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ObjectiveIncreased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC).DesignWe investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specific Fasn knockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type and Fasn knockout mice. Human HCC cell lines were used for in vitro studies.ResultsAblation of Fasn significantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged in Fasn knockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss of Fasn promoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis in Fasn knockout mice. Similarly, silencing of FASN resulted in increased SREBP2 activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR) expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture.ConclusionOur study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.

The last decade has seen an increase in the trend of HMG-CoA reductase inhibitor (statin) usage in the Western world, which does not come as a surprise noting that the latest American Heart Association heart and stroke statistics indicate an alarming prevalence of 80 million Americans (one in three) with one or more forms of diagnosed cardiovascular disease (CVD). Meta-analysis of several large-scale, randomized clinical trials has demonstrated statins to be efficacious in significantly reducing CVD-associated mortality in both primary and secondary prevention. Despite their proven efficacy, statins have also gained attention with respect to adverse drug reactions (ADRs) of muscle myopathy, derangements in hepatic function and even ADRs classified as psychiatric in nature. The depletion of cholesterol within the myocyte cell wall and/or the depletion of key intermediates within the cholesterol synthesis pathway are hypothesized as possible mechanisms of statin-associated ADRs. However, pharmacogenetic variability may also be a risk factor for ADRs and can include, for example, enzymes, transporters, cell membrane receptors, intracellular receptors or components of ion channels that contribute to the pharmacokinetics or pharmacodynamics of response to a particular drug. The cytochrome P450 (CYP) enzymatic pathways that comprise the polymorphic genes, CYP2D6, CYP3A4 and CYP3A5 , and also a hepatic transporter, solute carrier organic anion transporter (SLCO1B1) , which is a single nucleotide polymorphism discovered to be associated with statin-induced myopathy through a genome-wide association study, are discussed with respect to their effect on altering the pharmacokinetic profile of statin metabolism. Variants of the Apolipoprotein E (APO-E) gene, polymorphisms in the cholesteryl ester transfer protein (CETP) gene, the HMG-CoA reductase gene and other proteins are discussed with respect to altering the pharmacodynamic profile of statins. Pharmacogenetics and its application in medicine to individualize drug therapy has been previously shown to be clinically and economically beneficial through quality-adjusted life-year assessment. Therefore, polymorphisms affecting the pharmacokinetic and pharmacodynamic profiles of statins, which are widely used in therapy, with their potential application in the personalized prescribing of statin therapy, need further research. In this review, we update the recent literature with respect to genetic polymorphisms that may influence the pharmacokinetics and pharmacodynamics of statin therapy, and consider the relevance of these findings to the efficacy of treatment, prevention of ADRs and what this may mean for patient tolerance and compliance.

Preliminary assessment for anti-inflammatory and anti-lipidemic properties was done with different solvent extracts derived from Urtica urens and Polygonum chinense leaves through in vitro experimentation. To evaluate anti-inflammatory properties, the stability of human red blood cells membranes and the denaturation activity of proteins were assessed. For anti-lipidemic effects, an assay was conducted to measure the inhibition of HMG-CoA reductase. The results of membrane stabilization showed IC50 values of 480.96 ± 0.02 and 319.41 ± 0.19 µg/mL for ethyl acetate extract of U. urens and P. chinense, respectively. The standard drug Diclofenac sodium exhibited IC50 value of 240.37 ± 0.04 µg/mL. For protein denaturation, IC50 values were determined as 221.75 ± 0.2 and 315.76 ± 0.19 µg/mL for U. urens and P. chinense, respectively. The IC50 value of the standard drug was calculated as 126.7 ± 0.34. The IC50 values towards HMG-CoA reductase inhibition were subsequently determined as 29.84 ± 0.35 µg/mL for U. urens and 24.34 ± 0.04 µg/mL for P. chinense against the standard drug Diclofenac sodium (7.52 ± 0.43 µg/mL). GC-MS chromatograms revealed the presence of bioactive compounds in ethyl acetate extract of P. chinense leaves. This work is substantiation for the traditional therapeutic utilization of these extracts.

Testicular torsion (TT) is a urological emergency that results in ischemia/reperfusion (I/R) injury, leading to oxidative stress, cellular apoptosis, and impaired spermatogenesis. This study investigated the protective effects of the HMG-CoA reductase inhibitor rosuvastatin on TT-induced I/R injury and explored the underlying mechanisms. Male Balb/C mice ( n  = 28) were subjected to 720° testicular torsion for two hours, followed by 24 h of detorsion. Rosuvastatin was administered either acutely (post-torsion) or prophylactically (prior to injury). Histopathological evaluation, assessment of oxidative stress parameters, sperm motility and morphology analysis, and Western blot examination of survival and stress related signaling proteins (pAKT, pJNK1/2, pERK1/2, and Bcl-xL) were performed. Rosuvastatin treatment significantly reduced tissue damage decreased oxidative stress (as indicated by increased TAS and reduced TOS/OSI), and improved sperm motility and morphology. Both acute and prophylactic treatment regimens enhanced cell survival by increasing pAKT and Bcl-xL levels, reducing pERK1/2 activation, and modulating stress responsive JNK1/2 signaling. These findings suggest that rosuvastatin mitigates I/R induced testicular damage primarily through modulation of key intracellular pathways, particularly PI3K/AKT, and support its therapeutic potential in acute testicular injuries and related degenerative conditions.

Background EZH2 is a histone methyltransferase and a key component of polycomb repressive complex 2 (PRC2). It plays a critical role in genome remodeling, gene regulation and acts through PRC2-dependent and independent mechanisms, which comprise methylation of histone and non-histone substrates, and transcriptional activation through different transcriptional complexes. EZH2 is involved in many cancers, but its role in hepatoblastoma is poorly understood. Methods Potential correlation between EZH2 mRNA expression and clinical parameters was analyzed by computational and histological approaches using seven published transcriptomic datasets and tissue samples from patients with hepatoblastoma. EZH2 molecular function was deciphered using molecular approaches, gain- and loss-of-function genetic tools, proteomics, immunohistochemistry, pharmacological drugs, 2D cell- and spheroid-based assays, and four different animal models. Results Our data show that EZH2 mRNA expression correlated with poor prognostic markers such as tumor proliferation, and patients’ death and shorter survival. EZH2 protein potentiated hepatoblastoma cell proliferation, migration, survival and cisplatin resistance through its histone methyltransferase activity by repressing DUSP5 , and transcriptionally inducing DUSP9 and HMGCR . In vivo EZH2 sustained tumor cell proliferation, and tumor development and angiogenesis. The EZH2 inhibitor GSK126 synergized with HMG-CoA reductase inhibitor statins to eradicate hepatoblastoma cells in vitro and block tumor development in mice. This combination was also very effective on various hepatoblastoma and non-hepatoblastoma tumor cell lines. Conclusion Collectively, our data showed that the protein EZH2 promotes hepatoblastoma development, partly through its histone methyltransferase activity, by differentially modulating the expression of DUSP5 , DUSP9 and HMGCR genes and by supporting the MAPK/ERK pathway in hepatoblastoma cells already displaying high Wnt signal activity. EZH2 inhibitors triggered lipid synthesis in hepatoblastoma cells and synergized with cholesterol-lowering statins to block hepatoblastoma development in vitro and in vivo. Therefore, we demonstrate the key role of EZH2 in proliferative hepatoblastoma and the therapeutic benefit of combining EZH2 inhibitor and statin to treat patients with cancer.

The enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase is the key enzyme of the mevalonate pathway that produces cholesterol. Inhibition of HMG-CoA reductase reduces cholesterol biosynthesis in the liver. Synthetic drugs, statins, are commonly used for the treatment of hypercholesterolemia. Due to the side effects of statins, natural HMG-CoA reductase inhibitors of plant origin are needed. In this study, 25 medicinal plant methanol extracts were screened for anti-HMG-CoA reductase activity. Basella alba leaf extract showed the highest inhibitory effect at about 74%. Thus, B. alba was examined in order to investigate its phytochemical components. Gas chromatography with tandem mass spectrometry and reversed phase high-performance liquid chromatography analysis revealed the presence of phenol 2,6-bis(1,1-dimethylethyl), 1-heptatriacotanol, oleic acid, eicosyl ester, naringin, apigenin, luteolin, ascorbic acid, and α-tocopherol, which have been reported to possess antihypercholesterolemic effects. Further investigation of in vivo models should be performed in order to confirm its potential as an alternative treatment for hypercholesterolemia and related cardiovascular diseases.

Objective Our research was designed to figure out the influence and mechanism of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor on the improvement of elderly essential hypertension-induced vascular endothelial function impairment based on the JAK/STAT pathway. Methods Eighty-six elderly patients with essential hypertension were randomized into a control group (oral Amlodipine Besylate Tablets) and an observation group (oral Amlodipine Besylate Tablets + HMG-CoA reductase inhibitor atorvastatin calcium). Patients in both groups were treated with the drug for 12 weeks. Blood pressure, serum levels of inflammatory factors, and vascular endothelial function indicators, and levels of blood lipids were measured. The modeled rats were treated with atorvastatin calcium and a JAK/STAT pathway inhibitor (AG490), and the levels of cardiac function-related indices, left ventricular mass index, lipid levels, serum inflammatory factors and vascular endothelial function-related indices were detected in each group. Results HMG-CoA reductase inhibitor improved blood pressure levels, lipid levels, serum inflammatory factor levels and cardiac function in elderly patients with essential hypertension. Both HMG-CoA reductase inhibitor and AG490 improved blood pressure levels, lipid levels, serum inflammatory factor levels and cardiac function in SHR rats. Both HMG-CoA reductase inhibitor and AG490 decreased p-JAK2/JAK2 and p-STAT3/STAT3 expression levels. Conclusion Our study demonstrates that HMG-CoA reductase inhibitor improves elderly essential hypertension-induced vascular endothelial function impairment by blocking the JAK/STAT pathway.

Immune checkpoint blockade has become an effective strategy for inhibiting tumor growth, especially immune checkpoint inhibitors that target the programmed death 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) pathway, which have shown significant effects in tumor immunotherapy. In this study, we found that naturally sourced Cordyceps militaris extract can effectively downregulate the protein expression level of PD‐L1 in human colorectal cancer cell lines. Further systematic isolation, purification, and analysis of its active components revealed that cordycepin (COR) is the key active molecule mediating PD‐L1 degradation. Mechanistically, COR specifically and selectively targets the ubiquitin E3 ligase HMG‐CoA reductase degradation protein 1, thus promoting the degradation of PD‐L1 protein through the ubiquitin–proteasome pathway. This process significantly enhances the cytotoxic killing effect of effector T lymphocytes against colorectal cancer cells, ultimately achieving robust antitumor effects. Furthermore, this study also revealed that COR exhibits potential synergistic therapeutic effects when combined with anti‐CTLA4 antibodies in preclinical tumor treatment. In summary, COR, as the primary bioactive component of Cordyceps militaris, demonstrates considerable potential to act as a small‐molecule immune checkpoint modulator and inhibitor, thereby providing a novel therapeutic strategy for the immunotherapy of colorectal cancer. Using an activity‐based tracking approach, our study revealed that the component in Cordyceps militaris extract (CME) that reduces PD‐L1 activity is cordycepin, which demonstrates potential as an immune checkpoint inhibitor for colorectal cancer. Cordycepin targets HRD1, leading to PD‐L1 protein degradation via the ubiquitin–proteasome pathway, which enhances T cell cytotoxicity against cancer cells.

Background Only a few bladder cancer patients benefit from anti‐programmed cell death protein 1/programmed cell death ligand 1 immunotherapy. The cluster of differentiation 47 (CD47) plays an important role in tumor immune evasion. CD47 is a highly glycosylated protein, however, the mechanisms governing CD47 glycosylation and its potential role in immunosuppression are unclear. Therefore, this study aimed to evaluate the function of CD47 glycosylation in bladder cancer. Methods Western blotting, immunohistochemistry, and flow cytometry were used to measure protein expression, protein‐protein interactions, and phagocytosis in bladder cancer. A murine model was employed to investigate the impact of mannosidase alpha class 1B member 1 (MAN1B1) modification of CD47 on anti‐phagocytosis in vivo. An ex vivo model, patient‐derived tumor‐like cell clusters, was used to examine the effect of targeting MAN1B1 on phagocytosis. Results Our research identified that aberrant CD47 glycosylation was responsible for its immunosuppression. The glycosyltransferase MAN1B1 responsible for CD47 glycosylation was highly expressed in bladder cancer. Abnormal activation of extracellular signal‐regulated kinase (ERK) was significantly associated with MAN1B1 stability by regulating the interaction between MAN1B1 and the E3 ubiquitin ligase HMG‐CoA reductase degradation 1 (HRD1). Mechanistically, abnormally activated ERK stabilized MAN1B1, resulting in the glycosylation of CD47 and facilitating immune evasion by enhancing its interaction with signal‐regulatory protein alpha (SIRP‐α). In vitro and in vivo experiments demonstrated that MAN1B1 knockout weakened CD47‐mediated anti‐phagocytosis. MAN1B1 inhibitors promoted phagocytosis without causing anemia, offering a safe alternative to anti‐CD47 therapy. Conclusions This comprehensive analysis uncovered that ERK activation stabilizes MAN1B1 by regulating the interaction between MAN1B1 and HRD1, facilitates immune evasion via CD47 glycosylation, and presents new potential targets and strategies for cancer immunotherapy that do not cause anemia.

The current study aimed to investigate statin (HMG-CoA reductase inhibitor) mimic and free radical scavenging potential of phytoconstituents of the methanolic extract of Prosopis cineraria pod by in vitro, in silico, and in vivo assessments. The phytoconstituents of the chosen extract were screened out by using the LCMS and GCMS analyses. The in vitro assessment of the extract shown 78.3% (IC50 1.7786 μg/ml) inhibition of HMG-CoA reductase as compared with pravastatin (positive control). The administration of the extract made considerable (P ≤ 0.001) improvements in lipid profile, atherogenic indices and oxidative stress. The in silico studies of molecular docking revealed significant binding energy of key identified compounds obtained in test extracts, i.e., cinnerin C, prosogerin A, prosogerin B, prosopine, spicegrin, quercetin, alpha-d-mannofuranoside, methyl, undecanoic acid and l-gala-l-iodo-octose with target enzymes. The quercetin showed significant interaction with the target protein (HMG-CoA reductase) compared to atorvastatin with − 8.4 kcal/mol binding energy. Further, validations of ligands-protein interactions were examined by molecular dynamics at 100 ns through RSMD, RSMF, SASA and MMPBSA, which revealed the significant interactions of quercetin and atorvastatin with HMGCR. ADMET predictions shown significant pharmacokinetic profiles of phytoconstituents. The phytoconstituents of Prosopis cineraria pod of methanolic extract contains potent phytochemicals like quercetin which may be concerned to the inhibition of HMG-CoA reductase and free radical scavenging activities.