Search Results (242)

Background: Statins have been associated with a reduced risk of primary liver cancer (PLC), primarily hepatocellular carcinoma (HCC). However, the optimal use for effective protection and whether benefits vary by patient characteristics remain unclear. We evaluated the association between statin use and PLC risk in metabolic-dysfunction-associated steatotic liver disease (MASLD), considering cumulative exposure and potential effect modifiers. Methods: We conducted a retrospective cohort study using the Veteran Affairs electronic health records. Patients with chronically elevated liver enzymes and metabolic dysfunction, without other chronic liver diseases, were identified between 2007 and 2009 and followed through 2019 for incident PLC. Statin exposure was assessed at baseline and during the follow-up, with dose standardization by LDL-lowering potency (simvastatin-equivalent units). Time to PLC was analyzed using Cox models adjusted for covariates, considering potential interactions. Results: Among 329,577 patients (92% male; median age 62 years), 0.82% developed PLC (median follow-up of 9.7 years). Baseline statin use showed a significantly lower PLC risk (adjusted hazard ratio 0.64; 95% CI, 0.57–0.71; p < 0.0001). No significant interaction was observed with age, sex, metabolic syndrome, or cirrhosis. Higher cumulative statin exposure demonstrated a dose-dependent risk reduction, remaining significant at simvastatin-equivalent doses > 15,561 mg annually after accounting for incident cirrhosis. Atorvastatin/rosuvastatin use provided comparable protection, despite different lipophilicity, and demonstrated stronger effects than others. Conclusions: In MASLD, statin therapy was associated with a dose-dependent PLC risk reduction. High-intensity therapy (simvastatin-equivalent > 40 mg daily) conferred substantial protection regardless of age, sex, insulin resistance, or cirrhosis, supporting a potential statin-based PLC chemoprevention in MASLD. Full article

α-Bisabolol is naturally occurring in many plants and has great potential in health products and pharmaceuticals. However, the current extraction method from natural plants is unsustainable and cannot fulfil the increasing requirement. This study aimed to develop a sustainable strategy to enhance the biosynthesis of α-bisabolol by metabolic engineering. Integration of ERG20 (encoding farnesyl diphosphate synthase) and tHMG1 (encoding truncated 3-hydroxy-3-methylglutaryl-CoA reductase) genes with a constitutive strong promoter into the yeast genome elevated α-bisabolol production from 20.21 mg/L to 98.30 mg/L, representing a 4.86-fold increase. Further optimization of the mevalonate pathway and amplification of ERG20, tHMG1, and OsTPS1 copy numbers enhanced α-bisabolol synthesis to 423.01 mg/L, achieving a 20.93-fold improvement relative to the baseline. This work establishes a reference strategy for high-yield α-bisabolol biosynthesis in engineered yeast. Full article

Pancreatic ductal adenocarcinoma (PDAC) has limited effective therapeutic strategies. Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and may affect tumor cell fitness via the mevalonate pathway, mitochondrial function, and redox homeostasis. We systematically compared seven statins in patient-derived PDAC cell lines and related viability effects to mitochondrial, redox, cell-cycle, apoptotic, and metabolic responses. Statins were tested in three PDAC cell lines (PDAC-1/2/3) using MTT assays (5–20 µM; 24–120 h). Based on MTT responses, mechanistic profiling was performed after 72 h at 20 µM concentration using lipophilic statins, including apoptosis (Annexin V/7-AAD), cell-cycle distribution, mitochondrial membrane potential (Δψm), intracellular ROS, and ¹H-NMR quantification of intracellular and extracellular metabolites. Statins reduced viability in a concentration- and time-dependent manner, with lipophilic statins more active than hydrophilic. PDAC-1 was highly sensitive, PDAC-3 intermediate, and PDAC-2 comparatively resistant. PDAC-1 and PDAC-3 showed G0/G1 accumulation, Δψm depolarization, reactive oxygen species (ROS) elevation, and Annexin V–positive apoptosis, whereas PDAC-2 (high basal ROS) showed ROS reduction and limited apoptosis despite Δψm loss. Metabolomics indicated reduced glucose and amino-acid utilization and lactate secretion while preserving line-specific metabolic fingerprints. PDAC cell lines display marked inter-tumoral heterogeneity in statin responses, supporting evaluation of statins as chemosensitizing adjuvants in functionally guided PDAC treatment strategies. Full article

Disinfection byproducts (DBPs) are ubiquitous contaminants formed during drinking water treatment and are traditionally regulated based on cytotoxic and genotoxic endpoints. However, evidence suggests that DBPs may also act as metabolic disruptors interfering with hepatic metabolic pathways. This study investigates the early metabolic disruption and steatogenic effects of four regulated DBPs, bromoform (BR), bromodichloromethane (BDCM), monochloroacetic acid (MCA), and dichloroacetic acid (DCA), using the human hepatic cell models HepG2 (derived from hepatocellular carcinoma) and HUH7 (derived from hepatoblastoma). Cells were exposed to a broad concentration range (1 pM–100 µM) to capture both sub-cytotoxic and mechanistically informative responses at low, environmentally relevant levels. Effects on lipid and sterol metabolism were assessed through the transcriptional modulation of a panel of nuclear receptors (AHR, PXR, RXR, and LXR) and the sterol regulatory enzyme HMG-CoA reductase (HMGCR) as well as intracellular lipid accumulation; cytotoxicity and oxidative stress endpoints were concurrently evaluated. All DBPs tested induced significant, dose-dependent alterations in nuclear receptor signaling and also promoted lipid accumulation in the low-concentration range and without concurrent cytotoxicity; conversely, oxidative stress responses were limited or absent, and HMGCR emerged as a sensitive target, albeit with different patterns (upregulation by BR and MCA, and downregulation by BDCM and DCA). Relevant substance-specific aspects were also observed for other transcriptional targets, e.g., PXR upregulation was particularly evident for BR and BCDM while DCA downregulated the tested receptors. DBP-induced lipid accumulation was more pronounced in HUH7. Regulated DBPs can elicit early steatogenic and metabolic effects even at concentrations below current regulatory thresholds. The findings highlight that endocrine–metabolic disruption should be considered as a relevant endpoint in DBP risk assessment. Full article

Stingless bee honey (SBH) contains bioactive compounds which are influenced by its botanical origin, and these constituents are closely associated with its health-promoting properties. Interest in monofloral honey has been increasing owing to its distinctive sensory characteristics, relatively consistent nutritional composition, and higher market value. The growing burden of cardiometabolic disease underscores the need for additional studies examining the inhibition of enzymes relevant to these pathways. This study analyzed SBH from five botanical origins (acacia, coconut, elderberry, Singapore rhododendron, sunflecks). In vitro inhibition was evaluated against enzymes associated with cholesterol biosynthesis (HMG-CoA reductase), blood pressure regulation (ACE), lipid digestion (pancreatic lipase, cholesterol esterase), and postprandial glycaemia (α-amylase, α-glucosidase). Acacia SBH showed the most potent ACE inhibition (16.80 ± 0.30 mg/mL), while Singapore rhododendron SBH exhibited the strongest HMG-CoA reductase inhibition (18.05 ± 0.50 mg/mL). Sunflecks SBH showed the most potent inhibition of cholesterol esterase, with the lowest IC₅₀ (57.00 ± 0.01 mg/mL). The findings suggest the potential of SBH as a cardioprotective functional food with significant health benefits. Full article

Hyperlipidemia is a major global risk factor for cardiovascular disease, underscoring the need for safe, multi-target preventive strategies. In this study, two novel dietary supplements were developed by blending freeze-dried aqueous extracts of chamomile (CDS) or thyme (TDS) with linseed oil (1:1, w/w) and evaluated for their phytochemical composition, antioxidant capacity, and hypolipidemic efficacy. Total phenolics, total flavonoids, fatty acid composition, volatile constituents, and individual phenolic profiles were characterized, while antioxidant activity was assessed using DPPH· radical-scavenging and FRAP assays. Hypolipidemic activity was investigated in a Triton X-100-induced hyperlipidemia rat model through an assessment of plasma lipid parameters, oxidative stress and inflammatory markers, and liver and kidney function indices, supported by hepatic histopathology. Molecular docking was performed to explore the interactions of major bioactive compounds with AMP-activated protein kinase (AMPK) and HMG-CoA reductase. Both CDS and TDS exhibited strong antioxidant activity and high polyphenol content, with kaempferol and chlorogenic acid identified as the predominant phenolics in CDS and TDS, respectively. β-Farnesene and carvacrol were the main volatile constituents. In vivo, both formulations significantly reduced total cholesterol, triglycerides, LDL-C, lipid peroxidation markers, and TNF-α, while increasing HDL-C and improving cardiac risk indices, with more pronounced effects observed for TDS. Histopathological analyses confirmed marked hepatoprotection, particularly in the TDS-treated group. Docking analyses identified ellagic acid as the strongest dual binder to both AMPK and HMG-CoA reductase. Overall, these findings demonstrate that chamomile-linseed and thyme-linseed formulations exert synergistic, multi-target antioxidant and hypolipidemic effects, supporting their potential as nutraceutical strategies for the early prevention and management of hyperlipidemia and cardiometabolic risk. Full article

Background/Objectives: Botanical and nutraceutical approaches have increasingly been considered as alternatives or complements to conventional lipid-lowering therapies, particularly in individuals with mild-to-moderate dyslipidemia or statin intolerance. This study aimed to evaluate a multi-botanical formulation, combining black garlic, sesame, Gastrodia elata, and Primula veris extracts, for its effects on hepatic cholesterol regulation and the PCSK9–LDLr–SREBP-2 axis in vitro. Methods: Each extract was chemically characterised for its polysaccharide, polyphenol, flavonoid, and sesamin content. HepG2 cells were exposed to normal (5 mM) or high-glucose (30 mM) conditions to mimic metabolic stress. Dose–response studies identified optimal concentrations for cell viability. Hepatic safety was assessed via MTT and ROS assays, while cholesterol metabolism was evaluated by measuring HMG-CoA reductase levels, total cholesterol, LDL levels, bile acid production, free cholesterol levels, and the expression of PCSK9, LDLr, and SREBP-2 using ELISA and Western blot. Results: All individual extracts improved cell viability, reduced oxidative stress, and moderately modulated cholesterol metabolism. The multi-botanical combination exhibited synergistic effects, enhancing cell viability (+47.5% vs. untreated), suppressing ROS, reducing HMGR levels, and lowering total intracellular cholesterol more effectively than single extracts or the statin-like reference RYRF. Importantly, the combination strongly downregulated PCSK9 and inhibited SREBP-2 proteolytic activation while upregulating LDLr, indicating coordinated transcriptional and post-translational regulation. Bile acid production and free cholesterol excretion were also significantly increased, supporting improved cholesterol clearance. Conclusions: This four-botanical formulation effectively modulates hepatic cholesterol homeostasis via a multifactorial, synergistic mechanism distinct from statin-like agents. The results suggest its potential as a safe, non-statin strategy to support cardiometabolic health. Future studies are warranted to confirm long-term efficacy and clinical relevance. Full article

Endoplasmic reticulum-mediated protein quality control (ERQC) safeguards secretory pathway proteostasis by recognizing, retaining, repairing, and removing misfolded proteins, and is therefore essential for plant growth, development, and stress tolerance. This system relies on ER-associated degradation (ERAD), in which irreparably misfolded proteins are first recognized in the ER, then exported across the ER membrane to the cytosol, where they are ubiquitinated by ER membrane-anchored ubiquitin ligases, and subsequently degraded by the cytosolic proteasome. Studies in yeast and mammals have defined several conserved ERAD branches, including a multiprotein ERAD complex centered on the polytopic ER membrane E3 ligase HMG-CoA reductase degradation protein 1 (Hrd1), which integrates substrate recognition, membrane retrotranslocation, ubiquitin conjugation, and cytosolic extraction. Recent advances in Arabidopsis show that plants retain the core Hrd1 ERAD architecture while incorporating additional regulatory elements that adapt this machinery to plant-specific physiological demands. Genetic and biochemical analyses of misfolded receptor kinases and engineered substrates have uncovered conserved and plant-specific components of the plant Hrd1 complex, revealing how the plant ERAD pathway integrates ERQC with hormone signaling, stress adaptation, immune responses, and growth regulation. This review synthesizes recent advances in plant ERAD research and highlights key conceptual and mechanistic questions that remain to be resolved. Full article

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

The development of plant-based synbiotic beverages is gaining increasing attention as consumers seek sustainable, functional alternatives to dairy products. This preliminary study investigated the fortification of tibicos (water kefir) with lemon catnip (Nepeta cataria var. citriodora) hydrolate, an aromatic distillation byproduct rich in bioactive terpenoids. After 72 h-fermentation of tibicos, physicochemical, microbiological, health-promoting and sensory parameters were evaluated. Both control and fortified beverages exhibited typical fermentation kinetics, including a decrease in pH, reduction of soluble solids, and accumulation of organic acids. Lactic acid bacteria count remained stable, while yeast proliferation was slightly reduced in the hydrolate-fortified sample, consistent with the known yeast-sensitive nature of certain hydrolate-derived terpenoids. Importantly, hydrolate fortification significantly enhanced antioxidant capacity (DPPH: +34%; ABTS: +39%; RP: +38%). Enzyme-inhibitory activities also increased significantly in the hydrolate-fortified samples (α-Amylase and α-Glucosidase inhibition rates increased by 9% and 11%, respectively). ACE inhibition similarly increased from 32% to 44%, indicating an enhanced antihypertensive potential. HMG-CoA reductase inhibition increased from 31% to 42%, showing improved hypolipidemic activity. Sensory evaluation indicated improved sensory acceptability, imparting citrus–floral notes that balanced the acidic profile of tibicos. These findings highlight the potential of valorizing lemon catnip hydrolate as a functional fortifier in non-dairy synbiotic beverages. 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

Ginsenosides, the primary bioactive components of Panax ginseng, exhibit diverse pharmacological properties, ranging from anticancer to neuroprotective effects. However, traditional production by ginseng cultivation faces limitations due to extended growth cycles, insufficient yields, intricate extraction processes, and significant environmental dependencies. Synthetic biology and synthetic metabolic engineering offer promising alternatives for sustainable manufacturing of essential bioactive compounds, including ginsenosides. First, this review describes the ginsenoside biosynthesis pathways, emphasizing crucial enzymes (e.g., HMG-CoA reductase, squalene epoxidase, dammarenediol-II synthase, amyrin synthase, and various UDP-glycosyltransferases) and their regulatory networks. Understanding these fundamental pathways enables rational engineering of production systems. Second, it examines current synthetic biology approaches, encompassing plant cell, tissue, and hairy root cultures, engineered microbial hosts including Saccharomyces cerevisiae and Escherichia coli, and cell-free enzymatic synthesis. Third, it evaluates the medicinal significance, market prospects, and industrial feasibility of these biomanufactured compounds. Finally, it analyzes the sustainability of production models and explores the emerging potential of engineered plant chassis. These advanced methodologies directly address traditional agricultural constraints and establish a robust framework for future ginsenoside synthesis. Full article

Objective: The study investigates the dietary effects of Moringa oleifera leaf powder on obesity, blood biochemical parameters, and organ health in hyperlipidemic zebrafish (Danio rerio). Methodology: Adult hyperlipidemic zebrafish (n = 56/group) were fed for 12 weeks either with a high-cholesterol diet (HCD, 4% w/w) or HCD supplemented with 0.5% (w/w) M. oleifera leaf powder (0.5% MO) or HCD with 1.0% (w/w) M. oleifera leaf powder (1.0% MO). At different time points (0 to 12 weeks), the survivability and body weight (BW) of zebrafish were measured, while various biochemical and histological evaluations were performed after 12 weeks of feeding the respective diets. Additionally, an in silico approach was used to assess the binding interactions of MO phytoconstituents with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Results: Following 12-week supplementation, higher zebrafish survivability was observed in the MO-supplemented groups compared to the survivability of the HCD group. Relative to the initial BW, only 4% BW enhancement was observed post 12 weeks of dietary intake of 1.0% MO, in contrast to 27% BW gain in the HCD group. MO supplementation at both (0.5% and 1.0%) effectively mitigates the HCD-induced dyslipidemia and significantly minimizes the atherogenic coefficient and atherogenic index. Similarly, MO reduces elevated blood glucose levels, the ALT/AST ratio, and augments ferric ion reduction (FRA) and paraoxonase (PON) activity in a dose-dependent manner. Likewise, MO (particularly at 1.0%) effectively restrained HCD-induced steatosis, hepatic interleukin (IL)-6 production, and protected the kidneys, testes, and ovaries from oxidative stress and cellular senescence. The in silico findings underscore that the six phytoconstituents (chlorogenic acid, isoquercetin, kaempferol 3-O-rutinoside, astragalin, apigetrin, and myricetin) of MO exhibited a strong interaction with HMG-CoA reductase active and binding site residues via hydrogen and hydrophobic interactions. Conclusions: The findings demonstrated an antioxidant, anti-inflammatory, and hypoglycemic effect of MO, guiding the events to prevent HCD-induced metabolic stress and safeguard vital organs. 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