👤 Nastaran Najafi

The formation and progression of atherosclerotic plaques occur through cellular dysfunction and remodeling of the extracellular matrix in the sub-endothelial space of vessels. The immunity against specific antigens is suggested to mitigate the atherosclerosis process. Primarily, studies have suggested that certain antigens, such as ox-LDL, ApoB-100, CETP, PCSK9, HSP60, MHC-II-derived peptides, and interleukins, are involved in atherosclerosis. However, recognizing the intricate interplay between immune responses and the formation of arterial plaques is essential to optimize immunization against atherosclerosis. In this review, the roles of some genes were presented in triggering atherosclerotic plaque events. Furthermore, some immunization approaches are presented to target these genes. The studies suggested that vaccination against the progression of atherosclerosis is an essential and effective approach to reducing the high death rate in autoimmune diseases. Show less

Neurological disorders like Alzheimer's disease (AD) and Parkinson's disease (PD) manifest through gradually deteriorating cognitive functions. An encouraging strategy for addressing these disorders involves the inhibition of precursor-cleaving enzyme 1 (BACE1). In the current research, a virtual screening technique was employed to identify potential BACE1 inhibitors among selected herbal isolates. This study evaluated 79 flavonoids, anthraquinones (AQs), and cinnamic acid derivatives for their potential blood-brain barrier (BBB) permeability. Using the AutoDock 4.0 tool, molecular docking analysis was conducted to determine the binding affinity of BBB permeable compounds to the BACE1 active site. Molecular dynamics (MD) simulations were performed to assess the stability of the docked poses of the most potent inhibitors. The interactions between the most effective plant-based inhibitors and the residues within the BACE1 catalytic site were examined before and after MD simulations. Ponciretin, danthron, chrysophanol, and N-p-coumaroyltyramine were among the highest-ranking BACE1 inhibitors, with inhibition constant values calculated in the nanomolar range. Furthermore, during 10 ns simulations, the docked poses of these ligands were observed to be stable. The findings propose that ponciretin, danthron, chrysophanol, and N-p-coumaroyltyramine might serve as potential choices for the treatment of AD and PD, laying the groundwork for the creation of innovative BACE1 inhibitors. Show less

Since obesity and diabetes are prevalent worldwide, identifying the factors affecting these two conditions can effectively alter them. We decided to investigate the expression of obesity and diabetes genes in infants with birth weights lower than 2500 g in comparison with infants with normal birth weights. 215 healthy infants between the ages of 5-6 months were used in the current case-control research, which was conducted at health and treatment facilities in Kermanshah. Infants who were healthy were chosen for the research after their weight and height were measured and compared to the WHO diagram to ensure that they were well-grown and in good health. There were 137 infants in the control group and 78 infants in the case group. All newborns had 5 cc of blood drawn intravenously. To assess the expression of the genes MC4R, MTNR1B, PTEN, ACACB, PPAR-γ, PPAR-α, NRXN3, NTRK2, PCSK1, A2BP1, TMEM18, LXR, BDNF, TCF7L2, FTO and CPT1A, blood samples were gathered in EDTA-coated vials. Chi-square, Mann-Whitney U, and Spearman analyses were used to examine the data. A significant inverse correlation between birth weight and obesity and diabetes genes, including MTNR1B, NTRK2, PCSK1, and PTEN genes (r= -0.221, -0.235, -0.246, and - 0.418, respectively). In addition, the LBW infant's expression level was significantly up-regulated than the normal-weight infants (P = 0.001, 0.007, 0.001, and < 0.001, respectively). The expression level of the PPAR-a gene had a significantly positive correlation with birth weight (r = 0.19, P = 0.005). The expression level of the PPAR-a gene in the normal-weight infants was significantly up-regulated than the LBW infants (P = 0.049). The expression levels of MTNR1B, NTRK2, PCSK1, and PTEN genes were up-regulated in the LBW infants; however, the expression level of PPAR-a gene was significantly down-regulated in the LBW infants compared to the infants with normal birth weight. Show less

Late-infantile neuronal ceroid lipofuscinosis (LINCL) and juvenile neuronal ceroid lipofuscinosis (JNCL) are inherited neurodegenerative diseases caused by mutations in the genes encoding lysosomal proteins tripeptidyl peptidase 1 (TPP1) and CLN3 protein, respectively. TPP1 is well-understood and, aided by animal models that accurately recapitulate the human disease, enzyme replacement therapy has been approved and other promising therapies are emerging. In contrast, there are no effective treatments for JNCL, partly because the function of the CLN3 protein remains unknown but also because animal models have attenuated disease and lack robust survival phenotypes. Mouse models for LINCL and JNCL, with mutations in Tpp1 and Cln3, respectively, have been thoroughly characterized but the phenotype of a double Cln3/Tpp1 mutant remains unknown. We created this double mutant and find that its phenotype is essentially indistinguishable from the single Tpp1 Show less

Hypertrophic cardiomyopathy (HCM) has been associated with reduced β-adrenergic receptor (β-AR) signalling, leading downstream to a low protein kinase A (PKA)-mediated phosphorylation. It remained undefined whether all PKA targets will be affected similarly by diminished β-AR signalling in HCM. We aimed to investigate the role of β-AR signalling on regulating myofilament and calcium handling in an HCM mouse model harbouring a gene mutation (G > A transition on the last nucleotide of exon 6) in Mybpc3 encoding cardiac myosin-binding protein C. Cardiomyocyte contractile properties and phosphorylation state were measured in left ventricular permeabilized and intact cardiomyocytes isolated from heterozygous (HET) or homozygous (KI) Mybpc3-targeted knock-in mice. Significantly higher myofilament Ca²⁺sensitivity and passive tension were detected in KI mice, which were normalized after PKA treatment. Loaded intact cardiomyocyte force-sarcomere length relation was impaired in both HET and KI mice, suggesting a reduced length-dependent activation. Unloaded cardiomyocyte function revealed an impaired myofilament contractile response to isoprenaline (ISO) in KI, whereas the calcium-handling response to ISO was maintained. This disparity was explained by an attenuated increase in cardiac troponin I (cTnI) phosphorylation in KI, whereas the increase in phospholamban (PLN) phosphorylation was maintained to wild-type values. These data provide evidence that in the KI HCM mouse model, β-AR stimulation leads to preferential PKA phosphorylation of PLN over cTnI, resulting in an impaired inotropic and lusitropic response. Show less

Diastolic dysfunction is general to all idiopathic dilated (IDCM) and hypertrophic cardiomyopathy (HCM) patients. Relaxation deficits may result from increased actin-myosin formation during diastole due to altered tropomyosin position, which blocks myosin binding to actin in the absence of Ca(2+). We investigated whether ADP-stimulated force development (without Ca(2+)) can be used to reveal changes in actin-myosin blockade in human cardiomyopathy cardiomyocytes. Cardiac samples from HCM patients, harboring thick-filament (MYH7mut, MYBPC3mut) and thin-filament (TNNT2mut, TNNI3mut) mutations, and IDCM were compared with sarcomere mutation-negative HCM (HCMsmn) and nonfailing donors. Myofilament ADP sensitivity was higher in IDCM and HCM compared with donors, whereas it was lower for MYBPC3. Increased ADP sensitivity in IDCM, HCMsmn, and MYH7mut was caused by low phosphorylation of myofilament proteins, as it was normalized to donors by protein kinase A (PKA) treatment. Troponin exchange experiments in a TNNT2mut sample corrected the abnormal actin-myosin blockade. In MYBPC3trunc samples, ADP sensitivity highly correlated with cardiac myosin-binding protein-C (cMyBP-C) protein level. Incubation of cardiomyocytes with cMyBP-C antibody against the actin-binding N-terminal region reduced ADP sensitivity, indicative of cMyBP-C's role in actin-myosin regulation. In the presence of Ca(2+), ADP increased myofilament force development and sarcomere stiffness. Enhanced sarcomere stiffness in sarcomere mutation-positive HCM samples was irrespective of the phosphorylation background. In conclusion, ADP-stimulated contraction can be used as a tool to study how protein phosphorylation and mutant proteins alter accessibility of myosin binding on actin. In the presence of Ca(2+), pathologic [ADP] and low PKA-phosphorylation, high actin-myosin formation could contribute to the impaired myocardial relaxation observed in cardiomyopathies. Show less

Hypertrophic cardiomyopathy (HCM), the most common genetic cardiac disorder, is frequently caused by mutations in MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C). Moreover, HCM is the leading cause of sudden cardiac death (SCD) in young athletes. Interestingly, SCD is more likely to occur in male than in female athletes. However, the pathophysiological mechanisms leading to sex-specific differences are poorly understood. Therefore, we studied the effect of sex and exercise on functional properties of the heart and sarcomeres in mice carrying a MYBPC3 point mutation (G > A transition in exon 6) associated with human HCM. Echocardiography followed by isometric force measurements in left ventricular (LV) membrane-permeabilized cardiomyocytes was performed in wild-type (WT) and heterozygous (HET) knock-in mice of both sex (N = 5 per group) in sedentary mice and mice that underwent an 8-week voluntary wheel-running exercise protocol. Isometric force measurements in single cardiomyocytes revealed a lower maximal force generation (F max) of the sarcomeres in male sedentary HET (13.0 ± 1.1 kN/m(2)) compared to corresponding WT (18.4 ± 1.8 kN/m(2)) male mice. Exercise induced a higher F max in HET male mice, while it did not affect HET females. Interestingly, a low cardiac troponin I bisphosphorylation, increased myofilament Ca(2+)-sensitivity, and LV hypertrophy were particularly observed in exercised HET females. In conclusion, in sedentary animals, contractile differences are seen between male and female HET mice. Male and female HET hearts adapted differently to a voluntary exercise protocol, indicating that physiological stimuli elicit a sexually dimorphic cardiac response in heterozygous MYBPC3-targeted knock-in mice. Show less

High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce. To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins. Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca(2+) sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca(2+) sensitivity was similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values. High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM. Show less

Hypertrophic cardiomyopathy (HCM), typically characterized by asymmetrical left ventricular hypertrophy, frequently is caused by mutations in sarcomeric proteins. We studied if changes in sarcomeric properties in HCM depend on the underlying protein mutation. Comparisons were made between cardiac samples from patients carrying a MYBPC3 mutation (MYBPC3(mut); n=17), mutation negative HCM patients without an identified sarcomere mutation (HCM(mn); n=11), and nonfailing donors (n=12). All patients had normal systolic function, but impaired diastolic function. Protein expression of myosin binding protein C (cMyBP-C) was significantly lower in MYBPC3(mut) by 33±5%, and similar in HCM(mn) compared with donor. cMyBP-C phosphorylation in MYBPC3(mut) was similar to donor, whereas it was significantly lower in HCM(mn). Troponin I phosphorylation was lower in both patient groups compared with donor. Force measurements in single permeabilized cardiomyocytes demonstrated comparable sarcomeric dysfunction in both patient groups characterized by lower maximal force generating capacity in MYBPC3(mut) and HCM(mn,) compared with donor (26.4±2.9, 28.0±3.7, and 37.2±2.3 kN/m(2), respectively), and higher myofilament Ca(2+)-sensitivity (EC(50)=2.5±0.2, 2.4±0.2, and 3.0±0.2 μmol/L, respectively). The sarcomere length-dependent increase in Ca(2+)-sensitivity was significantly smaller in both patient groups compared with donor (ΔEC(50): 0.46±0.04, 0.37±0.05, and 0.75±0.07 μmol/L, respectively). Protein kinase A treatment restored myofilament Ca(2+)-sensitivity and length-dependent activation in both patient groups to donor values. Changes in sarcomere function reflect the clinical HCM phenotype rather than the specific MYBPC3 mutation. Hypocontractile sarcomeres are a common deficit in human HCM with normal systolic left ventricular function and may contribute to HCM disease progression. Show less