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Brain Sciences Jun 2022Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease which affects more than 50 million patients and represents 60-80% of all cases of...
BACKGROUND
Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease which affects more than 50 million patients and represents 60-80% of all cases of dementia. Mutations in the APP gene, mostly affecting the γ-secretase site of cleavage and presenilin mutations, have been identified in inherited forms of AD.
METHODS
In the present study, we performed a meta-analysis of the transcriptional signatures that characterize two familial AD mutations (APP and PSEN1) in order to characterize the common altered biomolecular pathways affected by these mutations. Next, an anti-signature perturbation analysis was performed using the AD meta-signature and the drug meta-signatures obtained from the L1000 database, using cosine similarity as distance metrics.
RESULTS
Overall, the meta-analysis identified 1479 differentially expressed genes (DEGs), 684 downregulated genes, and 795 upregulated genes. Additionally, we found 14 drugs with a significant anti-similarity to the AD signature, with the top five drugs being naftifine, moricizine, ketoconazole, perindopril, and fexofenadine.
CONCLUSIONS
This study aimed to integrate the transcriptional profiles associated with common familial AD mutations in neurons in order to characterize the pathogenetic mechanisms involved in AD and to find more effective drugs for AD.
PubMed: 35884634
DOI: 10.3390/brainsci12070827 -
International Journal of Nephrology and... 2022Lipoprotein glomerulopathy (LPG) is caused by a mutation in the apolipoprotein E gene () gene and is characterized by lipoprotein thrombi in glomerular capillaries....
Lipoprotein glomerulopathy (LPG) is caused by a mutation in the apolipoprotein E gene () gene and is characterized by lipoprotein thrombi in glomerular capillaries. Here, we describe a case of LPG, the first to be reported from Canada and the first case of LPG in North America to be associated with the Tokyo/Maebashi mutation (p.Leu162_Lys164del, traditional nomenclature 142_144del). A 49-year-old man of Chinese descent with a previous diagnosis of dyslipidemia and a new diagnosis of hypertension was found to have proteinuria on routine urinalysis. Renal biopsy showed markedly dilated glomerular capillaries filled with pale staining mesh-like material that stained positive for Oil-Red-O, consistent with lipoprotein thrombi. gene sequencing confirmed the diagnosis of LPG. The patient was treated with fenofibrate and perindopril. His lipid profile normalized and proteinuria dropped to minimal levels. Repeat renal biopsy 2 years after the first showed resolution of lipoprotein thrombi but with rare residual granular densities by electron microscopy consistent with lipoprotein in the subendothelial space, supporting the hypothesis that this subendothelial material contains precursors to lipoprotein thrombi.
PubMed: 35761986
DOI: 10.2147/IJNRD.S364890 -
Diabetes Therapy : Research, Treatment... Jul 2022Cardiovascular disease (CVD) is a leading cause of death globally, driven by the high rates of risk factors, such as diabetes and hypertension. As the prevalence of... (Review)
Review
Cardiovascular disease (CVD) is a leading cause of death globally, driven by the high rates of risk factors, such as diabetes and hypertension. As the prevalence of these risk factors is particularly high in the Gulf region, better diagnosis and management of type 2 diabetes (T2D) and hypertension has the potential to dramatically reduce adverse cardiovascular outcomes for individuals in that part of the world. This article provides a summary of presentations made during the EVIDENT summit, a virtual symposium on Evidence in Diabetes and Hypertension, held in September 2021, including a review of the various guidelines for both T2D and hypertension, as well as recent findings relevant to the safety and efficacy for therapies relating to these conditions. Of relevance to the Gulf region, the risk of hypoglycaemia with sulfonylureas during Ramadan was reviewed. For the management of T2D, sulfonylureas have been a long-standing medication used to achieve glycaemic control; however, differences have emerged between early and later generations, with recent studies suggesting improvements in the safety profiles of late-generation sulfonylureas. For patients with hypertension, incremental therapy changes are recommended to reduce the risk of cardiovascular complications that are associated with increasing blood pressure. For first-line therapy, angiotensin-converting enzyme inhibitors (ACEi), such as perindopril, have been demonstrated to reduce the risk of cardiovascular and all-cause mortality. The addition of calcium channel blockers and diuretics to ACEi has been shown to be effective in patients with poorly controlled hypertension. The different renin-angiotensin-aldosterone system inhibitors are reviewed, and the benefit of combination therapies, including amlodipine and indapamide in patients with difficult-to-control hypertension, is investigated. The benefits of lifestyle modifications for these patients are also discussed, with important clinical considerations that are expected to inform patient management in daily clinical practice.
PubMed: 35679010
DOI: 10.1007/s13300-022-01282-4 -
Evidence-based Complementary and... 2022Chronic kidney disease (CKD) is a major public health problem worldwide. Treatment with renin-angiotensin system inhibitors can achieve only partial efficacy on renal...
BACKGROUND
Chronic kidney disease (CKD) is a major public health problem worldwide. Treatment with renin-angiotensin system inhibitors can achieve only partial efficacy on renal function decline and renal fibrosis in CKD patients. Huangqi-Danshen decoction (HDD) is a basic Chinese herbal pair which is commonly used to treat CKD with good efficacy.
OBJECTIVES
The current study aimed to investigate the effect of perindopril erbumine (PE), an angiotensin-converting enzyme inhibitor, combined with HDD on adenine-induced CKD rat model and explore the possible mechanism from Sirtuin3/mitochondrial dynamics pathway.
METHOD
CKD rat model was established by feeding of 0.75% w/w adenine containing diet for 3 weeks. At the same time, the treatment groups were given PE (0.42 mg/kg/d) or HDD (4.7 g/kg/d) or PE combined with HDD by gavage for 4 weeks. Renal function was evaluated by the levels of serum creatinine (Scr) and blood urea nitrogen (BUN). The renal pathological injury was observed by periodic acid-Schiff (PAS) and Masson's trichrome staining. Proteins expression was determined by Western blot analysis. Mitochondrial morphology was observed by transmission electron microscopy.
RESULTS
PE in combination with HDD significantly improved renal function, reduced tubular injury and interstitial fibrosis in adenine-induced CKD rats. Moreover, PE + HDD treatment mainly activated the Sirtuin3 expression level. In addition, PE + HDD exhibited bidirectional regulation on mitochondrial dynamics by suppressing mitochondrial fission protein dynaminrelated protein 1 expression and elevating mitochondrial fusion protein optic atrophy 1 expression, resulted in restraint of mitochondrial fragmentation.
CONCLUSION
The combination of PE and HDD attenuated adenine-induced CKD in rats, which was possibly associated with Sirtuin3/mitochondrial dynamics pathway.
PubMed: 35677375
DOI: 10.1155/2022/5812105 -
Frontiers in Pharmacology 2022Recent studies have shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors play a beneficial role for normoglycemic patients with heart failure (HF). However, the...
Recent studies have shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors play a beneficial role for normoglycemic patients with heart failure (HF). However, the underlying mechanism remains largely unexplored. In the present study, we aimed to investigate the cardioprotective effect of SGLT2 inhibitors in a normoglycemic rabbit model of chronic heart failure (CHF) and its potential mechanism was also explored. A total of 24 male New Zealand white rabbits were randomly divided into the sham group, HF group, perindopril group, and dapagliflozin (DAPA) group. The normoglycemic CHF model was established by aortic constriction for 12 weeks. In the 13th week, DAPA (1 mg/kg/day) or perindopril (0.5 mg/kg/day) was administered by oral gavage daily for 10 weeks. Both the sham group and HF group were given normal saline gavage. After 10 weeks, the heart structure and function were evaluated by echocardiography and plasma NT-proBNP. Moreover, cardiac fibrosis was analyzed using immunohistochemistry, Masson's trichrome staining, and Western blotting analysis. The results showed that DAPA improved the myocardial structure and function of normoglycemic CHF rabbits and ameliorated myocardial fibrosis. Further study indicated that DAPA suppressed cardiac fibrosis by inhibiting the transforming growth factor β1 (TGF-β1)/Smad signaling pathway. Collectively, our findings showed that DAPA could ameliorate cardiac fibrosis in normoglycemic CHF rabbits by inhibiting the TGF-β1/Smad signaling pathway.
PubMed: 35645838
DOI: 10.3389/fphar.2022.873108 -
Pharmaceuticals (Basel, Switzerland) May 2022Colitis is one of the inflammatory states that affect the intestinal wall and may even predispose to malignancy due to chronic irritation. Although the etiology of...
Perindopril/Ambrosin Combination Mitigates Dextran Sulfate Sodium-Induced Colitis in Mice: Crosstalk between Toll-Like Receptor 4, the Pro-Inflammatory Pathways, and SIRT1/PPAR-γ Signaling.
Colitis is one of the inflammatory states that affect the intestinal wall and may even predispose to malignancy due to chronic irritation. Although the etiology of colitis is not yet fully explored, a combination of genetic and environmental factors is strongly incriminated. Perindopril is an angiotensin-converting enzyme inhibitor that is used for the management of a wide range of cardiovascular diseases. Ambrosin is a sesquiterpene lactone that was proven to have beneficial effects in disorders characterized by inflammatory nature. The objective of this study is to make a comparison between the effects of perindopril or ambrosin on dextran sulfate sodium (DSS)-induced colitis in mice and to explore the effect of their combination. The present findings indicate that each ambrosin or perindopril alone or in combination is able to ameliorate oxidative stress and suppress the proinflammatory pathways in the colonic tissues of DSS-treated mice via mechanisms related to toll-like receptor 4/nuclear factor kappa B signaling and modulation of peroxisome proliferator-activated receptor gamma/sirtuin-1 levels. In addition, each ambrosin or perindopril alone or in combination inhibits apoptosis and augments the mediators of autophagy in DSS-treated mice. These effects are reflected in the amelioration of the histopathological and electron microscopic changes in the colonic tissues. Interestingly, the most remarkable effects are those encountered with the perindopril/ambrosin combination compared to the groups treated with each of these agents alone. In conclusion, the perindopril/ambrosin combination might represent an effective modality for mitigation of the pathogenic events and the clinical sequelae of colitis.
PubMed: 35631426
DOI: 10.3390/ph15050600 -
Current Oncology (Toronto, Ont.) Apr 2022Two anti-cancer agents, doxorubicin (DOX) and trastuzumab (TRZ), are commonly used in the management of breast cancer in women. Despite their efficacy in reducing the...
BACKGROUND
Two anti-cancer agents, doxorubicin (DOX) and trastuzumab (TRZ), are commonly used in the management of breast cancer in women. Despite their efficacy in reducing the morbidity and mortality of individuals with breast cancer, the use of these agents is limited by adverse cardiotoxic side effects. Both the nutraceutical agent flaxseed (FLX) and the pharmaceutical drug perindopril (PER) have been studied individually in the prevention of chemotherapy-mediated cardiac dysfunction. The objective of this study was to determine whether the prophylactic administration of FLX is comparable and/or synergistic with PER in preventing DOX + TRZ-induced cardiotoxicity.
METHODS
Over a six-week period, 81 wild-type C57Bl/6 female mice (8-12 weeks old) were randomized to receive regular chow (RC) or 10% FLX-supplemented diets with or without PER (3 mg/kg/week; oral gavage). Starting at week 4, mice were randomized to receive a weekly injection of saline or DOX (8 mg/kg) + TRZ (3 mg/kg). Serial echocardiography was conducted weekly and histological and biochemical analyses were performed at the end of the study.
RESULTS
In mice treated with RC + DOX + TRZ, left ventricular ejection (LVEF) decreased from 75 ± 2% at baseline to 37 ± 3% at week 6. However, prophylactic treatment with either FLX, PER, or FLX + PER partially preserved left ventricular systolic function with LVEF values of 61 ± 2%, 62 ± 2%, and 64 ± 2%, respectively. The administration of FLX, PER, or FLX + PER was also partially cardioprotective in preserving cardiomyocyte integrity and attenuating the expression of the inflammatory biomarker NF-κB due to DOX + TRZ administration.
CONCLUSION
FLX was equivalent to PER at preventing DOX + TRZ-induced cardiotoxicity in a chronic in vivo murine model.
Topics: Animals; Breast Neoplasms; Cardiotoxicity; Doxorubicin; Female; Flax; Humans; Mice; Mice, Inbred C57BL; Perindopril; Trastuzumab
PubMed: 35621631
DOI: 10.3390/curroncol29050241 -
Dose-response : a Publication of... 2022Nitric oxide (NO) as a vaso- and cardio-protective agent could reduce vasomotor dysfunction in different cardiovascular diseases. One of the current therapeutics...
BACKGROUND
Nitric oxide (NO) as a vaso- and cardio-protective agent could reduce vasomotor dysfunction in different cardiovascular diseases. One of the current therapeutics targeted at NO availability in the vascular wall are highly diluted antibodies to endothelial NO-synthase (eNOS). This drug has previously shown its endothelium-protective effect and effectiveness in reducing hypertension. Current study was dedicated to evaluate the direct impact of highly diluted antibodies to eNOS on the vessel constriction and dilation ex vivo.
METHODS
For that purpose, we used thoracic aortas dissected from spontaneously hypertensive (SHR) rats. Endothelium-dependent relaxation in the presence of highly diluted antibodies to eNOS (1 mL) was examined after phenylephrine-induced pre-constriction of the aorta rings in response to gradually increased acetylcholine concentration (1 nM to 10 µM).
RESULTS
Highly diluted antibodies to eNOS enhanced acetylcholine-induced relaxation in a statistically significant manner. Moreover, it was demonstrated that observed effect was similar to perindopril, a well-known angiotensin-converting-enzyme inhibitor, which works through relaxing and widening blood vessels.
CONCLUSIONS
Our findings indicate that highly diluted antibodies to eNOS restored impaired endothelium function, as demonstrated by increased relaxation of SHR rats aorta rings. The revealed results suggest beneficial effect of highly diluted antibodies to eNOS to ameliorate hypertension and related diseases.
PubMed: 35602582
DOI: 10.1177/15593258221099281 -
Effects of glucose and blood pressure reduction on subclinical cardiac damage: Results from ADVANCE.International Journal of Cardiology Jul 2022Observational data suggest a potential for subclinical cardiac damage from intensive blood glucose or blood pressure (BP) control, particularly in adults with very low... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Observational data suggest a potential for subclinical cardiac damage from intensive blood glucose or blood pressure (BP) control, particularly in adults with very low blood glucose and BP levels. However, this has not been tested in a randomized trial.
METHODS
The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Research Controlled Evaluation (ADVANCE) study was a factorial, randomized trial designed to test the effects of intensive blood glucose (hemoglobin A1c ≤6.5% versus usual care) and intensive BP (combination of perindopril-indapamide versus placebo) control on vascular events in adults with diabetes. Using mixed effects tobit models, we determined the effect of the randomized interventions on change in subclinical cardiac injury (high sensitivity cardiac troponin T [hs-cTnT]) and strain (N-terminal b-type pro natriuretic peptide [NT-proBNP]), 1 year after randomization.
RESULTS
Among the 682 participants, mean age was 66.1 (SD, 6.5) years; 40% were women. Mean baseline hemoglobin A1c was 7.4% (SD, 1.5) and systolic/diastolic BP was 147 (SD,21)/81 (SD,11) mmHg. After 1 year, intensive versus standard glucose control did not significantly change hs-cTnT (1.5%; 95%CI:-4.9,8.2) or NT-proBNP (-10.3%; 95%CI: -20.2%,0.9%). Intensive versus standard BP control also did not affect hs-cTnT (-2.9%; 95%CI: -8.9,3.6), but did significantly lower NT-proBNP by 21.6% (95%CI:-30.2%,-11.9%). Changes in systolic BP at 1 year (versus baseline) were strongly associated with NT-proBNP (P = 0.004), but not hs-cTnT (P = 0.95).
CONCLUSIONS
In adults with diabetes, intensive BP control reduced NT-proBNP without increasing hs-cTnT, supporting the benefits and safety of intensive BP control in adults with diabetes. This trial is registered at clinicaltrials.gov, number: NCT00145925.
Topics: Aged; Biomarkers; Blood Glucose; Blood Pressure; Female; Glucose; Glycated Hemoglobin; Humans; Hypotension; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Troponin T
PubMed: 35439582
DOI: 10.1016/j.ijcard.2022.04.044 -
Advances in Therapy Jun 2022Most patients with hypertension in sub-Saharan Africa require two or more drugs to control their blood pressure. Triple fixed-dose combination therapy of perindopril... (Observational Study)
Observational Study
INTRODUCTION
Most patients with hypertension in sub-Saharan Africa require two or more drugs to control their blood pressure. Triple fixed-dose combination therapy of perindopril arginine/indapamide/amlodipine is more effective in lowering blood pressure, offers better target organ protection and has increased adherence compared to monotherapy and free combination therapy, and is safe to use. This observational study evaluates the effectiveness of perindopril arginine/indapamide/amlodipine in controlling blood pressure at least 1 month after treatment initiation and assesses patient- and physician- reported drug tolerance over a 3-month period in Madagascar and Mauritius.
METHODS
A total of 198 patients with hypertension in ambulatory care who had been on fixed-dose combination of perindopril arginine, indapamide, and amlodipine for at least 4 weeks were included. The main outcome measures were changes in systolic and diastolic blood pressure, attainment of blood pressure control under 140/90 mmHg and 130/80 mmHg, self-reported drug tolerance by the patient, and perceived drug tolerance by the treating physician. Data was collected at 1 month and 3 months.
RESULTS
Mean systolic blood pressure was significantly lower at the 1-month (- 3.4 mmHg, p = 0.002) and 3-month (- 8.5 mmHg, p < 0.0001) visits. Diastolic blood pressure also decreased significantly (- 2.4 mmHg at 1-month, p = 0.017 and - 5.4 mmHg at the 3-month visits, p < 0.0001). At 3 months, 80.4% of the patients attained blood pressure targets less than 140/90 mmHg and 42.7% attained targets less than 130/80 mmHg on the basis of their baseline blood pressure. Excellent drug tolerance was reported by more than 90% of patients and physicians at the 1-month visit and by more than 95% at the 3-month visit.
CONCLUSION
Triple fixed-dose therapy of perindopril arginine/indapamide/amlodipine continues to show additional blood pressure-lowering capacity even months after initiating the treatment in patients with hypertension in Madagascar and Mauritius. It is also well tolerated by patients with hypertension and assessed as safe to use by physicians.
Topics: Amlodipine; Antihypertensive Agents; Arginine; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Drug Combinations; Humans; Hypertension; Indapamide; Madagascar; Mauritius; Perindopril; Treatment Outcome
PubMed: 35438448
DOI: 10.1007/s12325-022-02134-0