021). In addition to the above-described compounds, other marine-derived molecules such as nucleotides, proteins, peptides, and amides have also shed light on cancer treatment opportunities owing to their bioactive properties, which encompass anti-angiogenic, antiproliferative and antimetastatic effects by arresting the cell cycle, or inducing apoptosis (Zuo and Kwok 2021). L-asparaginase (Fig. 3), purified from marine microorganisms, holds significant therapeutic value for leukemia and also plays a crucial role in the food industry by inhibiting the development of carcinogenic acrylamide in starch-based fried foods, exhibiting impressive activity and stability within a wide pH range from weak acidic to alkaline, thereby increasing the potential of leukemia treatments with minimal side effects due to its high affinity for asparagine and lack of glutaminase activity (Qeshmi et al. 2018). Polylysines of marine origin and their derivatives exhibit interesting properties, interacting with G-quadruplex DNA structures implicated in various pathological conditions, particularly cancer (Marzano et al. 2020), while small marine peptides, despite their advantages in targeted drug therapy, such as selective and rapid absorption, reduced gastrointestinal burden, and ease of modification and synthesis, continue to pose challenges in understanding their anticancer mechanisms (Zhang et al. 2021).

Fig. 3
figure 3

Three-dimensional views of L-asparaginase from the marine microorganism Pyrococcus horikoshii (A). Note how this enzyme plays a crucial role in nitrogen metabolism by breaking down the amino acid asparagine into aspartic acid and ammonia (B). Pictures in this figure are freely available through this link https://www.rcsb.org/3d-view/1WLS/1 (accessed on 16 December 2023)

Full size image

Finally, natural marine pigments, including chlorophyll, carotenoids, and phycobiliproteins, have gained prominence in recent years as potent substitutes in diverse domains of the food, cosmetic, and pharmaceutical industries, attributed to their exceptional biocompatibility, bioavailability, safety, and stability, with marine organisms serving as abundant reservoirs of these pigments, highlighting their significant biomedical potential and promising applications in human health, including the fight against cancer (Manivasagan et al. 2018). In conclusion, the exploration of marine-derived biomolecules further expands the range of therapeutic options, emphasizing the significant role of marine resources in advancing biomedical research and drug discovery (Pandey 2019; Morin-Crini et al. 2019). Overall, this section highlights the abundant potential of marine ecosystems, particularly oceans, as sources of bioactive compounds with significant pharmaceutical and biomedical applications, showcasing their diverse therapeutic potential, especially in cancer treatment, and emphasizing the promising avenues for developing novel compounds targeting various diseases (Fig. 1).

Conclusion

Oceans serve as abundant reservoirs for a substantial array of natural drugs, representing an endless source of medicines and therapeutic treatments hypothesized to have positive effects on human health through healing mechanisms often in need of interpretation but whose overall benefits cannot be denied. Herein, we examined the main putative effects of marine-derived drugs or water-dissolved chemical compounds, such as inorganic salts and organic compounds, with new functional compounds showing promise in treating various diseases, including cancer. Furthermore, the impact of water-based therapies in medicinal chemistry was investigated through the analysis of the outcomes provided by balneotherapy and thalassotherapy on human health, particularly beneficial in producing antioxidant, anti-inflammatory, anti-allergic, UV-protective, and anti-angiogenic effects for musculoskeletal, neurological, and dermatological disorders. The reduced connections between humans and nature, particularly involving the sea, were suggested to contribute to increasing susceptibility to respiratory illnesses in more densely populated areas, such as those affected by the COVID-19 pandemic, with contemporary urban settings and reduced access to natural spaces compromising various aspects of human health, particularly respiratory and mental well-being. Accordingly, humans can benefit holistically from water sources, and seas and oceans can help heal humans, a concept referred to as one-health, with positive interconnections significantly impacted by chemical pollution of marine ecosystems and the alarming rate of climate change and growing impact of human activities contributing to the deterioration of ocean health, posing serious risks to human health. Preserving these environments is imperative for sustaining and enjoying the recreational, therapeutic, and relaxing benefits offered by the sea, while restoring vital connections with nature, with a specific emphasis on the sea as a life-giving force for the entire planet, is a pivotal strategy for improving human health on multiple fronts.