👤 Hamid Abbasi

Peripheral nerve injury (PNI) is a significant health concern, affecting millions worldwide. Key neurotrophic factors, including nerve growth factor, brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor, have shown promise in facilitating neural regeneration. The effects of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids have been extensively studied, emphasizing the importance of appropriate timing and duration of administration. Antioxidants such as vitamin E and melatonin have exhibited neuroprotective effects in animal models, but further research is necessary to determine their efficacy, optimal dosage, and administration in humans. Immunosuppressive agents like tacrolimus (FK506) and cyclosporin A have demonstrated substantial potential in enhancing peripheral nerve recovery. Supportive strategies, including physical therapy and neuromodulation techniques such as electrical and transcranial stimulation, have shown effectiveness in promoting nerve regeneration. Advances in bioengineering, including nerve conduits and stem cell transplantation, which mimic natural nerve repair mechanisms, hold considerable promise for improving PNI treatments. In conclusion, PNI therapy is progressing towards an integrative approach, combining surgical techniques with pharmacological interventions, bioengineering, and regenerative medicine to enhance outcomes while minimizing adverse effects. This review explores recent advancements in peripheral nerve regeneration using both natural and synthetic agents, highlighting the shift toward more comprehensive treatment strategies. Show less

Human studies have reported inconsistent associations between early-life exposure to per- and polyfluoroalkyl substances (PFAS), particularly during critical windows of brain development, and neurodevelopmental outcomes. To address the lack of clarity regarding how PFAS affect neurodevelopment, this study developed the first unified adverse outcome pathway (AOP) network to explore the mechanisms involved in developmental neurotoxicity (DNT). Of 343 AOPs retrieved from AOP-Wiki, 19 linear AOPs associated with DNT satisfied the inclusion criteria. To pinpoint critical nodes and relationships, the constructed DNT-AOP network was examined using topological metrics. Through a combination of qualitative weight of evidence (WoE) assessment and network topology analysis, two critical paths were identified: one based on thyroid hormone disruption and the other on the intracellular calcium (Ca Show less

Alzheimer's disease (AD) is characterized by the gradual deterioration of cognitive functions, speech impairment, and memory loss. It can potentially be treated by targeting the beta-site amyloid precursor protein cleavage enzyme 1 (BACE1), which plays a key role in amyloid plaque formation, neurofibrillary tangles, and hyperphosphorylated tau protein. Current drugs have limitations in terms of safety, efficacy, and blood-brain barrier permeability. In view of this, this study was designed to determine the potential inhibitors of the BACE1 enzyme by virtual screening using a curated library of 415 natural products including terpenoids, phenolic compounds, and alkaloids from different medicinal plants. Based on the docking score and interaction analysis, 50 compounds were selected for the downstream analysis, such as ligand binding interactions, pharmacokinetics, druglikness and physicochemical parameters. Among the lead compounds, Palmatine (compound 45) and Berberine (compound 49), demonstrated optimal drug-likeness and blood-brain barrier permeability among the top compounds. 2-[(9Z,12Z)-heptadeca-9,12-dienyl]-6-hydroxybenzoic acid (compound 4) was inactive in most toxicity parameters. Pharmacophore analysis revealed that Palmatine and Berberine share similar features with the standard, highlighting their potential as effective compounds. Furthermore, structural chemistry analysis provided insights on their shared isoquinoline alkaloid framework, illustrating their structural similarities. Molecular dynamics simulations confirmed the stability of the Palmatine-BACE1 and Berberine-BACE1 complexes during a 50 ns production run. Overall, these findings highlighted the potential of Palmatine and Berberine as promising candidates for the experimental validation and the development of the drugs for the treatment of AD. Show less

Multiple sclerosis (MS) is a multifaceted neurodegenerative disorder influenced by genetics and lifestyle. This systematic literature review investigates the role of six obesity-associated genes, including fat mass and obesity-associated (FTO), FAS apoptosis inhibitory molecule 2 (FAIM2), Niemann-Pick disease type C1-like 1 (NPC1), glucosamine-6-phosphate deaminase 2 (GNPDA2), melanocortin-4 receptor (MC4R), and brain-derived neurotrophic factor (BDNF) in the context of MS. A literature search was executed using Embase, Scopus, Cochrane, Web of Science, and PubMed databases from inception to July 2024. The related keywords employed during the search process are "fas apoptotic inhibitory molecule 2," "Niemann-Pick disease type C1," "fat mass and obesity-associated," "melanocortin-4 receptor," "brain-derived neurotrophic factor," "glucosamine-6-phosphate deaminase 2," and "multiple sclerosis." Out of 2108 papers, 27 were entered into the present systematic literature review. The FTO gene may affect MS susceptibility through metabolic and inflammatory pathways. FAIM2 and NPC1 genes may contribute to MS pathogenesis, though their precise roles are still being elucidated. The GNPDA2 gene may have some connections with MS but requires further clarification. MC4R has demonstrated significant neuroprotective and anti-inflammatory effects, suggesting its potential impact on MS progression. BDNF plays a complex role in neuronal survival and repair and may influence the risk of MS. Our findings demonstrated that obesity-related genes may have a significant impact on MS risk and disease course, revealing novel insights into the genetic underpinnings of MS. Show less

Insulin resistance (IR) contributes to atherogenic dyslipidemia and elevated ASCVD risk. Apolipoprotein A1 (ApoA1)-associated lipoproteins have diverse anti-atherogenic functions, but it is unclear whether IR drives adverse changes in their proteomic composition. We hypothesized that IR is associated with an atherogenic ApoA1 proteome and that insulin-sensitizing interventions would improve its composition. We studied 861 participants without diabetes (age 47 ± 12 years, 65.5% female). IR was directly measured using the steady-state plasma glucose (SSPG) concentration via the insulin suppression test. ApoA1-associated proteins were quantified by mass spectrometry. A subset underwent interventions for 3 months (N total 108): pioglitazone, PIO Show less

A 50-year-old woman had triglyceride values up to 1640 mg/dL on routine laboratory tests. Despite the initiation of fenofibrate, icosapent ethyl, rosuvastatin, and a low-fat diet, her triglyceride values ranged from 1200 to more than 8200 mg/dL, and she had recurrent pancreatitis. Testing was negative for mutations in chylomicronemia genes such as LPL, APOC2, APOA5, LMF1, and GPIHBP1. Additional testing revealed elevated autoantibodies to GPIHBP1 up to 2,336 U/mL (normal <58 U/mL) and decreased GPIHBP1 to 2.5 pg/mL (normal range 570-1,625 pg/mL), confirming GPIHBP1 autoantibody syndrome (GPIHBP1-AAS). The patient received rituximab 1000 mg infusion, with 2 doses given 3 weeks apart. Triglycerides decreased from 1,746 to 81 mg/dL within 4 months and remained normal 12 months later without repeat dosing. GPIHBP1-AAS was only recently described and is associated with severe hypertriglyceridemia and recurrent pancreatitis. In our case, treatment with rituximab was very effective. GPIHBP1-AAS-associated hypertriglyceridemia should be recognized and can be successfully treated with rituximab. Show less

Alzheimer’s disease (AD) is a leading cause of dementia, imposing a substantial burden on individuals and society. While existing therapies can reduce the symptoms of AD, they do not offer genuine therapeutic effectiveness. Adiponectin Receptor Agonist (ADN-R Ag) has been proposed as a novel therapeutic agent for AD. This study aims to evaluate its efficacy in treating AD model mice. A systematic search of PubMed, Scopus, Cochrane Library, and Web of Science was conducted up to May 3, 2025. Research investigating the impact of ADN-R Ag on cognitive performance and associated molecular pathways in Alzheimer’s disease models, specifically APP/PS1, P301S, and 5XFAD mice, was incorporated. The Alzheimer’s disease models in the study were male and ranged in age from 5.5 to 8 months. Studies evaluating the effect of ADN-R Ag on AD model mice through cognitive function tests and related molecular mechanisms were included. Methodological quality assessment was performed using the CAMARADES tool for animal studies. The meta-analysis was performed following Cochrane guidelines. Six articles were included for the review. ADN-R Ag significantly improved cognitive function in the meta-analysis. The weighted mean difference of ADN-R Ag was 21.75 (95% CI: 16.61–26.88; Based on the current study, ADN-R Ag has therapeutic effects on AD. However, considering the complex underlying molecular mechanisms and limited prior studies, further research is needed. The online version contains supplementary material available at 10.1186/s12883-025-04356-5. Show less

Cardiovascular diseases are the leading causes of global mortality and morbidity. Hyperlipidemia is a significant risk factor for atherosclerosis and subsequent cardiovascular diseases. Hyperlipidemia is characterized by imbalances in blood cholesterol levels, particularly elevated low-density lipoprotein cholesterol and triglycerides, and is influenced by genetic and environmental factors. Current management consists of lifestyle modifications and pharmacological interventions most commonly consisting of statins. This review paper explores pathophysiology, management strategies, and pharmacotherapies including commonly used well-established medications including statins, fibrates, and ezetimibe, exciting novel therapies including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and RNA interference therapies (inclisiran), lomitapide, and bempedoic acid, highlighting their mechanisms of action, clinical efficacy, and safety profiles. Additionally, emerging therapies under clinical trials including ApoC-III inhibitors, DGAT2 inhibitors, ACAT2 Inhibitors, and LPL gene therapies are examined for their potential to improve lipid homeostasis and cardiovascular outcomes. The evolving landscape of hyperlipidemia management underscores the importance of continued research into both established therapies and promising new candidates, offering hope for more effective treatment strategies in the future. 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

Obesity is a complicated phenomenon which is a combination of genetic, environmental, and psychological factors. Genetic factors of obesity play an important role in individual risk. It is well known that obese children have disturbed puberty timing. To the best of our knowledge, no study has been performed to investigate the association between MC4R gene mutation and puberty timing. This study was performed as a cross-sectional study evaluating the near MC4R rs17782313 variation in 60 obese children and 98 healthy non obese children. Weight, height, BMI ( Body Mass Index ), BMI z-score (BMIz), family history of diabetes mellitus and obesity, the age of the obesity onset, overeating behavior, type of obesity (central or general) and puberty stage were evaluated in 60 obese children. The average age of the participants was 14.87 (+/- 1.3) years, with average weight and BMI of 90.77 (+/-12.2) Kg and 31.72 (+/-4.35) Kg/m2, respectively. Compared to healthy non obese patients, those with C-T genotype (C-T Vs. T-T and C-C) had higher odds of obesity than those with T-T and C-C genotype (p < 0.0001) while genotype TT showed significant protective effect (p = 0.0007). The heterozygote individuals (CT) have a higher BMIz than homozygote ones (CC and TT) (2.8 vs. 2.5 Kg/m children with CT genotype have 5.1 increased risk of obesity. While genotype TT showed significant obesity protective effect. We did not find association of this polymorphism with either childhood eating disorders or puberty. It is recommended to perform a cohort study in a larger sample. The online version contains supplementary material available at 10.1007/s40200-022-01011-5. Show less

Fragile X-associated tremor/ataxia syndrome (FXTAS), first described in 2001, is a neurodegenerative and movement disorder, caused by a premutation in the fragile X mental retardation 1 (FMR1) gene. To date, the biological mechanisms causing this condition are still not well understood, as not all premutation carriers develop FXTAS. To further understand this syndrome, we quantitatively compared the cerebrospinal fluid (CSF) proteome of FXTAS patients with age-matched controls using mass spectrometry. We identified 415 proteins of which 97 were altered in FXTAS patients. These proteins suggest changes in acute phase response signaling, liver X receptor/ retinoid X receptor (LXR/RXR) activation, and farnesoid X receptor (FXR)/RXR activation, which are the main pathways found to be affected. Additionally, we detected changes in many other proteins including amyloid-like protein 2, contactin-1, afamin, cell adhesion molecule 4, NPC intracellular cholesterol transporter 2, and cathepsin B, that had been previously noted to hold important roles in other movement disorders. Specific to RXR pathways, several apolipoproteins (APOA1, APOA2, APOA4, APOC2, and APOD) showed significant changes in the CSF of FXTAS patients. Lastly, CSF parameters were analyzed to investigate abnormalities in blood brain barrier function. Correlations were observed between patient albumin quotient values, a measure of permeability, and CGG repeat length as well as FXTAS rating scale scores. Show less

The study sought to assess the safety, feasibility, and effect of diltiazem as disease-modifying therapy for at-risk hypertrophic cardiomyopathy (HCM) mutation carriers. HCM is caused by sarcomere mutations and characterized by left ventricular hypertrophy (LVH) with increased risk of heart failure and sudden death. HCM typically cannot be diagnosed early in life, although subtle phenotypes are present. Animal studies indicate that intracellular calcium handling is altered before LVH develops. Furthermore, early treatment with diltiazem appeared to attenuate disease emergence. In a pilot, double-blind trial, we randomly assigned 38 sarcomere mutation carriers without LVH (mean 15.8 years of age) to therapy with diltiazem 360 mg/day (or 5 mg/kg/day) or placebo. Treatment duration ranged from 12 to 42 months (median 25 months). Study procedures included electrocardiography, echocardiography, cardiac magnetic resonance imaging, and serum biomarker measurement. Diltiazem was not associated with serious adverse events. Heart rate and blood pressure did not differ significantly between groups. However, mean left ventricular (LV) end-diastolic diameter improved toward normal in the diltiazem group but decreased further in controls (change in z-scores, +0.6 vs. -0.5; p < 0.001). Mean LV thickness-to-dimension ratio was stable in the diltiazem group but increased in controls (-0.02 vs. +0.15; p = 0.04). Among MYBPC3 mutation carriers, LV wall thickness and mass, diastolic filling, and cardiac troponin I levels improved in those taking diltiazem compared with controls. Four participants developed overt HCM, 2 in each treatment group. Pre-clinical administration of diltiazem is safe and may improve early LV remodeling in HCM. This novel strategy merits further exploration. (Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem; NCT00319982). Show less

Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we performed a genome-wide association study (GWAS) of 14 insulin sensitivity-related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2, and Stanford], MAGIC, and DIAGRAM). We identified four associations with three metabolites-glycine (rs715 at CPS1), serine (rs478093 at PHGDH), and betaine (rs499368 at SLC6A12; rs17823642 at BHMT)-and one association signal with glycine-to-serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits. Show less

OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes. Show less

Calcineurin is a serine/threonine protein phosphatase that plays a critical role in many physiologic processes such as T-cell activation, skeletal myocyte differentiation, and cardiac hypertrophy. We previously showed that active MEKK3 is capable of stimulating calcineurin/nuclear factor of activated T-cells (NFAT) signaling in cardiac myocytes through phosphorylation of modulatory calcineurin-interacting protein 1 (MCIP1). However, the protein kinases that function downstream of MEKK3 to mediate MCIP1 phosphorylation and the mechanism of MCIP1-mediated calcineurin regulation have not been defined. Here, we show that MEK5 and big MAP kinase 1 (BMK1) function downstream of MEKK3 in a signaling cascade that induces calcineurin activity through phosphorylation of MCIP1. Genetic studies showed that BMK1-deficient mouse lung fibroblasts failed to mediate MCIP1 phosphorylation and activate calcineurin/NFAT in response to angiotensin II, a potent NFAT activator. Conversely, restoring BMK1 to the deficient cells restored angiotensin II-mediated calcineurin/NFAT activation. Thus, using BMK1-deficient mouse lung fibroblast cells, we provided the genetic evidence that BMK1 is required for angiotensin II-mediated calcineurin/NFAT activation through MICP1 phosphorylation. Finally, we discovered that phosphorylated MCIP1 dissociates from calcineurin and binds with 14-3-3, thereby relieving its inhibitory effect on calcineurin activity. In summary, our findings reveal a previously unrecognized essential regulatory role of mitogen-activated protein kinase signaling in calcineurin activation through the reversible phosphorylation of a calcineurin-interacting protein, MCIP1. Show less