Simvastatin

Cellular Signaling Pathway Modulation

NF-κB Signaling Pathway

Simvastatin has been shown to modulate the Nuclear Factor-kappa B (NF-κB) signaling pathway, a key regulator of inflammation, cell proliferation, and apoptosis. Studies indicate that this compound can suppress NF-κB activation. For instance, in a mouse model of intracerebral hemorrhage, this compound treatment significantly downregulated NF-κB expression and activity, leading to reduced cellular apoptosis by suppressing the NF-κB-mediated MyD88/TRIF signaling pathway. spandidos-publications.comnih.gov This effect was also observed in human castration-resistant prostate cancer cells, where this compound reduced NF-κB expression and synergistically induced apoptotic cell death when combined with an NF-κB inhibitor. plos.org Furthermore, this compound has been found to potentiate TNF-α-induced apoptosis by downregulating NF-κB-dependent antiapoptotic gene products, and this effect can be reversed by mevalonate, highlighting the involvement of HMG-CoA reductase inhibition. aai.org In nasopharyngeal carcinoma cells, this compound inhibited NF-κB signaling by attenuating p65 phosphorylation and decreasing the expression of NF-κB-regulated genes like cyclin D1 and Bcl-2. europeanreview.org

Sterol Regulatory Element-Binding Protein (SREBP) Regulation

This compound significantly impacts the regulation of Sterol Regulatory Element-Binding Proteins (SREBPs), which are transcription factors vital for cholesterol and fatty acid synthesis. By inhibiting HMG-CoA reductase, this compound lowers intracellular cholesterol levels, leading to the activation of SREBP-2. researchgate.netoncotarget.comcore.ac.uk Activated SREBP-2 then translocates to the nucleus, increasing the expression of target genes involved in cholesterol synthesis, including HMG-CoA reductase itself, and the LDL receptor, which enhances LDL clearance from plasma. core.ac.uk In the context of renal cell carcinoma, this compound has been shown to downregulate SREBP-1 expression, thereby enhancing the cytotoxic effects of sunitinib. nih.gov During fasting, this compound can activate SREBP-2-dependent autophagy, which may amplify PPARα activation and modulate HDL levels and hepatic glucose metabolism. biorxiv.org

Hypoxia-Inducible Factor 1 (HIF-1) Inhibition

This compound has been observed to inhibit Hypoxia-Inducible Factor 1 (HIF-1), a transcription factor critical for cellular responses to hypoxia, including angiogenesis and inflammation. Studies suggest that this compound can suppress the expression of the HIF-1α subunit. nih.gov For example, this compound reduced the expression of proangiogenic proteins, including HIF-1α, in hepatic stellate cells. isciii.es While some studies suggest this compound increases HIF-1α expression in endothelial cells, others indicate that statins, including this compound, can attenuate HIF-1-dependent gene expression by accelerating the ubiquitination and degradation of HIF-1α, often through isoprenoid-dependent mechanisms involving small GTP-binding proteins like Rho and Rac. frontiersin.orgoup.comoup.com

Kruppel-Like Factor 2 (KLF-2) Upregulation

This compound is a strong inducer of Kruppel-Like Factor 2 (KLF-2), an atheroprotective transcription factor predominantly expressed in endothelial cells and macrophages. researchgate.netnih.govoup.comahajournals.org Upregulation of KLF-2 by this compound contributes to its anti-inflammatory and vascular protective effects. In human peripheral blood monocyte (HPBM)-macrophages, this compound upregulated KLF-2 while downregulating pro-inflammatory genes like monocyte chemotactic protein-1 (MCP-1) and tissue factor (TF). researchgate.netoup.com This induction of KLF-2 is dependent on the inhibition of cholesterol synthesis and the Rho pathway, requiring de novo transcription involving myocyte enhancer factor 2 (MEF2) proteins. ahajournals.orgresearchgate.net KLF-2 upregulation by this compound also mediates its inhibitory effects on maladaptive cardiac remodeling by repressing TGFβ1 expression in endothelial cells. nih.govthno.org

Gene Expression and Transcriptional Regulation

Beyond specific pathways, this compound exerts broad effects on gene expression and transcriptional regulation. Its ability to inhibit HMG-CoA reductase leads to a cascade of changes that influence the transcription of numerous genes. This compound can downregulate pro-inflammatory genes, including various chemokines, and upregulate atheroprotective factors like KLF-2. researchgate.netoup.com It also affects genes involved in protein prenylation pathways and regulators of small GTPases. atsjournals.org In human breast cancer cells, this compound can suppress NF-κB and LIN28B, subsequently upregulating let-7 microRNAs. plos.org this compound has also been shown to inhibit the expression of stemness-related genes such as Oct4, Sox2, and Nanog in various cancer cell types, potentially through its effects on the cytoskeleton. spandidos-publications.com Furthermore, this compound can decrease the expression of the Farnesoid X Receptor (FXR) at both RNA and protein levels and downregulate its DNA-binding activity, which has implications for lipoprotein and carbohydrate homeostasis. nih.gov It can also inhibit the transcription of the brain-derived neurotrophic factor (BDNF). nih.gov

Post-Translational Modifications (e.g., Protein Lipidation, Prenylation)

A cornerstone of this compound's pleiotropic effects is its inhibition of protein prenylation, a post-translational modification involving the covalent attachment of isoprenoid lipids (farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP)) to proteins. scielo.org.coahajournals.orgmdpi.comualberta.ca By blocking the mevalonate pathway, this compound reduces the availability of these isoprenoid intermediates, thereby preventing the prenylation of key proteins, particularly small GTPases like Ras, Rho, and Rac. scielo.org.coahajournals.orgmdpi.comualberta.capnas.org These GTPases require prenylation for proper membrane localization and function, where they regulate diverse cellular processes including cell proliferation, differentiation, apoptosis, and cytoskeleton organization. scielo.org.coahajournals.orgjci.org Inhibition of prenylation by this compound has been linked to various effects, such as the induction of the unfolded protein response (UPR) and developmental arrest in C. elegans. pnas.org It also affects the membrane localization of proteins like Rab and RhoA GTPase and the lipidation of LC3, which can inhibit processes like influenza replication. nih.gov The disruption of these modifications contributes to this compound's anti-inflammatory, antiproliferative, and anti-thrombotic actions. jci.org

Comparative Effectiveness Research in Cardiovascular Outcomes (e.g., vs. Atorvastatin)

Neuroprotective Mechanisms

Research has identified several neuroprotective mechanisms of this compound. These include anti-inflammatory effects, modulation of receptor activity, and antioxidant properties. frontiersin.orgmdpi.come-century.us

This compound has been shown to exert anti-inflammatory effects by reducing the expression of pro-inflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6 in experimental models of Parkinson's disease. e-century.us It may also inhibit the inflammatory process within nerve cells by acting on N-methyl-D-aspartate receptor 1 (NMDAR1). mdpi.com Furthermore, studies suggest that statins can reduce chronic neuroinflammation, which is considered a key mechanism for their neuroprotective effects in conditions like Alzheimer's disease. nih.gov

The compound's antioxidant properties are another key area of its neuroprotective action. In models of Parkinson's disease, this compound has demonstrated the ability to protect against oxidative damage by inhibiting the NADPH oxidase/p38 MAPK pathway and enhancing the expression of antioxidant proteins. frontiersin.org

Additionally, this compound has been found to modulate cognition-related receptors. For instance, in a rat model of Parkinson's disease, this compound treatment was associated with the attenuation of cognitive deficits through alterations of different receptors in various brain regions. e-century.us Animal studies have also indicated that this compound can protect against the loss of N-methyl-d-aspartate (NMDA) receptors. nih.gov

Research in Neurodegenerative Disorders (e.g., Alzheimer's, Parkinson's, Huntington's Disease)

This compound has been investigated for its potential role in several neurodegenerative disorders, with studies yielding mixed results. nih.govnih.gov

Alzheimer's Disease: Preclinical and epidemiological studies have suggested a potential protective effect of statins on Alzheimer's disease (AD). nih.gov Some retrospective and cross-sectional studies reported a significant reduction in the risk of dementia and AD with statin use. nih.gov Experimental evidence indicates that certain statins can cross the blood-brain barrier, influence brain cholesterol metabolism, and potentially reduce the production of amyloid-β (Aβ) peptide, a hallmark of AD. nih.gove-emj.org this compound, in particular, has been shown to reduce the levels of Aβ in both in vitro and in vivo models. neurology.org It has also been reported to enhance vascular activity in the brain, decrease neuroglia activation, and reduce dystrophic neurites induced by Aβ plaques. e-emj.org However, clinical trials have produced inconsistent findings. nih.gov One study found that while this compound affected brain cholesterol metabolism, it did not alter AD biomarkers in the cerebrospinal fluid or plasma after 12 weeks of treatment. nih.gov Another 18-month trial also showed no change in cognitive outcomes in patients with AD. neurology.org

Parkinson's Disease: Research into this compound for Parkinson's disease (PD) has also been extensive but has not yielded a definitive therapeutic role. neurologylive.comparkinsons.org.uk Epidemiological and preclinical data initially suggested a neuroprotective role for statins, with their use being associated with a lower incidence of PD. nih.govbmj.com Laboratory studies indicated that statins might protect brain cells from damaging processes involved in PD, such as inflammation, microglial activation, oxidative stress, and α-synuclein aggregation. nih.gov However, a significant clinical trial (PD-STAT) found that this compound was futile as a disease-modifying therapy for patients with moderate PD. neurologylive.comparkinsons.org.uk The trial showed that the motor scores of patients on this compound worsened slightly more than those on a placebo over 24 months. neurologylive.com

Huntington's Disease: The potential for this compound to delay the onset of movement disorders in Huntington's disease has been suggested. nih.govresearchgate.net Further research is needed to fully understand its effects in this specific neurodegenerative condition. mdpi.com

Brain Tumor Research

This compound has been investigated for its potential anti-cancer effects in brain tumors, particularly glioblastoma (GBM) and medulloblastoma. nih.govnih.gov The proposed mechanisms include inhibiting tumor cell growth and migration, inducing apoptosis (programmed cell death), and affecting key signaling pathways. iiarjournals.orgljmu.ac.uknih.gov

In glioblastoma research, studies have shown that this compound can inhibit the growth and migration of human glioma cells. iiarjournals.org It has been found to induce apoptosis in GBM cells through various mechanisms, including the inhibition of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway and caspase-3 activation. ljmu.ac.uknih.gov Research also suggests that this compound can affect GBM cells by inhibiting the Transforming Growth Factor-β (TGF-β) pathway, which is involved in angiogenesis, migration, and invasion. ljmu.ac.uk Furthermore, some studies have explored the combination of this compound with other anti-cancer agents like temozolomide, with results suggesting a synergistic effect in inducing apoptosis in GBM cells. mdpi.comjcancer.org However, the effects of this compound can be dose-dependent and complex. For instance, one in vivo study in a mouse glioblastoma model found that low-dose this compound increased necrosis and apoptosis, while high-dose this compound affected tumor vessel structure. iiarjournals.org

In medulloblastoma, another type of brain tumor, this compound has been shown to inhibit tumor growth by suppressing cancer cell proliferation and reducing the activation of the hedgehog signaling pathway. nih.gov Research has also demonstrated that this compound can induce dose-dependent apoptosis in different medulloblastoma cell lines. mdpi.com

Table 1: Summary of this compound Research in Brain Tumors

Stroke and Intracerebral Hemorrhage Research

This compound has been studied for its potential neuroprotective effects in the context of both ischemic stroke and intracerebral hemorrhage (ICH).

In ischemic stroke , research has suggested that statins, including this compound, may reduce the incidence of ischemic strokes. nih.gov A large-scale study, the Heart Protection Study, found that this compound therapy reduced the rate of ischemic strokes by about a quarter. nih.gov The proposed mechanisms for this protective effect are pleiotropic, extending beyond cholesterol-lowering to include anti-inflammatory, antioxidant, and antithrombotic effects. mdpi.comnih.gov However, clinical trials on the use of this compound in the acute phase of ischemic stroke have yielded mixed results regarding safety and efficacy, with some studies raising concerns about an increased risk of infection despite potential neurological improvement. researchgate.net

In the context of intracerebral hemorrhage (ICH) , research has explored the effects of this compound on recovery and brain injury. Animal studies have shown that this compound treatment can lead to significant improvements in neurological recovery, a decrease in tissue loss, and an increase in neurogenesis when administered after an ICH. nih.gov It has also been found to protect the integrity of the blood-brain barrier (BBB), reduce edema, and improve cerebral blood flow in the acute phase after an ICH in experimental models. scirp.org Mechanistically, this compound may attenuate brain edema and reduce cell death by suppressing the NF-κB-mediated MyD88/TRIF signaling pathway. spandidos-publications.com While some studies suggest a potential for worse outcomes with statin therapy in ICH patients, multiple retrospective studies have indicated favorable functional outcomes and reduced mortality with the continuation of statin therapy after an ICH. nih.gov

Multiple Sclerosis Research

This compound has been investigated as a potential treatment for secondary progressive multiple sclerosis (SPMS), primarily due to its anti-inflammatory and potential neuroprotective properties. mstrust.org.ukmscanada.ca

An initial phase II trial (MS-STAT) involving 140 people with SPMS showed encouraging results. mscanada.camssociety.org.uk Participants who received a high dose of this compound for two years had a 43% reduction in brain atrophy (shrinkage) compared to those who received a placebo. mstrust.org.ukmscanada.ca The this compound group also showed slower changes in disability scores. mscanada.ca These promising findings led to a larger phase III trial, MS-STAT2. mstrust.org.uk

However, the results of the MS-STAT2 trial, which included nearly 1,000 participants with SPMS, were disappointing. mstrust.org.ukmultiplesclerosisnewstoday.com The trial found no evidence that this compound had an effect on slowing disability progression compared to a placebo. mstrust.org.uknationalmssociety.org Despite the lack of efficacy in slowing progression, the treatment was found to be safe and well-tolerated. mstrust.org.ukmultiplesclerosisnewstoday.com

Table 2: Key Clinical Trials of this compound in Multiple Sclerosis

Effects on Neurogenesis and Neuroplasticity

Research indicates that this compound can positively influence neurogenesis and neuroplasticity, processes crucial for brain repair and function.

Studies have shown that this compound promotes adult hippocampal neurogenesis. nih.govnih.gov It has been found to enhance the proliferation of intermediate precursor cells in the subgranular zone of the dentate gyrus, leading to an increased number of newborn neurons. nih.gov The mechanism behind this appears to be the enhancement of Wnt/β-catenin signaling, a pathway crucial for cell proliferation and differentiation. nih.govnih.govresearchgate.net This effect is thought to be mediated by the inhibition of isoprenoid synthesis rather than through cholesterol reduction. nih.govnih.gov

In models of traumatic brain injury (TBI), both this compound and atorvastatin have demonstrated the ability to enhance neurogenesis in the dentate gyrus. mdpi.com This increase in neurogenesis has been associated with several positive outcomes, including:

Increased expression of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). mdpi.com

Reduced neuronal death in the hippocampus. mdpi.com

Improved spatial learning. mdpi.com

Furthermore, the inhibition of farnesylation, a process affected by this compound, has been linked to the enhancement of long-term potentiation between neurons in mice, a key component of neuroplasticity and learning. mdpi.com

Antitumor Mechanisms (e.g., Apoptosis, Cell Cycle Arrest)

This compound exerts its antitumor effects through several core mechanisms, primarily by inducing apoptosis (programmed cell death) and causing cell cycle arrest in cancer cells. nih.govoncotarget.com These actions are fundamentally linked to its inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway. oncotarget.comarchivesofmedicalscience.com The depletion of downstream products of this pathway, such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), is crucial for these anticancer activities. archivesofmedicalscience.comspandidos-publications.com

Apoptosis Induction: this compound promotes apoptosis by altering the balance of pro- and anti-apoptotic proteins. nih.govspandidos-publications.com Research has shown that it upregulates the expression of pro-apoptotic proteins like Bax and Bak, while simultaneously down-regulating the anti-apoptotic protein Bcl-2. nih.govspandidos-publications.comresearchgate.net This shift in the Bax/Bcl-2 ratio disrupts the mitochondrial membrane potential, leading to the release of cytochrome c and the subsequent activation of a cascade of caspases, including caspase-3, -8, and -9, which are the executioners of apoptosis. spandidos-publications.comresearchgate.net

Cell Cycle Arrest: A predominant effect of this compound on cancer cells is the induction of cell cycle arrest, most commonly in the G0/G1 phase. oncotarget.comspandidos-publications.come-century.us This halt in proliferation is achieved by modulating the expression of key cell cycle regulators. e-century.us this compound has been observed to downregulate the expression of cyclin D1 and cyclin-dependent kinases (CDKs), such as CDK2 and CDK4. spandidos-publications.come-century.us Concurrently, it increases the expression of CDK inhibitors like p21 and p27, which effectively block the progression of the cell cycle from the G1 to the S phase. archivesofmedicalscience.come-century.us

Table 1: Antitumor Mechanisms of this compound

Inhibition of Proliferation, Angiogenesis, and Metastasis

Beyond inducing apoptosis and cell cycle arrest, this compound actively inhibits other critical processes required for tumor growth and spread: proliferation, angiogenesis, and metastasis. mdpi.com

Inhibition of Proliferation: The inhibition of the mevalonate pathway is central to this compound's anti-proliferative effects. nih.gov By blocking the synthesis of FPP and GGPP, this compound prevents the post-translational lipid modification (prenylation) of small GTP-binding proteins like Ras and Rho. frontiersin.orgarchivesofmedicalscience.com These proteins are essential signal transducers in pathways that drive cell proliferation, such as the MAPK/ERK pathway. mdpi.com Their inactivation disrupts downstream signaling, leading to a decrease in cell proliferation. archivesofmedicalscience.commdpi.com

Inhibition of Angiogenesis: Angiogenesis, the formation of new blood vessels, is vital for supplying tumors with nutrients and oxygen. This compound has demonstrated anti-angiogenic properties by reducing the expression of pro-angiogenic factors, most notably Vascular Endothelial Growth Factor (VEGF). frontiersin.orgarchivesofmedicalscience.com It can also suppress angiogenesis by activating AMP-activated protein kinase (AMPK), which in turn blocks the hypoxia-inducible factor-1α (HIF-1α), a key regulator of pro-angiogenic factors. frontiersin.orgnih.gov

Inhibition of Metastasis: Metastasis, the spread of cancer cells to distant sites, is a major cause of cancer-related mortality. mdpi.com this compound can inhibit the key steps of metastasis, including cell migration and invasion. oncotarget.comdovepress.com This is achieved by interfering with the function of the Rho family of proteins, which control the cytoskeletal rearrangements necessary for cell movement. spandidos-publications.com Furthermore, this compound has been shown to decrease the expression and activity of matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, which are enzymes that degrade the extracellular matrix, allowing cancer cells to invade surrounding tissues. spandidos-publications.comresearchgate.netufmg.br

Cancer Stemness Modulation

Emerging evidence suggests that this compound can target cancer stem cells (CSCs), a subpopulation of tumor cells responsible for tumor initiation, recurrence, and resistance to therapy. spandidos-publications.com Studies have shown that this compound can reduce the population of CSCs, often identified by markers like CD44. frontiersin.orgspandidos-publications.com

The proposed mechanism involves the disruption of the mevalonate pathway, which appears to be crucial for maintaining the "stem-like" state. spandidos-publications.com By inhibiting the synthesis of GGPP, this compound interferes with the function of proteins like RhoA, which are involved in signaling pathways that regulate stemness, such as the Hippo/YAP pathway. spandidos-publications.combioscientifica.com Research indicates that this compound can downregulate the expression of key stemness-related genes, including Oct4, Sox2, and Nanog. spandidos-publications.com By targeting CSCs, this compound may help to overcome chemoresistance and reduce the likelihood of tumor relapse. spandidos-publications.com

Tumor Microenvironment Remodeling

This compound can influence the tumor microenvironment (TME), which is the complex ecosystem of cells, signaling molecules, and extracellular matrix that surrounds a tumor and plays a critical role in its development. frontiersin.orgaacrjournals.org

This compound has been shown to have immunomodulatory effects. frontiersin.org It can promote the repolarization of tumor-associated macrophages (TAMs) from the pro-tumoral M2 phenotype to the anti-tumoral M1 phenotype. frontiersin.org This shift can enhance the anti-cancer immune response. Additionally, some studies suggest statins can improve the function of cytotoxic T cells and natural killer (NK) cells, further bolstering the body's ability to fight the tumor. frontiersin.org this compound may also affect other components of the TME, such as cancer-associated fibroblasts (CAFs), which are known to support tumor growth. researchgate.net

Research in Specific Cancer Types (e.g., Breast Cancer, Lung Cancer, Melanoma, Colon Cancer)

The antitumor effects of this compound have been investigated across a wide range of cancer types in preclinical models.

Breast Cancer: this compound has been shown to inhibit the proliferation of breast cancer cells, including triple-negative breast cancer (TNBC) subtypes. spandidos-publications.comnih.gov It induces apoptosis by modulating Bcl-2 family proteins and activating caspases. spandidos-publications.com It also suppresses invasion by downregulating the expression of genes like PTTG1 and the activity of MMPs. spandidos-publications.comfrontiersin.org

Lung Cancer: In non-small cell lung cancer (NSCLC) models, this compound induces G1 cell cycle arrest and apoptosis. archivesofmedicalscience.comresearchgate.net It has been shown to inhibit tumor growth and metastasis by suppressing pathways like MAPK/ERK and downregulating MMPs. researchgate.netmdpi.com

Melanoma: Research indicates that this compound can induce apoptosis in melanoma cells while sparing normal cells. researchgate.netspandidos-publications.com It inhibits tumor growth and improves survival in murine models, and its effects are linked to the inhibition of Rho-dependent processes and the downregulation of growth factors. researchgate.netspandidos-publications.commdpi.com

Colon Cancer: this compound has been found to inhibit the proliferation and migration of colon cancer cells and promote apoptosis. ufmg.brwjgnet.com Studies suggest these effects are mediated through the modulation of pathways like EGFR/RhoA and the induction of ferroptosis. wjgnet.comfrontiersin.org

Table 2: Preclinical Research Findings of this compound in Specific Cancer Types

Combination Therapy Strategies in Cancer

A significant area of research is the use of this compound in combination with standard anticancer treatments, such as chemotherapy, radiotherapy, and targeted therapies. aacrjournals.org The rationale is that this compound may sensitize cancer cells to these treatments, thereby enhancing their efficacy. nih.gov

Chemotherapy: this compound has shown synergistic effects when combined with various chemotherapeutic agents, including doxorubicin and cisplatin. archivesofmedicalscience.comwaocp.org In some cases, it appears to enhance the cytotoxic effects of these drugs, allowing for potentially lower and less toxic doses. waocp.org For instance, in metastatic colorectal cancer, the addition of this compound to a XELOX and bevacizumab regimen was found to be feasible and showed comparable efficacy to the standard treatment alone. e-crt.org

Radiotherapy: Preclinical studies suggest that this compound can act as a radiosensitizer. nih.gov In esophageal cancer, for example, it was found to enhance radiosensitivity by inducing the tumor suppressor PTEN and inhibiting the PI3K/Akt pathway. mdpi.com

Targeted Therapy: this compound has been investigated for its ability to overcome resistance to tyrosine kinase inhibitors (TKIs) in lung cancer. aacrjournals.org Studies in patient-derived models showed that combining this compound with TKIs could overcome acquired resistance and lead to greater tumor reduction. aacrjournals.org It has also been shown to enhance responses to immune checkpoint blockade in models of head and neck cancer. bmj.com

Table 3: Examples of this compound Combination Strategies in Oncology Research

Modulating Inflammatory Cytokines (e.g., TNF-α, IL-6, CRP)

This compound has been shown to modulate the production of several key inflammatory cytokines. In hypercholesterolemic patients, treatment with this compound resulted in a significant decrease in serum levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). ahajournals.orgnih.gov Specifically, one study observed a distinct reduction of CRP and TNF-α in both asymptomatic men with high cholesterol and men with coronary heart disease; however, IL-6 levels only decreased in the group with markedly high cholesterol. nih.gov Another study in hypercholesterolemic patients found that this compound treatment led to a significant decrease in serum levels of IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1). ahajournals.org The reduction in these pro-inflammatory cytokines suggests a direct anti-inflammatory action of this compound. ahajournals.orgjacc.org

In preclinical models, this compound has also demonstrated the ability to suppress inflammatory cytokine production. For instance, in a rat model of lipopolysaccharide-induced inflammation, this compound pretreatment significantly suppressed the peak levels of TNF-α and IL-1β. sav.sk However, the effect on IL-6 was not observed in this particular study. sav.sk In a mouse model of sepsis, this compound treatment reduced the levels of TNF-α, IL-6, IL-1β, and macrophage migration inhibitory factor (MIF) in the peritoneal cavity. nih.gov These findings from various studies highlight the potential of this compound to mitigate inflammatory responses by downregulating the expression and production of key pro-inflammatory cytokines. ahajournals.orgsav.sknih.govoup.com

Table 1: Effect of this compound on Inflammatory Cytokines

T-cell Modulation and Lymphocyte Activity

Studies have also explored the impact of this compound on different T-cell subsets. For example, this compound has been shown to induce the expression of Foxp3, a key transcription factor for regulatory T cells (Tregs), which play a crucial role in maintaining immune tolerance. nih.govnih.gov This suggests that this compound may promote an anti-inflammatory environment by enhancing the activity of Tregs. nih.gov Furthermore, some research suggests that this compound can influence the balance between T-helper 1 (Th1) and T-helper 2 (Th2) responses, potentially suppressing Th1-mediated inflammation. archivesofmedicalscience.com In a murine model of allergic asthma, a Th2-driven condition, this compound treatment was associated with a reduction in IL-4 and IL-5 levels, key Th2 cytokines. aai.org Conversely, other studies indicate a potential for this compound to suppress Th2 responses. researchgate.net In a study on dendritic cells, this compound was found to promote Th2-type responses through the induction of the chitinase family member Ym1. pnas.org

Research in Autoimmune Diseases (e.g., Uveitis, Rheumatoid Arthritis)

The immunomodulatory properties of this compound have led to research into its potential therapeutic role in autoimmune diseases such as uveitis and rheumatoid arthritis. elsevier.esrusimmun.ru

In the context of non-infectious uveitis, an inflammatory condition of the eye, statins have shown promise. elsevier.esrusimmun.rumdpi.com Animal models of experimental autoimmune uveoretinitis have demonstrated that statins can reduce the clinical and histological signs of inflammation and inhibit the recruitment of T lymphocytes into the retina. nih.gov Observational studies in humans have also suggested a protective effect of statins against the development of uveitis. elsevier.esnih.gov A pilot study investigating this compound as an adjunct to conventional therapy for non-infectious uveitis found that it was associated with better control of inflammation and improved visual acuity. tandfonline.com

In research related to rheumatoid arthritis, statins have been shown to inhibit the production of pro-inflammatory cytokines by synovial cells. elsevier.es In vitro studies have demonstrated that this compound can suppress the production of pro-inflammatory cytokines by T-cell contact-activated macrophages, highlighting its potential to modulate the inflammatory processes central to rheumatoid arthritis. researchgate.net

Immunomodulation in Sepsis and Acute Inflammatory Conditions

This compound's immunomodulatory effects are also being investigated in the context of sepsis and other acute inflammatory conditions. frontiersin.orgahajournals.org Sepsis is characterized by a dysregulated systemic inflammatory response to infection. frontiersin.orgnih.gov

Preclinical studies using animal models of sepsis have shown that this compound can improve survival rates. frontiersin.orgahajournals.orgnih.gov In a murine model of sepsis induced by cecal ligation and puncture (CLP), prophylactic treatment with this compound was found to increase animal survival. frontiersin.orgnih.gov This was associated with a modulation of the immune response, including an increase in the activation and proliferation of CD4+ T cells and an increase in the production of IL-6 and MCP-1, suggesting a shift towards an effective antimicrobial response rather than a purely anti-inflammatory effect. frontiersin.org Another study showed that treatment with this compound after the onset of sepsis also improved survival in a CLP mouse model. ahajournals.org Furthermore, this compound has been shown to reduce the levels of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 in animal models of sepsis. nih.govscielo.br In a mouse model of acute inflammation induced by Staphylococcus aureus α-toxin, this compound was found to inhibit leukocyte rolling, adherence, and transmigration, key steps in the inflammatory cascade. ahajournals.org

Amino Acid Metabolism

Metabolomic studies have revealed that this compound treatment can influence amino acid metabolism. frontiersin.orgplos.orgnih.gov A study using a metabolomics platform to analyze the effects of this compound in participants found that the metabolic signature of drug exposure included changes in essential amino acids. plos.orgnih.gov The metabolites affected were enriched for the amino acid degradation pathway. plos.orgnih.gov

Fatty Acid Metabolism

This compound's influence extends beyond cholesterol synthesis to affect various aspects of fatty acid metabolism. Research indicates that by inhibiting HMG-CoA reductase, statins may increase the availability of acetyl-CoA for other metabolic processes, including fatty acid synthesis. ahajournals.org Studies in hypercholesterolemic men have shown that this compound treatment alters the composition of serum fatty acids. ahajournals.orgahajournals.org Specifically, it decreases the proportions of palmitic acid, linoleic acid, and α-linolenic acid, while increasing the proportions of γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid. ahajournals.orgahajournals.org These changes suggest that this compound enhances the activity of fatty acid elongase and desaturase enzymes, promoting the formation of long-chain polyunsaturated fatty acids. ahajournals.orgahajournals.org

In animal models, this compound has demonstrated effects on lipid accumulation. In high-fat diet-induced hyperlipidemic rats, this compound administration significantly inhibited lipid accumulation in the liver and reduced lipid deposition in both adipocytes and hepatocytes. frontiersin.org Conversely, in mice with skeletal muscle PGC-1α overexpression, this compound led to an increased accumulation of lipid droplets in the skeletal muscle. mdpi.com It has been suggested that statins may activate peroxisome proliferator-activated receptor-α (PPAR-α), which boosts the liver's uptake of fatty acids and promotes their beta-oxidation, thereby reducing the availability of fatty acids. unito.it

Table 1: Effect of this compound on Serum Fatty Acid Proportions

Nucleotide, Carbohydrate, Cofactor, and Vitamin Metabolism

This compound's metabolic influence includes complex interactions with carbohydrate, cofactor, and vitamin pathways.

Carbohydrate Metabolism: Research has yielded varied results regarding this compound's impact on glucose homeostasis. In-vitro studies on human myotubes show that this compound can reduce glucose uptake and oxidation in a dose-dependent manner. plos.org Both the lactone and active acid forms of this compound have been found to decrease glycolysis and mitochondrial ATP production in primary human muscle cells. nih.gov However, the two forms show differential effects on glucose storage; the lactone form increases glycogen synthesis, whereas the acid form impairs it. nih.gov

Clinical and animal studies present a conflicting picture. Some studies report that this compound may increase plasma glucose levels and decrease insulin sensitivity. scielo.brmdpi.comfrontiersin.org The proposed mechanisms include the inhibition of glucose-induced insulin secretion. scielo.brscielo.br This could be due to a reduction in the synthesis of coenzyme Q10 (CoQ10), which is essential for ATP production required for insulin release. e-dmj.org In contrast, other studies have reported no significant effect or even an improvement in glycemia. scielo.brscielo.br

Cofactor and Vitamin Metabolism: The impact of this compound on cofactors and vitamins is also an area of active investigation with some contradictory findings. As an inhibitor of the mevalonate pathway, this compound inherently reduces the synthesis of CoQ10, an essential component of the mitochondrial electron transport chain. e-dmj.orgahajournals.orgfrontiersin.org Studies have confirmed that this compound treatment can lower CoQ10 levels in muscle tissue and endothelial cells. ahajournals.orgmdpi.com

Regarding fat-soluble vitamins, one study in hypercholesterolemic patients found that 8 weeks of this compound treatment significantly increased the lipid-corrected plasma levels of retinol (vitamin A), α-tocopherol (vitamin E), and γ-tocopherol, while levels of CoQ10 and carotenoids remained unchanged. nih.gov Conversely, other sources suggest that statins may interfere with the absorption of fat-soluble vitamins (A, D, E, and K) and reduce the production of vitamin K2, which is also synthesized via the mevalonate pathway. ivdrip.uk The effect on vitamin D is particularly controversial, with different studies reporting either increased or decreased levels in patients taking statins. ameliaheartcenter.com

Table 2: Summary of this compound's Effects on Various Metabolites

Gut Microbiota Interactions

This compound interacts with the gut microbiota in a bidirectional manner; the drug can alter the composition of the gut microbiome, and the microbes can, in turn, metabolize the drug. frontiersin.orgfrontiersin.orgnih.gov In hyperlipidemic rats, this compound treatment was found to reduce microbial diversity and significantly remodel the composition of the fecal bacterial community. frontiersin.orgmdpi.com Notably, administration of this compound led to an increase in the abundance of certain bacteria, such as Ruminococcaceae and Lactobacillus. frontiersin.orgfrontiersin.org These alterations in the gut microbiota are believed to contribute to the lipid-lowering efficacy of this compound. mdpi.comfrontiersin.org

Research also shows that gut bacteria can metabolize this compound. plos.org In vitro studies demonstrate that this compound is subject to bioaccumulation within bacterial cells and can be biotransformed by bacterial enzymes, with the lactone ring being a likely site for reactions like hydrolysis. frontiersin.orgnih.gov This microbial metabolism could be an underlying mechanism for the varied bioavailability and therapeutic effects of this compound observed among individuals. frontiersin.orgnih.gov However, compared to other statins like fluvastatin, this compound's effect on altering the gut bacterial composition was found to be relatively static in one in vitro fermentation study. plos.org

Table 3: Reported Changes in Gut Microbiota with this compound Treatment

Uterine Fibroids

A novel area of research is the potential application of this compound for the treatment of uterine fibroids (leiomyomas), the most common benign tumors of the female reproductive system. utmb.edu Preclinical studies have shown that this compound exhibits anti-tumor effects on uterine fibroid cells. utmb.eduresearchgate.net Research has demonstrated that this compound impedes the growth of human uterine fibroid cells by inhibiting a critical step in a molecular pathway that promotes cell proliferation. utmb.edu Furthermore, it has been shown to halt the progression of existing tumor cells and trigger calcium-dependent cell death (apoptosis) in fibroid tumor cells. utmb.edu

Observational studies in humans have found that statin use is associated with a lower risk of developing uterine fibroids and experiencing fibroid-related symptoms such as menorrhagia and pelvic pain. researchgate.net Based on these promising preclinical findings, a phase II, double-blind, placebo-controlled clinical trial was initiated to formally evaluate the efficacy of this compound in reducing the size of uterine fibroids in women scheduled for surgery. clinicaltrials.govdrugbank.com This research signals a potential new, non-hormonal therapeutic strategy for managing uterine fibroids. researchgate.net

Table 4: Research Findings on this compound for Uterine Fibroids

Bone Turnover and Neovascularization

This compound has been identified as a potent modulator of bone metabolism, with research highlighting its dual capacity to promote bone formation and inhibit bone resorption. mdpi.comdovepress.com The anabolic effect on bone is largely attributed to its ability to stimulate the differentiation of osteoblasts, the cells responsible for bone formation. mdpi.comnih.gov This is achieved by upregulating the expression of key osteogenic factors, including Bone Morphogenetic Protein-2 (BMP-2) and osteocalcin. dovepress.comnih.govnih.gov Simultaneously, this compound inhibits bone resorption by reducing the activity and number of osteoclasts, the cells that break down bone tissue. mdpi.comnih.gov

A meta-analysis of randomized controlled trials confirmed that statins increase levels of the bone formation biomarker osteocalcin (OC) while decreasing levels of bone resorption markers such as C-terminal telopeptide of type I collagen (CTX) and N-terminal telopeptide (NTX). jst.go.jp

Crucially, the processes of bone regeneration and blood vessel formation (neovascularization) are tightly linked. This compound also promotes neovascularization by increasing the gene expression of Vascular Endothelial Growth Factor (VEGF) in osteoblastic cells. mdpi.comnih.govoup.com This stimulation of new blood vessel growth is vital for supplying oxygen and nutrients to support the reconstruction of bone tissue. mdpi.com

Table 5: Effects of this compound on Bone Turnover and Neovascularization

ABCB1 and ABCG2 Gene Variants

Real-World Evidence Studies