👤 Kaveh Hosseini

Familial hypercholesterolemia (FH) is the most common monogenic lipid disorder, primarily resulting from mutations in LDLR, APOB, and PCSK9 genes. These mutations cause persistently high levels of low-density lipoprotein cholesterol (LDL-C), predisposing affected individuals to premature atherosclerotic cardiovascular disease (ASCVD). Homozygous FH (HoFH), a rare but severe form, manifests early in life with cutaneous xanthomas and accelerated coronary and aortic disease. Early diagnosis and aggressive, lifelong management are crucial, yet challenges remain, particularly when follow-up is interrupted. We report the case of a 20-year-old female diagnosed with HoFH at age 13 after presenting with xanthomas. Initial evaluation revealed mild to moderate aortic stenosis and early coronary artery involvement. Genetic testing confirmed a homozygous LDLR mutation. Despite treatment with atorvastatin and evolocumab, partial lipid control was achieved, and follow-up was disrupted during the COVID-19 pandemic. At 20 years, she presented with worsening dyspnea, paroxysmal nocturnal dyspnea, and orthopnea. Advanced imaging documented severe heart failure with an ejection fraction of 20%, significant ventricular dilation, severe mitral regurgitation, and calcified aortic stenosis. Coronary angiography demonstrated critical coronary stenoses, while subsequent adjustments in her lipid-lowering regimen, including rosuvastatin, ezetimibe, increased evolocumab dosing, and bempedoic acid, failed to stabilize her condition. Despite recommendations for surgical intervention, the patient's critical status precluded operative management, and she tragically died on the day of her scheduled follow-up. This case underscores the aggressive natural history of HoFH and the dire consequences of interrupted follow-up care. Early detection and sustained, multidisciplinary management are essential to mitigate rapid cardiovascular deterioration in HoFH patients. Consistent monitoring and prompt therapeutic adjustments remain pivotal in improving outcomes and reducing the high mortality risk associated with advanced aortic and coronary complications in these patients. Show less

Lecanemab is an anti-amyloid monoclonal antibody, recently approved in the UK as a treatment for mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD) in adults who are apolipoprotein E ε4 gene ( Show less

It is unclear whether the different Alzheimer's disease (AD) progression trajectories of apolipoprotein E (APOE) ɛ4 carriers is reflected by blood phosphorylated tau (p-tau) analytes. We assessed longitudinal trajectories in plasma p-tau181, 217, and 231, in amyloid beta-positive (A+) and negative (A-) APOE ɛ4 carriers (E+) or non-carriers (E-). We included 2039 participants from the observational Translational Biomarkers in Aging and Dementia (TRIAD) and Alzheimer's Disease Neuroimaging Initiative cohorts, categorized into 840 A-E-, 251 A-E+, 386 A+E4-, and 616 A+E4+. Longitudinal data were available for 1045 participants. In TRIAD, ALZpath p-tau217 (β = 0.45, p = 0.02) and p-tau217+ These findings suggest p-tau217 as a marker of faster progression in APOE ɛ4 carriers, highlighting its potential in disease stratification. Blood phosphorylated tau (p-tau)217 increases faster in apolipoprotein E (APOE) ɛ4 carriers with amyloid pathology. p-tau181 and p-tau231 do not increase faster in APOE ɛ4 carriers. APOE ɛ4 carriership does not change p-tau in individuals without amyloid pathology. Show less

Glucomannan has been studied for various health benefits, but its effects on lipid profile in adults are not well understood. This meta-analysis aims to evaluate the impact of glucomannan supplementation on serum/plasma levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), Apo B1, Apo A1, APO-B/ A1 ratio, and LDL-C/ HDL-C in adults. A comprehensive search was conducted across Scopus, PubMed, Embase, and Web of Science from inception to June 2024 to identify randomized controlled trials (RCTs) assessing glucomannan supplementation on lipid profile in adults. Data were extracted and analyzed using random effects model to determine the standardized mean differences (SMDs) and 95% confidence intervals (CIs) for each biomarker. Glucomannan supplementation significantly decreased TC (SMD: -3.299; 95% CI: -4.955, -1.664, P < 0.001; I Glucomannan supplementation has a beneficial effect on the level of TC and LDL-C. Show less

The association of CETP Taq1B polymorphism with some metabolic traits is still controversial. The interaction of adherence to dietary indices with this polymorphism on the severity of coronary artery stenosis and serum lipid parameters needs to be investigated. This study aimed to test this hypothesis. This cross-sectional study included 453 patients who were referred from Afshar Hospital of Yazd and undergoing coronary angiography from 2020 to 2021. Dietary intake was evaluated by a 178-item validated and reliable dietary questionnaire. Dietary indices such as dietary antioxidant index (DAI), dietary antioxidant quality score (DAQS), and dietary phytochemical index (DPI) are determined according to dietary guidelines. The Taq1B variant was genotyped by the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Two-way ANOVA was used to test the interaction between Taq1B polymorphism and dietary indices. The results of the frequency analysis of Taq1B genotypes showed that 10.4% were B1B1, 72.4% B1B2, and 17.2% B2B2. No significant interaction was found between the Taq1B variant with high adherence to DAQS, DAI, and DPI on total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglyceride (TG) levels, and Gensini score (GS) and Syntax score (SS). In high-adherence dietary indices, lipid profile and coronary artery stenosis scores did not differ significantly in Taq1B genotypes. Due to the insignificant results in this research, further studies are needed to investigate the role of Taq1B SNP in modulating dyslipidemia and the severity of the CAD in interaction with dietary indices. Show less

Cardiovascular diseases [CVD] are the number one reason for morbidity and mortality in the modern world, and their incidence is increasing at an incredible pace. Increasing evidence has shown the significant functions of microRNAs in the cardiovascular system and has highlighted their potential application as a new era of diagnostic and therapeutic targets for CVD that can improve the prognosis and life expectancy of patients. Among more than 2,000 microRNAs, microRNA-21 [miR-21] is highly expressed in human hearts and has earned the interest of researchers as a potential biomarker in a wide range of common heart conditions. Here, we summarized recent research progress regarding the significant role of miR-21 in CVD, focusing on cardiotoxicity, heart arrhythmias, cardiomyopathies, and hypertension. Several signaling pathways [TGF-β1/Smad2 signaling, FGFR1/FGF21/PPARγ, NF-κB/miR-21/SMAD7, miR-21/SPRY1/ERK/mTOR …] and molecular targets [BTG2, PDCD4, PTEN, STAT3…] were reported to be controlled, at least partially, by miR-21 and are linked to CVD pathogenesis. Most investigations highlighted miR-21 cardioprotective functions in heart injury, while some other studies showed that this miR is elevated in the serum/tissue of patients, promoting fibrosis and cardiac dysfunction. This dual role can be explained by the fact that miR-21 has multiple regulatory functions depending on the microenvironment, downstream signaling, and target genes, which indicates that cell-type-specific investigations should receive more attention. With further investigations, miR-21 can be considered a novel tailored therapy with favorable outcomes. Show less

Pregnancy is a unique challenge for the immune system. Any disturbance in the immune system in the first trimester could result in further pregnancy complications. In this regard, the current study aimed to investigate the association between serum levels of a group of cytokines in the first trimester of pregnancy with the onset of preeclampsia (PE) and fetal growth restriction (FGR). Serum samples were collected from 550 pregnant women at their 11th - 13th weeks of pregnancy and followed up to delivery. Out of all cases, 15 women complicated with preeclampsia and 15 ones diagnosed with FGR were included in the study. The serum levels of IFN-γ, CCL2, IL-10, IL-35 and IL-27 were checked in the collected sera of mentioned patients and compared to 60 women with normal pregnancy outcomes. In the preeclampsia group, the mean level of IFN-γ was significantly higher (p < 0.001) while the CCL2 serum level was significantly lower (p < 0.003) as compared to control group. There was no significant difference between the preeclampsia group and controls regarding other cytokines. In the FGR group, the mean serum level of IFN-γ was significantly higher compared to the healthy pregnancy group (p < 0.001) but other cytokines showed no significant differences. In the FGR group, a significant positive correlation was found between IL-10 level and neonates' weight (p < 0.05). Based on the results of the present study, an elevated level of IFN-γ and a reduced level of CCL2 at the first trimester of pregnancy could lead to complications such as PE and/or FGR. Show less

BK virus associated nephropathy (BKVAN) is one of the common causes of graft loss among kidney transplanted recipients (KTRs). The current treatment for BKV nephropathy is decreasing the immunosuppressive regimen in KTRs. Interleukin-27 (IL-27) is a multifunctional cytokine that might be the front-runner of an important pathway in this regard. Therefore, in current study it is tried to evaluate the changes in the expression level of IL-27 and some related molecules, resulting from BKV reactivation in KTR patients. EDTA-treated blood samples were collected from all participants. Patients were divided into two groups, 31 kidney transplant recipients with active and 32 inactive BKV infection, after being monitored by Real time PCR (Taq-Man) in plasma. Total of 30 normal individuals were considered as healthy control group. Real time PCR (SYBR Green) technique is used to determine the expression level of studied genes. The results of gene expression comparisons showed that the expression level of IL-27, IFN-γ, TNF-α, TNFR2 and IRF7 genes was significantly higher in inactive group in comparison to active group. The expression level of TLR4 was lower in both active and inactive groups in comparison to control group. ROC curve analysis showed that IL-27 and IRF7 are significantly different amongst other studied genes. Finally, the analyses revealed that the expression level of most of the studied genes (except for TNF-α and TLR4) have significant correlation with viral load. Our findings revealed that IL-27, IFN-γ, TNF-α, TNFR2 and IRF7 expression level is higher in inactive group and TLR4 expression level is lower in patients' groups in comparison to control group. Also, ROC curve analysis showed IL-27 and IRF7 can significantly differentiate studied groups (BKV active vs. inactive). Therefore, these results might help elucidating the pattern in charge of BKV reactivation in kidney transplanted patients. Show less

Systemic sclerosis (SSc) is a connective tissue disease associated with vascular damage and multi organ fibrotic changes with unknown pathogenesis. Most SSc patients suffer from defective angiogenesis/vasculogenesis and cardiac conditions leading to high mortality rates. We aimed to investigate the cardiovascular phenotype of SSc by cardiogenic differentiation of SSc induced pluripotent stem cells (iPSC). In this experimental study, we generated iPSC from two diffuse SSc patients, followed by successful differentiation into endothelial cells (ECs) and cardiomyocytes (CMs). SSc-derived EC (SSc-EC) expressed KDR, a nearly EC marker, similar to healthy control-EC (C1-EC). After sorting and culturing KDR+ cells, the resulting EC expressed CD31, a late endothelial marker, but vascular endothelial (VE)-cadherin expression markedly dropped resulting in a functional defect as reflected in tube formation failure of SSc-EC. Interestingly, upregulation of SNAI1 (snail family transcriptional repressor 1) was observed in SSc-EC which might underlie VE-cadherin downregulation. Furthermore, SSc-derived CM (SSc-CM) successfully expressed cardiacspecific markers including ion channels, resulting in normal physiological behavior and responsiveness to cardioactive drugs. This study provides an insight into impaired angiogenesis observed in SSc patients by evaluating Show less

Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates. Show less

Vitiligo is a common skin disorder in which melanocytes are destroyed by auto-reactive immune responses. The loss of melanocytes results in the appearance of depigmented areas in different parts of the body. Cytokines have remarkable roles in the pathogenesis of vitiligo, such as IL-1, IL-6, and TNF-α; interleukin 27 (IL-27) is a new member of the IL-6/IL-12 family, mainly released by activated antigen-presenting cells. IL-27 has been suggested to function as a pro-inflammatory as well as an anti-inflammatory cytokine. Altered concentrations of IL-27 have been shown in various auto-immune diseases such as multiple sclerosis, rheumatoid arthritis, and psoriasis. No studies have been conducted to determine the expression of this cytokine in vitiligo patients. The objective of this study was to determine the serum concentration of IL-27 in vitiligo patients and compare it with normal individuals. The serum concentration of IL-27 in 79 vitiligo patients was evaluated in comparison to 45 healthy controls using ELISA assay. Results showed decreased concentration of IL-27 in vitiligo patients as compared with healthy subjects (p=0.026). Furthermore, no correlation between IL-27 concentrations and disease parameters such as vitiligo severity and the extension of the depigmented area was observed. A larger sample size would be more recommended for this study. The reduction in the serum levels of IL-27 in vitiligo patients compared to normal subjects suggested the possible anti-inflammatory role of this cytokine in vitiligo. Thus, IL-27 may be considered as a new target for the manipulation of the immune system in vitiligo patients. Show less

The objective of the study was to evaluate the effect of overfeeding a moderate energy diet and a 2,4-thiazolidinedione (TZD) injection on blood and hepatic tissue biomarkers of lipid metabolism, oxidative stress, and inflammation as it relates to insulin sensitivity. Fourteen dry non-pregnant cows were fed a control (CON) diet to meet 100% of NRC requirements for 3 wk, after which half of the cows were assigned to a moderate-energy diet (OVE) and half of the cows continued on CON for 6 wk. All cows received an intravenous injection of 4 mg TZD/kg of body weight (BW) daily from 2 wk after initiation of dietary treatments and for 2 additional week. Compared with CON cows and before TZD treatment, the OVE cows had lower concentration of total protein, urea and albumin over time. The concentration of cholesterol and tocopherol was greater after 2 wk of TZD regardless of diet. Before and after TZD, the OVE cows had greater concentrations of AST/GOT, while concentrations of paraoxonase, total protein, globulin, myeloperoxidase, and haptoglobin were lower compared with CON cows. Regardless of diet, TZD administration increased the concentration of ceruloplasmin, ROMt, cholesterol, tocopherol, total protein, globulin, myeloperoxidase and beta-carotene. In contrast, the concentration of haptoglobin decreased at the end of TZD injection regardless of diet. Prior to TZD injection, the mRNA expression of Based on molecular and blood data, administration of TZD enhanced some aspects of insulin sensitivity while causing contradictory results in terms of inflammation and oxidative stress. The bovine liver is TZD-responsive and level of dietary energy can modify the effects of TZD. Because insulin sensitizers have been proposed as useful tools to manage dairy cows during the transition period, further studies are required to investigate the potential hepatotoxicity effect of TZD (or similar compounds) in dairy cattle. Show less

The objective of this study was to study how changing the ratio of Lys to Thr, Lys to His, and Lys to Val affects the expression of lipogenic genes and microRNA (miRNA) in bovine mammary epithelial cells. Triplicate cultures with the respective "optimal" amino acid (AA) ratio (OPAA = Lys:Met 2.9:1; Thr:Phe 1.05:1; Lys:Thr 1.8:1; Lys:His 2.38:1; Lys:Val 1.23:1) plus rapamycin (OPAARMC; positive control), OPAA, Lys:Thr 2.1:1 (LT2.1), Lys:Thr 1.3:1 (LT1.3), Lys:His 3.05:1 (LH3.0), or Lys:Val 1.62:1 (LV1.6) were incubated in lactogenic medium for 12 h. The expression of 15 lipogenic genes and 7 miRNA were evaluated. Responses to LT2.1, LT1.3, LH3.0, and LV1.6 relative to the control (OPAARMC) included up-regulated expression of ACSS2, FABP3, ACACA, FASN, SCD, LPIN1, INSIG1, SREBF1, PPARD, and NR1H3 (commonly known as LXR-α). Furthermore, LV1.6 up-regulated expression of ACSL1, DGAT1, and RXRA and down-regulated PPARG expression. Although no effect of OPAA on expression of PPARG was observed, compared with the control, OPAA up-regulated expression of the PPAR targets ACSS2, FABP3, ACACA, FASN, SCD, LPIN1, INSIG1, and SREBF1. Compared with the control, the expression of the anti-lipogenic MIR27AB was down-regulated by OPAA, LT2.1, LT1.3 and LH3.0. In contrast, compared with the control, the expression of the pro-lipogenic MIR21 was up-regulated by LT2.1, LT1.3, LH3.0, and LV1.6. The observed up-regulation of lipogenic gene networks and the changes in expression of key miRNA involved in the control of lipogenic balance are indicative of a potentially important role of EAA ratios and mTOR signaling in the regulation of milk fat synthesis. Show less

The severe forms of hypertriglyceridaemia (HTG) are caused by mutations in genes that lead to the loss of function of lipoprotein lipase (LPL). In most patients with severe HTG (TG > 10 mmol L(-1) ), it is a challenge to define the underlying cause. We investigated the molecular basis of severe HTG in patients referred to the Lipid Clinic at the Academic Medical Center Amsterdam. The coding regions of LPL, APOC2, APOA5 and two novel genes, lipase maturation factor 1 (LMF1) and GPI-anchored high-density lipoprotein (HDL)-binding protein 1 (GPIHBP1), were sequenced in 86 patients with type 1 and type 5 HTG and 327 controls. In 46 patients (54%), rare DNA sequence variants were identified, comprising variants in LPL (n = 19), APOC2 (n = 1), APOA5 (n = 2), GPIHBP1 (n = 3) and LMF1 (n = 8). In 22 patients (26%), only common variants in LPL (p.Asp36Asn, p.Asn318Ser and p.Ser474Ter) and APOA5 (p.Ser19Trp) could be identified, whereas no mutations were found in 18 patients (21%). In vitro validation revealed that the mutations in LMF1 were not associated with compromised LPL function. Consistent with this, five of the eight LMF1 variants were also found in controls and therefore cannot account for the observed phenotype. The prevalence of mutations in LPL was 34% and mostly restricted to patients with type 1 HTG. Mutations in GPIHBP1 (n = 3), APOC2 (n = 1) and APOA5 (n = 2) were rare but the associated clinical phenotype was severe. Routine sequencing of candidate genes in severe HTG has improved our understanding of the molecular basis of this phenotype associated with acute pancreatitis and may help to guide future individualized therapeutic strategies. Show less