Search Results (106)

Chronic inflammation constitutes a well-established driver of colorectal carcinogenesis, yet the molecular circuitry linking inflammatory receptor signalling to tumour cell survival remains incompletely delineated. Here we demonstrate that the HMG-CoA reductase inhibitors atorvastatin and rosuvastatin modulate inflammatory survival pathways in colorectal cancer cells in a manner consistent with targeted interference with the protease-activated receptor 2 (PAR-2)–extracellular signal-regulated kinase (ERK)–tumour necrosis factor-α (TNF-α) signalling axis. Using lipopolysaccharide-stimulated HT-29 and Caco-2 cells as complementary models of inflammatory colorectal malignancy, we show that both statins selectively attenuate PAR-2 expression at the protein and transcript levels while leaving structurally related PAR-1 unaffected. This pattern of receptor modulation is accompanied by suppression of total ERK1/2 expression, ERK1/2 phosphorylation, and the transcriptional target DUSP6, together with attenuation of TNF-α secretion. Importantly, these signaling shifts are associated with dual apoptotic programs; the extrinsic pathway, reflected by transcriptional upregulation and proteolytic activation of caspase-8; and the intrinsic mitochondrial pathway, evidenced by reciprocal modulation of Bcl-2 family proteins favoring Bax over Bcl-2. Both pathways converge upon activation of executioner caspase-3 and an increase in Annexin V-defined apoptotic fractions, indicating re-engagement of programmed cell death under inflammatory stress. Notably, rosuvastatin consistently demonstrates superior potency across signaling endpoints, achieving comparable biological effects at lower concentrations than atorvastatin. Collectively, these data indicate that clinically deployed statins target the PAR-2–ERK axis and are associated with re-activation of apoptotic pathways in inflammatory colorectal cancer models, while leaving open the possibility that additional statin-responsive networks contribute to their pro-apoptotic effects. This mechanistic framework provides biological plausibility for epidemiologic observations linking statin use with reduced colorectal cancer risk and improved outcomes, and supports further translational evaluation of PAR-2-directed statin strategies in colorectal malignancy. Full article

Background/Objectives: Atorvastatin, a lipophilic HMG-CoA reductase inhibitor used for lipid lowering, also exhibits considerable anti-neoplastic activity. Although previous studies have shown that glucose starvation can potentiate several anticancer chemotherapies, atorvastatin has not been rigorously investigated for its impact on metabolic vulnerabilities and the effects on cholesterol-rich lipid rafts in aggressive tumors. This work aims to evaluate the combined anticancer activity of atorvastatin with metabolic interventions, specifically glucose starvation, on U-87 (glioblastoma) and MDA-MB-231 (triple-negative breast cancer) cell lines. Methods: U-87 and MDA-MB-231 cancer cells were cultured in either normal or glucose-free media and treated with different concentrations of atorvastatin. The impact of atorvastatin on these cancer cells was analyzed by examining cell viability, apoptosis, cell cycle, and changes in membrane order within lipid rafts. Results: This study found that glucose starvation increased the sensitivity of U-87 cells to atorvastatin by lowering IC₅₀ values and eliciting arrest in the G1 phase of the cell cycle. MDA-MB-231 cells were less dependent on glucose for viability; however, atorvastatin consistently induced S-phase arrest across both metabolic states. Additionally, atorvastatin induced apoptosis in both U-87 and MDA-MB-231 cells, with the effect being more pronounced and dose-dependent in the fasting state with glucose. Interestingly, both Caspase-3 and Caspase-9 were consistently downregulated by atorvastatin in U-87 cells, regardless of the fasting state, corresponding to the induction of cell cycle arrest. Membrane lipid rafts exhibited decreased membrane order under glucose starvation, which was further decreased in response to atorvastatin in both cell lines, indicating a reduction in cholesterol. Conclusions: These results demonstrate that atorvastatin exhibits anticancer activity, characterized by both contextual and metabolic targeted effects, including a reduction in cancer proliferation, the triggering of cell cycle arrest via the downregulation of caspase pathways, and a decrease in membrane order. Notably, the combined activity of combining antilipemic agents with glucose-fasting provides potential metabolic strategies that could help create more effective and personalized approaches to cancer treatment. Full article

Background/Objectives: In spite of substantial treatment progress, cancer persists as a leading health challenge. With the slow advancement in developing new anticancer agents, drug repurposing provides a promising strategy to enhance cancer therapy. This study investigates the antiproliferative and antimetastatic properties of two 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, atorvastatin and rosuvastatin, which represent lipophilic and hydrophilic statins, respectively. Methods: Growth inhibition was evaluated in a panel of human cancer cells using the standard MTT assay. Apoptotic effects were determined through flow cytometry, caspase-3 activity assay, mitochondrial membrane potential assessment, and Hoechst/Propidium iodide fluorescent double staining. Migration and invasion assays were conducted using wound-healing and Boyden chamber assays, respectively. Results: Atorvastatin demonstrated more pronounced growth-inhibitory effects than rosuvastatin, with the IC₅₀ values in the range of 2.57–61.01 µM. Atorvastatin exhibited both biochemical and morphological indicators of apoptosis. Flow cytometry revealed cell cycle disruptions and increased sub-G1 apoptotic populations in HPV-positive oral squamous carcinoma cells (UPCI-SCC-154) and HPV-negative cervical cancer cells (C33A). Atorvastatin also significantly inhibited cell migration and invasion in the tested cell lines. Conclusions: Our results highlight the promising anticancer potential of atorvastatin in cervical cancer and oral squamous carcinoma cells. However, these findings are limited to in vitro models and warrant further in vivo validation. Full article

Background and Objectives: Statins are among the most prescribed medications globally, primarily due to their potent lipid-lowering capabilities. This systematic review aims to identify, synthesize and evaluate current evidence regarding the potential protective effects of statins on sepsis mortality. Materials and Methods: A thorough and comprehensive database search was conducted in PubMed and Cochrane Library until 30 January 2025. Randomized control trials (RCTs) and cohort studies evaluating the effect of statin use on sepsis mortality were included. Risk-ratios (RRs) and 95% confidence intervals (CIs) were calculated. Statistical analysis and forest plot generation were performed using RevMan 5.4. Risk of bias was assessed using the RoB-2 and NOS tools. Results: A total of 49 studies were identified following application of the PRISMA guidelines. Of these, 16 studies were RCTs and 33 were cohort studies. The pooled analysis of RCTs demonstrated a non-significant 10% reduction in mortality in statin users (RR: 0.90, 95% CI 0.80–1.01). The pooled analysis of cohort studies showed that statin users have a 21% significantly reduced mortality risk (RR: 0.79, 95% CI 0.72–0.86). For the de novo statin users vs non-statin users, pooled analysis demonstrated a significant 25% reduction in mortality (RR: 0.75, 95% CI 0.69–0.81). The pooled analysis for the continuation of prior statin use vs discontinuation of statin use indicated 52% lower mortality in statin users who continued the use of statins (RR: 0.48, 95% CI 0.25–0.92). The pooled analysis of prior statin use and continuation of statins vs non-statin use revealed a significant 23% lower risk in statin users compared with non-statin users (RR: 0.77, 95% CI 0.69–086). Conclusions: According to our findings, statin use among septic patients is associated with a reduction in mortality, suggesting that statins may offer a beneficial therapeutic effect in the clinical setting. Clinicians may consider the continuation or potential incorporation of statin use as an additional regimen in the treatment of septic patients. Full article

Sim, a potent HMG-CoA reductase inhibitor, exhibits notable anabolic effects on bone and can upregulate osteogenic genes such as BMP-2, thereby promoting bone formation. An ideal drug delivery system for Sim involves its controlled and sustained release at the defect site to minimize adverse side effects. In this study, Sim was first modified via HP-γ-CD to form a hydrophilic Sim/HP-γ-CD inclusion complex, thereby improving drug solubility and dispersion in aqueous systems. A gelatin–sodium alginate (Gel/SA) hydrogel was then employed as the drug delivery matrix to construct a Gel-SA-Sim/HP-γ-CD hydrogel sustained release system. This hydrogel system exhibited a high water content (82%), along with enhanced mechanical properties, including a compressive strength of 0.284 MPa and a compressive modulus of 0.277 MPa, suggesting strong load-bearing capacity and favorable stiffness. Importantly, Sim was released in a controlled and sustained manner over 7 days, without exhibiting burst release behavior. In vitro osteogenic differentiation assays demonstrated that optimal concentrations of Sim effectively enhanced cellular bioactivity and osteoinductive performance, offering a promising approach to enhance the bioactivity, osteogenesis, and osseointegration of orthopedic implants. Full article

Monascus purpureus is a filamentous fungus known for producing pharmaceutically valuable secondary metabolites, including azaphilone pigments and lovastatin. Lovastatin is an HMG-CoA reductase inhibitor widely used to manage hypercholesterolaemia, while Monascus pigments serve as natural colourants with antioxidant and antimicrobial properties. This study evaluated the impact of quorum-sensing molecules (QSMs)—tyrosol (0.3 mM), farnesol (0.2 mM) and linoleic acid (0.4 mM)—on pigment and lovastatin yields in shake flasks and 2.5 L stirred-tank bioreactors. QSMs were introduced 48 h post-inoculation in shake flasks and 24 h in bioreactors. All QSMs increased yellow (OD₄₀₀), orange (OD₄₇₀), and red (OD₅₁₀) pigments and lovastatin concentration relative to the control, with scale-up further enhancing yields. Farnesol produced the most pronounced effect: in flasks, OD₄₀₀ 7.10 (1.86-fold), OD₄₇₀ 8.00 (2.12-fold), OD₅₁₀ 7.80 (2.08-fold), and 74.6 mg/L lovastatin (2.05-fold); in bioreactors, OD₄₀₀ 11.9 (2.06-fold), OD₄₇₀ 15.1 (2.71-fold), OD₅₁₀ 13.7 (2.47-fold), and 97.2 mg/L lovastatin (2.48-fold). This was followed by tyrosol treatment and then linoleic acid. These findings demonstrate that QSMs—particularly farnesol—significantly (p < 0.01) stimulate pigment and lovastatin biosynthesis in M. purpureus. Quorum sensing modulation represents a promising, scalable strategy to optimise fungal fermentation for industrial metabolite production. Full article

Triple-negative breast cancer (TNBC) is a highly aggressive and therapeutically challenging subtype of breast cancer due to its lack of estrogen receptors, progesterone receptors, and HER2 (Human epidermal growth factor receptor 2) expression, which severely limits available treatment options. Recently, Simvastatin—a widely used HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor for hyperlipidemia—has garnered interest for its potential anticancer effects. This study investigates the therapeutic potential of Simvastatin in triple-negative breast cancer (TNBC). The results demonstrate that Simvastatin significantly inhibits the proliferation of TNBC cells, particularly MDA-MB-231, in a dose- and time-dependent manner. Mechanistically, Simvastatin primarily induces G1 phase cell cycle arrest to exert its antiproliferative effects, with no significant evidence of apoptosis or necrosis. These findings support the potential repositioning of Simvastatin as a therapeutic agent to suppress TNBC cell growth. Further analysis shows that Simvastatin downregulates cyclin-dependent kinase 4 (CDK4), a key regulator of the G1/S cell cycle transition and a known marker of poor prognosis in breast cancer. These findings highlight a novel, apoptosis-independent mechanism of Simvastatin’s anticancer action in TNBC. Importantly, given that many breast cancer patients also suffer from hyperlipidemia, Simvastatin offers dual therapeutic benefits—managing both lipid metabolism and tumor cell proliferation. Thus, Simvastatin holds promise as an adjunctive therapy in the treatment of TNBC and warrants further clinical investigation. Full article

HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1/TLR-4/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NFκB p65 content resulting in decreased proinflammatory cytokines (TNF-α and IL-1β). Furthermore, LIRA upregulated GLP-1R gene expression and promoted autophagic influx via the activation of the pS473-Akt/pS486-AMPK/pS758-ULK1/Beclin-1 signaling cascade, along with inhibiting apoptosis by reducing caspase-3 content. In conclusion, LIRA attenuated ATO-induced oxidative stress and inflammation via activation of the Nrf-2/SOD cascade and inhibition of the HMGB1/TLR-4/RAGE /MAPK p38/NFκB p65 axis. In parallel, LIRA stimulated autophagy via the AMPK/ULK1/Beclin-1 axis and suppressed apoptosis, thus restoring the balance between autophagy and apoptosis. Full article

Novel derivatives of valproic acid with biologically active moieties, such as thiomorpholine, 4-aminopyridine, serine methyl ester, trolox and the cinnamic acid derivative [(E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid], were synthesized at satisfactory yields. The conjugation of these moieties was based on the rationale of design and evaluation of compounds with selected structural characteristics, aiming at derivatives with multiple targets. These compounds reduced acute inflammation considerably and, in most cases, more than several highly used, well-known, non-steroidal anti-inflammatory drugs. They also offered the inhibition of soybean lipoxygenase, and some of them (compounds 5 and 6) possessed radical scavenging and lipid peroxidation attenuating effects. Their antioxidant capacity was several times higher than that of the established antioxidant trolox. All the tested compounds decreased plasma lipid markers in tyloxapol-induced hyperlipidemia in rats. Compound 2 resulted in 71.1%, 52.8% and 79.1% decrease in total cholesterol, triglycerides and LDL-cholesterol, respectively, at 150 μmol/kg (i.p.). The effect on total and LDL cholesterol is comparable or equal to that of simvastatin, a hypocholesterolemic 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitor, however, with additionally great triglyceride-decreasing effect compared to simvastatin. Thus, the synthesized compounds may be a valuable addition to multi-functional agents acting against various degenerative disorders that implicate inflammation and lipid derangement. Full article

Background: Rhabdoid tumours (RTs) are aggressive neoplasms most often characterised by biallelic loss of the SMARCB1 gene, encoding a core subunit of the SWI/SNF chromatin-remodelling complex. Despite their relative genetic stability, RTs exhibit a highly malignant phenotype and poor prognosis. Methods: This review explores the mechanisms underlying SMARCB1 aberrations, their role in driving hallmarks of cancer, and emerging therapeutic strategies for RTs. Ongoing clinical trials listed on ClinicalTrials were reviewed to evaluate the translational potential of targeted therapies in SMARCB1-deficient rhabdoid tumours. Results: Loss of SMARCB1 drives multiple cancer hallmarks by disrupting key regulatory pathways. It promotes unchecked cell proliferation through alterations in p16INK4a and Myc signalling. SMARCB1-deficient tumours possess immune-evading capabilities via PD-L1 overexpression and immune checkpoint activation. SMARCB1 deficiency also alters cellular energetics. The nucleotide biosynthesis pathway has been demonstrated to be upregulated in RT organoids, as shown by increased levels of pathway metabolites. Enzymes of the mevalonate pathway such as HMG-CoA reductase and mevalonate kinase are also dysregulated. Targeting glutathione metabolism with eprenetapopt may induce oxidative stress and apoptosis. Widespread epigenetic aberrations, including increased EZH2 activity, are being targeted with inhibitors such as tazemetostat. Conclusions: SMARCB1 loss is a central driver of cancer hallmarks in RTs, enabling proliferation, immune evasion, metabolic reprogramming, and epigenetic dysregulation. Future horizons in RT treatment include immunotherapies, epigenetic modifiers, and gene therapies. The synergy and optimal timing of targeted therapy with conventional treatment requires further characterisation for clinical translation. Full article

Background/Objectives: Cardiovascular disease (CVD) remains the leading cause of death worldwide, and the effectiveness of statin therapy is critically dependent on patient adherence and persistence. The aim of this study was to evaluate adherence and persistence in newly started and previously treated statin patients, with reference to cardiovascular prevention. Methods: A retrospective cohort study was conducted to assess adherence and persistence in newly started and previously treated statin patients. Patients aged 18 years or older with a statin claim from 1 January 2021 to 31 December 2023 were included. Adherence was defined as a Medication Possession Rate (MPR) of 80% or greater. Persistence was defined as the time between the index date and treatment discontinuation. Binary logistic regression and Cox proportional hazard regression were used to analyze factors influencing adherence and persistence, respectively. Kaplan–Meier survival analysis was used to compare persistence between both cohorts. Results: Of the 411,956 patients on statins, 81.21% were adherent, with higher rates in the previously treated statin patients (83.05% vs. 73.73%; p = 0.001). Statin persistence decreased from 92.65% at 3 months to 78.28% at 12 months, with higher persistence rates in previously treated statin patients. Previously treated statin patients were more likely to be adherent (AOR: 1.29) and persistent (AHR: 2.08) than those newly started on statins. In secondary prevention patients, adherence was higher in the previously treated cohort (88.09% vs. 79.77%; p = 0.001) than in the newly started cohort (80.52% vs. 71.38%; p = 0.001). Similar results were observed for persistence; 82.97% vs. 81.65% (p = 0.001) and 65.08% vs. 61.57% (p = 0.001), respectively. Conclusions: Adherence and persistence to statins were higher in previously treated patients than in newly started patients, especially for secondary cardiovascular prevention. New strategies are needed to improve medication adherence and persistence in patients with poor cardiovascular prognosis. Full article

Despite extensive research, the exact cause of oral lichenoid lesions remains unknown. The chronic inflammatory tissue reaction mediated by T cells is the basis of the etiological process. However, oral lichenoid lesions often occur in the presence of certain drugs. Our aim was to conduct a preliminary retrospective study to assess the correlation between the administration of statins or HMG-inhibitor CoA reductase, which are commonly used for treating hypercholesterolemia, and the sartans or blockers of the angiotensin II receptor, which are used for treating hypertension, in relation to the occurrence of oral lichenoid lesions. This preliminary retrospective study included 2158 patients who attended the Oral Medicine and Maxillofacial Surgery (Mo-Max) Department of Oral Science and Maxillofacial Surgery, Sapienza University of Rome, from 2019 to 2022. A significant association was found between the presence of oral lichenoid lesions and the simultaneous administration of sartans and statins (χ² = 46.49; p < 0.001). Of the 2158 patients, 118 (5.5%) were diagnosed with oral lichenoid lesions. In the analysis of standardized residues, we found that pathology developed in 16.3% of patients taking statins and 15.9% of those taking sartans. Oral lichenoid lesions only developed in 4.4% of those not taking these drugs. Full article

Cerebral small vessel disease (cSVD) is a common cause of stroke and dementia. Ageing, hypertension, hyperglycaemia, and smoking make up the biggest risk factors for cSVD. They individually or collectively increase the levels of reactive oxygen species, pro-inflammatory cytokines and matrix metalloproteinases, decrease the bioavailability of nitric oxide, and, in the process, compromise the structural integrity and function of the vascular endothelium, blood–brain barrier, and brain parenchyma. These then appear as white matter hyperintensities, enlarged perivascular spaces, cerebral microbleeds, and atrophy in cerebral imaging. As there is currently no curative therapy for cSVD, prevention or delay of cSVD remains of particular importance to preserve quality of life for as long as possible. Bearing that in mind, this review explores whether drugs used for other neurovascular conditions may prevent neuroinflammation and oxidative damage and effectively maintain endothelial function and blood–brain barrier integrity. It also examines whether potential benefits may be extended to cSVD. The list of drugs includes anti-anginal drugs, acetylcholine esterase inhibitors, β-hydroxy β-methylglutaryl-CoA reductase inhibitors, lithium drugs, phosphodiesterase inhibitors, oral antihyperglycaemic drugs, and tetracycline antibiotics. This review discusses the mechanisms of action of these agents and critically evaluates preclinical, translational, and clinical research pertaining to cSVD. Full article

Integrin β4 (ITGB4) mediates lung endothelial cell (EC) inflammation attenuated by simvastatin, an HMG CoA-reductase inhibitor. The cytoplasmic domain of ITGB4 is predicted to bind kindlin-2. Kindlin-2 expression is mediated by SMURF1, an E3 ubiquitin ligase that promotes kindlin-2 ubiquitination and degradation. We hypothesized that increased kindlin-2 expression via the inhibition of SMURF1 mediates EC inflammatory responses relevant to acute lung injury (ALI). To investigate this, human lung ECs were treated with simvastatin (5 µM, 16 h) prior to the immunoprecipitation of kindlin-2 and Western blotting for ITGB4. Next, ECs were treated with a SMURF1 inhibitor, A01, and increased kindlin-2 expression was confirmed. In assays of barrier function, kindlin-2 was silenced (siRNA) in ECs prior to thrombin and measurements of transendothelial resistance (TER) and FITC-dextran transwell flux. Repeat assessments of barrier function were performed in A01-treated ECs. Finally, mice were pretreated with A01 prior to LPS; bronchoalveolar lavage (BAL) fluid was collected, and their lungs were used for histology. Simvastatin increased ITGB4:kindlin-2 association, while A01 increased kindlin-2 expression. Thrombin-induced EC barrier disruption was both increased after kindlin-2 silencing and decreased by A01. Finally, murine ALI was significantly attenuated by A01. Our findings suggest that the augmentation of kindlin-2 may serve as a novel ALI therapeutic strategy. Full article

Background/Objectives: Intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) are severe forms of stroke with high morbidity and mortality rates. HMG-CoA reductase inhibitors, commonly referred to as statins, known for their lipid-lowering abilities, also possess pleiotropic properties, including anti-inflammatory and neuroprotective effects. We aimed to evaluate the impact of statin therapy on the functional outcomes and survival in patients with ICH and SAH. Methods: This retrospective cohort study analyzed data from the Get With The Guidelines (GWTG) stroke registry at a tertiary care center, including patients diagnosed with ICH or SAH between January 2008 and June 2022. Patients were categorized based on prior initiation of statin therapy: no statin, low-intensity statin, or high-intensity statin. The primary outcome was the Modified Rankin Scale (mRS) score at discharge, dichotomized to good (0–2) and poor (3–6) outcomes. A multivariate logistic regression model controlled for age, gender, and National Institutes of Health Stroke Scale (NIHSS) score at admission. Results: A total of 663 patients with ICH and 159 patients with SAH were included in the analysis. In the ICH patients, low-intensity statin therapy was associated with significantly higher odds of a good functional outcome (aOR 2.56, 95% CI 1.247–5.246, p = 0.0104), as was high-intensity statin therapy (aOR 2.445, 95% CI 1.313–4.552, p = 0.0048). Among the SAH patients, all 39 deaths occurred in the no statin therapy group. Conclusions: Both low- and high-intensity statin therapy are associated with improved functional outcomes in ICH and may offer a survival benefit in SAH. These findings highlight the potential neuroprotective role of statins in hemorrhagic stroke. Further prospective studies and randomized controlled trials are needed to confirm these observations and to clarify the optimal use of statins in this patient population. Full article