Statins are widely prescribed lipid-lowering agents but are associated with adverse effects such as myopathy and, less commonly, cognitive disturbances. Increasing evidence suggests that plant-derived phytochemicals can interact with statins, producing both beneficial and potentially harmful effects. Preclinical and limited clinical evidence suggests that selected phytochemicals may enhance certain therapeutic effects of statins and may contribute to adverse effect mitigation; however, their potential to support statin dose reduction requires confirmation in well-designed clinical trials. Phytochemicals may reduce inflammation and oxidative stress, potentially enabling lower statin doses. By elucidating these interactions, healthcare providers can develop personalized treatment strategies that enhance therapeutic outcomes of statins while minimizing risks. This review aims to clarify the intricate relationship between specific phytochemicals and statins, emphasizing the need for further investigation into their combined effects on cardiovascular health. The strength of evidence varies considerably across the available literature, ranging from randomized controlled trials to preclinical in vitro and animal studies. Consequently, the translational applicability of many reported phytochemical-statin interactions remains uncertain and warrants further clinical investigation. In addition to potentially beneficial effects, several phytochemicals may pose clinically relevant safety concerns through mechanisms, such as CYP3A4 inhibition, leading to increased statin exposure and toxicity; OATP inhibition, potentially reducing hepatic statin uptake and therapeutic efficacy; and hERG channel blockade, which may increase the risk of QT prolongation. These interactions may contribute to adverse outcomes, including statin-associated myopathy and, in rare cases, rhabdomyolysis.

Atherosclerosis is characterized by the accumulation of plaques within arterial walls, with plaque progression and regression being dynamically influenced by macrophage behavior. This review examines the roles of macrophage trafficking and efferocytosis in atherosclerotic plaque regression, with particular emphasis on macrophage retention, egress, and the clearance of apoptotic cells. Retention of macrophages within plaques, mediated by regulators such as Netrin-1 and Semaphorin-3E, contributes to persistent inflammation and impaired plaque resolution. In contrast, macrophage egress through pathways involving CCR7 and CCL19 can promote inflammatory resolution and facilitate the removal of apoptotic cells. Effective efferocytosis is essential for maintaining tissue homeostasis, whereas its dysregulation contributes to continued inflammation and atherosclerosis progression. The review further discusses therapeutic strategies aimed at modulating macrophage behavior, including macrophage polarization, mTOR signaling, LXR activation, cholesterol efflux, and targeted approaches to enhance macrophage function. By integrating these mechanisms, this review highlights the interconnected roles of macrophage trafficking and efferocytosis in plaque regression and discusses their therapeutic potential for the development of strategies to promote atherosclerotic plaque resolution.

Sleep disturbance is prevalent among solid organ transplant recipients and significantly impairs posttransplant recovery and health-related quality of life (HRQOL). Transplant recipients often experience challenges related to inadequate sleep quality, daytime drowsiness, difficulty falling or staying asleep, as well as various sleep disorders like sleep apnea, narcolepsy, and restless legs syndrome, which are commonly observed in this population. The review paper offers a detailed and wide-ranging examination of the influence that sleep disruption exerts on the recuperation process and overall well-being of individuals following a transplant procedure. It covers the prevalence of sleep disturbance in different types of transplant recipients, the factors contributing to sleep disturbance, the impact of sleep disturbance on the recovery process and quality of life following transplantation, along with interventions which aim at enhancing sleep quality in transplant recipients, which are explored in the study. This is an integrative review linking immunosuppressive drug effects on specific neural circuits, neurotransmitter systems, and inflammatory pathways to post-transplant sleep disturbance. The discussed highlights offer perspectives for healthcare practitioners and researchers engaged in transplantation medicine and neural systems biology research.

The abscopal effect (AE) in oncology, where localized radiation therapy (RT) triggers a systemic anti-tumor immune response, holds great promise for revolutionizing cancer treatment. Emerging evidence suggests microRNAs (miRNAs), small non-coding RNAs, are essential in mediating the intricate interactions among the tumor, immune system, and tumor microenvironment underlying the AE. miRNAs, both within the tumor and circulating as exosomal cargo, can regulate gene expression to modulate the tumor microenvironment, enhance antigen presentation, and activate anti-tumor immunity. This miRNA-mediated intercellular communication can influence the radiation response, including tumor radiosensitivity, DNA damage repair, and apoptosis. Targeting specific miRNAs or leveraging miRNA-based therapies may sensitize tumors to radiation-induced immune responses, leading to more robust and durable AEs. Understanding the epigenetic regulation of the AE by miRNAs offers novel strategies to harness this phenomenon for improved cancer outcomes. Exploring the intersection of miRNAs, radiation, and the immune system holds the promise of developing more effective, personalized radiotherapy approaches that can unleash the body's defenses against metastatic disease. Unlocking the power of miRNA-mediated signaling may be the important key to unlocking the full potential of AE in the field of cancer treatment. The graphical abstract offers a summary of our comprehensive review, focusing on the abscopal effect mechanism and the potential of diverse strategies, including miRNA delivery, cell therapy, and immunotherapy, to enhance this phenomenon for improved cancer treatment outcomes. Various mechanisms are illustrated surrounding the central focus, including miRNA delivery, cell therapy, and immunotherapy. One of the mechanisms depicted involves the delivery of miRNAs, which can modulate gene expression and immune responses, thereby amplifying the abscopal effect. Another approach highlighted is cell therapy, which involves the infusion of genetically engineered cells to enhance anti-tumor immunity and augment the abscopal effect. Lastly, immunotherapy is portrayed as a pivotal strategy for boosting the abscopal effect. Immunotherapeutic interventions, such as immune checkpoint inhibitors or cancer vaccines, can activate and potentiate the immune system's ability to recognize and eradicate tumor cells both locally and systemically.

The interplay between the tumor suppressor protein p53 and high mobility group box 1 (HMGB1) is critical in cancer therapy, influencing responses to chemotherapy, radiotherapy, and immunotherapy. Despite the significance of these interactions, the relationship between these factors in treatment remains inadequately explored, underscoring the urgent need for further investigation. Hence, this review elucidates the mechanisms by which p53 and HMGB1 modulate cellular stress responses, apoptosis, and autophagy, highlighting their roles in multidrug resistance (MDR). Additionally, we conducted an in-silico study on the structure of the p53 protein, p53-DNA complex, the p53-HMGB1 complex, as well as the impact of their mutations within the p53-HMGB1-DNA binding dynamics. Recent advancements in nanotechnology offer promising strategies for enhancing therapeutic efficacy through targeted delivery systems that simultaneously modulate p53 and HMGB1 pathways. By integrating these molecular insights with nanotechnology, we propose a synergistic approach to overcoming treatment resistance and improving patient outcomes.

Neuroinflammation significantly contributes to stroke pathophysiology, leading to tissue damage and neurological deficits. Baicalein, a potent 12/15-LOX (12/15-lipoxygenase) inhibitor, demonstrates neuroprotective effects by reducing inflammatory lipid mediators, modulating key inflammatory pathways, and attenuating oxidative stress. Experimental studies indicate that baicalein can diminish infarct size and neurological deficits while improving safety and tolerability. Combination therapies with baicalein show promise in enhancing stroke outcomes. Overall, targeting 12/15-LOX and employing baicalein represents a promising approach to modulating neuroinflammation and improving recovery in stroke patients. This review highlights the therapeutic potential of inhibiting the 12/15-LOX pathway and utilizing the natural compound baicalein to mitigate poststroke neuroinflammation.

Substance use disorders (SUDs) involve a complex series of central and peripheral pathologies, leading to impairments in cognitive, behavioral, and physiological processes. Emerging evidence indicates a more significant role for the microbiome-gut-brain axis (MGBA) in SUDs than previously recognized. The MGBA is interconnected with various body systems by producing numerous metabolites, most importantly short-chain fatty acids (SCFAs), cytokines, and neurotransmitters. These mediators influence the human body's epigenome and transcriptome. While numerous epigenetic alterations in different brain regions have been reported in SUD models, the intricate relationship between SUDs and the MGBA suggests that the gut microbiome may partially contribute to the underlying mechanisms of SUDs. Promising results have been observed with gut microbiome-directed interventions in patients with SUDs, including prebiotics, probiotics, antibiotics, and fecal microbiota transplantation. Nonetheless, the long-term epigenetic effects of these interventions remain unexplored. Moreover, various confounding factors and study limitations have hindered the identification of molecular mechanisms and clinical applications of gut microbiome interventions in SUDs. In the present review, we will (i) provide a comprehensive discussion on how the gut microbiome influences SUDs, with an emphasis on epigenetic alterations; (ii) discuss the current evidence on the bidirectional relationship of gut microbiome and SUDs, highlighting potential targets for intervention; and (iii) review recent advances in gut microbiome-directed therapies, along with their limitations and future directions.

Bowman-Birk Inhibitors (BBIs) are plant-derived serine protease inhibitors with diverse biological activities and significant therapeutic potential. Originally isolated from soybeans, BBIs have demonstrated potent anticancer effects that surpass those of other soy-derived agents. This review comprehensively examines the multifaceted therapeutic applications of BBIs, including their anticancer, anti-inflammatory, antimicrobial, and gastrointestinal protective properties. We explore the structural and stability features and evolutionary relationships that underpin BBIs’ unique dual-inhibitory activity against serine proteases. The molecular mechanisms through which BBIs exert their effects—such as modulation of key signaling pathways, immune regulation, and microbial membrane disruption—are also discussed. Advances in synthetic peptide mimics, exemplified by sunflower trypsin inhibitor-1 (SFTI-1), highlight opportunities for therapeutic optimization. Additionally, clinical trial data on Bowman-Birk Inhibitor Concentrate (BBIC), a BBI-enriched soybean extract, demonstrate safety and efficacy without neutralizing antibody development. This review synthesizes current insights into BBIs, underscoring their remarkable versatility and promising role in cancer prevention, inflammatory disease management, and antimicrobial therapy, while addressing ongoing challenges and future directions.

Cancer is a leading cause of global mortality, significantly impacted by treatment resistance and the toxicity of conventional therapies like chemotherapy and radiation. Recent studies show that anastasis-the recovery of cells from near-death states-as a key mechanism promoting cancer relapse and apoptosis resistance. During anastasis, stress-induced caspase activation allows cancer cells to survive, increase chemoresistance, and enhance metastatic potential. Heat shock proteins (HSPs) reinforce this resilience by repairing damaged proteins and maintaining cell viability under stress. This review presents novel nanotechnology-based strategies that disrupt these survival pathways by targeting HSP inhibitors and caspase modulators directly to tumors using advanced nanoparticles. By focusing on the interplay between anastasis and apoptosis, our approach aims to inhibit the mechanisms that enable cancer cells to evade death while enhancing treatment delivery precision and minimizing systemic toxicity. These nanotech-enhanced strategies promise to overcome treatment resistance and lead to safer, more effective anticancer therapies. Such innovations could significantly advance our understanding of cell death and survival in cancer, paving the way for next-generation therapeutic interventions.

Gut microbiota plays a critical role in maintaining health and is implicated in various diseases. Probiotics, prebiotics, synbiotics, and postbiotics (PPSPs) are potential therapeutic approaches for modifying the gut microbiota to prevent or treat associated disorders. This modulation influences apoptotic cell clearance (efferocytosis) and inflammation resolution. These processes are vital for immune function and tissue homeostasis. Evidence from animal and human studies indicates that PPSPs can enhance efferocytosis, leading to reduced inflammation and tissue damage. Additionally, PPSPs may ameliorate diseases such as metabolic syndrome, gastrointestinal disorders, and neurodegenerative conditions, by modulating gut microbiota composition and metabolite production. Notably, non-viable probiotics also enhance natural defense against infections, boost vaccine responses, and reduce common cold incidence. Clinical trials show promising outcomes for PPSPs in treating inflammatory bowel disease and certain cancers. However, further research is needed to determine the specific strains, dosages, and durations of PPSPs for optimizing their therapeutic efficacy. Overall, modulating gut microbiota through PPSPs represents a promising avenue for disease prevention and treatment, particularly in enhancing apoptotic cell clearance and attenuating inflammation and tissue damage.

AbstractGlioblastomas (GBMs) are the most common and aggressive malignant brain tumors, presenting significant challenges for treatment due to their invasive nature and localization in critical brain regions. Standard treatment includes surgical resection followed by radiation and adjuvant chemotherapy with temozolomide (TMZ). Recent advances in immunotherapy, including the use of mRNA vaccines, offer promising alternatives. This review focuses on the emerging use of mRNA vaccines for GBM treatment. We summarize recent advancements, evaluate current obstacles, and discuss notable successes in this field. Our analysis highlights that while mRNA vaccines have shown potential, their use in GBM treatment is still experimental. Ongoing research and clinical trials are essential to fully understand their therapeutic potential. Future developments in mRNA vaccine technology and insights into GBM-specific immune responses may lead to more targeted and effective treatments. Despite the promise, further research is crucial to validate and optimize the effectiveness of mRNA vaccines in combating GBM. Graphical Abstract

This article explores the potential therapeutic implications of phytochemicals on the gut-brain axis (GBA), which serves as a communication network between the central nervous system and the enteric nervous system. Phytochemicals, which are compounds derived from plants, have been shown to interact with the gut microbiota, immune system, and neurotransmitter systems, thereby influencing brain function. Phytochemicals such as polyphenols, carotenoids, flavonoids, and terpenoids have been identified as having potential therapeutic implications for various neurological disorders. The GBA plays a critical role in the development and progression of various neurological disorders, including Parkinson's disease, multiple sclerosis, depression, anxiety, and autism spectrum disorders. Dysbiosis, or an imbalance in gut microbiota composition, has been associated with a range of neurological disorders, suggesting that modulating the gut microbiota may have potential therapeutic implications for these conditions. Although these findings are promising, further research is needed to elucidate the optimal use of phytochemicals in neurological disorder treatment, as well as their potential interactions with other medications. The literature review search was conducted using predefined search terms such as phytochemicals, gut-brain axis, neurodegenerative, and Parkinson in PubMed, Embase, and the Cochrane library.

Inflammatory and autoimmune disorders, characterized by dysregulated immune responses leading to tissue damage and chronic inflammation, present significant health challenges. This review uniquely focuses on efferocytosis—the phagocyte-mediated clearance of apoptotic cells—and its pivotal role in these disorders. We delve into the intricate mechanisms of efferocytosis’ four stages and their implications in disease pathogenesis, distinguishing our study from previous literature. Our findings highlight impaired efferocytosis in conditions like atherosclerosis and asthma, proposing its targeting as a novel therapeutic strategy. We discuss the therapeutic potential of efferocytosis in modulating immune responses and resolving inflammation, offering a new perspective in treating inflammatory disorders.

Resolvins are specialized pro-resolving mediators derived from omega-3 fatty acids that can suppress several cancer-related molecular pathways, including important activation of transcription parameters in the tumor cells and their microenvironment, inflammatory cell infiltration, cytokines as well as chemokines. Recently, an association between resolvins and an important anti-inflammatory process in apoptotic tumor cell clearance (efferocytosis) was shown. The inflammation status or the oncogene activation increases the risk of cancer development via triggering the transcriptional agents, including nuclear factor kappa-light-chain-enhancer of activated B cells by generating the pro-inflammatory lipid molecules and infiltrating the tumor cells along with the high level of pro-inflammatory signaling. These events can cause an inflammatory microenvironment. Resolvins might decrease the leukocyte influx into the inflamed tissues. It is widely accepted that resolvins prohibit the development of debris-triggered cancer via increasing the clearance of debris, especially by macrophage phagocytosis in tumors without any side effects. Resolvins D2, D1, and E1 might suppress tumor-growing inflammation by activation of macrophages clearance of cell debris in the tumor. Resolvin D5 can assist patients with pain during treatment. However, the effects of resolvins as anti-inflammatory mediators in cancers are not completely explained. Thus, based on the most recent studies, we tried to summarize the most recent knowledge on resolvins in cancers.

Recent research has shed light on the intricate connection between efferocytosis and infertility, revealing its dysregulation as a contributing factor in various reproductive diseases. Despite the multifaceted nature of infertility etiology, the impact of insufficient clearance of apoptotic cells on fertility has emerged as a focal point. Notably, the removal of apoptotic cells through phagocytosis in the female reproductive system has been a subject of extensive investigation in the field of infertility. Additionally, special functions performed by immune system cell types, such as macrophages and Sertoli cells, in the male reproductive system underscore their significance in spermatogenesis and the efferocytosis of apoptotic germ cells. Dysregulation of efferocytosis emerges as a critical factor contributing to reproductive challenges, such as low pregnancy rates, miscarriages, and implantation failures. Moreover, defective efferocytosis can lead to compromised implantation, recurrent miscarriages, and unsuccessful assisted reproductive procedures. This review article aims to provide a comprehensive overview of efferocytosis in the context of infertility. Molecular mechanisms underlying efferocytosis, its relevance in both female and male infertility, and its implications in various reproductive diseases are elucidated. The elucidation of the intricate relationship between efferocytosis and infertility not only facilitates diagnosis but also paves the way for targeted therapeutic interventions.

Cancer remains a challenging disease worldwide, necessitating innovative approaches to better comprehend its underlying molecular mechanisms and devise effective therapeutic strategies. Over the past decade, microRNAs (miRNAs) have emerged as crucial players in cancer progression due to their regulatory roles in various cellular processes. Moreover, the involvement of unwanted soluble receptors has gained increasing attention because they contribute to tumorigenesis or drug resistance by disrupting normal signaling pathways and neutralizing ligands. This comprehensive review explores the intricate interplay between miRNAs and unwanted-soluble receptors in the context of cancer biology. This study provides an analysis of the regulatory interactions between miRNAs and these receptors, elucidating how miRNAs can either suppress or enhance their expression. MiRNAs can directly target receptor transcripts, thereby regulating soluble receptor levels. They also modulate the proteolytic cleavage of membrane-bound receptors into soluble forms by targeting sheddases, such as ADAMs and MMPs. Furthermore, the review delves into the therapeutic potential of manipulating miRNAs to modulate unwanted soluble receptors. Various strategies, including synthetic miRNA mimics or anti-miRNAs, hold promise for restoring or inhibiting miRNA function to counteract aberrant receptor activity. Moreover, exploring miRNA-based delivery systems may provide targeted and precise therapies that minimizing off-target effects. In conclusion, this review sheds light on the intricate regulatory networks involving miRNAs and unwanted soluble receptors in cancer biology thereby uncovering novel therapeutic targets, and paving the way for developing innovative anti-cancer therapies.

Efferocytosis, the clearance of apoptotic cells, is a critical process that maintains tissue homeostasis and immune regulation. Defective efferocytosis is linked to the development of chronic inflammatory conditions, including atherosclerosis, neurological disorders, and autoimmune diseases. Moreover, the interplay between autophagy and efferocytosis is crucial for inflammation control, as autophagy enhances the ability of phagocytic cells. Efficient efferocytosis, in turn, regulates autophagic pathways, fostering a balanced cellular environment. Dysregulation of this balance can contribute to the pathogenesis of various disorders. Phytochemicals, bioactive compounds found in plants, have emerged as promising therapeutic agents owing to their diverse pharmacological properties, including antioxidant, anti-inflammatory, and immunomodulatory effects. This review aims to highlight the pivotal role of phytochemicals in enhancing efferocytosis and autophagy and explore their potential in the prevention and treatment of related disorders. This study examines how phytochemicals influence key aspects of efferocytosis, including phagocytic cell activation, macrophage polarization, and autophagy induction. The therapeutic potential of phytochemicals in atherosclerosis and neurological diseases is highlighted, emphasizing their ability to enhance efferocytosis and autophagy and reduce inflammation. This review also discusses innovative approaches, such as nanoformulations and combination therapies to improve the targeting and bioavailability of phytochemicals. Ultimately, this study inspires further research and clinical applications in phytochemical-mediated efferocytosis enhancement for managing chronic inflammatory and autoimmune conditions.

The link between type 2 diabetes mellitus (T2DM) and an increased risk of breast cancer (BC) has prompted the exploration of novel therapeutic strategies targeting shared metabolic pathways. This review focuses on the emerging evidence surrounding the potential anti-cancer effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in the context of BC. Preclinical studies have demonstrated that various SGLT2 inhibitors, such as canagliflozin, dapagliflozin, ipragliflozin, and empagliflozin, can inhibit the proliferation of BC cells, induce apoptosis, and modulate key cellular signaling pathways. These mechanisms include the activation of AMP-activated protein kinase (AMPK), suppression of mammalian target of rapamycin (mTOR) signaling, and regulation of lipid metabolism and inflammatory mediators. The combination of SGLT2 inhibitors with conventional treatments, including chemotherapy and radiotherapy, as well as targeted therapies like phosphoinositide 3-kinases (PI3K) inhibitors, has shown promising results in enhancing the anti-cancer efficacy and potentially reducing treatment-related toxicities. The identification of specific biomarkers or genetic signatures that predict responsiveness to SGLT2 inhibitor therapy could enable more personalized treatment selection and optimization, particularly for challenging BC subtypes [e, g., triple negative BC (TNBC)]. Ongoing and future clinical trials investigating the use of SGLT2 inhibitors, both as monotherapy and in combination with other agents, will be crucial in elucidating their translational potential and guiding their integration into comprehensive BC care. Overall, SGLT2 inhibitors represent a novel and promising therapeutic approach with the potential to improve clinical outcomes for patients with various subtypes of BC, including the aggressive and chemo-resistant TNBC.

Breast cancer (BC) is viewed as a significant public health issue and is the primary cause of cancer-related deaths among women worldwide. Triple-negative breast cancer (TNBC) is a particularly aggressive subtype that predominantly affects young premenopausal women. The tumor suppressor p53 playsa vital role in the cellular response to DNA damage, and its loss or mutations are commonly present in many cancers, including BC. Recent evidence suggests that mutant p53 proteins can aggregate and form prion-like structures, which may contribute to the pathogenesis of different types of malignancies, such as BC. This review provides an overview of BC molecular subtypes, the epidemiology of TNBC, and the role of p53 in BC development. We also discuss the potential implications of prion-like aggregation in BC and highlight future research directions. Moreover, a comprehensive analysis of the current therapeutic approaches targeting p53 aggregates in BC treatment is presented. Strategies including small molecules, chaperone inhibitors, immunotherapy, CRISPR-Cas9, and siRNA are discussed, along with their potential benefits and drawbacks. The use of these approaches to inhibit p53 aggregation and degradation represents a promising target for cancer therapy. Future investigations into the efficacy of these approaches against various p53 mutations or binding to non-p53 proteins should be conducted to develop more effective and personalized therapies for BC treatment.

Stroke stands as a predominant cause of mortality and morbidity worldwide, and there is a pressing need for effective therapies to improve outcomes and enhance the quality of life for stroke survivors. In this line, effective efferocytosis, the clearance of apoptotic cells, plays a crucial role in neuroprotection and immunoregulation. This process involves specialized phagocytes known as “professional phagocytes” and consists of four steps: “Find-Me,” “Eat-Me,” engulfment/digestion, and anti-inflammatory responses. Impaired efferocytosis can lead to secondary necrosis and inflammation, resulting in adverse outcomes following brain pathologies. Enhancing efferocytosis presents a potential avenue for improving post-stroke recovery. Several therapeutic targets have been identified, including osteopontin, cysteinyl leukotriene 2 receptor, the µ opioid receptor antagonist β-funaltrexamine, and PPARγ and RXR agonists. Ferroptosis, defined as iron-dependent cell death, is now emerging as a novel target to attenuate post-stroke tissue damage and neuronal loss. Additionally, several biomarkers, most importantly CD163, may serve as potential biomarkers and therapeutic targets for acute ischemic stroke, aiding in stroke diagnosis and prognosis. Non-pharmacological approaches involve physical rehabilitation, hypoxia, and hypothermia. Mitochondrial dysfunction is now recognized as a major contributor to the poor outcomes of brain stroke, and medications targeting mitochondria may exhibit beneficial effects. These strategies aim to polarize efferocytes toward an anti-inflammatory phenotype, limit the ingestion of distressed but viable neurons, and stimulate efferocytosis in the late phase of stroke to enhance post-stroke recovery. These findings highlight promising directions for future research and development of effective stroke recovery therapies.