Current antiepileptic drugs are effective in suppressing motor seizures; however, they often do not address the underlying factors such as oxidative stress, inflammation, and neurotrophic imbalances t Show more
Current antiepileptic drugs are effective in suppressing motor seizures; however, they often do not address the underlying factors such as oxidative stress, inflammation, and neurotrophic imbalances that contribute to the development of epilepsy. Recently, flavonoids sourced from diet have attracted attention as neuromodulators that can target these root causes. This study evaluated the protective effects of sakuranetin-a flavonoid found in edible Prunus species-against pentylenetetrazole (PTZ)-induced seizures and neurochemical changes in mice. Swiss albino mice (n = 6/group) were treated with saline, PTZ (35 mg/kg, intraperitoneally), or PTZ combined with sakuranetin (10 or 20 mg/kg, orally) every other day for 28 days. The study assessed seizure activity, oxidative stress markers, inflammatory cytokines, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), and caspase-3 activity. Additionally, in silico docking and 100 ns molecular dynamics simulations were performed to investigate sakuranetin's interactions with BDNF, TrkB, and D₂-like receptors. The results showed that sakuranetin treatment significantly improved seizure parameters. The onset latency was extended with both doses. The duration of clonic-tonic seizures was reduced by half, and mortality rates dropped from 50% to 8%. PTZ-induced reductions in neurotransmitters (such as GABA, dopamine, norepinephrine, serotonin, and acetylcholine) were restored, antioxidant defenses (including superoxide dismutase, catalase, and glutathione) were enhanced, and both lipid peroxidation (measured by malondialdehyde) and nitrosative stress (nitric oxide) were significantly decreased. Pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) were reduced, BDNF and TrkB levels approached control levels, and caspase-3 activity was diminished. Docking studies and MM-GBSA analyses indicated that BDNF was the most favorable binding partner for sakuranetin (with a binding free energy of approximately - 57 kcal/mol), and the simulations affirmed the stability of the complex. These findings suggest that sakuranetin has substantial, multi-target anticonvulsant effects by restoring neurotransmitter balance, enhancing antioxidant capacity, suppressing neuroinflammation, and revitalizing BDNF/TrkB signaling. Given its dietary origin, sakuranetin warrants further investigation as a potential nutraceutical candidate for managing epilepsy. Show less
Hypertrophic cardiomyopathy (HCM) is the most prevalent genetic hereditary cardiomyopathy characterized by sudden cardiac death. Mutations in the MYBPC3 gene are often the most prevalent genetic abnor Show more
Hypertrophic cardiomyopathy (HCM) is the most prevalent genetic hereditary cardiomyopathy characterized by sudden cardiac death. Mutations in the MYBPC3 gene are often the most prevalent genetic abnormality in HCM with a prevalence ranging from 20.0 to 42.0%. The mutation spectrum is available for different countries, but such studies are lacking in the Asian population including Bangladeshi patients. A cross-sectional descriptive study was conducted for mutation analysis of the whole MYBPC3 gene on a cohort of 75 HCM Bengali Bangladeshi probands through Next Generation Sequencing at the Genetic Research Lab of Bangabandhu Sheikh Mujib Medical University from 2016 to 2019. The structural and functional impact of the mutations was further analyzed by in silico process. We analyzed the data and found 103 variants in 102 locations in the MYBPC3 gene. Variants were identified in both the coding region and the non-coding region. We found one possibly novel variant in the MYBPC3 gene. The findings of this research will help to develop a genetic database of HCM which will help in the early diagnosis and proper management of HCM patients in Bangladesh. One pathogenic splice donor variant (47356592 C >T) was found in the intronic region. Among the variants in the coding region, one missense mutation was pathogenic (NP₋000247.2: p.Asp770Asn) which was found in seven patients and another one is of conflicting interpretations of pathogenicity (NP₋000247.2: p.Ser217Gly) which was found in two patients. We have identified one in-frame deletion (NP₋000247.2: p.Ala433del) that is possible a novel variant responsible for the development of HCM. Show less
Aberrant activation of the Wnt/β-catenin signaling pathway is common in human cervical cancers and has great potential therapeutic value. We show that tigecycline, a FDA-approved antibiotic drug, targ Show more
Aberrant activation of the Wnt/β-catenin signaling pathway is common in human cervical cancers and has great potential therapeutic value. We show that tigecycline, a FDA-approved antibiotic drug, targets cervical squamous cell carcinoma through inhibiting Wnt/β-catenin signaling pathway. Tigecycline is effective in inducing apoptosis, inhibiting proliferation and anchorage-independent colony formation of Hela cells. The inhibitory effects of tigecycline are further enhanced upon combination with paclitaxel, a most commonly used chemotherapeutic drug for cervical cancer. In a cervical xenograft model, tigecycline inhibits tumor growth as a single agent and its combination with paclitaxel significantly inhibits more tumor growth throughout the duration of treatment. We further show that tigecycline decreases level of both cytoplasmic and nuclear β-catenin and suppressed Wnt/β-catenin-mediated transcription through increasing levels of Axin 1 in Hela cells. In addition, stabilization or overexpression of β-catenin using pharmacological and genetic approaches abolished the effects of tigecycline in inhibiting proliferation and inducing apoptosis of Hela cells. Our study suggests that tigecycline is a useful addition to the treatment armamentarium for cervical cancer and targeting Wnt/β-catenin represents a potential therapeutic strategy in cervical cancer. Show less