Murad Hossain

The Receptor-interacting serine/threonine-protein kinase 1 (RIPK1), a crucial regulator of necroptosis, has been implicated in the pathophysiology of vario

Oxidative stress is a key feature of Alzheimer’s disease (AD) and other neurodegenerative disorders. The Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2–related factor 2 (Nrf2) pathway controls redox balance, and disrupting the Keap1–Nrf2 protein–protein interaction (PPI) has become a promising therapeutic approach. Marine natural products (MNPs), because of their structural diversity and bioactivity, are an underexplored source of potential neuroprotective compounds. This study aimed to identify novel marine-derived inhibitors of the Keap1–Nrf2 interaction using a comprehensive in silico pipeline. A total of 14,492 compounds from an open-access MNP database were virtually screened against the Keap1 Kelch domain through molecular docking. The top 1,329 candidates exhibited strong binding affinities, with several reaching scores comparable to the co-crystallized reference ligand L5F. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling was employed to assess pharmacokinetic properties, brain penetration, and safety, leading to the identification of compound 145398-61-4 as the most promising hit. Molecular dynamics (MD) simulations verified the structural stability of the Keap1–145398-61-4 complex, while binding free energy calculations indicated energetically favorable interactions. Additional validation using principal component analysis (PCA) and highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) energy analysis further confirmed the stability of this interaction. Overall, our in silico study identified compound 145398-61-4 as a novel Keap1–Nrf2 inhibitor, highlighting its potential as a lead candidate for developing treatments for Alzheimer’s disease and other neurodegenerative disorders, such as amyotrophic lateral sclerosis and multiple sclerosis.

Background and Aims: Cervical cancer is characterized by abnormal cell growth in the lining of cervix and it is the second major cause of cancer‐related deaths among females in Bangladesh. Interleukin‐6 (IL‐6) is a multifunctional cytokine that has been heavily linked with cervical cancer. Our aim was to investigate the association of two promoter single‐nucleotide polymorphisms (SNPs) ofIL‐6(rs1800795 and rs1800797) with the susceptibility of cervical cancer in Bangladeshi women.Methods: DNA was extracted from venous blood samples from cervical cancer patients (n = 126) and healthy controls (n = 120). Polymerase chain reaction‐restriction fragment length polymorphism was used for genotyping of the selected SNPs. Logistic regression was performed to calculate the odds ratio (OR) with 95% confidence interval (CI) andpvalues.Results: We found a significant association between rs1800795 and rs1800797 polymorphisms and cervical cancer. For, rs1800795 (G > C) the GC heterozygous genotype (OR = 2.80, 95% CI = 1.55–5.07,p = 0.0007) and CC mutant homozygous genotype (OR = 3.5, 95% CI = 1.29–9.51,p = 0.014) conferred an increased risk of cervical cancer. In case of rs1800797 (G > A) polymorphism, the AG heterozygous genotype (OR = 6.94, 95% CI = 3.76–12.81,p < 0.0001) and AA mutant homozygous genotype (OR = 3.88, 95% CI = 1.12–13.51,p = 0.0332) also exhibited an elevated risk of cervical cancer. Use of contraceptives was found as risk factor and patients who smoke were carriers of both the risk alleles and thus had an increased risk of cervical cancer.Conclusion: Our findings suggest that polymorphism of rs1800795 and rs1800797 of theIL‐6gene play a significant role in cervical cancer susceptibility in Bangladeshi women.

The development of externally controlled drug delivery systems that can rapidly trigger drug release is widely expected to change the landscape of future drug carriers. In this study, a drug delivery system was developed for on-demand therapeutic effects. The thermoresponsive paraffin film can be loaded on the basis of therapeutic need, including local anesthetic (lidocaine) or topical antibiotic (neomycin), controlled remotely by a portable mini-heater. The application of mild temperature (45 °C) to the drug-loaded paraffin film allowed a rapid stimulus response within a short time (5 min). This system exploits regular drug release and the rapid generation of mild heat to trigger a burst release of 80% within 6 h of any locally administered drug. The in vitro drug release studies and in vivo therapeutic activity were observed for local anesthesia and wound healing using a neomycin-loaded film. The studies demonstrated on-demand drug release with minimized inflammation and microbial infection. This temperature-responsive drug-loaded film can be triggered remotely to provide flexible control of dose magnitude and timing. Our preclinical studies on these remotely adjustable drug delivery systems can significantly improve patient compliance and medical practice.

Amphetamine is a potent psychostimulant also used to treat attention deficit/hyperactivity disorder and narcolepsy. In vivo and in vitro data have demonstrated that amphetamine increases the amount of extra synaptic dopamine by both inhibiting reuptake and promoting efflux of dopamine through the dopamine transporter. Previous studies have shown that chronic use of amphetamine causes tolerance to the drug. Thus, since the molecular mechanisms underlying tolerance to amphetamine are still unknown, an animal model to identify the neurochemical mechanisms associated with drug tolerance is greatly needed. Here we took advantage of a unique behavior caused by amphetamine in Caenorhabditis elegans to investigate whether this simple, but powerful, genetic model develops tolerance following repeated exposure to amphetamine. We found that at least 3 treatments with 0.5 mM amphetamine were necessary to see a reduction in the amphetamine-induced behavior and, thus, to promote tolerance. Moreover, we found that, after intervals of 60/90 minutes between treatments, animals were more likely to exhibit tolerance than animals that underwent 10-minute intervals between treatments. Taken together, our results show that C. elegans is a suitable system to study tolerance to drugs of abuse such as amphetamines.