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Asiaticoside and Madecassoside from Centella asiatica Demethylate the Nrf2 Promoter and Enhance Neuroprotection In Vitro Akmal Hasan; Wisnu Wardhana Putra
Eureka Herba Indonesia Vol. 6 No. 2 (2025): Eureka Herba Indonesia
Publisher : HM Publisher in collaboration with CMHC Research Center

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.37275/ehi.v6i2.141

Background: Centella asiatica (L.) Urban (Apiaceae), known as pegagan in Indonesian Jamu and as Mandukaparni (regionally Brahmi) in Ayurveda, contains triterpene saponins with reported neuroprotective properties, yet the epigenetic mechanisms underlying these effects remain poorly understood. Objective: This study investigated whether a triterpene-enriched fraction (TEF) standardized to asiaticoside (28.4%) and madecassoside (22.7%) modulates activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway through promoter demethylation and histone acetylation in oxidatively stressed SH-SY5Y neuroblastoma cells. Methods: Cells were pre-treated with TEF (25, 50, and 100 μg/mL) for 24 h before H2O2 (200 μM) challenge. Cell viability, reactive oxygen species (ROS), Nrf2 and HO-1 expression, Nrf2 promoter methylation (bisulfite sequencing), DNA methyltransferase 1 (DNMT1) protein, and histone H3 lysine-27 acetylation (H3K27ac) at the Nrf2 promoter were quantified. Results: TEF at 100 μg/mL restored cell viability to 82.4 ± 4.3% versus 47.8 ± 4.1% in H2O2-only cells (p < 0.001, Cohen’s d = 8.22), reduced ROS to 1.52 ± 0.15-fold (p < 0.001), and upregulated Nrf2 mRNA 2.83 ± 0.21-fold and HO-1 protein 3.14 ± 0.24-fold. Bisulfite sequencing revealed dose-dependent Nrf2 promoter demethylation from 67.8 ± 4.2% to 31.2 ± 2.6% (p < 0.001), paralleled by DNMT1 suppression (2.74 to 1.12-fold) and H3K27ac enrichment (0.34 to 1.43-fold) at the Nrf2 locus. A strong inverse correlation between methylation and Nrf2 expression (r = −0.912) and closely aligned IC50 values for ROS suppression (62.4 μg/mL) and demethylation (58.7 μg/mL) support a coordinated epigenetic-transcriptional mechanism. Conclusion: These findings provide the first evidence that Centella asiatica triterpenes activate neuroprotective pathways through dual epigenetic remodeling, offering a molecular rationale for the traditional cognitive-enhancing applications of this ethnopharmacologically significant herb.

Retinal Microvascular Changes on OCT-Angiography in Preclinical Alzheimer’s Disease: A Prospective Indonesian Cohort Study Taufiq Indera Jayadi; Eva Naritawati; Akmal Hasan
Sriwijaya Journal of Ophthalmology Vol. 8 No. 1 (2025): Sriwijaya Journal of Ophthalmology
Publisher : Department of Opthalmology, Faculty of Medicine, Universitas Sriwijaya

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.37275/sjo.v8i1.134

Introduction: Preclinical Alzheimer’s disease (AD) involves cerebral amyloid deposition in cognitively normal individuals 15–20 years before symptom onset. Optical coherence tomography angiography (OCT-A) may detect early retinal microvascular changes reflecting cerebral pathology. This study evaluated OCT-A parameters as biomarkers for preclinical AD in Indonesian elderly. Methods: This prospective cohort enrolled 180 cognitively normal participants aged ≥60 years (90 preclinical AD with amyloid-PET positivity, 90 controls) at two private hospital ophthalmology clinics in Palembang and Jakarta, Indonesia (January 2022–June 2024). OCT-A (RTVue XR Avanti) measured superficial capillary plexus (SCP) and deep capillary plexus (DCP) vessel density, foveal avascular zone (FAZ) area, and perfusion density. SD-OCT assessed RNFL and GCL-IPL thickness. The unit of analysis was the individual eye (342 eyes after quality exclusion). Results: SCP vessel density was significantly reduced in preclinical AD (43.2 ± 3.1% vs 47.8 ± 2.9%; Bonferroni-adjusted p < 0.001; Cohen’s d = 1.53). FAZ area was enlarged (0.38 ± 0.08 vs 0.31 ± 0.06 mm²; p < 0.001). The combined model (SCP + FAZ + GCL-IPL) achieved a bootstrap-validated AUC of 0.898 (95% CI: 0.859–0.937). SCP vessel density was the strongest predictor (OR 0.72; 95% CI: 0.63–0.82; p < 0.001). Conclusion: OCT-A parameters, particularly SCP vessel density, demonstrated strong discriminative ability for preclinical AD. These findings support OCT-A as a potential non-invasive screening biomarker, warranting validation in community-based populations.

Diffusion Tensor Imaging and Resting-State Functional MRI Reveal Coupled Microstructural and Default-Mode Network Alterations in Mild Cognitive Impairment: A Diagnostic Accuracy Study Taryudi Suharyana; Akmal Hasan; Jason Willmare
Sriwijaya Journal of Radiology and Imaging Research Vol. 3 No. 2 (2025): Sriwijaya Journal of Radiology and Imaging Research
Publisher : Phlox Institute: Indonesian Medical Research Organization

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.59345/sjrir.v3i2.285

Introduction: Early-stage neurodegeneration — clinically expressed as mild cognitive impairment (MCI) — lacks accessible imaging biomarkers that link microstructural white-matter injury to functional network disruption. We evaluated whether integrating diffusion tensor imaging (DTI) and resting-state functional MRI (rs-fMRI) at 3.0-Tesla improves detection of MCI and substantiates a structural-to-functional disconnection mechanism. Methods: In this STARD-2015-compliant, prospective cross-sectional diagnostic accuracy study at a tertiary hospital in Palembang, Indonesia, 85 participants (45 MCI, 40 age-, sex- and education-matched controls) underwent single-scanner 3.0-T MRI. DTI metrics (fractional anisotropy [FA], mean diffusivity [MD]) were derived by tract-based spatial statistics and posterior-cingulate-seeded Default Mode Network (DMN) connectivity by CONN. Consensus clinical diagnosis (Petersen criteria) was the blinded reference standard. Diagnostic accuracy used ROC/DeLong AUC, Wilson 95% confidence intervals (CIs), Cohen κ, and multivariable logistic regression. Results: Posterior-cingulum FA was lower (0.399 ± 0.058 vs 0.489 ± 0.052, p<0.001) and MD higher in MCI; PCC–mPFC connectivity was reduced (0.392 ± 0.124 vs 0.586 ± 0.136, p<0.001). FA discriminated MCI with AUC 0.903 (95% CI 0.831–0.974; sensitivity 82.2%, specificity 90.0%); a combined FA+FC model reached AUC 0.901 with sensitivity 95.6% and NPV 93.8% but did not exceed FA alone (DeLong p=0.90). FA and connectivity were strongly correlated (r=0.79, 95% CI 0.69–0.86, p<0.001). Inter-reader agreement was substantial (κ=0.74 and 0.67). Conclusion: Multimodal 3.0-T DTI and rs-fMRI provides an accurate, radiation-free signature of early-stage neurodegeneration; the coupling between cingulum microstructure and DMN connectivity is consistent with structural disconnection being associated with functional decoupling and offers a deployable tool for tertiary referral centres.

Retinal Microvascular Changes on OCT-Angiography in Preclinical Alzheimer’s Disease: A Prospective Indonesian Cohort Study Taufiq Indera Jayadi; Eva Naritawati; Akmal Hasan
Sriwijaya Journal of Ophthalmology Vol. 8 No. 1 (2025): Sriwijaya Journal of Ophthalmology
Publisher : Department of Ophthalmology, Faculty of Medicine, Universitas Sriwijaya

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.37275/sjo.v8i1.134

Introduction: Preclinical Alzheimer’s disease (AD) involves cerebral amyloid deposition in cognitively normal individuals 15–20 years before symptom onset. Optical coherence tomography angiography (OCT-A) may detect early retinal microvascular changes reflecting cerebral pathology. This study evaluated OCT-A parameters as biomarkers for preclinical AD in Indonesian elderly. Methods: This prospective cohort enrolled 180 cognitively normal participants aged ≥60 years (90 preclinical AD with amyloid-PET positivity, 90 controls) at two private hospital ophthalmology clinics in Palembang and Jakarta, Indonesia (January 2022–June 2024). OCT-A (RTVue XR Avanti) measured superficial capillary plexus (SCP) and deep capillary plexus (DCP) vessel density, foveal avascular zone (FAZ) area, and perfusion density. SD-OCT assessed RNFL and GCL-IPL thickness. The unit of analysis was the individual eye (342 eyes after quality exclusion). Results: SCP vessel density was significantly reduced in preclinical AD (43.2 ± 3.1% vs 47.8 ± 2.9%; Bonferroni-adjusted p < 0.001; Cohen’s d = 1.53). FAZ area was enlarged (0.38 ± 0.08 vs 0.31 ± 0.06 mm²; p < 0.001). The combined model (SCP + FAZ + GCL-IPL) achieved a bootstrap-validated AUC of 0.898 (95% CI: 0.859–0.937). SCP vessel density was the strongest predictor (OR 0.72; 95% CI: 0.63–0.82; p < 0.001). Conclusion: OCT-A parameters, particularly SCP vessel density, demonstrated strong discriminative ability for preclinical AD. These findings support OCT-A as a potential non-invasive screening biomarker, warranting validation in community-based populations.

Dorsolateral Prefrontal Cortex Co-expression Modules and Cell-Type Composition in Major Depressive Disorder and Suicide Akmal Hasan; Jason Willmare
Scientia Psychiatrica Vol. 7 No. 2 (2026): Scientia Psychiatrica
Publisher : HM Publisher in collaboration with CMHC Research Center

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.37275/scipsy.v7i2.212

Background. Major depressive disorder (MDD) and death by suicide may involve transcriptional and cellular shifts in the dorsolateral prefrontal cortex (DLPFC). Bulk transcriptomes mix within-cell regulation with tissue composition, so signals may not reproduce. Objective. To identify covariate-adjusted DLPFC co-expression modules associated with MDD and suicide, relate them to cell-type signatures, and assess external reproducibility. Methods. This secondary analysis of public datasets used GSE101521 (29 controls, 21 MDD donors who died by suicide [MDD-S], and 9 who died otherwise [MDD-NS]). After covariate residualization, the 5,000 most variable genes entered signed weighted gene co-expression network analysis. Eigengenes were tested with empirical-Bayes models and false-discovery rate (FDR) correction. GSE144136 supplied cell signatures and donor-level composition; scores were tested in 15 matched GSE54568 pairs. Results. The brown module (509 genes; inflammatory enrichment) was nominally lower in MDD (β = −0.499; p = 0.045; FDR = 0.316) and MDD-S (β = −0.570; p = 0.039; FDR = 0.274) than controls; blue showed the largest MDD-S versus MDD-NS estimate (β = −0.807; p = 0.015; FDR = 0.105). No module or bulk-deconvolved cell fraction reached FDR < 0.05. In GSE144136 (male donors), MDD-S showed lower relative astrocyte (FDR = 0.002) and higher excitatory and inhibitory neuronal (both FDR = 0.024) composition. No module replicated in GSE54568; two of five were directionally concordant. Conclusion. Inflammatory and oligodendrocyte-related modules lacked multiplicity-adjusted or external support for phenotype associations. Donor-level composition gave stronger yet constrained evidence. The findings prioritize immune-glial and neuronal hypotheses for replication, not biomarker use.

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