Therapeutic Possibilities Research Articles

Cost-effectiveness of genetic testing of endocrine tumor patients using a comprehensive hereditary cancer gene panel.

Heterogenous clinical manifestations, overlapping phenotypes and complex genetic backgrounds are common in patients with endocrine tumors. There are no comprehensive recommendations for genetic testing and counselling of these patients compared to other hereditary cancer syndromes. The application of multigene panel testing is common in clinical genetic laboratories, but their performance for patients with endocrine tumors has not been assessed. As a national reference center, we prospectively tested the diagnostic utility and cost-efficiency of a multigene panel covering 113 genes representing genetic susceptibility for solid tumors. 1279 patients (including 96 cases with endocrine tumors) were evaluated between October 2021 and December 2022 who were suspected to have hereditary tumor syndromes. The analytical performance of the hereditary cancer panel was suitable for diagnostic testing. Clinical diagnosis was confirmed in 24% (23/96); incidental findings in genes not associated with the patient's phenotype were identified in 5% (5/96). A further 7% of pathogenic/likely pathogenic variants were detected in genes with potential genetic susceptibility roles but currently no clear clinical consequence. Cost-benefit analysis showed that the application of a more comprehensive gene panel in a diagnostic laboratory yielded a shorter turnaround time and provided additional genetic results with the same cost and workload. Using comprehensive multigene panel results in faster turnaround time and cost-efficiently identifies genetic alterations in hereditary endocrine tumor syndromes. Incidentally identified variants in patients with poor prognoses may serve as a potential therapeutic target in tumors where therapeutic possibilities are limited.

Emotional Experiences in Online, Text-Based Tabletop Role-Playing Games

Background This study explores the emotional experiences of players in online, text-based tabletop role-playing games (TTRPGs) and their potential impact on players. The goal is to understand the therapeutic and educational possibilities arising from these emotional experiences. Methods Through qualitative analysis, themes were identified based on participants' narratives. Eight participants who engaged in online, text-based TTRPGs were interviewed to gather data on their emotional experiences and effects outside the game. Result The study identified three main categories of emotions experienced by players: emotions related to the community, emotions associated with the game world and characters, and emotions linked to game mechanics. These emotions were found to impact players beyond the gaming environment, influenced by the players' emotional immersion. Additionally, the study revealed two distinct approaches to immersion among players and highlighted emotions as motivating factors for gameplay. Discussion The findings emphasize the role of TTRPGs in providing creative outlets, social interaction, and recreation, facilitating skill development, and broadening perspectives based on players' emotional experiences. Additionally, this study highlights the potential for immersion in online, text-based TTRPGs linked to therapeutic and educational uses. Limitations This study employs an in-depth phenomenological qualitative interview method. While this approach yields detailed and nuanced data, it may not provide extensive generalizability. Future research endeavors could benefit from more significant and diverse participant pools to enhance the understanding of emotional experiences in TTRPG players. Furthermore, exploring additional factors such as genres, narrative structures, and player-character relationships could offer more profound insights. Conclusion This study demonstrates that online, text-based TTRPGs allow players to experience various emotions with implications beyond the game's boundaries. The findings suggest that interventions based on role-playing activities may benefit from the online text-based method due to its accessibility and lower barriers to entry.

Abstract PO3-29-03: An Emerging Class of ER mutations Enhances ER Dimerization and Promotes ER Activity

Abstract Physiological activation of estrogen receptor alpha (ERα) requires the binding of estradiol (E2) to the ligand binding domain (LBD) of the receptor. This interaction triggers a repositioning of helix 12 (H12), facilitating the recruitment of coactivator proteins to the unoccupied coactivator binding groove. However, in the context of breast cancer, point mutations of ERα at H12 lead to its repositioning and self-activation in the absence of E2. Through MSK clinical sequencing breast cancer cohort (MSK-IMPACT), we assayed 8302 samples of ER+ breast cancer patients and identified 649 mutations within the LBD of ERα. 471 of these mutations (73%) were located at H11-H12 loops (D538, Y537, L536), while the remaining 27% were located near the dimer interface of ERα (V422, G442, F461, S463P, L469). Through in vitro biochemical and cell assays, we identified that these mutations promote dimer formation and hormone-independent transcriptional activity. Tumors expressing these mutations exhibited significantly accelerated growth compared to their wild-type controls. Unlike Y537S, cells harboring mutations at the dimer interface maintain their sensitivity to Selective Estrogen Receptor Degraders (SERDs), including Fulvestrant, recently FDA-approved Elacestrant, and Camizestrant, as well as Selective Estrogen Receptor Modulators (SERMs) including Tamoxifen and Raloxifene. By utilizing machine learning and computational structural analyses, we uncovered that these mutants, unlike Y537 repositions H12, act distinctly through conformational change across the ERα dimer interface. Further cell assays proved that the dimerization leads to increased stability of the receptor and facilitates its nuclear localization, which is required for ERα activation. Collectively, our finding unveiled a new class of ER mutations that enforce receptor dimerization and activation of the ER signaling pathway. The discovery opens up a new therapeutic interventional possibility, suggesting that targeting dimerization could emerge as a new strategy to combat these malignancies. Citation Format: Seema Irani, Wuwei Tan, Qing Li, Weiyi Toy, Catherine Jones, Mayur Gadiya, Antonio Marra, John Katzenellenbogen, Kathryn Carlson, Benita S. Katzenellenbogen, Yang Shen, Sarat Chandarlapaty. An Emerging Class of ER mutations Enhances ER Dimerization and Promotes ER Activity [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-29-03.

Stem Cell and Regenerative Therapies for the Treatment of Osteoporotic Vertebral Compression Fractures.

Osteoporotic vertebral compression fractures (OVCFs) significantly increase morbidity and mortality, presenting a formidable challenge in healthcare. Traditional interventions such as vertebroplasty and kyphoplasty, despite their widespread use, are limited in addressing the secondary effects of vertebral fractures in adjacent areas and do not facilitate bone regeneration. This review paper explores the emerging domain of regenerative therapies, spotlighting stem cell therapy's transformative potential in OVCF treatment. It thoroughly describes the therapeutic possibilities and mechanisms of action of mesenchymal stem cells against OVCFs, relying on recent clinical trials and preclinical studies for efficacy assessment. Our findings reveal that stem cell therapy, particularly in combination with scaffolding materials, holds substantial promise for bone regeneration, spinal stability improvement, and pain mitigation. This integration of stem cell-based methods with conventional treatments may herald a new era in OVCF management, potentially improving patient outcomes. This review advocates for accelerated research and collaborative efforts to translate laboratory breakthroughs into clinical practice, emphasizing the revolutionary impact of regenerative therapies on OVCF management. In summary, this paper positions stem cell therapy at the forefront of innovation for OVCF treatment, stressing the importance of ongoing research and cross-disciplinary collaboration to unlock its full clinical potential.

Decoding the ribosome's hidden language: rRNA modifications as key players in cancer dynamics and targeted therapies.

Ribosomal RNA (rRNA) modifications, essential components of ribosome structure and function, significantly impact cellular proteomics and cancer biology. These chemical modifications transcend structural roles, critically shaping ribosome functionality and influencing cellular protein profiles. In this review, the mechanisms by which rRNA modifications regulate both rRNA functions and broader cellular physiological processes are critically discussed. Importantly, by altering the translational output, rRNA modifications can shift the cellular equilibrium towards oncogenesis, thus playing a key role in cancer development and progression. Moreover, a special focus is placed on the functions of mitochondrial rRNA modifications and their aberrant expression in cancer, an area with profound implications yet largely uncharted. Dysregulation in these modifications can lead to metabolic dysfunction and apoptosis resistance, hallmark traits of cancer cells. Furthermore, the current challenges and future perspectives in targeting rRNA modifications are highlighted as a therapeutic approach for cancer treatment. In conclusion, rRNA modifications represent a frontier in cancer research, offering novel insights and therapeutic possibilities. Understanding and harnessing these modifications can pave the way for breakthroughs in cancer treatment, potentially transforming the approach to combating this complex disease.

Novel Inhibitory Site Revealed by XAP044 Mode of Action on the Metabotropic Glutamate 7 Receptor Venus Flytrap Domain.

Metabotropic glutamate (mGlu) receptors play a key role in modulating most synapses in the brain. The mGlu7 receptors inhibit presynaptic neurotransmitter release and offer therapeutic possibilities for post-traumatic stress disorders or epilepsy. Screening campaigns provided mGlu7-specific allosteric modulators as the inhibitor XAP044 (Gee et al. J. Biol. Chem. 2014). In contrast to other mGlu receptor allosteric modulators, XAP044 does not bind in the transmembrane domain but to the extracellular domain of the mGlu7 receptor and not at the orthosteric site. Here, we identified the mode of action of XAP044, combining synthesis of derivatives, modeling and docking experiments, and mutagenesis. We propose a unique mode of action of these inhibitors, preventing the closure of the Venus flytrap agonist binding domain. While acting as a noncompetitive antagonist of L-AP4, XAP044 and derivatives act as apparent competitive antagonists of LSP4-2022. These data revealed more potent XAP044 analogues and new possibilities to target mGluRs.

Cold Atmospheric Pressure Plasma-Activated Medium Modulates Cellular Functions of Human Mesenchymal Stem/Stromal Cells In Vitro.

Cold atmospheric pressure plasma (CAP) offers a variety of therapeutic possibilities and induces the formation of reactive chemical species associated with oxidative stress. Mesenchymal stem/stromal cells (MSCs) play a central role in tissue regeneration, partly because of their antioxidant properties and ability to migrate into regenerating areas. During the therapeutic application, MSCs are directly exposed to the reactive species of CAP. Therefore, the investigation of CAP-induced effects on MSCs is essential. In this study, we quantified the amount of ROS due to the CAP activation of the culture medium. In addition, cell number, metabolic activity, stress signals, and migration were analyzed after the treatment of MSCs with a CAP-activated medium. CAP-activated media induced a significant increase in ROS but did not cause cytotoxic effects on MSCs when the treatment was singular and short-term (one day). This single treatment led to increased cell migration, an essential process in wound healing. In parallel, there was an increase in various cell stress proteins, indicating an adaptation to oxidative stress. Repeated treatments with the CAP-activated medium impaired the viability of the MSCs. The results shown here provide information on the influence of treatment frequency and intensity, which could be necessary for the therapeutic application of CAP.

Intra‐Articular Injection of Nanomaterials for the Treatment of Osteoarthritis: From Lubrication Function Restoration to Cell and Gene Therapy

AbstractOsteoarthritis (OA), a prevalent joint disease affecting many people globally, presents significant challenge in current treatments, which often only manage symptoms without halting disease progression. This review illuminates novel approaches in OA therapy, focusing mainly on intra‐articular injection of nanomaterials. The innovative materials, designed to either mimic or augment natural joint lubrication, show promise in restoring joint biomechanics and alleviating pain. The review delves into an array of biomimetic lubricants, including polymer brush, nanocomposite hydrogel, and nanoparticles, underscoring their roles in anti‐inflammation, targeting, cartilage repair, and drug delivery. Furthermore, the potential of mesenchymal stem cells to differentiate into chondrocytes, coupled with the delivery of these cells and their exosomes via nanomaterials, has promoted cell therapy avenues for OA. The review also highlights the function of non‐coding RNAs such as miRNA, siRNA, circRNA, lncRNA, and antisense oligonucleotides in impeding OA progression, with nanomaterials facilitating their delivery, thus facilitating advanced therapeutic possibilities including immune evasion and bone cell proliferation. Overall, this review encapsulates the evolution of nanomaterials in OA treatment from material to cell, and ultimately to gene therapy, forecasting a future where nanomaterials evolve toward integrated, personalized diagnostics and therapeutics for OA.

THE CURRENT STATE OF STEM CELL THERAPY FOR SPINAL CORD INJURY AND OTHER SYSTEMIC INJURIES

The pathomechanism of many diseases affecting the human brain and spinal cord has not been fully elucidated. Some organs of the human body have the ability to rebuild and regenerate in the event of apoptosis or necrosis of some cells. An organ with a high self-regeneration capacity is, for example, the liver. In this respect, the human nervous system is its opposite. This is related to the strict functional specialization of neurons and the fact that the function of the nervous system is influenced not only by the operation of individual cells, but also by efficient transmission in often huge and complex networks of neuronal connections, the damage of which is practically impossible to repair. This limited regenerative capacity is why cell loss and nerve fiber disruption are irreversible losses. This constitutes a significant problem in the treatment of patients with spinal cord injuries or suffering from diseases involving rapid (stroke) or constantly progressive (neurodegenerative diseases) loss of nerve cells. The aim of this work: This work presents the current and most interesting directions of research on the possibility of using stem cells in attempts to regenerate spinal cord and brain injuries. Methods: Selected articles from Pubmed and specialist textbooks were analyzed in detail. We focused on selected disease states in which stem cells may have therapeutic possibilities. Conclusion: Currently, cell therapies are mainly used in bone marrow diseases such as leukemias and myelodysplastic syndromes. If our level of knowledge allows it, in the future stem cells may become a tool in the fight against numerous diseases currently considered incurable and help in the regeneration of organs with a low degree of self-renewal, such as the spinal cord and brain, but also the heart, pancreas and many others.

A Review on the Potential Use of Medicinal Plants from the Apiaceae and the Rosaceae Families in Cardiovascular Diseases—Experimental Evidence and Traditional Applications

Cardiovascular diseases are the leading cause of mortality worldwide. The World Health Organization has presented alarming data stating that in 2019, 17.9 million people globally died due to cardiovascular diseases, constituting 32% of all deaths. Despite increasingly advanced pharmacological and procedural treatment methods for these diseases, there is still a quest for new therapeutic possibilities that promise even greater efficacy and safety. The overriding purpose of this study is to provide an insight into the traditional uses of species from the Apiaceae and Rosaceae families as well as to systematize knowledge regarding their scientifically proven cardiovascular activities (animal studies and clinical trials). The review is intended to indicate knowledge gaps for future studies concerning plants used in traditional medicine but without scientific research. As a result, various plant species from both Apiaceae and Rosaceae family have been collected and described based on their study that has proven their effectiveness and uses in cardiovascular diseases. Most of these plants have a hypotensive effect, followed by anti-hyperlipidemic, vasorelaxant, antithrombotic, and diuretic activity. These are the mechanisms that contribute to various cardiovascular diseases, such as heart attack, coronary heart disease, hypertension, and stroke.

Expression of Selected miRNAs in Undifferentiated Carcinoma with Osteoclast-like Giant Cells (UCOGC) of the Pancreas: Comparison with Poorly Differentiated Pancreatic Ductal Adenocarcinoma.

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas represents a rare subtype of pancreatic ductal adenocarcinoma (PDAC). Despite a distinct morphology and specific clinical behavior, UCOGCs exhibit unexpected similarities in regard to DNA mutational profiles with conventional PDAC. Treating pancreatic ductal adenocarcinoma is particularly challenging, with limited prospects for cure. As with many other malignant neoplasms, the exploration of microRNAs (miRNAs, miRs) in regulating the biological characteristics of pancreatic cancer is undergoing extensive investigation to enhance tumor diagnostics and unveil the therapeutic possibilities. Herein, we evaluated the expression of miR-21, -96, -148a, -155, -196a, -210, and -217 in UCOGCs and poorly differentiated (grade 3, G3) PDACs. The expression of miR-21, miR-155, and miR-210 in both UCOGCs and G3 PDACs was significantly upregulated compared to the levels in normal tissue, while the levels of miR-148a and miR-217 were downregulated. We did not find any significant differences between cancerous and normal tissues for the expression of miR-96 and miR-196a in G3 PDACs, whereas miR-196a was slightly, but significantly, downregulated in UCOGCs. On the other hand, we have not observed significant differences in the expression of the majority of miRNAs between UCOGC and G3 PDAC, with the exception of miR-155. UCOGC samples demonstrated lower mean levels of miR-155 in comparison with those in G3 PDACs.

PKIB, a Novel Target for Cancer Therapy.

The serine-threonine kinase protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent intracellular protein with multiple roles in cellular biology including metabolic and transcription regulation functions. The cAMP-dependent protein kinase inhibitor β (PKIB) is one of three known endogenous protein kinase inhibitors of PKA. The role of PKIB is not yet fully understood. Hormonal signaling is correlated with increased PKIB expression through genetic regulation, and increasing PKIB expression is associated with decreased cancer patient prognosis. Additionally, PKIB impacts cancer cell behavior through two mechanisms; the first is the nuclear modulation of transcriptional activation and the second is the regulation of oncogenic AKT signaling. The limited research into PKIB indicates the oncogenic potential of PKIB in various cancers. However, some studies suggest a role of PKIB in non-cancerous disease states. This review aims to summarize the current literature and background of PKIB regarding cancer and related issues. In particular, we will focus on cancer development and therapeutic possibilities, which are of paramount interest in PKIB oncology research.

Sleep and Long COVID—A Review and Exploration of Sleep Disturbances in Post Acute Sequelae of SARS-COV-2 (PASC) and Therapeutic Possibilities

Sleep and Long COVID—A Review and Exploration of Sleep Disturbances in Post Acute Sequelae of SARS-COV-2 (PASC) and Therapeutic Possibilities

Unravelling driver genes as potential therapeutic targets in ovarian cancer via integrated bioinformatics approach

Target-driven cancer therapy is a notable advancement in precision oncology that has been accompanied by substantial medical accomplishments. Ovarian cancer is a highly frequent neoplasm in women and exhibits significant genomic and clinical heterogeneity. In a previous publication, we presented an extensive bioinformatics study aimed at identifying specific biomarkers associated with ovarian cancer. The findings of the network analysis indicate the presence of a cluster of nine dysregulated hub genes that exhibited significance in the underlying biological processes and contributed to the initiation of ovarian cancer. Here in this research article, we are proceeding our previous research by taking all hub genes into consideration for further analysis. GEPIA2 was used to identify patterns in the expression of critical genes. The KM plotter analysis indicated that the out of all genes 5 genes are statistically significant. The cBioPortal platform was further used to investigate the frequency of genetic mutations across the board and how they affected the survival of the patients. Maximum mutation was reported by ELAVL2. In order to discover viable therapeutic candidates after competitive inhibition of ELAVL2 with small molecular drug complex, high throughput screening and docking studies were used. Five compounds were identified. Overall, our results suggest that the ELAV-like protein 2-ZINC03830554 complex was relatively stable during the molecular dynamic simulation. The five compounds that have been found can also be further examined as potential therapeutic possibilities. The combined findings suggest that ELAVL2, together with their genetic changes, can be investigated in therapeutic interventions for precision oncology, leveraging early diagnostics and target-driven therapy.

Maternal Immune Activation and Autism Spectrum Disorder: Complex Interactions and Therapeutic Possibilities

This review examines the intricate association between maternal immune activation (MIA) and autism spectrum disorder (ASD), emphasizing the impact of maternal infections during pregnancy. Epidemiological studies link viral and bacterial infections to an elevated risk of ASD, revealing the complex interplay between environmental factors and neurodevelopmental outcomes. Immunological mechanisms, including cytokine dysregulation and neuroinflammation, involve key players such as interleukin-6 and tumor necrosis factor-alpha, influencing fetal brain development and ASD risk. Genetic and environmental interactions contribute to individual susceptibility, with specific variants influencing MIA's impact on ASD risk. Epigenetic modifications provide a molecular link between environmental exposures, including MIA, and enduring neurodevelopmental changes. Recognizing critical periods during fetal neurodevelopment susceptible to MIA is crucial. Long-term studies highlight enduring consequences on behavior and cognition into childhood and adolescence. Exploring potential therapeutic interventions, including immunomodulatory strategies during pregnancy, offers hope for mitigating MIA's impact on ASD outcomes. Despite progress, knowledge gaps persist, motivating future research guided by emerging technologies and interdisciplinary approaches to unravel the intricate MIA-ASD relationship.

Metastasis and the Microbiome: The Impact of Bacteria in Disseminated Colorectal Cancer.

Metastasis remains a leading cause of mortality for patients with solid tumors. An expanding body of literature suggests interplay between the host, gut, and tumoral microbiomes may play a role in cancer initiation and distant dissemination. These associations have been particularly well-studied in colorectal cancer, where gut dysbiosis and an endotoxin-induced inflammatory milieu foster premalignant polyp formation, setting the stage for carcinogenesis. Subsequent violation of the gut vascular barrier enables dissemination of bacterial agents to sites such as the liver, where they contribute to establishment of pre-metastatic niches, which promote tumor cell extravasation and metastatic outgrowth. Intriguingly, breakdown of this vascular barrier has been shown to be aided by the presence of tumoral bacteria. The presence of similar species, including Fusobacterium nucleatum and Escherichia Coli, in both primary and metastatic colorectal tumors, supports this hypothesis and their presence is associated with chemotherapy resistance and an overall poor prognosis. Specific gut microbial populations are also associated with differential response to immunotherapy, which has a growing role in microsatellite unstable colorectal cancers. Recent work suggests that modulation of gut microbiome using dietary modification, targeted antibiotics, or fecal microbiota transplantation may improve response to immunotherapy and oncologic outcomes. Elucidation of the precise mechanistic links between the microbiome and cancer dissemination will open the doors to additional therapeutic possibilities.

Acute Intestinal Invagination in Adults Relating to Internal Hernia: A Case Report

Acute intestinal intussusception is a pathology of infants and small children. Its occurrence in adults is rare. Its etiology is diverse. In the vast majority of cases, it is secondary to a tumor, which may be benign or malignant. We report the case of a 31-year-old patient, operated on in August 2022 for appendicular peritonitis, admitted to the emergency department of the Hassan II University Hospital in Fez, Morocco, for an intestinal obstruction. The abdominal CT scan showed an acute intestinal intussusception, and treatment was open surgical resection. Based on this new case and a review of the literature, we discuss the clinical features, diagnosis and therapeutic possibilities of this rare pathology.

Cryo-EM structure of human HCN3 channel and its regulation by cAMP

HCN channels are important for regulating heart rhythm and nerve activity and have been studied as potential drug targets for treating depression, arrhythmia, nerve pain and epilepsy.Despite possessing unique pharmacological properties, HCN channels share common characteristics in that they are activated by hyperpolarization and modulated by cAMP and other membrane lipids. However, the mechanisms of how these ligands bind and modulate HCN channels are unclear. In this study, we solved structures of full-length human HCN3 using cryo-EM and captured two different states, including a state without any ligand bound and a state with cAMP bound. Our structures reveal the novel binding sites for cholesteryl hemisuccinate in apo-state and show how cholesteryl hemisuccinate and cAMP binding cause conformational changes in different states. These findings explain how these small modulators are sensed in mammals at the molecular level.The results of our study could help design more potent and specific compounds to influence HCN channel activity and offer new therapeutic possibilities for diseases that lack effective treatment.

Polyomavirus-positive Merkel cell carcinoma: the beginning of the beginning.

Merkel cell carcinoma (MCC) is an aggressive, fast-growing, highly metastatic neuroendocrine skin cancer. The Merkel cell polyomavirus (MCPyV) is an oncogenic driver in the majority of MCC tumors. In this issue of the JCI, Hansen and authors report on their tracking of CD8+ T cells reactive to MCPyV T antigen (T-Ag) in the peripheral blood of 26 patients with MCC who were undergoing frontline anti-programmed cell death protein-1 (anti-PD-1) immunotherapy. They discovered unique T cell epitopes and used the power of bar-coded tetramers to portray immune checkpoint inhibitor-induced immunogenicity as a predictor of clinical response. These findings provide the foundation for therapeutic possibilities for MCC, including vaccines and adoptive T cell- and T cell receptor-driven (TCR-driven) treatments.

Role of Herbal Active Compound in Cardiac Failure Treatment

The prevalence of cardiovascular diseases (CVDs) is constantly rising, making them a major health burden. In terms of global mortality and morbidity, they are still at the top. An alternate method of treating many illnesses, including CVDs, is the use of medicinal herbs. There is a current, unprecedented push to include herbal remedies into contemporary healthcare systems. The widespread conviction in their safety and the fact that they offer more effective treatment at a lower cost than conventional modern medicines are two of the main factors propelling this movement. However, there has not been enough testing of the purported safety of herbal remedies. As a result, people need to know that medical herbs can be toxic, have possibly fatal side effects, and can interact negatively with other drugs. Experimental evidence suggests that medicinal herbs may be useful in the treatment of cardiovascular diseases (CVDs) due to their ability to inhibit multiple risk factors for these conditions. So, in order to successfully use herbs in CVD therapy, there have been numerous initiatives to transition medicinal herb research from the lab to the clinic. Presented below are cardiovascular diseases (CVDs) and the variables that put people at risk for developing them. Next, we provide a synopsis of herbal medicine's role in the treatment of disease, with a focus on cardiovascular diseases. In addition, information is compiled and examined about the ethnopharmacological therapeutic possibilities and medicinal qualities against cardiovascular diseases of four commonly used plants: ginseng, gingko biloba, ganoderma lucidum, and gymnostemma pentaphyllum. The use of these four plants in the treatment of cardiovascular diseases (CVDs) including myocardial infarction, hypertension, peripheral vascular disorders, coronary heart disease, cardiomyopathies, and dyslipidemias has been well examined. We are also making an effort to describe the current in vitro and in vivo investigations that have attempted to examine the cellular and molecular underpinnings of the four plants' cardio-protective effects. Lastly, we highlighted the effectiveness, safety, and toxicity of these four medicinal herbs by reviewing and reporting the results of current clinical trials.
 GRAPHICAL ABSTRACT