ABSTRACT Heart failure is a progressive clinical disorder characterized by adverse remodeling of the myocardium and a reduced left ventricular ejection fraction. G protein‐coupled receptor kinase 2 (GRK2) is a well‐established target in the treatment of heart failure, belonging to the serine/threonine protein kinase family, which phosphorylates and desensitizes beta‐adrenergic receptors (βAR). Considering the need to explore potential scaffolds for GRK2 inhibition, the Comprehensive Marine Natural Products Database (CMNPD) is explored in this work using BIOVIA Discovery Studio 2024 software. The molecules were filtered using the ligand‐based pharmacophore model followed by docking the top hits with GRK2. We observed that the Arg199, Phe202, Val205, Asp272, Asp278, and Leu324 amino acids played a crucial role in forming nonbonded interactions with the hit molecules. Interaction stability of the receptor‐ligand complexes of Mol 16228 (CMNPD8267) and Mol 35946 (CMNPD22622) and the co‐crystallized ligand W4D was studied using molecular dynamics simulation integrated with MMPBSA binding energy calculations and was found to be stable over 300 ns of simulation time. The identified hit molecules represent preliminary computational leads that warrant further biochemical, cellular, and in vivo validation for their potential as GRK2 inhibitors.

Wound healing is a dynamic biological process involving haemostasis, inflammation, proliferation, and tissue remodelling. Disruption of these phases in chronic wounds leads to prolonged inflammation, oxidative stress, and microbial infections, posing significant clinical challenges. Marine macroalgae are a promising source of bioactive compounds, including sulfated polysaccharides (fucoidan, carrageenan, alginate), polyphenols (phlorotannins), pigments (fucoxanthin), fatty acids, and sterols, that exhibit antioxidant, anti-inflammatory, antimicrobial, and cell-regenerative properties essential for wound repair. These compounds modulate key molecular pathways such as NF-kappa B, MAPK, COX-2, and Nrf2 to reduce oxidative damage, suppress proinflammatory cytokines, and inhibit biofilm-forming pathogens. Recent advances demonstrate the incorporation of seaweed-derived bioactives into hydrogels, nanocomposites, and scaffolds, improving wound closure, drug delivery, and synergistic interactions with conventional treatments. This review summarizes the pharmacological mechanisms of algal bioactives, explores their integration with advanced biomaterials, and highlights synergistic approaches that enhance therapeutic outcomes. In this review we have constructed a synergistic map of seaweed-derived bioactives and their molecular targets to visualize potential synergistic interactions. A crossphylum analysis is performed to compare the pharmacological activities. Additionally, recent limitations and advances in omics-based approaches for elucidating seaweed-host interactions are discussed.

The human gut microbiota regulates various aspects of Alzheimer's disease (AD) pathophysiology, influencing neuroinflammation and metabolic homeostasis. Dietary polyphenols, specifically phlorotannins from brown macroalgae, are known to mitigate AD's pathological effects due to their ability to pass through the blood-brain barrier. Marine polyphenols extracted from Sargassum wightii were processed through simulated gastrointestinal digestion and in vitro fermentation. Characterization was performed using ultraviolet (UV), Fourier transform infrared spectroscopy (FTIR), HPLC, and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) both before and after biotransformation. We evaluated their metal chelation capacity (Cu2⁺ and Fe2⁺) and acetylcholinesterase (AChE) inhibitory activity using colorimetric assays. Additionally, the antioxidant capacity of the polyphenol extract was evaluated before and upon fermentation using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), and ferric reducing antioxidant potential (FRAP) assays. The extraction yield of polyphenols from S. wightii was 2.67 ± 0.27 mg PGE/g of macroalgae. In vitro biotransformation of these polyphenols resulted in the formation of various low-molecular weight (LMW) compounds with enhanced metal chelation and AChE inhibition activities. Additionally, a substantial rise in antioxidant activity was observed postbiotransformation. S. wightii polyphenols become more effective after biotransformation, with enhanced bioactive properties and promising for use in diets to prevent and manage AD.

AKT is one of the overexpressed targets in nonsmall cell lung cancer (NSCLC) and plays an important role in its progression and offers an attractive target for the therapy. The PI3K/AKT/mTOR pathway is upregulated in NSCLC. Acridone is an important heterocycle compound which treats cancer through various mechanisms including AKT as a target. In the present work, the study was designed to evaluate the safety profile of three acridone derivatives (AC-2, AC-7, and AC-26) by acute and repeated dose oral toxicity. In addition to this, we also checked the pAKT overexpression and its control by these derivatives in tumor xenograft model. The results from acute and repeated dose toxicity showed these compounds to be highly safe and free from any toxicity, mortality, or significant alteration in body weight, food, and water intake in the rats. In the repeated dose toxicity, compounds showed negligible variations in a few hematological parameters at 400 mg/kg. The histopathology, biochemical, and urine parameters remained unchanged. The xenograft model study demonstrated AC-2 to be inhibiting HOP-62 induced tumor via reduction in p-AKT1 (Ser473) expression significantly. In immunofluorescence staining AC-2 treated tissue section showed 2.5 fold reduction in the expression of p-AKT1 (Ser473). Histopathology studies showed the destruction of tumor cells with increased necrosis after treatment. The study concluded that AC-2 causes cell necrosis in tumor cells via blocking the p-AKT1 expression. The findings may provide a strong basis for further clinical applications of acridone derivatives in NSCLC.

Osteoporosis is one of the most significant health issues on the globe. The activity of osteoclast cells is connected to altered hormone levels and other factors such as age. The condition is characterized by increased bone fragility and loss of bone tissue. Osteoporosis, osteopetrosis, and Paget's disease are frequently caused by an imbalance in the production and function of osteoclasts and osteoblasts. The disease's early signs are scarcely noticeable. It results in gradual bone loss, which eventually makes the patients more prone to fractures. Osteoporosis must be avoided since the fractures caused by it have substantial medical expenses and morbidity. Bisphosphonates are used in the treatment of osteoporosis, along with hormone therapy, selective estrogen receptor modulators (SERMs), calcitonin, strontium ranelate (SR), and other treatments. Marine Natural Products (MNPs) have also had a significant impact on bone metabolism by preventing osteoclastogenesis. These MNPs are generated from a variety of marine resources, including marine cyanobacteria, soft corals, mollusks, fish, dinoflagellates, algae, sponges, and mangroves. Numerous plant and herb species are also effective in the treatment of osteoporosis. We check if these plant-based bio-actives may replace hormonal and synthetic drug-based treatments. This chapter also throws light on any possible effect of COVID-19 that might be on the body, particularly the musculoskeletal system.

Aging is a visible indicator of malfunctioning or toxic proteins that sensitize other proteins to oxidative damage which is most prominently observed on the skin. Protein misfolding is caused by the protein following an incorrect folding pathway which may lead to spontaneous misfolding while oxidative stress refers to the disruption of the balance between antioxidant defenses and reactive oxygen species production. Oxidation may alter noncovalent interactions within proteins, peptide chain fragmentation, and protein cross-linking, which causes protein misfolding and further skin aging. A feedback loop is observed in all three processes. A proper understanding of these events is significant in the formulation of anti-aging preparations and further understanding of the mechanism of aging. In this Chapter, we will be discussing some natural antioxidants available to combat oxidative stress which facilitate healthy aging and normal functioning of the body. We will be elaborating on the body’s natural defense mechanism against these problems such as the role of Chaperones. We will be looking at the detailed mechanism of oxidative stress, protein misfolding, and their correlation with skin aging along with factors influencing it. The biomarkers for oxidative stress will be enlisted. A brief correlation between these processes in a test worm and how it correlates to humans and its importance will be explained in this chapter.

The rising rates of cancer globally have prompted the exploration of newer therapeutic alternatives, to arrest disease progression and offer minimal side effects along with therapeutically beneficial outcomes. Clinically beneficial bioactives isolated from microalgae have been observed to offer advantages over conventional chemotherapeutic agents and have improved the overall quality of life and average survival time of patients. In addition to this, their abundant availability and relatively easy isolation have resulted in an increase in their popularity as chemopreventive agents. However, much like other agents of natural origin, they offer solubility and bioavailability challenges, posing a limitation to their delivery and attainment of sufficient systemic concentrations to elicit significant pharmacological responses. In order to overcome these drawbacks, recent advancements in nanotechnology and formulation studies have paved the way for targeted delivery and enhanced systemic availability of these agents, thereby optimizing therapeutic regimes and minimizing the possibility of adverse effects. The key highlights of this chapter include the rationale for microalgae usage in cancer management, the molecular mechanisms by which these agents act, advancements in delivery to overcome challenges, and future perspectives for usage in cancer management.

Achieving targeted, customized, and combination therapies with clarity of the involved molecular pathways is crucial in the treatment as well as overcoming multidrug resistance (MDR) in cancer. Nanotechnology has emerged as an innovative and promising approach to address the problem of drug resistance. Developing nano-formulation-based therapies using therapeutic agents poses a synergistic effect to overcome MDR in cancer. In this review, we aimed to highlight the important pathways involved in the progression of MDR in cancer mediated through nanotechnology-based approaches that have been employed to circumvent them in recent years. Here, we also discussed the potential use of marine metabolites to treat MDR in cancer, utilizing active drug-targeting nanomedicine-based techniques to enhance selective drug accumulation in cancer cells. The discussion also provides future insights for developing complex targeted, multistage responsive nanomedical drug delivery systems for effective cancer treatments. We propose more combinational studies and their validation for the possible marine-based nanoformulations for future development. Nano-marine drug strategy combating cancer multidrug resistance to conventional treatments. Utilizing nanotechnology for the development of marine drug delivery systems. image

Steroidal alkaloids are secondary metabolites that are often found in plants, fungi and sponges. These compounds are considered as a source of bioactive compounds for the treatment of chronic diseases, such as neurological disorder like Alzheimer's disease (AD). Some examples of alkaloid derivatives currently used to treat AD symptoms include galantamine, huperzine A, and other alkaloids. AD is a multifactorial disease caused by multiple factors such as inflammation, oxidative stress, and protein aggregation. Based on the various important neuroprotective activities and different pharmacological effects of steroidal alkaloids with polypharmacological modulatory effects, they can lead to the development of new drugs for the treatment of AD. There are limited studies on the involvement of steroidal alkaloids in AD. Therefore, the mechanisms and neuroprotective abilities of these compounds are still poorly understood. The purpose of this review article is to provide an overview of the mechanism, toxicity and neuroprotective benefits of steroidal alkaloids and to discuss future possibilities to improve the application of steroidal alkaloids as anti-AD agents. The therapeutic value and limitations of the steroidal alkaloid are investigated to provide new perspectives for future clinical development studies.

Cancer is the second largest killer in the world, and there is vigorous ongoing interest in the discovery of cost-effective anticancer molecules from plants and marine origin. The focus of this chapter is to highlight the anticancer activities of macromolecules derived from marine origin. Further, this chapter also provides an overview of the different classes of anticancer macromolecules undergoing clinical trials and approved by the US-FDA. Since the existing anticancer therapies not only target the cancer cells but also cause serious injury to normal cells and tissues as well as produce drug resistance in cancer cells, there is an urgent need for developing safe and efficacious novel anticancer compounds from natural origin, which have the promising therapeutic potential to cure cancer. This chapter will describe the underlying anticancer mechanism of action of macromolecules of marine origin chemically linked to carbohydrates, sulfated polysaccharide, chitosan, SPS-CF, EPS-CS, fucoidans, and peptide molecules. Currently, 13 compounds isolated from marine source are undergoing clinical trials in different phases. A limited number of clinical studies have shown that trabectedin has a good therapeutic effect against ovarian cancer. Lyngabyal lectin, a peptide molecule, has also revealed desired effectiveness against some cancer types. Peptidoglycan and its muropeptide metabolites have shown immunomodulating properties through Freund's complete adjuvant (FCA) that throws favorable light on the anticancer potential of this class of macromolecules.

Glioblastoma, the most aggressive form of brain tumor, poses significant challenges in terms of treatment success and patient survival. Current treatment modalities for glioblastoma include radiation therapy, surgical intervention, and chemotherapy. Unfortunately, the median survival rate remains dishearteningly low at 12-15 months. One of the major obstacles in treating glioblastoma is the recurrence of tumors, making chemotherapy the primary approach for secondary glioma patients. However, the efficacy of drugs is hampered by the presence of the blood-brain barrier and multidrug resistance mechanisms. Consequently, considerable research efforts have been directed toward understanding the underlying signaling pathways involved in glioma and developing targeted drugs. To tackle glioma, numerous studies have examined kinase-downstream signaling pathways such as RAS-RAF-MEK-ERK-MPAK. By targeting specific signaling pathways, heterocyclic compounds have demonstrated efficacy in glioma therapeutics. Additionally, key kinases including phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase, cytoplasmic tyrosine kinase (CTK), receptor tyrosine kinase (RTK) and lipid kinase (LK) have been considered for investigation. These pathways play crucial roles in drug effectiveness in glioma treatment. Heterocyclic compounds, encompassing pyrimidine, thiazole, quinazoline, imidazole, indole, acridone, triazine, and other derivatives, have shown promising results in targeting these pathways. As part of this review, we propose exploring novel structures with low toxicity and high potency for glioma treatment. The development of these compounds should strive to overcome multidrug resistance mechanisms and efficiently penetrate the blood-brain barrier. By optimizing the chemical properties and designing compounds with enhanced drug-like characteristics, we can maximize their therapeutic value and minimize adverse effects. Considering the complex nature of glioblastoma, these novel structures should be rigorously tested and evaluated for their efficacy and safety profiles.

The detrimental effects of synthetic antifouling ingredients has underscored the necessity for the development of eco-friendly antifouling compounds. Phlorotannins are secondary metabolites biosynthesized exclusively in brown seaweeds with a potential as an antifouling compound. This study optimized the extraction of phlorotannins from Stoechospermum marginatum using Box–Behnken design of response surface methodology and evaluated its potential for antifouling activity against marine microfouling bacteria isolated from the hull of fishing boat. Based on biofilm formation index, 13 bacterial isolates identified by 16S rRNA sequencing were found to have the ability to form biofilm in the initial stage in biofouling. The conditions that produced the highest phlorotannin content of 2.75 ± 0.02 mg of phloroglucinol equivalents/g are as follows: ethanol concentration of 78.6

Polyphenols contribute as one of the largest groups of compounds among all the phytochemicals. Common sources of dietary polyphenols are vegetables, fruits, berries, cereals, whole grains, etc. Owing to their original form, they are difficult to get absorbed. Dietary polyphenols after undergoing gut microbial metabolism form bioaccessible and effective metabolites. Polyphenols and derived metabolites are all together a diversified group of compounds exhibiting pharmacological activities against cardiovascular, cancer, oxidative stress, inflammatory, and bacterial diseases. The formed metabolites are sometimes even more bioavailable and efficacious than the parent polyphenols. Studies on gut microbial metabolism of dietary polyphenols have introduced new approach for the use of polyphenol-rich food in the form of supplementary diet. This review provides insights on various aspects including classification of polyphenols, gut microbiota-mediated metabolism of polyphenols, chemistry of polyphenol metabolism, and pharmacological actions of gut microbial metabolites of polyphenols. It also suggests the use of polyphenols from marine source for the microbial metabolism studies. Till date, gut microbial metabolism of polyphenols from terrestrial sources is extensively studied as compared to marine polyphenols. Marine ecosystem is a profound but partially explored source of phytoconstituents. Among them, edible seaweeds contain high concentration of polyphenols, especially phlorotannins. Hence, microbial metabolism studies of seaweeds can unravel the pharmacological potential of marine polyphenol-derived metabolites.

The primary goal of this study is to synthesize and characterize N -substituted Acetamido derivatives of acridone, where the acetamido moiety has been considered a linker which is crucial for several biological activities, including anti-cancer activity. In this context, the anti-proliferative activity of synthesized derivatives was evaluated against human breast (MCF-7, MDA-MB-231), lung (A-549), and skin (A-431) cancer cell lines. Results revealed that compounds 8 h , 8i , 9 h , and 9i showed the most potent activity against MCF-7 cell lines with IC 50 values of 13.96 µM , 8.25 µM, 9.45 µM, and 6.76 µM, respectively. In addition, all these compounds were found to be non-toxic against normal cells (NIH/3T3). Further, AKT kinase inhibition assay results showed that compounds 8i and 9i have the efficacy to inhibit the AKT kinase with potential anti-cancer activity. The cell cycle analysis revealed that compounds 8i and 9i could arrest the G 0 /G 1 phase of the cell cycle and absorption titration with CT-DNA identified that these molecules could interact with DNA. In order to understand the drug-likeness properties, all the compounds were evaluated by various in silico screening, and these compounds exhibited optimal physicochemical features as excellent lead molecules. Finally, in vitro results were validated using a molecular docking study, which revealed binding interactions in the active site of AKT.

Alzheimer's disease is characterized by amyloid-beta aggregation and neurofibrillary tangles. Acetylcholinesterase (AChE) hydrolyses acetylcholine and induces amyloid-beta aggregation. Acetylcholinesterase inhibitors (AChEI) inhibit this aggregation by binding to AChE, making it a potential target for the treatment of AD. In this study, we have focused on the identification of potent and safe AChEI from the Comprehensive Marine Natural Product Database (CMNPD) using computational tools. For the screening of CMNPD, a structure-based pharmacophore model was generated using a structure of AChE complexed with the co-crystallized ligand galantamine (PDB ID: 4EY6). The 330 molecules that passed through the pharmacophore filter were retrieved, their drug-likeness was determined, and they were then subjected to molecular docking studies. The top ten molecules were selected depending upon their docking score and were submitted for toxicity profiling. Based on these studies, molecule 64 (CMNPD8714) was found to be the safest and was subjected to molecular dynamics simulations and density functional theory calculations. This molecule showed stable hydrogen bonding and stacked interactions with TYR341, mediated through a water bridge. In silico results can be correlated with in vitro studies for checking its activity and safety in the future.

The skin care industry has been expanding in recent times and is expected to grow to about 190 US billion dollars by 2025. Because skin disorders can severely affect the quality of life, they require attention by the pharmaceuticals and cosmetics industries to give sustainable solutions. There are many causes of skin disorders, such as injury; bacterial, fungal, or viral infections; smoking; and ultraviolet radiations. Owing to the damage caused by an increased exposure to UV radiations, it can lead to skin cancer, photoaging complications, and increased production of reactive oxygen species (ROS). Antioxidants have been found to show promising results in treating diseases that involve increased ROS levels. Hence with the aim of safer and effective natural substances, antioxidants from marine flora and fauna, marine microbes, and macroalgae are being extensively researched for skin care treatment. Furthermore, many studies have explored the potential use of these marine antioxidants for improving skin health. We give an insight into these studies and cover the various sources and classes of marine antioxidants along with their respective contribution to skin health. This chapter also highlights the increasing importance of these marine sources in the cosmetics industry and explains why marine antioxidants should be explored further for their potential use in the skin care industry. Their application can potentially give a boost to skin care products and related cosmetics.

This report describes a protocol for utilization of aquaculture wastewater for biomass production, high value pigment recovery and carbon sequestration through a cyanobacterium Spirulina (Arthrospira) platensis through a green process. The dry weight (2.76 ± 0.03 g/L) was almost comparable with the control showing a negligible decrease of 0.89%. During the 6 to 8 days of the culture duration, the biomass composition of amended aquaculture wastewater demonstrated a maximum cell productivity (0.0734 ± 0.0050 g/L/day), carbon sequestration (0.0314 ± 0.0021 g/L/day) and CO2 sequestration (0.1151 ± 0.0078 g/L/day), showing a substantial 20% improvement compared to the control. The yield of a pharmaceutically important pigment phycocyanin was 101.95 ± 1.49 mg/g DW in the wastewater grown cultures showing a negligible decrease (0.83%) compared to the synthetic medium grown cultures. The reduction in the cost of the synthetic medium through utilization of aquaculture wastewaters after certain amendments is a novel approach for an environmentally friendly and cost-effective production of S. platensis. The quality of biomass and phycocyanin in amended wastewater grown cultures was not altered. This report provides baseline data about aquaculture wastewater utilization for cyanobacterial biomass production, carbon sequestration and recovery of a valuable pigment phycocyanin through a simple and low-cost downstream process.