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Double filtration plasmapheresis (DFPP) is a semi‐selective blood purification modality derived from the plasma exchange modality. DFPP can be applied to a variety of refractory disorders including metabolic disorders, organ transplants, rheumatic disorders, neurological disorders, and dermatologic disorders. Familial hypercholesterolemia and lipoprotein (a) hyperlipoproteinemia are major chronic metabolic disorders. Lipoprotein apheresis (LA) is applied for those patients to remove low‐density lipoprotein cholesterol (LDL‐C) and lipoprotein (a) (Lp(a)). DFPP is used as one of the modalities in LA. In addition to removing LDL‐C and Lp(a), DFPP has pleiotropic effects such as removal of lipid metabolism‐related substances, C‐reactive protein lowering effect, removal of adhesion molecules, removal of inflammatory cytokines, and anti‐oxidative effect. This article summarizes the pleiotropic effects of DFPP based on recent clinical articles. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a growing concern due to the aging population and increasing prevalence of comorbidities. Despite advances in treatment, HF remains a significant burden, necessitating novel therapeutic approaches. Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have emerged as a promising treatment option, demonstrating benefits across the entire spectrum of HF, regardless of left ventricular ejection fraction (LVEF). This review explores the multifaceted mechanisms through which SGLT2is exert cardioprotective effects, including modulation of energy metabolism, reduction of oxidative stress, attenuation of inflammation, and promotion of autophagy. SGLT2is shift myocardial energy substrate utilization from carbohydrates to more efficient fatty acids and ketone bodies, enhancing mitochondrial function and reducing insulin resistance. These inhibitors also mitigate oxidative stress by improving mitochondrial biogenesis, reducing reactive oxygen species (ROS) production, and regulating calcium-signaling pathways. Inflammation, a key driver of HF progression, is alleviated through the suppression of proinflammatory cytokines and modulation of immune cell activity. Additionally, SGLT2is promote autophagy, facilitating the clearance of damaged cellular components and preserving myocardial structure and function. Beyond their glucose-lowering effects, SGLT2is provide significant benefits in patients with chronic kidney disease (CKD) and HF, reducing the progression of CKD and improving overall survival. The pleiotropic actions of SGLT2is highlight their potential as a cornerstone in HF management. Further research is needed to fully elucidate their mechanisms and optimize their use in clinical practice. [ABSTRACT FROM AUTHOR]

Rice quality has a major impact on its economic value, necessitating the breeding of high-quality grain varieties. In addition, varieties with superior germination and growth at low temperatures are required for direct sowing, which enables the low-cost production of rice. We developed Akikei770, a near-isogenic line from the high-quality, good-tasting cultivar Akitakomachi, carrying the qLTG3-1 gene from the Maratelli cultivar, which enhances low-temperature germinability. Although Akikei770 exhibited improved low-temperature germinability, it was inferior to Akitakomachi in appearance quality of brown rice and in eating quality of cooked rice. In Akikei770, a short arm region of up to 222 kb on chromosome 3 from Maratelli was introgressed, and only the qLTG3-1 gene exhibited polymorphisms within the coding region compared to Akitakomachi. The qLTG3-1 genotype was significantly associated with brown rice quality in the F2 population, which indicates that the qLTG3-1 gene was involved in this trait with no involvement of other chromosomal regions of Akikei770. The functional qLTG3-1 allele in Akikei770, encoding a hybrid glycine-rich protein (HyGRP) that is localized on the cell wall or membrane, enhanced the low-temperature germinability. Because a loss-of-function allele of qLTG3-1 increased the appearance quality of brown rice in a recessive manner, it was concluded that HyGRP, which enhances low-temperature germinability, has a pleiotropic effect that reduces the appearance quality of brown rice. [ABSTRACT FROM AUTHOR]

Aims : This review summarizes the findings of preclinical studies evaluating the pleiotropic effects of ticagrelor. These include attenuation of ischemia–reperfusion injury (IRI), inflammation, adverse cardiac remodeling, and atherosclerosis. In doing so, it aims to provide novel insights into ticagrelor's mechanisms and benefits over other P2Y12 inhibitors. It also generates viable hypotheses for the results of seminal clinical trials assessing ticagrelor use in acute and chronic coronary syndromes. Methods and Results: A comprehensive review of the preclinical literature demonstrates that ticagrelor protects against IRI in the setting of both an acute myocardial infarction (MI), and when MI occurs while on chronic treatment. Maintenance therapy with ticagrelor also likely mitigates adverse inflammation, cardiac remodeling, and atherosclerosis, while improving stem cell recruitment. These effects are probably mediated by ticagrelor's ability to increase local interstitial adenosine levels which activate downstream cardio-protective molecules. Attenuation and augmentation of these pleiotropic effects by high-dose aspirin and caffeine, and statins respectively may help explain variable outcomes in PLATO and subsequent randomized controlled trials (RCTs). Conclusion: Most RCTs and meta-analyses have not evaluated the pleiotropic effects of ticagrelor. We need further studies comparing cardiovascular outcomes in patients treated with ticagrelor versus other P2Y12 inhibitors that are mindful of the unique pleiotropic advantages afforded by ticagrelor, as well as possible interactions with other therapies (e.g., aspirin, statins, caffeine). [ABSTRACT FROM AUTHOR]

Direct oral anticoagulants (DOACs) are the standard treatment for thromboembolic protection in atrial fibrillation (AF) patients. Epigenetic modifications, such as DNA methylation and microRNAs, have emerged as potential biomarkers of AF. The epigenetics of DOACs is still an understudied field. It is largely unknown whether epigenetic modifications interfere with DOAC response or whether DOAC treatment induces epigenetic modifications. To fill this gap, we started the miR-CRAFT (Circulating microRNAs and DNA methylation as regulators of Direct Oral Anticoagulant Response in Atrial Fibrillation) research study. In miR-CRAFT, we follow, over time, changes in DNA methylation and microRNAs expression in naïve AF patients starting DOAC treatment. The ultimate goal of miR-CRAFT is to identify the molecular pathways epigenetically affected by DOACs, beyond the coagulation cascade, that are potentially mediating DOAC pleiotropic actions and to propose specific microRNAs as novel circulating biomarkers for DOAC therapy monitoring. We herein describe the study design and briefly present the progress in participant enrolment. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a growing concern due to the aging population and increasing prevalence of comorbidities. Despite advances in treatment, HF remains a significant burden, necessitating novel therapeutic approaches. Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have emerged as a promising treatment option, demonstrating benefits across the entire spectrum of HF, regardless of left ventricular ejection fraction (LVEF). This review explores the multifaceted mechanisms through which SGLT2is exert cardioprotective effects, including modulation of energy metabolism, reduction of oxidative stress, attenuation of inflammation, and promotion of autophagy. SGLT2is shift myocardial energy substrate utilization from carbohydrates to more efficient fatty acids and ketone bodies, enhancing mitochondrial function and reducing insulin resistance. These inhibitors also mitigate oxidative stress by improving mitochondrial biogenesis, reducing reactive oxygen species (ROS) production, and regulating calcium-signaling pathways. Inflammation, a key driver of HF progression, is alleviated through the suppression of proinflammatory cytokines and modulation of immune cell activity. Additionally, SGLT2is promote autophagy, facilitating the clearance of damaged cellular components and preserving myocardial structure and function. Beyond their glucose-lowering effects, SGLT2is provide significant benefits in patients with chronic kidney disease (CKD) and HF, reducing the progression of CKD and improving overall survival. The pleiotropic actions of SGLT2is highlight their potential as a cornerstone in HF management. Further research is needed to fully elucidate their mechanisms and optimize their use in clinical practice.

Melatonin is a ubiquitous regulator in plants and performs a variety of physiological roles, including resistance to abiotic stress, regulation of growth and development, and enhancement of plant immunity. Melatonin exhibits the characteristics of a phytohormone with its pleiotropic effects, biosynthesis, conjugation, catabolism, effective concentration, and the shape and location of its dose–response curves. In addition, CAND2/PMTR1, a phytomelatonin receptor candidate belonging to the G protein-coupled receptors (GPCRs), supports the concept of melatonin as a phytohormone. However, the biochemistry of plant melatonin receptors needs to be further characterized. In particular, some of the experimental findings to date cannot be explained by known GPCR signaling mechanisms, so further studies are needed to explore the possibility of novel signaling mechanisms. [ABSTRACT FROM AUTHOR]

The rise in comorbid conditions with type 2 diabetes requires novel drug targets which benefits not only in glycaemic management but provide beneficial effects to other co-existing conditions too. One such drug available in market is the sodium glucose cotransport-2 inhibitor which is known for its pleiotropic effects. Keyword based comprehensive search was made in PubMed, Scopus and Google Scholar. Critical appraisal of all the collected literature was done and the key findings were used. The novel class of oral anti-diabetics act by reducing hyperglycaemia by rising urinary glucose excretion independently of insulin secretion or action. Clinical trials have shown its effects not only in controlling glycaemic levels but other effects such as reducing hypertension, providing cardiovascular benefits and positive renal outcomes too. Despite the positive outcomes, a segment of adverse effects such as lower limb amputations, risk of genital infections has set as drawbacks to bringing the drug into extensive clinical practice. This review provides an overview of the current evidence available so far on the therapeutic potential of the sodium glucose cotransporter-2 inhibitors for the treatment of type 2 diabetes mellitus and suggests the use of drug into practice to obtain evidences at a large level. [ABSTRACT FROM AUTHOR]

HMG-CoA reductase inhibitors, commonly known as statins, are the primary treatment choice for cardiovascular diseases, which stand as the leading global cause of mortality. Statins also offer various pleiotropic effects, including improved endothelial function, anti-inflammatory properties, reduced oxidative stress, anti-thrombotic effects, and the stabilization of atherosclerotic plaques. However, the usage of statins can be accompanied by a range of adverse effects, such as the development of type 2 diabetes mellitus, muscular symptoms, liver toxicity, kidney diseases, cataracts, hemorrhagic strokes, and psychiatric complications. These issues are referred to as statin-associated symptoms (SAS) and are relatively infrequent in clinical trials, making it challenging to attribute them to statin use definitively. Therefore, these symptoms can lead to significant problems, necessitating dose adjustments or discontinuation of statin therapy. This review aims to provide a comprehensive overview of the mechanism of action, potential advantages, and associated risks of statin utilization in clinical settings. [ABSTRACT FROM AUTHOR]

Aim. To study the effect of 48-week therapy with atorvastatin and ezetimibe on laboratory parameters, structural and functional arterial characteristics and heart failure markers in the post-infarction period.Material and methods. A total of 87 patients with acute myocardial infarction were included. In the first 24 hours, atorvastatin 80 mg/day was prescribed. During hospitalization, after 5-6, 24, 48 weeks, clinical and paraclinical examinations were performed. In the level of low-density lipoprotein cholesterol (LDL-C) >1,4 mmol/l and the decrease

In recent decades, the prevalence of osteoarthritis (OA), one of the most disabling diseases, has increased worldwide, which imposes a significant burden on society. At the international multidisciplinary meeting, experts of various specialties (rheumatology, neurology, endocrinology, geriatrics, rehabilitation, traumatology and orthopedics) from Russia, Uzbekistan, and Kazakhstan discussed the importance of an individualized approach to the treatment of patients with OA, taking into account comorbidities, identified the most important and common clinical phenotypes of the disease, discussed known symptom- and structure-modifying effects of a combination of glucosamine and chondroitin sulfate, and new data on additional (pleiotropic) effects of these drugs that may have a positive impact on the course of comorbid diseases and conditions. The resolution of the Expert Council summarizes the results of the discussion and focuses on issues that are important for the further development of therapeutic approaches and recommendations for the management of such patients.

Direct Oral Anticoagulants (DOACs) have simplified the treatment of thromboembolic disease. In addition to their established anticoagulant effects, there are indications from clinical and preclinical studies that DOACs exhibit also non-anticoagulant actions, such as anti-inflammatory and anti-oxidant actions, advocating overall cardiovascular protection. In the present study, we provide a comprehensive overview of the existing knowledge on the pleiotropic effects of DOACs on endothelial cells (ECs) in vitro and their underlying mechanisms, while also identifying potential differences among DOACs. DOACs exhibit pleiotropic actions on ECs, such as anti-inflammatory, anti-atherosclerotic, and anti-fibrotic effects, as well as preservation of endothelial integrity. These effects appear to be mediated through inhibition of the proteinase-activated receptor signaling pathway. Furthermore, we discuss the potential differences among the four drugs in this class. Further research is needed to fully understand the pleiotropic effects of DOACs on ECs, their underlying mechanisms, as well as the heterogeneity between various DOACs. Such studies can pave the way for identifying biomarkers that can help personalize pharmacotherapy with this valuable class of drugs. [ABSTRACT FROM AUTHOR]

Abstract Background Observational studies and conventional Mendelian randomization (MR) studies showed inconclusive evidence to support the association between omega-3 fatty acids and type 2 diabetes. We aim to evaluate the causal effect of omega-3 fatty acids on type 2 diabetes mellitus (T2DM), and the distinct intermediate phenotypes linking the two. Methods Two-sample MR was performed using genetic instruments derived from a recent genome-wide association study (GWAS) of omega-3 fatty acids (N = 114,999) from UK Biobank and outcome data obtained from a large-scale T2DM GWAS (62,892 cases and 596,424 controls) in European ancestry. MR-Clust was applied to determine clustered genetic instruments of omega-3 fatty acids that influences T2DM. Two-step MR analysis was used to identify potential intermediate phenotypes (e.g. glycemic traits) that linking omega-3 fatty acids with T2DM. Results Univariate MR showed heterogenous effect of omega-3 fatty acids on T2DM. At least two pleiotropic effects between omega-3 fatty acids and T2DM were identified using MR-Clust. For cluster 1 with seven instruments, increasing omega-3 fatty acids reduced T2DM risk (OR: 0.52, 95%CI 0.45–0.59), and decreased HOMA-IR (β = − 0.13, SE = 0.05, P = 0.02). On the contrary, MR analysis using 10 instruments in cluster 2 showed that increasing omega-3 fatty acids increased T2DM risk (OR:1.10; 95%CI 1.06–1.15), and decreased HOMA-B (β = − 0.04, SE = 0.01, P = 4.52 × 10–5). Two-step MR indicated that increasing omega-3 fatty acid levels decreased T2DM risk via decreasing HOMA-IR in cluster 1, while increased T2DM risk via decreasing HOMA-B in cluster 2. Conclusions This study provides evidence to support two distinct pleiotropic effects of omega-3 fatty acids on T2DM risk influenced by different gene clusters, which could be partially explained by distinct effects of omega-3 fatty acids on insulin resistance and beta cell dysfunction. The pleiotropic feature of omega-3 fatty acids variants and its complex relationships with T2DM need to be carefully considered in future genetic and clinical studies.

For many years, statins have been the most commonly used drugs in cholesterol-lowering therapy. In addition to these therapeutic effects, statins exhibit other, pleiotropic effects that can be beneficial, but also harmful to cells and tissues. The aim of this research was to determine and compare the pleiotropic effects of structurally different statins: atorvastatin, simvastatin and rosuvastatin at different concentrations on hepatocellular carcinoma (HepG2) cells. The MTT assay was used to determine the cytotoxic effects of statins. The influence of statins on the production of reactive oxygen species (ROS) was determined by measuring fluorescent response of 2,7-dichlorofluorescein diacetate (DCFH-DA). The effect of statins on glucose production and excretion was determined with glucose production assay. The obtained results confirmed that all tested statins exhibit cytotoxic effects, increase the production of ROS as well as the production and excretion of glucose from HepG2 cells. It was observed that all the mentioned effects are more pronounced with lipophilic statins, atorvastatin and simvastatin compared to hydrophilic rosuvastatin. The less pronounced pleiotropic effects of rosuvastatin on HepG2 cells are probably due to differences in structure and solubility compared to atorvastatin and simvastatin. Transporter-dependent and a slower influx of rosuvastatin into cells compared to the tested lipophilic statins probably lead to a weaker accumulation of rosuvastatin in HepG2 cells, which results in less pronounced pleiotropic effects compared to lipophilic atorvastatin and simvastatin. [ABSTRACT FROM AUTHOR]

Women with polycystic ovary syndrome (PCOS), the most common endocrinopathy in reproductive age, are characterized by increased cardiometabolic risk. Similar hormonal and metabolic changes were found in their siblings. The purpose of our study was to compare blood pressure–lowering and pleiotropic effects of lisinopril between sisters of women with PCOS and their unrelated peers. The study included two age‐, body mass index–, and blood pressure–matched groups of women with grade 1 hypertension: 26 sisters of PCOS probands (Group 1) and 26 individuals without a family history of PCOS (Group 2), receiving 10–40 mg of lisinopril daily. Blood pressure, glucose homeostasis markers, plasma levels of lipids (androgens, estradiol, high‐sensitivity C‐reactive protein (hsCRP), homocysteine, fibrinogen, and uric acid), and urinary albumin‐to‐creatinine ratio (UACR) were measured before lisinopril treatment and 6 months later. At baseline, the study groups differed in insulin sensitivity, testosterone, free androgen index (FAI), hsCRP, homocysteine, and UACR. Blood pressure–lowering properties of lisinopril did not differ between the groups. The decrease in homocysteine and UACR, although observed in both groups, was stronger in Group 2 than in Group 1. Only in women without a family history of PCOS lisinopril improved insulin sensitivity and reduce hsCRP, fibrinogen, and uric acid. The remaining markers did not change throughout the study. Cardiometabolic effects of lisinopril correlated with testosterone, free androgen index, and changes in insulin sensitivity. The obtained results suggest that cardiometabolic effects of lisinopril may be slightly less pronounced in sisters of women with PCOS than in women without a family history of this disorder. [ABSTRACT FROM AUTHOR]

Influenza vaccines are designed to mimic natural influenza virus exposure and stimulate a long-lasting immune response to future infections. The evolving nature of the influenza virus makes vaccination an important and efficacious strategy to reduce healthcare-related complications of influenza. Several lines of evidence indicate that influenza vaccination may induce nonspecific effects, also referred to as heterologous or pleiotropic effects, that go beyond protection against infection. Different explanations are proposed, including the upregulation and downregulation of cytokines and epigenetic reprogramming in monocytes and natural killer cells, imprinting an immunological memory in the innate immune system, a phenomenon termed "trained immunity". Also, cross-reactivity between related stimuli and bystander activation, which entails activation of B and T lymphocytes without specific recognition of antigens, may play a role. In this review, we will discuss the possible nonspecific effects of influenza vaccination in cardiovascular disease, type 1 diabetes, cancer, and Alzheimer's disease, future research questions, and potential implications. A discussion of the potential effects on infections by other pathogens is beyond the scope of this review. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through the regulation of a wide range of HIF-responsive gene expressions. However, the systemic biological effects of HIF-PHIs in CKD patients have not been fully explored. In this prospective, single-center study, we comprehensively investigated changes in plasma metabolomic profiles following the switch from an erythropoiesis-stimulating agent (ESA) to an HIF-PHI, daprodustat, in 10 maintenance hemodialysis patients. Plasma metabolites were measured before and three months after the switch from an ESA to an HIF-PHI. Among 106 individual markers detected in plasma, significant changes were found in four compounds (erythrulose, n-butyrylglycine, threonine, and leucine), and notable but non-significant changes were found in another five compounds (inositol, phosphoric acid, lyxose, arabinose, and hydroxylamine). Pathway analysis indicated decreased levels of plasma metabolites, particularly those involved in phosphatidylinositol signaling, ascorbate and aldarate metabolism, and inositol phosphate metabolism. Our results provide detailed insights into the systemic biological effects of HIF-PHIs in hemodialysis patients and are expected to contribute to an evaluation of the potential side effects that may result from long-term use of this class of drugs. [ABSTRACT FROM AUTHOR]

Background: Previous evidence yielded contradictory findings on the relationship between metformin and anemia. This study aims to assess whether metformin use is associated with iron-deficiency anemia (IDA) risk in patients with type 2 diabetes (T2D) in Beijing, China. Methods: Overall, 60,327 newly diagnosed T2D patients were included based on a historical cohort study design. The information pertaining to these patients was gathered from the Beijing Medical Claim Data for Employees Database. These patients were then categorized into the metformin and non-metformin groups and matched on a 1:1 propensity score based on their initial antidiabetic prescription. The Cox proportional hazards models were utilized to calculate the incidences and the hazard ratios (HRs). Results: The study enrolled 27,960 patients with type 2 diabetes, with 13,980 patients in each of the initial glucose-lowering prescription groups: metformin and non-metformin. During a median follow-up period of 4.84 years, 4832 patients developed IDA. The incidence of IDA was significantly lower in the metformin group (26.08/1000 person-years) than in the non-metformin group (43.20/1000 person-years). Among the three groups divided by the proportion of days covered by metformin, we found a negative correlation between the proportion of days covered by metformin and the risk of IDA. The risk of IDA in patients with a proportion of days covered by metformin of <20%, 20–79%, and ≥80% was 0.43 (0.38, 0.48), 0.37 (0.34, 0.42), and 0.91 (0.85, 0.98), respectively, compared to the non-metformin group. We also performed subgroup analyses and sensitivity analyses: the incidence of IDA in the metformin group was lower than that in the non-metformin group in all subgroups, and the protective effect was more significant in subgroups of patients aged ≥65, with Charlson comorbidity index (CCI) ≥2, and with gastric acid inhibitor use. Conclusions: In Chinese patients with T2DM, metformin treatment was associated with a decreased risk of IDA admission, and this risk responded positively to the proportion of days covered by metformin. These findings suggest that metformin may have a pleiotropic effect on IDA in patients with type 2 diabetes. Our study has important clinical implications for the management of patients with diabetes and other conditions that increase the risk of IDA. [ABSTRACT FROM AUTHOR]

Pod coloration is a domestication-related trait in soybean, with modern cultivars typically displaying brown or tan pods, while their wild relative, Glycine soja , possesses black pods. However, the factors regulating this color variation remain unknown. In this study, we cloned and characterized L1 , the classical locus responsible for black pods in soybean. By using map-based cloning and genetic analyses, we identified the causal gene of L1 and revealed that it encodes a hydroxymethylglutaryl-coenzyme A (CoA) lyase-like (HMGL-like) domain protein. Biochemical assays showed that L1 functions as a eucomic acid synthase and facilitates the synthesis of eucomic acid and piscidic acid, both of which contribute to coloration of pods and seed coats in soybean. Interestingly, we found that L1 plants are more prone to pod shattering under light exposure than l1 null mutants because dark pigmentation increases photothermal efficiency. Hence, pleiotropic effects of L1 on pod color and shattering, as well as seed pigmentation, likely contributed to the preference for l1 alleles during soybean domestication and improvement. Collectively, our study provides new insights into the mechanism of pod coloration and identifies a new target for future de novo domestication of legume crops. This study characterizes the domestication-associated L1 gene and demonstrates that it encodes an HMGL-like domain protein that functions as a eucomic acid synthaseand facilitates the synthesis of eucomic acid and piscidic acid, both of which contribute to the black color of soybean pods. Black-podded L1 plants are more susceptible to pod shattering due to the higher photothermal efficiency of dark pigmentation, potentially contributing to selection of l1 alleles with lighter pod color during domestication and improvement of soybeans. [ABSTRACT FROM AUTHOR]

In T. gondii, as well as in other model organisms, gene knock-out using CRISPR-Cas9 is a suitable tool to identify the role of specific genes. The general consensus implies that only the gene of interest is affected by the knock-out. Is this really the case? In a previous study, we generated knock-out (KO) clones of TgRH88_077450 (SRS29B; SAG1) which differed in the numbers of the integrated dihydrofolate-reductase-thymidylate-synthase (MDHFR-TS) drug-selectable marker. Clones 18 and 33 had a single insertion of MDHFR-TS within SRS29B. Clone 6 was disrupted by the insertion of a short unrelated DNA-sequence, but the marker was integrated elsewhere. In clone 30, the marker was inserted into SRS29B, and several other MDHFR-TS copies were found in the genome. KO and wild-type (WT) tachyzoites had similar shapes, dimensions, and vitality. This prompted us to investigate the impact of genetic engineering on the overall proteome patterns of the four clones as compared to the respective WT. Comparative shotgun proteomics of the five strains was performed. Overall, 3236 proteins were identified. Principal component analysis of the proteomes revealed five distinct clusters corresponding to the five strains by both iTop3 and iLFQ algorithms. Detailed analysis of the differentially expressed proteins revealed that the target of the KO, srs29B, was lacking in all KO clones. In addition to this protein, 20 other proteins were differentially expressed between KO clones and WT or between different KO clones. The protein exhibiting the highest variation between the five strains was srs36D encoded by TgRH_016110. The deregulated expression of SRS36D was further validated by quantitative PCR. Moreover, the transcript levels of three other selected SRS genes, namely SRS36B, SRS46, and SRS57, exhibited significant differences between individual strains. These results indicate that knocking out a given gene may affect the expression of other genes. Therefore, care must be taken when specific phenotypes are regarded as a direct consequence of the KO of a given gene. [ABSTRACT FROM AUTHOR]

Purpose of Review: Familial hypercholesterolemia (FH) and hyperlipoproteinemia(a) are relatively common disorders, posing a significant health burden due to increased risk of atherosclerotic cardiovascular disease (ASCVD). Development of electronic health record–based strategies with a linkage to the genetic test results has increased awareness, detection, and control of heritable lipid disorders. This review attempts to critically examine available data to provide a summary of the current evidence for lipoprotein apheresis in FH and elevated lipoprotein(a) (Lp(a)). Review Findings: Availability and indications for lipoprotein apheresis vary across the globe. On average, greater than 60% of atherogenic apoB-containing lipoproteins are immediately reduced following a single procedure, translating in substantial reduction of incident ASCVD events, and preventing accelerated vascular aging. Simultaneous lipid-lowering therapy targeting low-density lipoprotein (LDL) and Lp(a) enhances the efficacy of lipoprotein apheresis. Lipoprotein apheresis alters the proteomics of the lipoprotein particles, including reduction in the concentration of the oxidized-LDL and Lp(a) particles, and proinflammatory apoE bound to HDL particles and remnant lipoproteins. Other effects attributed to lipoprotein apheresis include improvement in blood rheology, endothelial function, microvascular flow, myocardial perfusion, reduction in circulating inflammatory markers. Development of lipoprotein apheresis registries provides data on benefits, challenges, and barriers to inform pertinent healthcare policies. Summary: Lipoprotein apheresis is a safe and effective procedure for lowering cholesterol in patients with combined and isolated FH and elevated Lp(a). It reduces the burden of ASCVD and improves long-term prognosis. A team approach is required by the patient, medical staff, and healthcare provider to initiate and maintain a lipoprotein apheresis program. [ABSTRACT FROM AUTHOR]

Background: Observational studies and conventional Mendelian randomization (MR) studies showed inconclusive evidence to support the association between omega-3 fatty acids and type 2 diabetes. We aim to evaluate the causal effect of omega-3 fatty acids on type 2 diabetes mellitus (T2DM), and the distinct intermediate phenotypes linking the two. Methods: Two-sample MR was performed using genetic instruments derived from a recent genome-wide association study (GWAS) of omega-3 fatty acids (N = 114,999) from UK Biobank and outcome data obtained from a large-scale T2DM GWAS (62,892 cases and 596,424 controls) in European ancestry. MR-Clust was applied to determine clustered genetic instruments of omega-3 fatty acids that influences T2DM. Two-step MR analysis was used to identify potential intermediate phenotypes (e.g. glycemic traits) that linking omega-3 fatty acids with T2DM. Results: Univariate MR showed heterogenous effect of omega-3 fatty acids on T2DM. At least two pleiotropic effects between omega-3 fatty acids and T2DM were identified using MR-Clust. For cluster 1 with seven instruments, increasing omega-3 fatty acids reduced T2DM risk (OR: 0.52, 95%CI 0.45–0.59), and decreased HOMA-IR (β = − 0.13, SE = 0.05, P = 0.02). On the contrary, MR analysis using 10 instruments in cluster 2 showed that increasing omega-3 fatty acids increased T2DM risk (OR:1.10; 95%CI 1.06–1.15), and decreased HOMA-B (β = − 0.04, SE = 0.01, P = 4.52 × 10–5). Two-step MR indicated that increasing omega-3 fatty acid levels decreased T2DM risk via decreasing HOMA-IR in cluster 1, while increased T2DM risk via decreasing HOMA-B in cluster 2. Conclusions: This study provides evidence to support two distinct pleiotropic effects of omega-3 fatty acids on T2DM risk influenced by different gene clusters, which could be partially explained by distinct effects of omega-3 fatty acids on insulin resistance and beta cell dysfunction. The pleiotropic feature of omega-3 fatty acids variants and its complex relationships with T2DM need to be carefully considered in future genetic and clinical studies. [ABSTRACT FROM AUTHOR]

Introduction: Polycystic ovary syndrome (PCOS) is a frequent endocrinopathy in young women with significantly increased cardiometabolic risk. Siblings of women with this disorder are at increased risk of insulin resistance and androgen excess. The current study was aimed at investigating cardiometabolic effects of atorvastatin in sisters of women with PCOS. Methods: This prospective observational study compared two age-, body mass index-, blood pressure-, and plasma lipid-matched groups of women with hypercholesterolemia: sisters of PCOS probands (group A) and unrelated control subjects (group B), receiving atorvastatin (40 mg daily). Plasma lipids, glucose homeostasis markers, concentrations of sex hormones, high-sensitivity C-reactive protein (hsCRP), homocysteine, fibrinogen and uric acid, and the urinary albumin-to-creatinine ratio (UACR) were measured before entering the study and 6 months later. Results: Both groups differed in the degree of insulin resistance, testosterone, free androgen index (FAI), circulating levels of hsCRP and homocysteine, and UACR. There were no between-group differences in the impact of atorvastatin on plasma lipids. Despite reducing hsCRP and homocysteine in both groups of women, the effect on these biomarkers was stronger in group B than in group A. Only in group B, atorvastatin did reduce fibrinogen, uric acid, and UACR. Only in group A, atorvastatin did worsen insulin sensitivity and tended to reduce testosterone and FAI. The impact of atorvastatin on hsCRP, homocysteine, fibrinogen, uric acid, and UACR inversely correlated with testosterone and FAI. Conclusion: The obtained results suggest that sisters of women with PCOS may benefit to a lesser degree from atorvastatin treatment than other women. [ABSTRACT FROM AUTHOR]

Introduction: Autoimmune thyroiditis seems to be associated with increased cardiometabolic risk. Statins, the mainstay of cardiovascular risk reduction and prevention, were found to reduce thyroid antibody titers. The aim of this study was to investigate plasma markers of cardiometabolic risk in statin-treated women with thyroid autoimmunity. Methods: We compared two matched groups of euthyroid women with hypercholesterolemia receiving atorvastatin treatment: subjects with autoimmune (Hashimoto's) thyroiditis (group A, n = 29) and subjects without thyroid pathology (group B, n = 29). Plasma lipids, glucose homeostasis markers, as well as circulating levels of uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen, homocysteine, and 25-hydroxyvitamin D were measured before atorvastatin treatment and 6 months later. Results: At entry, both groups differed in antibody titers, insulin sensitivity, and plasma levels of uric acid, hsCRP, fibrinogen, homocysteine, and 25-hydroxyvitamin D. Atorvastatin-induced reduction in hsCRP and homocysteine, but not in total cholesterol and LDL-cholesterol, was more pronounced in group B than in group A. Only in group B, the drug decreased uric acid and fibrinogen and increased 25-hydroxyvitamin D. In group A, atorvastatin reduced insulin responsiveness. Conclusion: The obtained results indicate that euthyroid women with Hashimoto's thyroiditis may benefit to a lesser degree from atorvastatin treatment than other populations of women with hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Plant height is an important agronomic trait related to plant architecture and grain yield in wheat. We investigated the effects of the gibberellic acid (GA)-insensitive Rht-B1b and Rht-D1b semi-dwarfing alleles in a set of 599 F4:5 spring wheat breeding lines grown in rainfed and supplemental irrigation conditions at Setif semi-arid high plateaus region (Algeria). Genotyping of diagnostic markers was performed using Kompetitive Allele Specific PCR assays. The Rht-B1b mutant allele was present in 66% of the evaluated lines, while the Rht-D1b allele was found only in 8% of the lines. Relative to wild-type, Rht-B1b or Rht-D1b alone reduced plant height by 16.0 and 16.3% in rainfed, and by 20.7 and 21.8% in irrigated environments, respectively. The two dwarfing alleles when combined decreased height by 39.3 and 56.6% in rainfed and irrigated conditions, respectively. The semi-dwarf breeding lines generally outperformed the tall genotypes for yield and yield components including the number of grains per spike and harvest index irrespective of environment. Variation in heading date under the influence of dwarfing alleles has not been found. In addition, above-ground biomass was reduced in most of the short statured lines, compared to their tall counter parts across environments. We also demonstrate clear yield and yield components penalty for Rht-B1b + Rht-D1b double dwarf backgrounds. [ABSTRACT FROM AUTHOR]

Direct Oral Anticoagulants (DOACs) have simplified the treatment of thromboembolic disease. In addition to their established anticoagulant effects, there are indications from clinical and preclinical studies that DOACs exhibit also non-anticoagulant actions, such as anti-inflammatory and anti-oxidant actions, advocating overall cardiovascular protection. In the present study, we provide a comprehensive overview of the existing knowledge on the pleiotropic effects of DOACs on endothelial cells (ECs) in vitro and their underlying mechanisms, while also identifying potential differences among DOACs. DOACs exhibit pleiotropic actions on ECs, such as anti-inflammatory, anti-atherosclerotic, and anti-fibrotic effects, as well as preservation of endothelial integrity. These effects appear to be mediated through inhibition of the proteinase-activated receptor signaling pathway. Furthermore, we discuss the potential differences among the four drugs in this class. Further research is needed to fully understand the pleiotropic effects of DOACs on ECs, their underlying mechanisms, as well as the heterogeneity between various DOACs. Such studies can pave the way for identifying biomarkers that can help personalize pharmacotherapy with this valuable class of drugs.

High rates of cardiovascular (CV) morbidity and mortality dictates the need to determine approaches to therapy that would reduce complications rate and improve patient’s prognosis. High-intensity statin therapy is an integral part of the treatment of patients with high and very high cardiovascular risk. At the same time, there is a large cohort of patients who would benefit from moderate intensity statin therapy. In the present article we have summarized available data on hypolipidemic effects, pleiotropic effects and role of moderate intensity statin therapy, atorvastatin particularly, in reding the risk of major adverse cardiac events.

HMG-CoA reductase inhibitors, commonly known as statins, are the primary treatment choice for cardiovascular diseases, which stand as the leading global cause of mortality. Statins also offer various pleiotropic effects, including improved endothelial function, anti-inflammatory properties, reduced oxidative stress, anti-thrombotic effects, and the stabilization of atherosclerotic plaques. However, the usage of statins can be accompanied by a range of adverse effects, such as the development of type 2 diabetes mellitus, muscular symptoms, liver toxicity, kidney diseases, cataracts, hemorrhagic strokes, and psychiatric complications. These issues are referred to as statin-associated symptoms (SAS) and are relatively infrequent in clinical trials, making it challenging to attribute them to statin use definitively. Therefore, these symptoms can lead to significant problems, necessitating dose adjustments or discontinuation of statin therapy. This review aims to provide a comprehensive overview of the mechanism of action, potential advantages, and associated risks of statin utilization in clinical settings.

This review is focused on the issue of terminology in patients with multiple coexisting diseases in modern clinical practice. We articulate that multimorbidity is one of the leading problems in the field of public healthcare and that the treatment of these patients demands an integral approach derived from the combined nature of the pathology . It was shown that multiple coexisting diseases have a negative effect both on the course of osteoarthritis (OA) and its concomitant ailments, including higher risk of polypharmacy and death. Extra attention is paid to slow-acting symptomatic drugs, which often have positive pleiotropic effects towards both the OA and the concomitant diseases. In particular, there is more and more research showing evidence of the beneficial effects of chondroitin sulfate both on the OA treatment effectiveness as well as on the terms of cardiometabolic prognosis, mitigation of glucose metabolism deficiency and mortality.

Apical periodontitis (AP) is an inflammatory dental disease caused by bacterial infections of the endodontic system. The correlation between AP and cardiovascular diseases. (CVD) has been consistently investigated. Statins are a class of drugs that are used to treat hypercholesterolemia and prevent atherosclerotic vascular diseases. They have other beneficial pleiotropic effects such as anti-inflammatory, antithrombotic, and antioxidant activities. The aim of this study was to evaluate the oral health status and prevalence of AP in patients treated with statins (Group S) in comparison with untreated patients (Group C) to understand whether the anti-inflammatory action of these drugs can influence the prevalence of AP. The records of seventy-nine patients (43 men and 36 women, mean age 68 ± 11 years, 1716 teeth) treated with statins and referred to the University clinic for dental evaluation were reviewed. Seventy patients free from systemic diseases and without therapy (39 men and 31 women, mean age 62 ± 9 years, 1720 teeth) constituted the control group. All subjects underwent complete oral, dental, and radiographic examinations to determine the presence and severity of AP. Periapical index (PAI) and decayed, missed, and filled teeth (DMFT) scores were obtained. AP was significantly less common in Group S (22,8%) than in Group C (50%) (P < 0.05). Furthermore, the mean value of the qualitative rank of the severity of AP (PAI score) was higher in Group C than in Group S (P ≤ 0.05). Our results suggest that statins can attenuate the prevalence of AP, which is associated to CVD. [ABSTRACT FROM AUTHOR]

Abstract Background Economically important milk production traits including milk volume, milk fat and protein yield vary considerably across dairy goats in New Zealand. A significant portion of the variation is attributable to genetic variation. Discovery of genetic markers linked to milk production traits can be utilised to drive selection of high-performance animals. A previously reported genome wide association study across dairy goats in New Zealand identified a quantitative trait locus (QTL) located on chromosome 19. The most significantly associated single nucleotide polymorphism (SNP) marker for this locus is located at position 26,610,610 (SNP marker rs268292132). This locus is associated with multiple milk production traits including fat, protein and volume. The predicted effect of selection for the beneficial haplotype would result in an average production increase of 2.2 kg fat, 1.9 kg protein and 73.6 kg milk yield. An outstanding question was whether selection for the beneficial allele would co-select for any negative pleiotropic effects. An adverse relationship between milk production and udder health traits has been reported at this locus. Therefore, a genome wide association study was undertaken looking for loci associated with udder traits. Results The QTL and production associated marker rs268292132 was identified in this study to also be associated with several goat udder traits including udder depth (UD), fore udder attachment (FUA) and rear udder attachment (RUA). Our study replicates the negative relationship between production and udder traits with the high production allele at position 19:26,610,610 (SNP marker rs268292132) associated with an adverse change in UD, FUA and RUA. Conclusions Our study has confirmed the negative relationship between udder traits and production traits in the NZ goat population. We have found that the frequency of the high production allele is relatively high in the NZ goat population, indicating that its effect on udder conformation is not significantly detrimental on animal health. It will however be important to monitor udder conformation as the chromosome 19 locus is progressively implemented for marker assisted selection. It will also be of interest to determine if the gene underlying the production QTL has a direct effect on mammary gland morphology or whether the changes observed are a consequence of the increased milk volume.

Objectives: Mean platelet volume (MPV) has been shown to be a predictor of platelet activation and plays a crucial role in the pathogenesis of atherosclerosis. Red cell distribution width (RDW) is a measure of the variability of erythrocyte volumes and might reflect underlying chronic inflammation. Both MPV and RDW are related to increased risk for cardiovascular disease. Since statins have pleiotropic effects, we aim to investigate the effect of statins on this possible hematologic markers of atherosclerotic risk in stable coronary artery disease (CAD). Materials and Methods: One hundred and twenty-one statin-naive patients who had undergone coronary angiography for stable CAD between June 2012 and June 2013 were retrospectively enrolled in this study. Patients were treated with atorvastatin or rosuvastatin. The lipid profile and hematological parameters were measured at baseline and after statin treatment. Results: One hundred and twenty-one patients were included in the study. The mean age was 60.5 ± 9 years and 38% of patients were women. Out of 121 patients, 106 (87.6%) patients received atorvastatin therapy and 15 (12.4%) patients received rosuvastatin therapy. After a median follow-up period of 36 days, statin treatment markedly reduced low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) levels (P = 0.0001, for all). For hematological parameters, only RDW significantly decreased after statin treatment (P = 0.0001). The Δ RDW were not associated with Δ LDL-C (r = 0.03; P = 0.72), ΔTG (r = 0.06; P = 0.49) and Δ TC levels (r = 0.05; P = 0.55). Statins had no effect on MPV levels (P = 0.32). Conclusions: Statin therapy significantly reduces the RDW levels in stable CAD irrespective of cholesterol levels, which might confirm the anti-inflammatory effect of statins. However, the association between decreased RDW levels and prognosis in stable CAD has to be established by multi-center, prospective studies in large populations.

Cardiovascular disease is a leading cause of mortality worldwide, which is caused mainly by atherosclerosis, a chronic inflammatory disease of blood vessels. Therefore, atherosclerosis represents a complex disorder, which induces damage or imbalance on different levels: for example, genes, cytokines, lipoproteins, cells, vessels, and organs. Lipoprotein apheresis (LA) is a well‐established extracorporeal treatment of severe hyperlipoproteinemia. In addition, LA may have simultaneously crucial effects on many other atherogenic factors during the treatments, for example, as vascular inflammation, rheology, mobilization of adult stem cells and gene expressions in blood or endothelial cells, which will be discussed in this short review. In addition, stable microRNAs besides tissues also appear in extracellular compartments, for example, vessels, involved in atherosclerotic processes, were found to be reduced by LA treatments. In summary, LA represents a complex therapeutic procedure, that provides an ideal tool for the treatment of complex disorders such as atherosclerosis. [ABSTRACT FROM AUTHOR]

Statins are primary drugs in the treatment of hyperlipidemias. This group of drugs is known for its beneficial pleiotropic effects (e.g., reduction of inflammatory state). However, a growing body of evidence suggests its diabetogenic properties. The culpable mechanism is not completely understood and might be related to the damage to pancreatic beta cells. Therefore, we conceived an in vitro study to explore the impact of atorvastatin on pancreatic islet beta cells line (1.1.E7). We evaluated the influence on viability, insulin, low-density lipoprotein (LDL) receptor, and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. A significant drop in mRNA for proinsulin and insulin expression was noted. Concurrently, a rise in LDL receptor at the protein level in cells exposed to atorvastatin was noted. Further experiments have shown that exenatide -belonging to glucagon-like peptide 1 (GLP-1) analogs that are used in a treatment of diabetes and known for its weight reducing properties -can alleviate the observed alterations. In this case, the mechanism of action of exenatide was dependent on a protein kinase A pathway. In conclusion, our results support the hypothesis that statin may have diabetogenic properties, which according to our study is related to reduced insulin expression. The concomitant use of GLP-1 receptor agonist seemed to successfully revert insulin expression. [ABSTRACT FROM AUTHOR]

Objectives: Mean platelet volume (MPV) has been shown to be a predictor of platelet activation and plays a crucial role in the pathogenesis of atherosclerosis. Red cell distribution width (RDW) is a measure of the variability of erythrocyte volumes and might reflect underlying chronic inflammation. Both MPV and RDW are related to increased risk for cardiovascular disease. Since statins have pleiotropic effects, we aim to investigate the effect of statins on this possible hematologic markers of atherosclerotic risk in stable coronary artery disease (CAD). Materials and Methods: One hundred and twenty-one statin-naive patients who had undergone coronary angiography for stable CAD between June 2012 and June 2013 were retrospectively enrolled in this study. Patients were treated with atorvastatin or rosuvastatin. The lipid profile and hematological parameters were measured at baseline and after statin treatment. Results: One hundred and twenty-one patients were included in the study. The mean age was 60.5 ± 9 years and 38% of patients were women. Out of 121 patients, 106 (87.6%) patients received atorvastatin therapy and 15 (12.4%) patients received rosuvastatin therapy. After a median follow-up period of 36 days, statin treatment markedly reduced low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) levels (P = 0.0001, for all). For hematological parameters, only RDW significantly decreased after statin treatment (P = 0.0001). The Δ RDW were not associated with Δ LDL-C (r = 0.03; P = 0.72), ΔTG (r = 0.06; P = 0.49) and Δ TC levels (r = 0.05; P = 0.55). Statins had no effect on MPV levels (P = 0.32). Conclusions: Statin therapy significantly reduces the RDW levels in stable CAD irrespective of cholesterol levels, which might confirm the anti-inflammatory effect of statins. However, the association between decreased RDW levels and prognosis in stable CAD has to be established by multi-center, prospective studies in large populations. [ABSTRACT FROM AUTHOR]

Influenza vaccines are designed to mimic natural influenza virus exposure and stimulate a long-lasting immune response to future infections. The evolving nature of the influenza virus makes vaccination an important and efficacious strategy to reduce healthcare-related complications of influenza. Several lines of evidence indicate that influenza vaccination may induce nonspecific effects, also referred to as heterologous or pleiotropic effects, that go beyond protection against infection. Different explanations are proposed, including the upregulation and downregulation of cytokines and epigenetic reprogramming in monocytes and natural killer cells, imprinting an immunological memory in the innate immune system, a phenomenon termed “trained immunity”. Also, cross-reactivity between related stimuli and bystander activation, which entails activation of B and T lymphocytes without specific recognition of antigens, may play a role. In this review, we will discuss the possible nonspecific effects of influenza vaccination in cardiovascular disease, type 1 diabetes, cancer, and Alzheimer’s disease, future research questions, and potential implications. A discussion of the potential effects on infections by other pathogens is beyond the scope of this review.

The single nucleotide polymorphism (SNP) rs4148727 in ABCB1 (encoding p-glycoprotein) is associated with lipid levels; however, its association with type 2 diabetes (T2DM) and its the genetic correlation with lipid profiles and T2DM are unclear. We included 2300 participants from 593 families. A generalized estimating equations (GEE) model and Cox regression models were used to estimate the SNP's effects on T2DM and lipid profiles. The participation of the SNP in T2DM pathogenesis through lipid-associated pathways was tested using mediation analysis. The G allele of the SNP was related to a 32% (6–64%, p = 0.015) increase in T2DM risk. It was also associated with a 10% (1–20%, p = 0.029), 17% (3–32%, p = 0.015), and 4% (1–7%, p = 0.015) increment in total cholesterol (TC), triglyceride (TG), and apolipoprotein A (Apo-A) concentrations, respectively. According to the mediation analysis, only TG (6.9%) and Apo-B (4.0%) had slight but significant mediation effects on the total impact of the SNP on T2DM. The pleiotropic effects of the ABCB1 variant on T2DM and lipids likely act via different pathways. The biological mechanisms should be verified in a future study. [ABSTRACT FROM AUTHOR]

Aim. To study the lipid-lowering and pleiotropic vasoprotective effects of atorvastatin depending on the achievement of the target low-density lipoprotein cholesterol (LDL-C) level in patients after ST-segment elevation myocardial infarction (STEMI) within 48-week follow-up period.Material and methods. A total of 125 patients with STEMI, randomized to receive atorvastatin 40 or 80 mg per day for 48 weeks, were examined. On days 7-9, after 24, 48 weeks, we performed biochemical blood tests, echocardiography, as well as assessed the carotid arteries and endothelial function. The subjects were divided into the following groups: high-efficiency therapy (HET) — 41 patients who reached target LDL-C at control visits; moderate-efficiency therapy (MET) — 35 patients who achieved target LDL-C at one visit; low-efficiency therapy effective (LET) — 49 people who did not reach the target LDL-C. Differences were considered significant at p

Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect. Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction. Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 activator colivelin partially rescued the expression of TF. Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis. [ABSTRACT FROM AUTHOR]

The diversity of physiological effects and pharmacological actions of glucocorticoids determines their use in the treatment of diseases and pathological conditions in rheumatology, nephrology, allergology, hematology, transplantology, hepatology, neurology, intensive care etc. Experimental and clinical research in recent decades has revealed new aspects of pharmacological and pleiotropic effects based on elucidation of the genomic and non-genomic mechanism; influence on different ways of transmitting and regulating the intracellular signal; variability of cellular and tissue responses depending on physiological or pathological condition; the diversity of pharmacological or adverse effects depending on the dose and dosing regimen, purpose of treatment; pharmacokinetic characteristics depending on the structure and physicochemical properties. The pharmacodynamic and pharmacokinetic aspects of glucocorticoids allow the practitioner to rationally select the glucocorticoid in order to perform an effective and harmless therapy. [ABSTRACT FROM AUTHOR]

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has profoundly affected the lives of millions of people. To date, there is no approved vaccine or specific drug to prevent or treat COVID-19, while the infection is globally spreading at an alarming rate. Because the development of effective vaccines or novel drugs could take several months (if not years), repurposing existing drugs is considered a more efficient strategy that could save lives now. Statins constitute a class of lipid-lowering drugs with proven safety profiles and various known beneficial pleiotropic effects. Our previous investigations showed that statins have antiviral effects and are involved in the process of wound healing in the lung. This triggered us to evaluate if statin use reduces mortality in COVID-19 patients. Results After initial recruitment of 459 patients with COVID-19 (Shiraz province, Iran) and careful consideration of the exclusion criteria, a total of 150 patients, of which 75 received statins, were included in our retrospective study. Cox proportional-hazards regression models were used to estimate the association between statin use and rate of death. After propensity score matching, we found that statin use appeared to be associated with a lower risk of morbidity [HR = 0.85, 95% CI = (0.02, 3.93), P = 0.762] and lower risk of death [(HR = 0.76; 95% CI = (0.16, 3.72), P = 0.735)]; however, these associations did not reach statistical significance. Furthermore, statin use reduced the chance of being subjected to mechanical ventilation [OR = 0.96, 95% CI = (0.61–2.99), P = 0.942] and patients on statins showed a more normal computed tomography (CT) scan result [OR = 0.41, 95% CI = (0.07–2.33), P = 0.312]. Conclusions Although we could not demonstrate a significant association between statin use and a reduction in mortality in patients with COVID19, we do feel that our results are promising and of clinical relevance and warrant the need for prospective randomized controlled trials and extensive retrospective studies to further evaluate and validate the potential beneficial effects of statin treatment on clinical symptoms and mortality rates associated with COVID-19.

The circulating low-density lipoprotein concentration in blood can be reduced by the administration of statins. Frequently simvastatin (SV) is prescribed. Due to the reported pleiotropic effects of SV the aim of this study was to evaluate mineralization effects on human adipose tissue-derived stromal cells upon administration of SV. After informed consent human adipose tissue-derived stromal cells were obtained from tissue surplus of regular treatments of 14 individuals. According to established protocols after adding various SV concentrations (0.01 µM, 0.1 µM, 1.0 µM, 2.0 µM), alkaline phosphate (osteoblastic marker), mineralization capability and viability were determined at day 18, 21 and 28. The Kruskal–Wallis test was performed for statistical analysis. After adding SV a dose-dependent significant decreased viability and levels of alkaline phosphatase (p < 0.01) and a significantly increased mineralization (p < 0.01) of the primary cultures was recognized during the late mineralization stage. Mineralization of the human adipose tissue-derived stromal cells was induced by SV, possibly originated from alternative pathways than the alkaline phosphatase pathway. Further investigations should be performed regarding switching into the osteoblastic differentiation and as a possible source of cells that can be used as the basis for a potential bone graft substitute, which may allow an extension of the field of application.

Heart rate (HR) lowering during acute coronary syndrome (ACS) is beneficial as it reduces myocardial oxygen consumption. However, the role of ivabradine as an HR-lowering agent in the setting of ACS is not clear. We aimed to systematically review and synthesize the current evidence on the role of ivabradine use in the ACS. A systematic review was conducted for eligible randomized clinical trials and quasi-experimental studies, between 2009 and 2020, that investigated the use of ivabradine in ACS. Various clinical endpoints were evaluated such as major adverse cardiovascular events, efficacy in HR control, impact on left ventricular (LV) dimensions and function, and overall safety. Eleven publications were included encompassing a total of 1833 patients. The mean age of the examined cohort was 57 ± 11 years and 80 % were men. Seven studies were in the setting of ST-segment elevation myocardial infarction (MI) while the remaining studies also included patients with unstable angina and non-ST-segment elevation MI. Ivabradine was administered as a peroral drug with dosing from 2.5 to 7.5 mg b.i.d. Overall, the addition of ivabradine was superior to the control arm concerning HR control with a good safety profile. Beneficial effects on LV function and potential impact on infarct size reduction were observed as well. The use of ivabradine appeared to not affect short-term mortality. In conclusion, the use of ivabradine for HR control is safe, feasible, and efficacious for HR control in the ACS. Further studies are required to elucidate other potentially beneficial effects of ivabradine.