Glioma coined as 'butterfly tumor' exhibits intense heterogeneity at the molecular and cellular levels. Although, Temozolomide exerted a long-ranging and prevailing therapeutic effect against glioma, albeit it has provided modest survival outcome. Fucoidan, (marine brown algal derivative) has demonstrated potent anti-tumor effects including glioma. Nevertheless, there is paucity of studies conducted on Fucoidan to enhance the anti-glioma efficacy of Temozolomide. The present study aimed to explore the plausible synergistic anti-glioma efficacy of Fucoidan in combination with Temozolomide in an in vivo experimental model. The dual-drug combination significantly inhibited tumor growth in in vivo and prolonged the survival rate when compared with the other treatment and tumor-control groups, via down-regulation of inflammatory cascade- IL-6/T LR4 and JAK/STAT3 as per the immunohistochemistry findings. Furthermore, the ultrastructural analysis indicated that the combinatorial treatment had restored the normal neuronal architecture of glioma-induced rats. Overall, the dual-drug cocktail might enhance the therapeutic outcome in glioma patients.

Osteoarthritis (OA) is a debilitating joint disorder characterized by cartilage degradation and chronic inflammation, accompanied by high oxidative stress. In this study, we utilized the monosodium iodoacetate (MIA)-induced OA model to investigate the efficacy of oligo-fucoidan-based formula (FF) intervention in mitigating OA progression. Through its capacity to alleviate joint bearing function and inflammation, improvements in cartilage integrity following oligo-fucoidan-based formula intervention were observed, highlighting its protective effects against cartilage degeneration and structural damage. Furthermore, the oligo-fucoidan-based formula modulated the p38 signaling pathway, along with downregulating cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, contributing to its beneficial effects. Our study provides valuable insights into targeted interventions for OA management and calls for further clinical investigations to validate these preclinical findings and to explore the translational potential of an oligo-fucoidan-based formula in human OA patients.

The regulation of gene expression is fundamental to health and life and is essentially carried out at the promoter region of the DNA of each gene. Depending on the molecular context, this region may be accessible or non-accessible (possibility of integration of RNA polymerase or not at this region). Among enzymes that control this process, DNA methyltransferase enzymes (DNMTs), are responsible for DNA demethylation at the CpG islands, particularly at the promoter regions, to regulate transcription. The aberrant activity of these enzymes, i.e. their abnormal expression or activity, can result in the repression or overactivation of gene expression. Consequently, this can generate cellular dysregulation leading to instability and tumor development. Several reports highlighted the involvement of DNMTs in human cancers. The inhibition or activation of DNMTs is a promising therapeutic approach in many human cancers. In the present work, we provide a comprehensive and critical summary of natural bioactive molecules as primary inhibitors of DNMTs in human cancers. The active compounds hold the potential to be developed as anti-cancer epidrugs targeting DNMTs.

Glioma coined as a "butterfly" tumor associated with a dismal prognosis. Marine algal compounds with the richest sources of bioactive components act as significant anti-tumor therapeutics. However, there is a paucity of studies conducted on Fucoidan to enhance the anti-glioma efficacy of Temozolomide. Therefore, the present study aimed to evaluate the synergistic anti-proliferative, anti-inflammatory and pro-apoptotic effects of Fucoidan with Temozolomide in in vitro and in silico experimental setup. The anti-proliferative effects of Temozolomide and Fucoidan were evaluated on C6 glioma cells by MTT and migration assay. Modulation of inflammatory markers and apoptosis induction was affirmed at the morphological and transcriptional level by dual staining and gene expression. Molecular docking (MD) and molecular dynamics simulation (MDS) studies were performed against the targets to rationalize the inhibitory effect. The dual-drug combination significantly reduced the cell viability and migration of glioma cells in a synergistic dose-dependent manner. At the molecular level, the dual-drug combination significantly down-regulated inflammatory genes with a concomitant upregulation of pro-apoptotic marker. In consensus with our in vitro findings, molecular docking and simulation studies revealed that the anti-tumor ligands: Temozolomide, Fucoidan with 5-(3-Methy1-trizeno)-imidazole-4-carboxamide (MTIC), and 4-amino-5-imidazole-carboxamide (AIC) had the potency to bind to the inflammatory proteins at their active sites, mediated by H-bonds and other non-covalent interactions. The dual-drug combinatorial treatment synergistically inhibited the proliferation, migration of glioma cells and promoted apoptosis; conversely with the down-regulation of inflammatory genes. However, pre-clinical experimental evidence is warranted for the possible translation of this combination.

The online version contains supplementary material available at 10.1007/s13205-023-03814-6.

In this study, a novel heteropolysaccharide (ASPA80-1) with an average molecular weight of 5.48 × 104 Da was isolated and structurally elucidated from custard apple pulp (Annona squamosa) through DEAE-cellulose, Sephadex G-100 and Sephacryl S-300 HR chromatography and spectral analysis. ASPA80-1 is a water-soluble polysaccharide and it is a polymer consisting of predominant amounts of (1 → 3)-linked-L-arabinose (Ara) residues, small amounts of (1 → 6)-linked-D-galactose (Gal), (1 → 3,5)-linked-L-arabinose (Ara) residues and terminal linked-L-arabinose (Ara) residues, trace amount of (1 → 4)-linked-D-glucose (Glc) residues and (1 → 2)-linked-L-rhamnose (Rham) residues. ASPA80-1 showed significant effect on antigen-presenting cells (APCs) activation. On the one hand, ASPA80-1 activated RAW264.7 macrophage cells by inducing morphology change, enhancing phagocytic ability, increasing nitric oxide (NO) secretion and promoting expression of major histocompatibility complex class II (MHC II) and cluster of differentiation 86 (CD 86). On the other hand, ASPA80-1 promoted the maturation of dendritic cells (DCs) by inducing longer dendrites, decreasing phagocytic ability and increasing MHC II and CD86 expression. Furthermore, mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways were activated after the intervention of ASPA80-1 on RAW264.7 cells or DCs. Thus, the novel heteropolysaccharide ASPA80-1 has the potential to be used as an immunoenhancing component in functional foods.

It has recently been proven that epigenetic dysregulation is importantly involved in cell transformation and therefore induces cancerous diseases. The development of molecules called epidrugs, which target specifically different epigenetic modifications to restore cellular memory and therefore the treatment, became a real challenge currently. Currently, bioactive compounds of medicinal plants as epidrugs have been can identified and explored in cancer therapy. Indeed, these molecules can target specifically different epigenetic modulators including DNMT, HDAC, HAT, and HMT. Moreover, some compounds exhibit stochastic epigenetic actions on different pathways regulating cell memory. In this work, pharmacodynamic actions of natural epidrugs belonging to cannabinoids, carotenoids, chalcones, fatty acids, lignans, polysaccharides, saponins, secoiridoids, steroids, tannins, tanshinones, and other chemical classes we reported and highlighted. In this review, the effects of several natural bioactive compounds of epigenetic medications on cancerous diseases were highlighted. Numerous active molecules belonging to different chemical classes such as cannabinoids, carotenoids, fatty acids, lignans, polysaccharides, saponins, secoiridoids, steroids, tannins, and tanshinones are discussed in this review.

Cancer has been traditionally viewed as a disease characterised by excessive and uncontrolled proliferation, leading to the development of cytotoxic therapies against highly proliferating malignant cells. However, tumours frequently relapse due to the presence of slow-cycling cancer stem cells eluding chemo and radiotherapy. Since these malignant stem cells are largely undifferentiated, inducing their lineage commitment has been proposed as a potential intervention strategy to deplete tumours from their most resistant components. Pro-differentiation approaches have thus far yielded clinical success in the reversion of acute promyelocytic leukaemia (APL), and new developments are fast widening their therapeutic applicability to solid carcinomas. Recent advances in cancer differentiation discussed here highlight the potential and outstanding challenges of differentiation-based approaches.

Primary malignant brain tumors are a major cause of morbidity and mortality in both adults and children, with a dismal prognosis despite multimodal therapeutic approaches. In the last years, a specific subpopulation of cells within the tumor bulk, named cancer stem cells (CSCs) or tumor-initiating cells, have been identified in brain tumors as responsible for cancer growth and disease progression. Stemness features of tumor cells strongly affect treatment response, leading to the escape from conventional therapeutic approaches and subsequently causing tumor relapse. Recent research efforts have focused at identifying new therapeutic strategies capable of specifically targeting CSCs in cancers by taking into consideration their complex nature. Aberrant epigenetic machinery plays a key role in the genesis and progression of brain tumors as well as inducing CSC reprogramming and preserving CSC characteristics. Thus, reverting the cancer epigenome can be considered a promising therapeutic strategy. Three main epigenetic mechanisms have been described: DNA methylation, histone modifications, and non-coding RNA, particularly microRNAs. Each of these mechanisms has been proven to be targetable by chemical compounds, known as epigenetic-based drugs or epidrugs, that specifically target epigenetic marks. We review here recent advances in the study of epigenetic modulators promoting and sustaining brain tumor stem-like cells. We focus on their potential role in cancer therapy.

Despite their low incidence rate globally, high-grade gliomas (HGG) remain a fatal primary brain tumor. The recommended therapy often is incapable of resecting the tumor entirely and exclusively targeting the tumor leads to tumor recurrence and dismal prognosis. Additionally, many HGG patients are not well suited for standard therapy and instead, subjected to a palliative approach. HGG tumors are highly infiltrative and the complex tumor microenvironment as well as high tumor heterogeneity often poses the main challenges towards the standard treatment. Therefore, a one-fit-approach may not be suitable for HGG management. Thus, a multimodal approach of standard therapy with immunotherapy, nanomedicine, repurposing of older drugs, use of phytochemicals, and precision medicine may be more advantageous than a single treatment model. This multimodal approach considers the environmental and genetic factors which could affect the patient's response to therapy, thus improving their outcome. This review discusses the current views and advances in potential HGG therapeutic approaches and, aims to bridge the existing knowledge gap that will assist in overcoming challenges in HGG.

Ingredients of brown seaweed like fucoidans are often described for their beneficial biological effects, that might be interesting for a medical application. In this study, we tested an extract from Dictyosiphon foeniculaceus (DF) to evaluate the effects in glioblastoma and uveal melanoma, looking for a possible anti-cancer treatment. We investigated toxicity, VEGF (vascular endothelial growth factor) secretion and gene expression of tumor and non-tumor cells. SVGA (human fetal astrocytes), the human RPE (retinal pigment epithelium) cell line ARPE-19, the tumor cell line OMM-1 (human uveal melanoma), and two different human primary glioblastoma cultures (116-14 and 118-14) were used. Tests for cell viability were conducted with MTS-Assay (3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium), and the proliferation rate was determined with cell counting. VEGF secretion was assessed with ELISA (enzyme-linked immunosorbent assay). The gene expression of VEGF receptor 1 (VEGFR1), VEGF receptor 2 (VEGFR2) and VEGF-A was determined with real-time qPCR (quantitative polymerase chain reaction). DF lowered the cell viability of OMM-1. Proliferation rates of ARPE-19 and OMM-1 were decreased. The VEGF secretion was inhibited in ARPE-19 and OMM-1, whereas it was increased in SVGA and 116-14. The expression of VEGFR1 was absent and not influenced in OMM-1 and ARPE-19. VEGFR2 expression was lowered in 116-14 after 24 h, whereas VEGF-A was increased in 118-14 after 72 h. The extract lowered cell viability slightly and was anti-proliferative depending on the cell type investigated. VEGF was heterogeneously affected. The results in glioblastoma were not promising, but the anti-tumor properties in OMM-1 could make them interesting for further research concerning cancer diseases in the human eye.

Targeted drug delivery systems represent valuable tools to enhance the accumulation of therapeutics in the brain. Here, the presence of the blood brain barrier strongly hinders the passage of foreign substances, often limiting the effectiveness of pharmacological therapies. Among the plethora of materials used for the development of these systems, natural polysaccharides are attracting growing interest because of their biocompatibility, muco-adhesion, and chemical versatility which allow a wide range of carriers with tailored physico-chemical features to be synthetized. This review describes the state of the art in the field of targeted carriers based on natural polysaccharides over the last five years, focusing on the main targeting strategies, namely passive and active transport, stimuli-responsive materials and the administration route. In addition, in the last section, the efficacy of the reviewed carriers in each specific brain diseases is summarized and commented on in terms of enhancement of either blood brain barrier (BBB) permeation ability or drug bioavailability in the brain.

Clinically, gliomas are classified into four grades, with grade IV glioblastoma multiforme being the most malignant and deadly, which accounts for 50% of all gliomas. Characteristically, glioblastoma involves the aggressive proliferation of cells and invasion of normal brain tissue, outcomes as poor patient prognosis. With the current standard therapy of glioblastoma; surgical resection and radiotherapy followed by adjuvant chemotherapy with temozolomide, it remains fatal, because of the development of drug resistance, tumor recurrence, and metastasis. Therefore, the need for the effective therapeutic option for glioblastoma remains elusive. Previous studies have demonstrated the chemopreventive role of naturally occurring pharmacological agents through preventing or reversing the initiation phase of carcinogenesis or arresting the cancer progression phase. In this review, we discuss the role of natural phytochemicals in the amelioration of glioblastoma, with the aim to improve therapeutic outcomes, and minimize the adverse side effects to improve patient's prognosis and enhancing their quality of life.

Marine invertebrates are extremely diverse, largely productive, untapped oceanic resources with chemically unique bioactive lead compound contributing a wide range of screening for the discovery of anticancer compounds. The lead compounds have unfurled an extensive array of pharmacological properties owing to the presence of polyphenols, alkaloids, terpenoids and other secondary metabolites. The antioxidant, immunomodulatory and anti-tumor activities exhibited, are possibly regulated by the apoptosis induction, scavenging of ROS and modulation of cellular signaling pathways to defy the cellular deafness during carcinogenesis. Despite the enriched bioactive compounds, the marine invertebrates are largely unexplored as identification, screening, pre-clinical and clinical assessment of lead compounds and their synthetic analogs remain a major task to be solved. In the current review, we focus on the principle strategy and underlying mechanisms deployed by the bioactive anticancer compounds derived from marine invertebrates to combat cancer with special insight into the cell death mechanism.

The development of cancer is not just the growth and proliferation of a single transformed cell, but its surrounding environment also coevolves with it. Indeed, successful cancer progression depends on the ability of the tumor cells to develop a supportive tumor microenvironment consisting of various types of stromal cells. The interactions between the tumor and stromal cells are bidirectional and mediated through a variety of growth factors, cytokines, metabolites, and other biomolecules secreted by these cells. Tumor-stromal crosstalk creates optimal conditions for the tumor growth, metastasis, evasion of immune surveillance, and therapy resistance, and its targeting is being explored for clinical management of cancer. Natural agents from plants and marine life have been at the forefront of traditional medicine. Numerous epidemiological studies have reported the health benefits imparted on the consumption of certain fruits, vegetables, and their derived products. Indeed, a significant majority of anti-cancer drugs in clinical use are either naturally occurring compounds or their derivatives. In this review, we describe fundamental cellular and non-cellular components of the tumor microenvironment and discuss the significance of natural compounds in their targeting. Existing literature provides hope that novel prevention and therapeutic approaches will emerge from ongoing scientific efforts leading to the reduced tumor burden and improve clinical outcomes in cancer patients.

Glioblastoma (GBM) is an extremely malignant tumor of the central nervous system, characterized by low response to treatments and reoccurrence. This therapeutic resistance is believed to arise mostly from the presence of a subpopulation of tumorigenic stem cells, known as cancer stem cells (CSCs). In addition, the surrounding microenvironment is known to maintain CSCs, thus supporting tumor development and aggressiveness. This review focuses on a therapeutic strategy involving the stem cell trans-differentiating ability of graphene and its derivatives. Graphene distinguishes itself from other carbon-based nanomaterials due to an array of properties that makes it suitable for many purposes, from bioengineering to biomedical applications. Studies have shown that graphene is able to promote and direct the differentiation of CSCs. In addition, potential usage of graphene in GBM treatment represents a challenge in respect to its administration method. The present review also provides a general outlook of the potential side effects (e.g., cell toxicity) that graphene could have. Overall, this report discusses certain graphene-based therapeutic strategies targeting CSCs, which can be considered as prospective effective GBM treatments.