👤 Raheela Ashfaq

Dibutyl phthalate (DBP) is a member of phthalate esters which are considered as potent environmental toxicant owing to their damaging effects on different organs including testis. Glabridin (GLN) is a polyphenolic substance that is found in the roots of Glycyrrhiza glabra and exhibits a wide range of pharmacological activities. This research investigation explored the ameliorative potential of GLN against DBP instigated testicular toxicity. Forty-eight male Sprague Dawley rats were categorized into control, DBP (200 mg/kg), DBP (200 mg/kg) + GLN (50 mg/kg), and GLN (50 mg/kg) group. We found that DBP administration exacerbated the gene expression of β-catenin, WNT1, and TCF7L2 while suppressed the gene expression of APC, AXIN1 as well as GSK3β. Furthermore, DBP exposure promoted the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) while suppressing the activities of superoxide dismutase (SOD), heme oxygenase-1 (HO-1), glutathione reductase (GSR), glutathione Peroxidase (GPx), catalase (CAT), and glutathione (GSH). Moreover, DPB administration exacerbated Caspase-9, Bax and Caspase-3 while diminishing Bcl-2 concentrations. A notable escalation was observed in the levels of interleukin-6 (IL-6), tumor necrosis factor- α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and nuclear factor- kappa B (NF-κB) following the administration of DBP. Besides, DBP intoxication distorted the normal morphology of testicular tissues. Nonetheless, GLN therapy significantly alleviated testicular impairments via regulating aforementioned biochemical and histological abnormalities. These findings suggest he palliative efficacy of GLN against DPN induced testicular damages thereby recommending the use of GLN to promote reproductive health in male. Show less

Current medications for Alzheimer's disease (AD) provide symptomatic relief only and fail to prevent neurodegeneration, necessitating the development of new therapeutic agents. This study aimed to evaluate benzimidazole (BIM) analogs as potential inhibitors for AD. In vitro screening identified 1-benzyl-3-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1H-benzo[d]imidazole-3-ium chloride (IMS48) as a potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC Show less

Identifying new genetic variants linked to plasma lipoprotein-lipid concentrations is of significant public health importance, as it can aid in developing genetic markers for CVD risk assessment, diagnosis, and prognosis. Our work aimed to investigate the relationship between lipoprotein lipase (LPL) genetic polymorphisms and hyperlipidemia in Pakistani population. To achieve this goal, 400 blood samples were obtained. DNA was extracted for the measurement of biochemical variables and genetic profiling. A lipid lowering agent, fibrate (200mg/day) is administered to the patients for two months. The online genetic epidemiology tool (http/www.oege.org) was used to determine the allelic and genomic frequencies. Odds ratio (OR) and 95% CI were calculated by chi-square. Single nucleotide polymorphism (SNP) in LPL gene, rs258 (T > C) and rs268 (A>G) were genotyped in 300 hypertriglyceridemia patients and 100 healthy/control individuals. The LPL gene showed a significant association with a high risk of hyperlipidemia diseases when differentiate the genotype evaluations between treated and untreated patients. Lipid levels were significantly (p<0.05) reduced after treatment. LPL SNP rs258 and rs268 were observed to be associated to hypertriglyceridemia in the Pakistani patients. Fibrate therapy showed a positive effect on the serum lipid levels after treating the patients with 200mg/day for two months. Show less

Intracranial aneurysms (IAs) are the major cause of subarachnoid hemorrhage. Stent-assisted coiling, especially with the Neuroform Atlas stent (NAS), has proved more effective than coiling alone for treating these aneurysms. To perform a systematic review and meta-analysis to investigate the efficacy and safety of the NAS in treating IAs. A comprehensive literature search was conducted on PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and clinicaltrials.gov from inception until June 2024. We included studies on ruptured and unruptured IAs treated with the NAS, covering experimental, observational, and case series across all age groups. The aneurysm occlusion rate was assessed by using the Raymond-Roy classification (RROC). The mRS and adverse events related to stent use were also recorded. The statistical analysis was conducted on R Version 4.3.2 by using the packages "meta" and "metasens." We reported our results as proportions with their corresponding CIs. Meta-regression, leave-one-out, and sensitivity analyses were conducted to confirm the robustness of our results. A total of 42 studies including 2434 participants with a mean age of 51 to 73 years were included. Among angiographic outcomes, the final RROC 1/RROC 2 was achieved in 95% of the patients, final RROC 1 in 82%, RROC 2 in 12%, and RROC 3 in 5% of the patients. Additionally, 93% of the patients showed mRS grade 0, 5% showed mRS grade 1, 3% showed mRS grade 2, 2% showed mRS grade 3, 0% showed mRS grade 4, 0% showed mRS grade 5, and 1% showed mRS grade 6. All adverse events had a ≤5% rate. Due to limited cause-specific data, we were unable to analyze mortality specific to the stent placement and complications. Despite the large number of studies included, comparative studies were still observed to be scarce. Although the generalizability of our findings is limited, this study demonstrates that the NAS is highly effective for treating IAs, with high occlusion rates and a low incidence of adverse events. The stent's performance, supported by comprehensive analysis, highlights its safety and efficacy in managing both ruptured and unruptured aneurysms. Show less

The epidermal growth factor receptor (EGFR) gene is commonly amplified and rearranged in glioblastoma multiforme leading to overexpression of wild-type and mutant EGFRs. Expression of wild-type EGFR ligands, such as transforming growth factor-alpha (TGF-alpha) or heparin-binding EGF (HB-EGF), is also often increased in gliomas resulting in an autocrine loop that contributes to the growth autonomy of glioma cells. Glioblastoma multiformes express a characteristic EGFR mutant (EGFRvIII, de 2-7) that does not bind ligand, signals constitutively, and is more tumorigenic than the wild-type receptor. However, the downstream signals that mediate this increased tumorigenicity are not well understood. We hypothesized that signals induced specifically by EGFRvIII and not the wild-type receptor are more likely to mediate its increased tumorigenic activity and examined the gene expression profiles resulting from inducible expression of comparable levels of either wild-type EGFR or EGFRvIII in a U251-MG glioma cell line. Expression of EGFRvIII resulted in specific up-regulation of a small group of genes. Remarkably, all these genes, which include TGFA, HB-EGF, EPHA2, IL8, MAP4K4, FOSL1, EMP1, and DUSP6, influence signaling pathways known to play a key role in oncogenesis and function in interconnected networks. Increased expression of EGFRvIII-induced genes was validated by real-time PCR. The mutant receptor does not bind ligand, and EGFRvIII-induced expression of TGF-alpha and HB-EGF suggests that EGFRvIII plays a role in generating an autocrine loop using the wild-type EGFR in glioma. It also raises the possibility that EGFRvIII may signal, at least in part, through the wild-type receptor. Indeed, we show that inhibiting the activity of HB-EGF, a potent mitogen, with neutralizing antibodies reduces cell proliferation induced by expression of EGFRvIII. This suggests that the EGFRvIII-HB-EGF-wild-type EGFR autocrine loop plays an important role in signal transduction by EGFRvIII in glioma cells. We also show by immunohistochemistry that HB-EGF expression correlates with the presence of EGFRvIII in glioblastoma multiforme. Thus, our study provides a new insight into oncogenic signaling by EGFRvIII and improves our understanding of how autocrine loops are generated in glioma. Show less

Pancreatic endocrine neoplasms (PENs) are rare, mostly well-differentiated endocrine neoplasms, whose biology has been poorly characterized. Global expression microarrays can document abnormal pathways that impact on tumorigenesis and disease progression. RNA was extracted from eight well-differentiated PENs and three highly enriched pancreatic islet cell samples (80-90% purity), and examined using the Affymetrix U133A oligonucleotide microarray. Microarray data were normalized using dCHIP for identification of differentially expressed genes. PEN tissue microarrays were constructed from 53 archival PENs for immunohistochemical validation of microarray data. Sixty-six transcripts were overexpressed > or =3-fold in PENs compared with normal islet cells, including putative oncogenes (MLLT10/AF10), growth factors [insulin-like growth factor-binding protein 3 (IGFBP3)], cell adhesion and migration molecules (fibronectin), and endothelial elements (MUC18/MelCAM and CD31). A total of 119 transcripts were underexpressed < or =3-fold in PENs compared with normal islet cells, including cell cycle checkpoint proteins (p21/Cip1), the MIC2 (CD99) cell surface glycoprotein, putative metastasis suppressor genes (NME3), and junD, a MEN1-regulated transcription factor. Using PEN tissue microarrays, we confirmed the differential up-regulation of IGFBP3 (70%) and fibronectin (22%) and differential down-regulation of p21 (46%) and MIC2 (CD99; 91%) in PENs versus normal pancreatic islets. IGFBP3 overexpression was significantly more common in metastatic (93%) versus primary PEN lesions (60%), P=0.022. Fibronectin overexpression demonstrated a trend toward significance in lymphatic PEN metastases (55%) compared with primary PEN lesions (24%; P=0.14). Global expression analysis provides insight into tumorigenic pathways in PENs and may identify potential prognostic and therapeutic markers for these uncommon neoplasms. Show less