Centromeres in cancer: Unraveling the link between chromosomal instability and tumorigenesis.

Centromeres are critical structures involved in chromosome segregation, maintaining genomic stability, and facilitating the accurate transmission of genetic information. They are key in coordinating the assembly and help keep the correct structure, location, and function of the kinetochore, a proteinaceous structure vital for ensuring proper chromosome segregation during cell division. Abnormalities in centromere structure can lead to aneuploidy or chromosomal instability, which have been implicated in various diseases, including cancer. Accordingly, abnormalities in centromeres, such as structural rearrangements and dysregulation of centromere-associated proteins, disrupt gene function, leading to uncontrolled cell growth and tumor progression. For instance, altered expression of CENP-A, CENP-E, and others such as BUB1, BUBR1, MAD1, and INCENP, have been shown to ascribe to centromere over-amplification, chromosome missegregation, aneuploidy, and chromosomal instability; this, in turn, can culminate in tumor progression. These centromere abnormalities also promoted tumor heterogeneity by generating genetically diverse cell populations within tumors. Advanced techniques like fluorescence in situ hybridization (FISH) and chromosomal microarray analysis are crucial for detecting centromere abnormalities, enabling accurate cancer classification and tailored treatment strategies. Researchers are exploring strategies to disrupt centromere-associated proteins for targeted cancer therapies. Thus, this review explores centromere abnormalities in cancer, their molecular mechanisms, diagnostic implications, and therapeutic targeting. It aims to advance our understanding of centromeres' role in cancer and develop advanced diagnostic tools and targeted therapies for improved cancer management and treatment.

The Effect of Monobenzone Cream on Oxidative Stress and Its Relationship With Serum Levels of IL-1ß and IL-18 in Vitiligo Patients.

BACKGROUND: Monobenzyl ether hydroquinone (MEBHQ) is a cream that promotes the spread and evenness of skin patches in vitiligo. Our aim was to investigate the oxidative and inflammatory effects of this cream on vitiligo patients consuming MEBHQ. METHODS: A case-control study was conducted with three groups of 30 people from the control group, vitiligo patients before and after treatment. The percentage of vitiligo spots was determined by a specialist doctor. The levels of biochemical factors, oxidative stress profile and inflammatory factors were measured by enzymatic, colorimetric and ELISA methods, respectively. RESULTS: Vitiligo patients showed a high level of inflammation and oxidative stress compared to healthy people. Although after 3 months of using MBEHQ cream, the percentage of skin spots in vitiligo patients increased from an average of 63%-91% and the skin color became almost uniform, but it still increased the level of oxidative stress and inflammation in these patients. Although the level of oxidative stress increased significantly in these patients, there was no significant increase in the level of malondialdehyde. The lack of significant differences in the levels of biochemical factors between healthy people and vitiligo patients before and after using the treatment shows the absence of side effects. CONCLUSION: The use of MBEHQ increased the size of skin spots and uneven skin color in vitiligo patients. Although MBEHQ did not show side effects such as diabetes, liver and kidney diseases, it increased the levels of oxidative stress and inflammatory cytokines, which needs further study.

Potential promising of synthetic lethality in cancer research and treatment.

Cancer is a complex disease driven by multiple genetic changes, including mutations in oncogenes, tumor suppressor genes, DNA repair genes, and genes involved in cancer metabolism. Synthetic lethality (SL) is a promising approach in cancer research and treatment, where the simultaneous dysfunction of specific genes or pathways causes cell death. By targeting vulnerabilities created by these dysfunctions, SL therapies selectively kill cancer cells while sparing normal cells. SL therapies, such as PARP inhibitors, WEE1 inhibitors, ATR and ATM inhibitors, and DNA-PK inhibitors, offer a distinct approach to cancer treatment compared to conventional targeted therapies. Instead of directly inhibiting specific molecules or pathways, SL therapies exploit genetic or molecular vulnerabilities in cancer cells to induce selective cell death, offering benefits such as targeted therapy, enhanced treatment efficacy, and minimized harm to healthy tissues. SL therapies can be personalized based on each patient's unique genetic profile and combined with other treatment modalities to potentially achieve synergistic effects. They also broaden the effectiveness of treatment across different cancer types, potentially overcoming drug resistance and improving patient outcomes. This review offers an overview of the current understanding of SL mechanisms, advancements, and challenges, as well as the preclinical and clinical development of SL. It also discusses new directions and opportunities for utilizing SL in targeted therapy for anticancer treatment.

Promising potential effects of resveratrol on oral and dental health maintenance: a comprehensive review.

Resveratrol (RV-3, 5, 4'-trihydroxystilbene) is a natural compound found in plants like red grapes, berries, and peanuts, with promising effects on dental health. It helps strengthen tooth enamel by promoting remineralization, making the teeth more resistant to decay caused by acid-producing bacteria. RV also shields dentin, a vulnerable layer beneath the enamel, from erosion and sensitivity. Its anti-inflammatory properties can reduce inflammation associated with dental conditions such as pulpitis and endodontic diseases. Moreover, RV's antimicrobial activity inhibits the growth of bacteria involved in dental plaque and biofilm formation, preventing their accumulation on the tooth surface. This contributes to a healthier oral environment and prolongs the lifespan of dental restorative materials. However, the research on RV's impact on dental health is in its early stages, and further studies are needed to confirm potential benefits. Important factors such as determining the optimal dosage, understanding its bioavailability, and assessing potential side effects require further investigation. This review focuses on the important role of RV in promoting dental health. It delves into various aspects, including its impact on root health, maintenance of the dental pulp, care for tooth enamel, effectiveness of dental restorative materials, and health of dentin.

Photodynamic Therapy: A Novel Approach for Head and Neck Cancer Treatment with Focusing on Oral Cavity.

Oral cancers, specifically oral squamous cell carcinoma (OSCC), pose a significant global health challenge, with high incidence and mortality rates. Conventional treatments such as surgery, radiotherapy, and chemotherapy have limited effectiveness and can result in adverse reactions. However, as an alternative, photodynamic therapy (PDT) has emerged as a promising option for treating oral cancers. PDT involves using photosensitizing agents in conjunction with specific light to target and destroy cancer cells selectively. The photosensitizers accumulate in the cancer cells and generate reactive oxygen species (ROS) upon exposure to the activating light, leading to cellular damage and ultimately cell death. PDT offers several advantages, including its non-invasive nature, absence of known long-term side effects when administered correctly, and cost-effectiveness. It can be employed as a primary treatment for early-stage oral cancers or in combination with other therapies for more advanced cases. Nonetheless, it is important to note that PDT is most effective for superficial or localized cancers and may not be suitable for larger or deeply infiltrating tumors. Light sensitivity and temporary side effects may occur but can be managed with appropriate care. Ongoing research endeavors aim to expand the applications of PDT and develop novel photosensitizers to further enhance its efficacy in oral cancer treatment. This review aims to evaluate the effectiveness of PDT in treating oral cancers by analyzing a combination of preclinical and clinical studies.

The role of periodontitis in cancer development, with a focus on oral cancers.

Periodontitis is a severe gum infection that begins as gingivitis and can lead to gum recession, bone loss, and tooth loss if left untreated. It is primarily caused by bacterial infection, which triggers inflammation and the formation of periodontal pockets. Notably, periodontitis is associated with systemic health issues and has been linked to heart disease, diabetes, respiratory diseases, adverse pregnancy outcomes, and cancers. Accordingly, the presence of chronic inflammation and immune system dysregulation in individuals with periodontitis significantly contributes to the initiation and progression of various cancers, particularly oral cancers. These processes promote genetic mutations, impair DNA repair mechanisms, and create a tumor-supportive environment. Moreover, the bacteria associated with periodontitis produce harmful byproducts and toxins that directly damage the DNA within oral cells, exacerbating cancer development. In addition, chronic inflammation not only stimulates cell proliferation but also inhibits apoptosis, causes DNA damage, and triggers the release of pro-inflammatory cytokines. Collectively, these factors play a crucial role in the progression of cancer in individuals affected by periodontitis. Further, specific viral and bacterial agents, such as hepatitis B and C viruses, human papillomavirus (HPV), Helicobacter pylori (H. pylori), and Porphyromonas gingivalis, contribute to cancer development through distinct mechanisms. Bacterial infections have systemic implications for cancer development, while viral infections provoke immune and inflammatory responses that can lead to genetic mutations. This review will elucidate the link between periodontitis and cancers, particularly oral cancers, exploring their underlying mechanisms to provide insights for future research and treatment advancements.

Catharanthine, an anticancer vinca alkaloid: an in silico and in vitro analysis of the autophagic system as the major mechanism of cell death in liver HepG2 cells.

Catharanthine, a component of the anticancer drug vinblastine along with vindoline, disrupts the cell cycle by interfering with mitotic spindle formation. Apart from their antioxidant properties, vinca alkaloids like catharanthine inhibit phosphodiesterase activity and elevate intracellular cAMP levels. The aim of this study was to investigate how catharantine affects apoptosis and autophagy. This study conducted experiments on HepG2 liver carcinoma cells with varying doses of catharanthine to evaluate cell death rates and viability and determine the IC50 concentration via MTT assays. The apoptotic and autophagic effects of catharanthine were assessed using flow cytometry with annexin V and PI staining, while the expression of autophagy-related genes was analyzed through quantitative PCR. Additionally, molecular docking and molecular dynamics simulations were employed to further investigate catharanthine's impact on autophagy mechanisms. The study showed that catharanthine reduced oxidative stress and triggered apoptosis in HepG2 cells in a dose-dependent manner. Catharanthine also upregulated the expression of autophagy-related genes like LC3, Beclin1, and ULK1. Notably, catharanthine increased sirtuin-1 levels, a known autophagy inducer, while decreasing Akt expression compared to untreated cells. Molecular docking results indicated rapamycin had a stronger binding affinity with FRB (-10.7 KJ/mol-1) than catharanthine (-7.3 KJ/mol-1). Additionally, molecular dynamics simulations revealed that catharanthine interacted effectively with the FRB domain of mTOR, displaying stability and a strong binding affinity, although not as potent as rapamycin. In summary, besides its cytotoxic and pro-apoptotic effects, catharanthine activates autophagy signaling pathways and induces autophagic necrosis by inhibiting mTOR.

Revolutionizing type 1 diabetes management: Exploring oral insulin and adjunctive treatments.

Type 1 diabetes (T1D) is a chronic autoimmune condition that affects millions of people worldwide. Insulin pumps or injections are the standard treatment options for this condition. This article provides a comprehensive overview of the several type 1 diabetes treatment options, focusing on oral insulin. The article is divided into parts that include immune-focused treatments, antigen vaccination, cell-directed interventions, cytokine-directed interventions, and non-immunomodulatory adjuvant therapy. Under the section on non-immunomodulatory adjunctive treatment, the benefits and drawbacks of medications such as metformin, amylin, sodium-glucose cotransporter inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 Ras), and verapamil are discussed. The article also discusses the advantages of oral insulin, including increased patient compliance and more dependable and regular blood sugar control. However, several variables, including the enzymatic and physical barriers of the digestive system, impair the administration of insulin via the mouth. Researchers have looked at a few ways to get over these challenges, such as changing the structure of the insulin molecule, improving absorption with the use of absorption enhancers or nanoparticles, and taking oral insulin together with other medications. Even with great advancements in the use of these treatment strategies, T1D still needs improvement in the therapeutic difficulties. Future studies in these areas should focus on creating tailored immunological treatments, looking into combination medications, and refining oral insulin formulations in an attempt to better control Type 1 Diabetes. The ultimate objective is to create accurate, customized strategies that will enhance glycemic management and the quality of life for individuals with the condition.

Biotechnological applications of amyloid fibrils.

Protein aggregates and amyloid fibrils have special qualities and are used in a variety of biotechnological applications. They are extensively employed in bioremediation, biomaterials, and biocatalysis. Because of their capacity to encapsulate and release pharmaceuticals and their sensitivity to certain molecules, respectively, they are also used in drug delivery and biosensor applications. They have also demonstrated potential in the domains of food and bioremediation. Additionally, amyloid peptides have drawn interest in biological applications, especially in the investigation of illnesses like Parkinson's and Alzheimer's. The unique characteristics of amyloid fibrils, namely their mechanical strength and ß-sheet structure, make them adaptable to a wide range of biotechnological uses. Even with their promise, one important factor to keep in mind before widely using modified amyloid materials is their potential toxicity. Thus, current research aims to overcome safety concerns while maximizing their potential.

The Impact of Terminal Peptide Extensions of Retinal Inosine 5´Monophosphate Dehydrogenase 1 Isoforms on their DNA-binding Activities.

The main structural difference between the mutation-susceptible retinal isoforms of inosine 5´-monophosphate dehydrogenase-1 (IMPDH-1) with the canonical form resides in the C- and N-terminal peptide extensions with unknown structural/functional impacts. In this report, we aimed to experimentally evaluate the functional impact of these extensions on the specific/non-specific single-stranded DNA (ssDNA)-binding activities relative to those of the canonical form. Our in silico findings indicated the possible contribution of the C-terminal segment to the reduced flexibility of the Bateman domain of the enzyme. In addition, the in silico data indicated that the N-terminal tail acts by altering the distance between the tetramers in the concave octamer complex (the native form) of the enzyme. The overall impact of these predicted structural variations became evident, first, through higher Km values with respect to either of the substrates relative to the canonical isoform, as reported previously (Andashti et al. in Mol Cell Biochem 465(1):155-164, 2020). Secondary, the binding of the recombinant mouse retinal isoform IMPDH1 (603) to its specific Rhodopsin target gene was significantly augmented while its binding to non-specific ssDNA was lower than that of the canonical isoform. The DNA-binding activity of the other mouse retinal isoform, IMPDH1(546), to specific and non-specific ssDNA was lower than that of the canonical form most probably due to the in silico predicted rigidity created in the Bateman domain by the C-terminal peptide extension. Furthermore, the DNA binding to the Rhodopsin target gene by each of the IMPDH isoforms influenced in the presence of GTP (Guanosine triphosphate) and ATP (Adenosine triphosphate).

Increased V-ATPase activity can lead to chemo-resistance in oral squamous cell carcinoma via autophagy induction: new insights.

Oral squamous cell carcinoma (OSCC) is a cancer type with a high rate of recurrence and a poor prognosis. Tumor chemo-resistance remains an issue for OSCC patients despite the availability of multimodal therapy options, which causes an increase in tumor invasiveness. Vacuolar ATPase (V-ATPase), appears to be one of the most significant molecules implicated in MDR in tumors like OSCC. It is primarily responsible for controlling the acidity in the solid tumors' microenvironment, which interferes with the absorption of chemotherapeutic medications. However, the exact cellular and molecular mechanisms V-ATPase plays in OSCC chemo-resistance have not been understood. Uncovering these mechanisms can contribute to combating OSCC chemo-resistance and poor prognosis. Hence, in this review, we suggest that one of these underlying mechanisms is autophagy induced by V-ATPase which can potentially contribute to OSCC chemo-resistance. Finally, specialized autophagy and V-ATPase inhibitors may be beneficial as an approach to reduce drug resistance to anticancer therapies in addition to serving as coadjuvants in antitumor treatments. Also, V-ATPase could be a prognostic factor for OSCC patients. However, in the future, more investigations are required to demonstrate these suggestions and hypotheses.

COVID-19 in patients with anemia and haematological malignancies: risk factors, clinical guidelines, and emerging therapeutic approaches.

Extensive research in countries with high sociodemographic indices (SDIs) to date has shown that coronavirus disease 2019 (COVID-19) may be directly associated with more severe outcomes among patients living with haematological disorders and malignancies (HDMs). Because individuals with moderate to severe immunodeficiency are likely to undergo persistent infections, shed virus particles for prolonged periods, and lack an inflammatory or abortive phase, this represents an overall risk of morbidity and mortality from COVID-19. In cases suffering from HDMs, further investigation is needed to achieve a better understanding of triviruses and a group of related variants in patients with anemia and HDMs, as well as their treatment through vaccines, drugs, and other methods. Against this background, the present study aimed to delineate the relationship between HDMs and the novel COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Besides, effective treatment options for HDM cases were further explored to address this epidemic and its variants. Therefore, learning about how COVID-19 manifests in these patients, along with exploiting the most appropriate treatments, may lead to the development of treatment and care strategies by clinicians and researchers to help patients recover faster. Video Abstract.

Therapeutic applications of melatonin in disorders related to the gastrointestinal tract and control of appetite.

Most animals have large amounts of the special substance melatonin, which is controlled by the light/dark cycle in the suprachiasmatic nucleus. According to what is now understood, the gastrointestinal tract (GIT) and other areas of the body are sites of melatonin production. According to recent studies, the GIT and adjacent organs depend critically on a massive amount of melatonin. Not unexpectedly, melatonin's many biological properties, such as its antioxidant, anti-inflammatory, pro-apoptotic, anti-proliferative, anti-metastasis, and antiangiogenic properties, have drawn the attention of researchers more and more. Because melatonin is an antioxidant, it produces a lot of secretions in the GIT's mucus and saliva, which shields cells from damage and promotes the development of certain GIT-related disorders. Melatonin's ability to alter cellular behavior in the GIT and other associated organs, such as the liver and pancreas, is another way that it functions. This behavior alters the secretory and metabolic activities of these cells. In this review, we attempted to shed fresh light on the many roles that melatonin plays in the various regions of the gastrointestinal tract by focusing on its activities for the first time.

Unveiling the potential effects of resveratrol in lung cancer treatment: Mechanisms and nanoparticle-based drug delivery strategies.

Lung cancer ranks among the most prevalent forms of cancer and remains a significant factor in cancer-related mortality across the world. It poses significant challenges to healthcare systems and society as a whole due to its high incidence, mortality rates, and late-stage diagnosis. Resveratrol (RV), a natural compound found in various plants, has shown potential as a nanomedicine for lung cancer treatment. RV has varied effects on cancer cells, including promoting apoptosis by increasing pro-apoptotic proteins (Bax and Bak) and decreasing anti-apoptotic proteins (Bcl-2). It also hinders cell proliferation by influencing important signaling pathways (MAPK, mTOR, PI3K/Akt, and Wnt/ß-catenin) that govern cancer progression. In addition, RV acts as a potent antioxidant, diminishing oxidative stress and safeguarding cells against DNA damage. However, using RV alone in cancer treatment has drawbacks, such as low bioavailability, lack of targeting ability, and susceptibility to degradation. In contrast, nanoparticle-based delivery systems address these limitations and hold promise for improving treatment outcomes in lung cancer; nanoparticle formulations of RV offer advantages such as improved drug delivery, increased stability, controlled release, and targeted delivery to lung cancer cells. This article will provide an overview of lung cancer, explore the potential of RV as a therapeutic agent, discuss the benefits and challenges of nanoparticle-based drug delivery, and highlight the promise of RV nanoparticles for cancer treatment, including lung cancer. By optimizing these systems for clinical application, future studies aim to enhance overall treatment outcomes and improve the prognosis for lung cancer patients.

A Review of the Potential Role of CoQ10 in the Treatment of Hepatocellular Carcinoma.

The coenzyme ubiquinone-10 (CoQ10) is not only an important part of the electron transport chain of the mitochondrial inner membrane but also has complex biological functions beyond mitochondrial respiration. It is a natural nutrient that is not only produced by the body but is also found in foods, such as meat, eggs, fish, and vegetable oils. Because some types of cancer reduce CoQ10 blood levels, the use of CoQ10 supplements is recommended for the treatment of cancer patients. The anti-cancer effects of CoQ10 supplementation have been reported in several cancers, including colon and breast cancer. CoQ10 scavenges free radicals to reduce oxidative stress and minimize tissue damage. CoQ10 protects the body from damage caused by chemotherapy drugs by reducing the production of inflammatory cytokines and other inflammatory factors. Recent studies suggest that CoQ10 may be a supplement to pharmacotherapy for hepatocellular carcinoma. This article examines the effects of CoQ10 in hepatocellular carcinoma.

Revisiting of Properties and Modified Polyethylenimine-Based Cancer Gene Delivery Systems.

A new era of medical technology in cancer treatment is a directly specific modification of gene expression in tumor cells by nucleic acid delivery. Currently, the main challenge to achieving this goal is to find a non-toxic, safe, and effective strategy for gene transfer to cancer cells. Synthetic composites based on cationic polymers have historically been favored in bioengineering due to their ability to mimic bimolecular structures. Among them, polyethylenimines (PEIs) with superior properties such as a wide range of molecular weight and a flexible structure may propel the development of functional combinations in the biomedical and biomaterial fields. Here, in this review, we will focus on the recent progressions in the formulation optimization of PEI-based polyplex in gene delivery to treat cancer. Also, the effect of PEI's intrinsic characteristics such as structure, molecular weight, and positive charges which influence the gene delivery efficiency will be discussed.

Potential promising anticancer applications of ß-glucans: a review.

ß-Glucans are valuable functional polysaccharides distributed in nature, especially in the cell walls of fungi, yeasts, bacteria, and cereals. The unique features of ß-glucans, such as water solubility, viscosity, molecular weight, and so on, have rendered them to be broadly applied in various food systems as well as in medicine to improve human health. Moreover, inhibition of cancer development could be achieved by an increase in immune system activity via ß-glucans. ß-glucans, which are part of a class of naturally occurring substances known as biological response modifiers (BRMs), have also shown evidence of being anti-tumorogenic, anti-cytotoxic, and anti-mutagenic. These properties make them attractive candidates for use as pharmaceutical health promoters. Along these lines, they could activate particular proteins or receptors, like lactosylceramide (LacCer), Dickin-1, complement receptor 3 (CR3), scavenge receptors (SR), and the toll-like receptor (TLR). This would cause the release of cytokines, which would then activate other antitumor immune cells, like macrophages stimulating neutrophils and monocytes. These cells are biased toward pro-inflammatory cytokine synthesis and phagocytosis enhancing the elicited immunological responses. So, to consider the importance of ß-glucans, the present review introduces the structure characteristics, biological activity, and antitumor functions of fungal ß-glucans, as well as their application.

Promising applications of nanotechnology in inhibiting chemo-resistance in solid tumors by targeting epithelial-mesenchymal transition (EMT).

The resistance of cancer cells to chemotherapy, also known as chemo-resistance, poses a significant obstacle to cancer treatment and can ultimately result in patient mortality. Epithelial-mesenchymal transition (EMT) is one of the many factors and processes responsible for chemo-resistance. Studies have shown that targeting EMT can help overcome chemo-resistance, and nanotechnology and nanomedicine have emerged as promising approaches to achieve this goal. This article discusses the potential of nanotechnology in inhibiting EMT and proposes a viable strategy to combat chemo-resistance in various solid tumors, including breast cancer, lung cancer, pancreatic cancer, glioblastoma, ovarian cancer, gastric cancer, and hepatocellular carcinoma. While nanotechnology has shown promising results in targeting EMT, further research is necessary to explore its full potential in overcoming chemo-resistance and discovering more effective methods in the future.

Autophagy induced by Helicobacter Pylori infection can lead to gastric cancer dormancy, metastasis, and recurrence: new insights.

According to the findings of recent research, Helicobacter Pylori (H. pylori) infection is not only the primary cause of gastric cancer (GC), but it is also linked to the spread and invasion of GC through a number of processes and factors that contribute to virulence. In this study, we discussed that H. pylori infection can increase autophagy in GC tumor cells, leading to poor prognosis in such patients. Until now, the main concerns have been focused on H. pylori's role in GC development. According to our hypothesis, however, H. pylori infection may also lead to GC dormancy, metastasis, and recurrence by stimulating autophagy. Therefore, understanding how H. pylori possess these processes through its virulence factors and various microRNAs can open new windows for providing new prevention and/or therapeutic approaches to combat GC dormancy, metastasis, and recurrence which can occur in GC patients with H. pylori infection with targeting autophagy and eradicating H. pylori infection.

Fighting against amyotrophic lateral sclerosis (ALS) with flavonoids: a computational approach to inhibit superoxide dismutase (SOD1) mutant aggregation.

Protein aggregation is a biological process that occurs when proteins misfold. Misfolding and aggregation of human superoxide dismutase (hSOD1) cause a neurodegenerative disease called amyotrophic lateral sclerosis (ALS). Among the mutations occurring, targeting the E21K mutation could be a good choice to understand the pathological mechanism of SOD1 in ALS, whereof it significantly reduces life hopefulness in patients. Naturally occurring polyphenolic flavonoids have been suggested as a way to alleviate the amyloidogenic behavior of proteins. In this study, computational tools were used to identify promising flavonoid compounds that effectively inhibit the pathogenic behavior of the E21K mutant. Initial screening identified Pelargonidin, Curcumin, and Silybin as promising leads. Molecular dynamics (MD) simulations showed that the binding of flavonoids to the mutated SOD1 caused changes in the protein stability, hydrophobicity, flexibility, and restoration of lost hydrogen bonds. Secondary structure analysis indicated that the protein destabilization and the increased propensity of ß-sheet caused by the mutation were restored to the wild-type state upon binding of flavonoids. Free energy landscape (FEL) analysis was also used to differentiate aggregation, and results showed that Silybin followed by Pelargonidin had the most therapeutic efficacy against the E21K mutant SOD1. Therefore, these flavonoids hold great potential as highly effective inhibitors in mitigating ALS's fatal and insuperable effects.Communicated by Ramaswamy H. Sarma.