-
European Heart Journal Aug 2023The variant p.Arg149Cys in ACTA2, which encodes smooth muscle cell (SMC)-specific α-actin, predisposes to thoracic aortic disease and early onset coronary artery...
AIMS
The variant p.Arg149Cys in ACTA2, which encodes smooth muscle cell (SMC)-specific α-actin, predisposes to thoracic aortic disease and early onset coronary artery disease in individuals without cardiovascular risk factors. This study investigated how this variant drives increased atherosclerosis.
METHODS AND RESULTS
Apoe-/- mice with and without the variant were fed a high-fat diet for 12 weeks, followed by evaluation of atherosclerotic plaque formation and single-cell transcriptomics analysis. SMCs explanted from Acta2R149C/+ and wildtype (WT) ascending aortas were used to investigate atherosclerosis-associated SMC phenotypic modulation. Hyperlipidemic Acta2R149C/+Apoe-/- mice have a 2.5-fold increase in atherosclerotic plaque burden compared to Apoe-/- mice with no differences in serum lipid levels. At the cellular level, misfolding of the R149C α-actin activates heat shock factor 1, which increases endogenous cholesterol biosynthesis and intracellular cholesterol levels through increased HMG-CoA reductase (HMG-CoAR) expression and activity. The increased cellular cholesterol in Acta2R149C/+ SMCs induces endoplasmic reticulum stress and activates PERK-ATF4-KLF4 signaling to drive atherosclerosis-associated phenotypic modulation in the absence of exogenous cholesterol, while WT cells require higher levels of exogenous cholesterol to drive phenotypic modulation. Treatment with the HMG-CoAR inhibitor pravastatin successfully reverses the increased atherosclerotic plaque burden in Acta2R149C/+Apoe-/- mice.
CONCLUSION
These data establish a novel mechanism by which a pathogenic missense variant in a smooth muscle-specific contractile protein predisposes to atherosclerosis in individuals without hypercholesterolemia or other risk factors. The results emphasize the role of increased intracellular cholesterol levels in driving SMC phenotypic modulation and atherosclerotic plaque burden.
Topics: Mice; Animals; Plaque, Atherosclerotic; Actins; Mice, Knockout, ApoE; Atherosclerosis; Cholesterol; Hyperlipidemias; Myocytes, Smooth Muscle; Muscle, Smooth; Apolipoproteins E; Mice, Inbred C57BL; Mice, Knockout
PubMed: 37377039
DOI: 10.1093/eurheartj/ehad373 -
Microorganisms Jun 2023is an intestinal protozoan that is often neglected, despite causing abdominal pain and diarrhea. Previous research has demonstrated that lipids can be synthesized by...
is an intestinal protozoan that is often neglected, despite causing abdominal pain and diarrhea. Previous research has demonstrated that lipids can be synthesized by or can accumulate in growth medium, but their function and mechanisms in the pathogenesis of remain unclear. Our study found that lipid-rich ST7-B can increase inflammation and disrupt Caco-2 cells more than the same parasite without the lipovenoes supplement. Additionally, the cysteine protease of , a virulence factor, is upregulated and has higher activity in lipid-rich . In order to better understand the effects of lipids on pathogenesis, we treated lipid-lowering pravastatin during ST7-B culturing with a lipovenoes supplement, which decreased the lipid levels of the and reduced the -induced inflammation and cell disruption of Caco-2 cells. We also analyzed the fatty acid composition and possible synthesis pathway in ST7-B, finding significantly higher ratios of arachidonic acid, oleic acid, and palmitic acid than in the other lipid components in lipid-rich ST7-B. These results suggest that lipids play a significant role in the pathogenesis of and provide important information on the molecular mechanisms of and potential treatments for infection.
PubMed: 37375084
DOI: 10.3390/microorganisms11061582 -
American Journal of Cancer Research 2023Statins are cholesterol-lowering agents that act as inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzymeA (HMG CoA) reductase. Recently, statins have received a lot of...
Statins exert anti-growth effects by suppressing YAP/TAZ expressions via JNK signal activation and eliminate the immune suppression by downregulating PD-L1 expression in pancreatic cancer.
Statins are cholesterol-lowering agents that act as inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzymeA (HMG CoA) reductase. Recently, statins have received a lot of attention, especially regarding how statins act on the immune system. Here, the clinical impact of statin intake was examined in patients with resected pancreatic cancer, and the underlying mechanisms were investigated in and in . We found that statin intake was associated with favorable prognostic outcomes in patients with resectable pancreatic cancer. Statins, especially lipophilic statins, exert anti-proliferative effects on pancreatic cancer cells in (simvastatin > fluvastatin > atorvastatin > rosuvastatin > pravastatin). Simvastatin had an anti-proliferative effect on pancreatic cancer cells with decreased the yes-associated protein (YAP)/PDZ-binding motif (TAZ) expression by activating the JNK pathway, and simvastatin treatment with oxaliplatin revealed additive anti-growth effects. Furthermore, lipophilic and hydrophilic statins suppressed programmed cell death ligand 1 (PD-L1) expression by downregulating TAZ. Simvastatin treatment with an anti-PD-1 drug (BP0273) provided immediate anti-growth effects compared to controls, such as anti-PD-1 only and simvastatin only, and suppressed progressive disease during the early period of anti-PD-1 treatment in . In conclusion, Statins display two distinct anti-cancer effects (direct anti-growth effect and elimination of immune suppression by downregulating PD-L1 expression) by targeting YAP/TAZ expression.
PubMed: 37293171
DOI: No ID Found -
Frontiers in Nutrition 2023Maternal obesity has been associated with a higher risk of pregnancy-related complications in mothers and offspring; however, effective interventions have not yet been...
Calorie restriction and pravastatin administration during pregnancy in obese rhesus macaques modulates maternal and infant metabolism and infant brain and behavioral development.
BACKGROUND
Maternal obesity has been associated with a higher risk of pregnancy-related complications in mothers and offspring; however, effective interventions have not yet been developed. We tested two interventions, calorie restriction and pravastatin administration, during pregnancy in a rhesus macaque model with the hypothesis that these interventions would normalize metabolic dysregulation in pregnant mothers leading to an improvement in infant metabolic and cognitive/social development.
METHODS
A total of 19 obese mothers were assigned to either one of the two intervention groups ( = 5 for calorie restriction; = 7 for pravastatin) or an obese control group ( = 7) with no intervention, and maternal gestational samples and postnatal infant samples were compared with lean control mothers ( = 6) using metabolomics methods.
RESULTS
Gestational calorie restriction normalized one-carbon metabolism dysregulation in obese mothers, but altered energy metabolism in her offspring. Although administration of pravastatin during pregnancy tended to normalize blood cholesterol in the mothers, it potentially impacted the gut microbiome and kidney function of their offspring. In the offspring, both calorie restriction and pravastatin administration during pregnancy tended to normalize the activity of AMPK in the brain at 6 months, and while results of the Visual Paired-Comparison test, which measures infant recognition memory, was not significantly impacted by either of the interventions, gestational pravastatin administration, but not calorie restriction, tended to normalize anxiety assessed by the Human Intruder test.
CONCLUSIONS
Although the two interventions tested in a non-human primate model led to some improvements in metabolism and/or infant brain development, negative impacts were also found in both mothers and infants. Our study emphasizes the importance of assessing gestational interventions for maternal obesity on both maternal and offspring long-term outcomes.
PubMed: 37255938
DOI: 10.3389/fnut.2023.1146804 -
Saudi Pharmaceutical Journal : SPJ :... May 2023Statins have been reported to have potential anti-proliferative effects through an unknown mechanism. This study aims to investigate the anti-proliferative activities of...
Statins have been reported to have potential anti-proliferative effects through an unknown mechanism. This study aims to investigate the anti-proliferative activities of five statins, including simvastatin, rosuvastatin, fluvastatin, atorvastatin, and pravastatin, against five different cancer cell lines; cervical epithelial carcinoma DoTc2 4510, malignant melanoma A-375, muscle Ewing's sarcoma A-673, hepatocellular carcinoma HUH-7, as well as breast cancer cells MCF-7. At 100 µM, simvastatin and atorvastatin significantly inhibited 70% of cellular proliferation. At the same concentration, rosuvastatin and fluvastatin showed about 50% of inhibition only in A-375 and A-673 cancer cells in a time- and dose-dependent manner. Of all the statin drugs used, pravastatin had the least inhibitory effect on all the cancer cell lines. Western Blot analysis showed a decrease in mTOR level, and the expression of p53 tumour suppression and BCL-2 proteins was relatively elevated compared to the untreated cells. Simvastatin and atorvastatin may inhibit cellular proliferation via BCL-2/p53, Bax/Bak, and PI3K/Akt/mTOR signalling pathways. This is the first research to evaluate the anti-cancer effects of simvastatin, rosuvastatin, fluvastatin, atorvastatin, and pravastatin against five different cell lines from distinct origins and provided a relevant comparison of their efficacies for their anti-proliferative activity.
PubMed: 37181137
DOI: 10.1016/j.jsps.2023.03.013 -
MedRxiv : the Preprint Server For... Apr 2023Considering the non-specific nature of muscle symptoms, studies of statin-induced myopathy (SIM) in electronic health records require accurate algortihms that can...
OBJECTIVE
Considering the non-specific nature of muscle symptoms, studies of statin-induced myopathy (SIM) in electronic health records require accurate algortihms that can reliably identify true statin-related cases. However, prior algorithms have been constructed in study populations that preclude broad applicability. Here we developed and validated an algorithm that accurately defines SIM from electronic health records using structured data elements and conducted a study of determinants of SIM after applying the algorithm.
MATERIALS AND METHODS
We used electronic records from an integrated health care delivery system (including comprehensive pharmacy dispensing records) and defined SIM as elevated creatine kinase (CK) ≥4 x upper limit of normal. A diverse cohort of participants receiving a variety of statin regimens met the criteria for study inclusion.
RESULTS
We identified multiple conditions strongly associated with elevated CK independent of statin use. A 2-step algorithm was developed using these all-cause conditions as secondary causes (step 1) along with evidence of a statin regimen change (step 2). We identified 1,262 algorithm-derived statin-induced elevated CK cases. Gold standard SIM cases determined from manual chart reviews on a random subset of the all-cause elevated CK cases were used to validate the algorithm, which had a 76% sensitivity and 77% specificity for detecting the most certain cases. Pravastatin use was associated with a 2.18 odds (95% confidence interval 1.39-3.40, P=0.0007) for statin-induced CK elevation compared to lovastatin use after adjusting for dose and other factors.
CONCLUSIONS
We have produced an efficient, easy-to-apply methodological tool that can improve the quality of future research on statin-induced myopathy.
PubMed: 37162948
DOI: 10.1101/2023.04.24.23289059 -
The Journal of Toxicological Sciences 2023The biliary excretion of pharmaceutical and food-related compounds is an important factor for assessing pharmacokinetics and toxicities in humans, and a highly...
Construction of extended and functional bile canaliculi using long-term sandwich-cultured cryopreserved human hepatocytes and the application of hepatocytes for predicting the biliary excretion of pharmaceutical and food-related compounds.
The biliary excretion of pharmaceutical and food-related compounds is an important factor for assessing pharmacokinetics and toxicities in humans, and a highly predictive in vitro method for human biliary excretion is required. We have developed a simple in vitro culture method for generating extended and functional bile canaliculi using cryopreserved human hepatocytes. We evaluated the uptake of compounds by hepatocytes and bile canaliculi, and the biliary excretion index (BEI) was calculated. After 21 days of culture, the presence of extended and functional bile canaliculi was confirmed by the uptake of two fluorescent substrates. Positive BEIs were observed for taurocholic acid-d, rosuvastatin, pitavastatin, pravastatin, valsartan, olmesartan, and topotecan (reported biliary-excreted compounds in humans), but no difference in BEI was observed for salicylic acid (a nonbiliary-excreted compound). Furthermore, 8 of 21 food-related compounds with specific structures and reported biliary transporter involvement exhibited positive BEIs. The developed in vitro system was characterized by functional bile canaliculus-like structures, and it could be applied to the prediction of the biliary excretion of pharmaceutical and food-related compounds.
Topics: Humans; Bile Canaliculi; Hepatobiliary Elimination; Cells, Cultured; Hepatocytes; Pharmaceutical Preparations
PubMed: 37121740
DOI: 10.2131/jts.48.251 -
Pharmaceuticals (Basel, Switzerland) Mar 2023to examine the impact of statins on reducing all-cause mortality among individuals diagnosed with type 2 diabetes. This investigation explored the potential correlations...
PURPOSE
to examine the impact of statins on reducing all-cause mortality among individuals diagnosed with type 2 diabetes. This investigation explored the potential correlations between dosage, drug classification, and usage intensity with the observed outcomes.
METHODS
The research sample consisted of individuals aged 40 years or older diagnosed with type 2 diabetes. Statin usage was determined as a frequent usage over a minimum of one month subsequent to type 2 diabetes diagnosis, where the average statin dose was ≥28 cumulative defined daily doses per year (cDDD-year). The analysis employed an inverse probability of treatment-weighted Cox hazard model, utilizing statin usage status as a time-varying variable, to evaluate the impact of statin use on all-cause mortality.
RESULTS
The incidence of mortality was comparatively lower among the cohort of statin users (n = 50,804 (12.03%)), in contrast to nonusers (n = 118,765 (27.79%)). After adjustments, the hazard ratio (aHR; 95% confidence interval (CI)) for all-cause mortality was estimated to be 0.32 (0.31-0.33). Compared with nonusers, pitavastatin, rosuvastatin, pravastatin, simvastatin, atorvastatin, fluvastatin, and lovastatin users demonstrated significant reductions in all-cause mortality (aHRs (95% CIs) = 0.06 (0.04-0.09), 0.28 (0.27-0.29), 0.29 (0.28-0.31), 0.31 (0.30-0.32), 0.31 (0.30-0.32), 0.36 (0.35-0.38), and 0.48 (0.47-0.50), respectively). In Q1, Q2, Q3, and Q4 of cDDD-year, our multivariate analysis demonstrated significant reductions in all-cause mortality (aHRs (95% CIs) = 0.51 (0.5-0.52), 0.36 (0.35-0.37), 0.24 (0.23-0.25), and 0.13 (0.13-0.14), respectively; for trend <0.0001). Because it had the lowest aHR (0.32), 0.86 DDD of statin was considered optimal.
CONCLUSIONS
In patients diagnosed with type 2 diabetes, consistent utilization of statins (≥28 cumulative defined daily doses per year) was shown to have a beneficial effect on all-cause mortality. Moreover, the risk of all-cause mortality decreased as the cumulative defined daily dose per year of statin increased.
PubMed: 37111264
DOI: 10.3390/ph16040507 -
International Journal of Molecular... Apr 2023Cholesterol is an important component of cell membranes, and also a precursor for the synthesis of sex hormones, playing an important role in reproduction. However, few...
Cholesterol is an important component of cell membranes, and also a precursor for the synthesis of sex hormones, playing an important role in reproduction. However, few studies have focused on cholesterol and reproductive health. To investigate the toxic effects of different cholesterol levels on the spermatogenesis of rare minnows, we regulate the cholesterol content in fish by feeding them a high-cholesterol diet and cholesterol inhibitor pravastatin, and cholesterol levels, sex hormone (T and 11KT) levels, testis histology, sperm morphology and function, and the expression of genes related to sex hormone synthesis were investigated. The research findings indicate that increasing cholesterol levels significantly increases the liver weight and hepatic-somatic index, as well as the total cholesterol and free cholesterol levels in the testis, liver, and plasma of rare minnow, while inhibiting cholesterol has the opposite effect ( < 0.05). However, both increasing and decreasing cholesterol levels can suppress rare minnow testicular development, as evidenced by a decrease in testis weight, lowered gonadosomatic index, suppressed sex hormone levels, and reduced mature sperm count. Further exploration revealed that the expression of sex hormone synthesis-related genes, including star, cyp19a1a, and hsd11b2, was significantly affected ( < 0.05), which may be an important reason for the decrease in sex hormone synthesis and consequent inhibition of testicular development. At the same time, the fertilization ability of mature sperm in both treatment groups significantly decreased. Scanning electron microscopy and fluorescence polarization tests showed that reducing cholesterol levels significantly increased the rate of sperm head cell membrane damage, while both increasing and decreasing cholesterol levels led to a reduction in sperm cell membrane fluidity, which may be the main reason for the decrease in sperm fertilization ability. This study demonstrates that both increasing and decreasing the levels of cholesterol are detrimental to the fish spermatogenesis, providing fundamental information for the study of fish reproduction and also a reference for the causes of male reproductive dysfunction.
Topics: Animals; Male; Cholesterol, Dietary; Semen; Spermatogenesis; Testis; Gonadal Steroid Hormones; Cyprinidae
PubMed: 37108655
DOI: 10.3390/ijms24087492