The role of HMGCR expression in combination therapy of simvastatin and FAC treated locally advanced breast cancer patients.

OBJECTIVE: Several studies have shown the role of statin added to the patient's chemotherapy regimen and the role of Hydroxymethylglutaryl-CoA Reductase (HMGCR) expression in predicting breast cancer patient outcomes. In our previous study, adding statins improved clinical and pathological responses in LABC patients. Furthermore, we planned to study statin's role as a combination to neoadjuvant chemotherapy (NAC) in treating locally advanced breast cancers on the basis of HMGCR expression. Moreover, we aimed to study the association between the patients' clinicopathological characteristics and HMGCR expression. METHODS: This study is a randomized, double-blinded, placebo-controlled trial in two health centers in Indonesia. Each patient enrolled with written informed consent and then randomized to receive either simvastatin 40 mg/day or a placebo, combined with the fluorouracil, adriamycin, and cyclophosphamide (FAC) NAC. RESULTS: HMGCR was associated with low staging and normal serum cholesterol in the high Ki67 level group (p = 0.042 and p = 0.021, respectively). The pre-and post-chemotherapy tumor sizes are significantly correlated in two groups (HMGCR negative expression, p = 0.000 and HMGCR moderate expression, p = 0.001) with a more considerable average decrease in tumor size compared to HMGCR strong expression group. CONCLUSION: Statin therapy might work better in HMGCR-negative or low-expression tumors, although HGMCR expression is associated with better clinical parameters in our study.

Pretreatment of hydroethanolic extract of Dillenia indica L. attenuates oleic acid induced NAFLD in HepG2 cells via modulating SIRT-1/p-LKB-1/AMPK, HMGCR & PPAR-α signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Dillenia indica L. is an edible plant from the Dilleniaceae family present in the forest of India and other Asian countries. Different parts of this plant are being used in the traditional system of medicines for various diseases like diabetes, indigestion, asthma, jaundice, and rheumatic pain by various rural communities. This plant is very common among Khamptis traditional healers, the rural community of the Dhemaji district of Assam, ethnic communities of Dibru-Saikhowa Biosphere Reserve of Northeast, India for various medicinal uses. It is observed as a 'vat' suppressant and 'pitta' boosting medicine in Ayurveda. AIM OF THE STUDY: The aim of this research was to evaluate the effect of hydroethanolic extract of Dillenia indica leaf (DI-HET) against non-alcoholic fatty liver disease (NAFLD) as it is reported effective against jaundice in traditional medicine. We are also planning to see the various molecular mechanisms responsible for its effect if it is efficacious. STUDY DESIGN/METHOD: An in vitro model for NAFLD was employed in this study. For this HepG2 cells were incubated with 100 µM of oleic acid (OA) for 24 h. For evaluation of the effect of DI-HET, the extracts (5 or 10 µg/mL) were pretreated to the OA group. Fenofibrate was the positive control. Various parameters relevant to lipogenesis and ß-oxidation of fatty acids like intracellular lipid accumulation, reactive oxygen species (ROS), mitochondrial stress, and key proteins were studied. RESULTS: DI-HET significantly reduced the intracellular lipid accumulation in OA treated cells. And also substantially decreased the expression of lipogenic proteins and increased ß-oxidation in the OA group. OA induced ROS generation was found to reduce with DI-HET treatment. Western blot analysis showed that the expression of LXR-α, SREBP-1C, SREBP-2, HMGCR, FAS, CD-36, and ACOX-1 were downregulated while that of SIRT-1, p-LKB-, p-AMPK, p-ACC, CPT-1, and PPAR-α upregulated in DI-HET treatment. LCMS/MS analysis showed the presence of polyphenols like naringenin, catechin, epicatechin, shikimic acid, syringic acid, vanillic acid, and kaempferol. CONCLUSION: These results suggest that DI-HET is effective against NAFLD by activation of the SIRT-1/p-LKB-1/AMPK signaling pathway via polyphenols present in the extract.

Identification of HMGCR, PPGARG and prohibitin as potential druggable targets of dihydrotestosterone for treatment against traumatic brain injury using system pharmacology.

BACKGROUND: Traumatic Brain Injury (TBI) has long-term devastating effects for which there is no accurate and effective treatment for inflammation and chronic oxidative stress. As a disease that affects multiple signalling pathways, the search for a drug with a broader spectrum of pharmacological action is of clinical interest. The fact that endocrine disruption (e.g hypogonadism) has been observed in TBI patients suggests that endogenous therapy with testosterone, or its more androgenic derivative, dihydrotestosterone (DHT), may attenuate, at least in part, the TBI-induced inflammation, but the underlying molecular mechanisms by which this occurs are still not completely clear. AIMS AND METHODS: In this study, the main aim was to investigate proteins that may be related to the pathophysiological mechanism of TBI and also be pharmacological targets of DHT in order to explore a possible therapy with this androgen using network pharmacology. RESULTS AND CONCLUSIONS: We identified 2.700 proteins related to TBI and 1.567 that are potentially molecular targets of DHT. Functional enrichment analysis showed that steroid (p-value: 2.1-22), lipid metabolism (p-value: 2.8-21) and apoptotic processes (p-value: 5.2-21) are mainly altered in TBI. Furthermore, being mitochondrion an organelle involved on these molecular processes we next identified that out of 32 mitochondrial-related proteins 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), peroxisome proliferator activated receptor gamma (PPGARG) and prohibitin are those found highly regulated in the network and potential targets of DHT in TBI. In conclusion, the identification of these cellular nodes may prove to be essential as targets of DHT for therapy against post-TBI inflammation.

Efecto en la vida real sobre el control de los factores de riesgo asociado al inicio con polipíldora cardiovascular a partir de fármacos equipotentes / Real-life effect on the control of risk factors associated with initiation of the cardiovascular polypill created from equipotent drugs

Objetivo: Analizar el impacto del inicio del tratamiento con la polipíldora-cardiovascular (CV) del Centro Nacional de Investigaciones Cardiovasculares (CNIC-Ferrer), en las cifras de presión arterial (PA) y colesterol ligado a lipoproteínas de baja densidad (LDL), de los pacientes de nuestra área sanitaria que previamente recibían dosis equipotentes de estatinas y antihipertensivos. Material y métodos: Se registraron todos los pacientes de nuestra área sanitaria (Santiago de Compostela) que a 31 de diciembre de 2019 tenían una prescripción activa de polipíldora-CV (CNIC-Ferrer), desde el 16 de enero de 2015. La fecha índice fue la fecha de inicio de prescripción de polipíldora-CV, y se analizaron los fármacos que previamente recibía el paciente para dislipemia e hipertensión arterial, clasificándose por equipotencias con atorvastatina y ramipril. Se analizó mediante la prueba t-Student para muestras apareadas las variaciones de colesterol LDL y PA. Resultados: Analizamos 547 pacientes con una edad media de 71,5±11,5 años y la mayoría varones (60,6%). Observamos un descenso del colesterol LDL (−10,6 [IC95%: −7,0, −14,3], p<0,001) en los pacientes (n=471) que iniciaron la polipíldora-CV con dosis previas equipotentes de atorvastatina. Documentamos una reducción de la PA sistólica (−3,7 [IC95%: −0,4, −6,9], p=0,029) en los pacientes (n=360) con inicio a partir de dosis equipotentes de ramipril. En 88 pacientes, el inicio de la polipíldora-CV se hizo a partir de dosis equipotentes de atorvastatina y ramipril observándose un descenso del colesterol LDL (−8,7 [IC95%: −3,8, −13,6], p=0,001) y de la PA sistólica (−3,6 [IC95%: −7,8, 0,5], p=0,085). Conclusiones: El inicio del tratamiento con la polipíldora-CV, en pacientes que previamente recibían tratamientos equipotentes de atorvastatina y ramipril, se asoció a una mayor reducción del colesterol LDL y la PA sistólica (AU)

Objective: This work aims to analyze the impact of Spain's National Center for Cardiovascular Research (CNIC-Ferrer)’s cardiovascular (CV)-polypill on blood pressure (BP) and low-density lipoprotein cholesterol (cLDL) levels in patients in our healthcare area who previously took equipotent doses of statins and antihypertensives. Material and methods: All patients in our healthcare area (Santiago de Compostela, Spain) who, as of December 31, 2019, had an active prescription for the CV-polypill (CNIC-Ferrer) since January 16, 2015 were registered. The index date was the start date of the CV-polypill prescription. The drugs the patient had previously received for dyslipidemia and hypertension were analyzed, classifying them by their equivalent potency to atorvastatin and ramipril. Changes in cLDL and BP were analyzed by means of Student's t-test for paired samples. Results: We analyzed 547 patients with a mean age of 71.5±11.5 years. The majority were men (60.6%). We observed a decrease in cLDL (−10.6 [95% CI: −7.0, −14.3], p<.001) in patients who started taking the CV-polypill who had previously taken equally potent doses of atorvastatin (n=471). We documented a reduction in systolic BP (−3.7 [95% CI: −0.4, −6.9], p=.029) in patients who had previously taken equally potent doses of ramipril (n=360). In 88 patients, the CV-polypill was started via equally potent doses of atorvastatin and ramipril, with a decrease in cLDL (−8.7 [95% CI: −3.8, −13.6], p=.001) and systolic BP (−3.6 [95% CI: −7.8, 0.5], p=.085). Conclusions: The initiation of treatment with the CV-polypill in patients who previously received equally potent treatment with atorvastatin and ramipril was associated with a greater reduction in cLDL and systolic BP (AU)

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies: incidence using different testing criteria, and case series.

OBJECTIVES: To estimate the incidence of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies utilising different testing criteria, and review the clinical details of a series of patients with associated autoimmune myopathy. METHODS: The incidence of anti-HMGCR antibodies in 2019 from 3 groups, South West London, Berkshire/Surrey and Southampton, were compared in the adult population. Anti-HMGCR antibodies were measured by commercial chemiluminescent and immunodot assays. The case notes of patients with anti-HMGCR antibodies were reviewed for the case series. RESULTS: The estimated incidence of anti-HMGCR antibodies in the first 2 groups was 1.94 per million adults per year, and in the third group 10.3 per million adults per year. In the first 2 groups the test criteria restricted analysis to specific clinician request for anti-HMGCR. In the third group test criteria included cases with less specific clinical features or a cytoplasmic indirect immunofluorescence anti-nuclear antibody pattern. The latter strategy had a positive predictive value of 66.1% for anti-HMGCR associated myopathy. A case series of 27 patients with anti-HMGCR antibodies revealed 19 with myopathy, oesophageal involvement in 26% and median peak CK 8000 IU/L. Response to treatment, including intravenous immunoglobulin, was good with CK normalising after median 5.5 months. In 8 cases there was no evidence of autoimmune muscle disease, 7 not statin exposed. CONCLUSIONS: Varying criteria result in a 5-fold difference in estimated incidence of anti-HMGCR antibodies, revealing positive cases without evidence of myopathy. Patients with anti-HMGCR myopathy respond well to immune suppression, supporting wider testing for these antibodies amongst patients with myopathy.

Role of statin as inducer of Hmox-1 system in treatment of preeclampsia.

Preeclampsia is the major cause of both maternal and neonatal morbidity and mortality. Its insidence remains high and the management has not been established yet because its etiology and pathophysiological are still poorly understood. Theories regarding etiopathogenesis and management of preeclampsia have been postulated yet it remains controversial. Placental ischemic and angiogenic imbalance are suggested to be predisposing factors of preeclampsia. It is thereby targeted in prevention of preeclampsia. Unfortunately, both primary and secondary prevention using various supplements and drugs fails to exhibit good outcome. Overall, these efforts are considered useless. In recent years, researchers have been using statin derivative in management of preclampsia. It has been reported that statin provides protective effect in endothelial cells by inducing expression of Hmox-1 and inihibiting release of sFlt-1 as well as potent antioxidant properties. Thus, statin has been proposed as promising agent to significantly reduce anti-angiogenic in preeclamptic patients which is overviewed in this review based on recent studies.

Statin Use After Diagnosis of Colon Cancer and Patient Survival.

BACKGROUND & AIMS: Statin use has been associated with a reduced incidence of colorectal cancer and might also affect survival of patients diagnosed with colon cancer. Statins are believed to inhibit Ras signaling and may also activate the bone morphogenetic protein (BMP) signaling pathway in colorectal cancer cells. We investigated the effects of statins on overall survival of patients with a diagnosis of colon cancer, and whether their effects were associated with changes in KRAS or the BMP signaling pathways. METHODS: Data were derived from the PHARMO database network (Netherlands) and linked to patients diagnosed with colon cancer from 2002 through 2007, listed in the Eindhoven Cancer Registry. We obtained information on causes of death from statistics Netherlands. We constructed a tissue microarray of 999 colon cancer specimens from patients who underwent surgical resection from 2002 through 2008. Survival was analyzed with statin user status after diagnosis as a time-dependent covariate. Multivariable Poisson regression survival models and Cox analyses were used to study the effect of statins on survival. Tumor tissues were analyzed by immunohistochemistry for levels of SMAD4, BMPR1A, BMPR1B, and BMPR2 proteins. Tumor tissues were considered to have intact BMP signaling if they contained SMAD4 plus BMPR1A, BMPR1B, or BMPR2. DNA was isolated from tumor tissues and analyzed by quantitative polymerase chain reaction to detect mutations in KRAS. The primary outcome measures were overall mortality and cancer-specific mortality. RESULTS: In this cohort, 21.0% of the patients (210/999) were defined as statin users after diagnosis of colon cancer. Statin use after diagnosis was significantly associated with reduced risk of death from any cause (adjusted relative risk [RR], 0.67; 95% confidence interval [CI], 0.51-0.87; P = .003) and death from cancer (adjusted RR, 0.66; 95% CI, 0.49-0.89; P = .007). Statin use after diagnosis was associated with reduced risk of death from any cause or from cancer for patients whose tumors had intact BMP signaling (adjusted RR, 0.39; 95% CI, 0.22-0.68; P = .001), but not for patients whose tumors did not have BMP signaling (adjusted RR, 0.81; 95% CI, 0.55-1.21; P = .106; P < .0001 for the interaction). Statin use after diagnosis was not associated with reduced risk of death from any cause or from cancer for patients whose tumors did not contain KRAS mutations (adjusted RR, 0.81; 95% CI, 0.56-1.18; P = .273) or whose tumors did have KRAS mutations (adjusted RR, 0.59; 95% CI 0.35-1.03; P = .062; P = .90 for the interaction). CONCLUSIONS: In an analysis of 999 patients with a diagnosis of colon cancer, we associated statin with reduced risk of death from any cause or from cancer. The benefit of statin use is greater for patients whose tumors have intact BMP signaling, independent of KRAS mutation status. Randomized controlled trials are required to confirm these results.

Regional variations in ambulatory care and incidence of cardiovascular events.

BACKGROUND: Variations in the prevalence of traditional cardiac risk factors only partially account for geographic variations in the incidence of cardiovascular disease. We examined the extent to which preventive ambulatory health care services contribute to geographic variations in cardiovascular event rates. METHODS: We conducted a cohort study involving 5.5 million patients aged 40 to 79 years in Ontario, Canada, with no hospital stays for cardiovascular disease as of January 2008, through linkage of multiple population-based health databases. The primary outcome was the occurrence of a major cardiovascular event (myocardial infarction, stroke or cardiovascular-related death) over the following 5 years. We compared patient demographics, cardiac risk factors and ambulatory health care services across the province's 14 health service regions, known as Local Health Integration Networks (LHINs), and evaluated the contribution of these variables to regional variations in cardiovascular event rates. RESULTS: Cardiovascular event rates across LHINs varied from 3.2 to 5.7 events per 1000 person-years. Compared with residents of high-rate LHINs, those of low-rate health regions received physician services more often (e.g., 4.2 v. 3.5 mean annual family physician visits, p value for LHIN-level trend = 0.01) and were screened for risk factors more often. Low-rate LHINs were also more likely to achieve treatment targets for hypercholes-terolemia (51.8% v. 49.6% of patients, p = 0.03) and controlled hypertension (67.4% v. 53.3%, p = 0.04). Differences in patient and health system factors accounted for 74.5% of the variation in events between LHINs, of which 15.5% was attributable to health system factors alone. INTERPRETATION: Preventive ambulatory health care services were provided more frequently in health regions with lower cardiovascular event rates. Health system interventions to improve equitable access to preventive care might improve cardiovascular outcomes.

Treating the Host Response to Ebola Virus Disease with Generic Statins and Angiotensin Receptor Blockers.

Treatments targeting the Ebola virus may eventually be shown to work, but they will not have an impact on overall Ebola mortality in West Africa. Endothelial dysfunction is responsible for the fluid and electrolyte imbalances seen in Ebola patients. Because inexpensive generic statins and angiotensin receptor blockers restore endothelial barrier integrity, they can be used to treat the host response in these patients. In Sierra Leone, approximately 100 Ebola patients were treated with this combination, and reports indicate that survival was greatly improved.

Comparison of effects of morning versus evening administration of ezetimibe/simvastatin on serum cholesterol in patients with primary hypercholesterolemia.

BACKGROUND: Ezetimibe, a first-in-its-class inhibitor of cholesterol absorption, is an effective agent for combined use with statins to achieve low-density lipoprotein cholesterol (LDL-C) goals. Ezetimibe in combination with simvastatin as a single-tablet formulation has proven to be highly effective in reducing serum LDL-C through the dual inhibition of cholesterol absorption and biosynthesis. The effect of time of administration on efficacy of this combination therapy has not been evaluated. OBJECTIVE: To compare the effects of morning versus evening administration of ezetimibe/simvastatin on serum cholesterol levels of patients with primary hypercholesterolemia. METHODS: In this multicenter, open-label, randomized, 2-sequence, 2-period crossover study, patients with primary hypercholesterolemia randomly received ezetimibe/simvastatin 10 mg/20 mg once daily, either in the morning (within 1 hour of breakfast) or in the evening (within 1 hour of dinner) for 6 weeks. RESULTS: Data on 171 patients (87 in the morning administration group and 84 in the evening administration group) were analyzed. A significant reduction (p ≤ 0.001) in the total cholesterol, triglyceride, high-density lipoprotein cholesterol, LDL-C, apo-lipoprotein B, and high-sensitivity C-reactive protein (hs-CRP) from baseline was achieved after each treatment. Noninferiority of morning administration versus evening administration was shown in the percentage reduction of the LDL-C level from baseline (difference, -1.62%; 90% CI -4.94 to 1.70). No significant difference was found between groups with respect to the percentage of changes in other lipid parameters from baseline. Furthermore, there was no significant difference in the percentage of change in hs-CRP as an antiinflammatory marker between the morning and evening administration groups. The frequency of adverse events was similar between groups. CONCLUSIONS: Morning administration of ezetimibe/simvastatin 10 mg/20 mg is noninferior to evening administration with respect to LDL-C-lowering ability.

Regulation of steroid 5-alpha reductase type 2 (Srd5a2) by sterol regulatory element binding proteins and statin.

In this study, we show that sterol regulatory element binding proteins (SREBPs) regulate expression of Srd5a2, an enzyme that catalyzes the irreversible conversion of testosterone to dihydroxytestosterone in the male reproductive tract and is highly expressed in androgen-sensitive tissues such as the prostate and skin. We show that Srd5a2 is induced in livers and prostate from mice fed a chow diet supplemented with lovastatin plus ezitimibe (L/E), which increases the activity of nuclear SREBP-2. The three fold increase in Srd5a2 mRNA mediated by L/E treatment was accompanied by the induction of SREBP-2 binding to the Srd5a2 promoter detected by a ChIP-chip assay in liver. We identified a SREBP-2 responsive region within the first 300 upstream bases of the mouse Srd5a2 promoter by co-transfection assays which contain a site that bound SREBP-2 in vitro by an EMSA. Srd5a2 protein was also induced in cells over-expressing SREBP-2 in culture. The induction of Srd5a2 through SREBP-2 provides a mechanistic explanation for why even though statin therapy is effective in reducing cholesterol levels in treating hypercholesterolemia it does not compromise androgen production in clinical studies.

Thoracic aortic dissection: are matrix metalloproteinases involved?

Thoracic aortic dissection, one of the major diseases affecting the aorta, carries a very high mortality rate. Improving our understanding of the pathobiology of this disease may help us develop medical treatments to prevent dissection and subsequent aneurysm formation and rupture. Dissection is associated with degeneration of the aortic media. Recent studies have shown increased expression and activation of a family of proteolytic enzymes-called matrix metalloproteinases (MMPs)-in dissected aortic tissue, suggesting that MMPs may play a major role in this disease. Inhibition of MMPs may be beneficial in reducing MMP-mediated aortic damage associated with dissection. This article reviews the recent literature and summarizes our current understanding of the role of MMPs in the pathobiology of thoracic aortic dissection. The potential importance of MMP inhibition as a future treatment of aortic dissection is also discussed.

Pravastatin inhibits arrhythmias induced by coronary artery ischemia in anesthetized rats.

We have reported that chronically administered pravastatin prevented coronary artery reperfusion-induced lethal ventricular fibrillation (VF) in anesthetized rats without lowering the serum cholesterol level. The present study was undertaken to evaluate whether pravastatin prevents ischemia-induced lethal VF, simultaneously examining myeloperoxidase (MPO) activity in ischemic myocardial tissues. Anesthetized rats were subjected to 30-min ischemia and 60-min reperfusion after chronic administration of pravastatin (0.02, 0.2, and 2 mg/kg), fluvastatin (2 and 4 mg/kg), or vehicle for 22 days, orally, once daily. ECG and blood pressure were continually recorded, and MPO was measured by a spectrophotometer. Pravastatin and fluvastatin significantly (P<0.05) decreased MPO activities, but only pravastatin decreased the incidence of ischemia-induced lethal VF. Both statins had no significant effects on body weight, blood pressure, heart rate, and QT interval as we reported earlier. Our results prove further that pravastatin has benefits to decrease cardiovascular mortality beyond its cholesterol-lowering effect. Pravastatin is more potent than fluvastatin in prevention of arrhythmias. A decrease in the neutrophil infiltration may be partly involved in the inhibitory effect of pravastatin on the ischemia-induced VF.