👤 Amir Amiri

Chronic inflammation constitutes a well-established driver of colorectal carcinogenesis, yet the molecular circuitry linking inflammatory receptor signalling to tumour cell survival remains incompletely delineated. Here we demonstrate that the HMG-CoA reductase inhibitors atorvastatin and rosuvastatin modulate inflammatory survival pathways in colorectal cancer cells in a manner consistent with targeted interference with the protease-activated receptor 2 (PAR-2)-extracellular signal-regulated kinase (ERK)-tumour necrosis factor-α (TNF-α) signalling axis. Using lipopolysaccharide-stimulated HT-29 and Caco-2 cells as complementary models of inflammatory colorectal malignancy, we show that both statins selectively attenuate PAR-2 expression at the protein and transcript levels while leaving structurally related PAR-1 unaffected. This pattern of receptor modulation is accompanied by suppression of total ERK1/2 expression, ERK1/2 phosphorylation, and the transcriptional target DUSP6, together with attenuation of TNF-α secretion. Importantly, these signaling shifts are associated with dual apoptotic programs; the extrinsic pathway, reflected by transcriptional upregulation and proteolytic activation of caspase-8; and the intrinsic mitochondrial pathway, evidenced by reciprocal modulation of Bcl-2 family proteins favoring Bax over Bcl-2. Both pathways converge upon activation of executioner caspase-3 and an increase in Annexin V-defined apoptotic fractions, indicating re-engagement of programmed cell death under inflammatory stress. Notably, rosuvastatin consistently demonstrates superior potency across signaling endpoints, achieving comparable biological effects at lower concentrations than atorvastatin. Collectively, these data indicate that clinically deployed statins target the PAR-2-ERK axis and are associated with re-activation of apoptotic pathways in inflammatory colorectal cancer models, while leaving open the possibility that additional statin-responsive networks contribute to their pro-apoptotic effects. This mechanistic framework provides biological plausibility for epidemiologic observations linking statin use with reduced colorectal cancer risk and improved outcomes, and supports further translational evaluation of PAR-2-directed statin strategies in colorectal malignancy. Show less

X-linked mutations are highly important in clinical diagnosis, and at least 533 disorders are related to the genes located on the X chromosome. A 21-year-old Caucasian woman with a 24-year-old Caucasian man as her fiancé referred Clinical genetic lab for premarital genetic counseling (carrier screening). None of them had any abnormal manifestations. Following genetic counseling, Whole Exome Sequencing (WES) test performed to find the possible pathogenic mutations. Also, after drawing the couple's pedigree, candidate mutations were examined in the woman's parents as well as her uncles. Additionally, Conclusively, the current study emphasizes the non-pathogenic effect of missense mutation R1362Q in the 35th exon of CACNA1F in association with ocular diseases. This will ensure the reports of this mutation as healthy instead of uncertain in the literature and databanks. Show less

FADS1 rs174556 polymorphism influences on dietary fats metabolism and type 2 diabetes (T2DM). This study aimed to compare the effect of three oils of sesame, canola and sesame-canola on cardio metabolic factors across genotypes of rs174556 variant in patients with type 2 of diabetes. This study was a randomized triple-blind three-way cross-over clinical trial. 95 Subjects with T2DM replaced their regular dietary oil with sesame oil, canola oil, or sesame-canola oil for three 9-week phases and completed the study. There were three anthropometric measurements, blood sampling and biochemical assessments at the beginning, middle, and at the end of each phase for assessments. Genotyping was conducted using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. In the crude model, there was an interaction between consumed oils and rs174556 variant on serum concentration of Apolipoprotein A-I (ApoA-1). During intake of sesame oil, lower levels of triglycerides (TG) were observed in individuals with TT genotype compared to C allele carriers' allele, which remained significant in adjusted models. Compared to C allele carrier's, the people with TT genotype experienced significant increase and decrease in serum levels of HDL and TG, respectively in adjusted models. Also, the subjects who consumed sesame-canola oil had lower serum concentrations of fasting blood glucose than those who received sesame and canola oils, regardless of used oils and genotypes. FADS1 Gene variant (rs174556) might modify cardiometabolic changes following dietary vegetable oils. Larger longitudinal studies especially randomized clinical trials are needed to clarify these associations. Show less

The study aimed to investigate the immunomodulatory effects of propranolol hydrochloride (PRO) in combination with chitosan nanoparticles (CS NPs) as an adjuvant to develop an effective vaccine against T. gondii. A total of 105 BALB/c mice were randomly divided into seven equal groups including PBS alone, CS NPs, SAG1 (Surface antigen 1), CS-SAG1 NPs, CS-PRO NPs, SAG1-PRO, and CS-SAG1-PRO NPs. The immunostimulatory effect of each adjuvant used for vaccine delivery was evaluated in a mice immunization model. The results showed that the mice immunized with CS-SAG1-PRO NPs exhibited the highest lymphocyte proliferation rate, along with increased secretion of IFN-γ, TNF-α, IL-6, IL-12, IL-17, and IL-23, as well as elevated levels of protective cytokines such as TGF-β, IL-27, and IL-10. Although, the CS-SAG1-PRO NPs immunized mice showed the highest level of T. gondii specific IgG compared to the other groups, a significant production of IgG2a and IgG1 was observed in the sera of mice immunized with the CS-SAG1-PRO NPs compared to the other group (p <0.001). The higher IgG2a/IgG1 ratio observed in the CS-SAG1-PRO NPs group indicates a bias towards Th1 cell polarization, suggesting the promotion of Th1 cell-mediated immune responses. Considering the combination of the highest lymphocyte proliferation and survival rates, IgG2a/IgG1 ratio, and cytokine levels in the mice immunized with CS-SAG1-PRO NPs, this approach holds promise for immunostimulation and vaccine delivery against T. gondii infection. Show less

Multiple sclerosis (MS) is an autoimmune central nervous system (CNS) disorder indicated by demyelination, chronic inflammation, and neuronal destruction. Regional demyelination, inflammation responses, scar development, and various axonal damage are pathological characteristics of MS. Curcumin is a hydrophobic polyphenol extracted from the rhizome of the turmeric plant. In addition to anti-inflammatory effects, beneficial therapeutic effects such as antioxidant, anti-cancer and nerve protection have also been seen from this compound. The purpose of the current investigation was to provide light on the potential benefits of Curcumin in treating experimental autoimmune encephalomyelitis (EAE), the animal model of MS. in Female C57BL/6 mice were used to induce EAE through myelin oligodendroglial glycoprotein (MOG). Curcumin doses of 100 and 200 mg/kg were administered orally in the treatment groups starting on the first day of EAE induction. Brains and splenocytes were extracted from euthanized animals on day 25 following EAE induction. Demyelination and leukocyte infiltration, proliferation, cytokine, and gene expression profiles were assessed. Our findings demonstrate that both low and high doses of Curcumin decreased the progression of EAE. Histological analyses revealed low infiltration of leukocytes into the CNS. Curcumin therapy enhanced Th2 and Treg cell secretion of IL-4, IL-10, and TGF-β although considerably decreasing IFN-γ and TNF-α. Curcumin-induced Th2 and Treg cell cytokine production and transcription factor gene expression (IL-13, GATA3, STAT6 and IL-35, CTLA4, Foxp3) and anti-inflammatory cytokines (IL-27, IL-33). Overall, these findings provide additional evidence that Curcumin can slow disease development and alleviate symptoms in EAE through stimulating Treg and Th2 cell polarization. They support Curcumin's potential therapeutic role in MS. Show less

Microglia are the immune cells of the central nervous system involved in a variety of developmental processes, such as regulation of cell death and survival, spatial patterning, and contribute to the development of Purkinje cells (PCs) during migration. Microglia express immunoglobulin G Fc receptors (FcgRs). In this report, we describe microglial FcgR expression and its relation to abnormal PC migration in the cerebellum during development. To detect microglial FcgR, the direct anti-IgG (secondary antisera) and high concentrations of Triton X-100 were applied as a method for labeling microglial cells without the use of any specific primary antiserum. By using Acp2 Show less

Lysosomes are membrane-bound organelles that are responsible for degrading and recycling macromolecules. Lysosomal dysfunction occurs in enzymatic and non-enzymatic deficiencies, which result in abnormal accumulation of materials. Although lysosomal storage disorders affect different organs, the central nervous system is the most vulnerable. Evidence shows the role of lysosomal dysfunction in different neurodegenerative diseases, such as Niemann-Pick Type C disease, juvenile neuronal ceroid lipofuscinosis, Alzheimer's disease and Parkinson's disease. Lysosomal enzymes such as lysosomal acid phosphatase 2 (Acp2) play a critical role in mannose-6-phosphate removal and Acp2 controls molecular and cellular functions in the brain during development and adulthood. Acp2 is essential in cerebellar development, and mutations in this gene cause severe cerebellar neurodevelopmental and neurodegenerative disorders. In this mini-review, we highlight lysosomal dysfunctions in the pathogenesis of neurodevelopmental and/or neurodegenerative diseases with special attention to Acp2 dysfunction. Show less