👤 Venugopal Balakrishnan

Familial Alzheimer's disease (fAD) is a hereditary disease that develops at an unusually early age. The deposition of toxic amyloid-beta (Aβ) is a hallmark of fAD. Despite their genetic origin and increasing prevalence, no effective drugs currently exist. THICAPA, a novel compound containing a tetrahydroisoquinoline group of amines, is naturally found in the brain and food and has diverse medicinal properties. However, its potential role in modulating amyloidogenesis in patients with fAD has not yet been explored. We investigated the effects of THICAPA on the amyloid precursor protein (APP) processing pathway in fibroblasts derived from patients with fAD. The in vitro cytotoxicity assay revealed no significant THICAPA cytotoxicity in fAD (AG06840) or healthy fibroblast cell lines (GM05879). Aβ scavenging assay revealed that 50 µM THICAPA potentially scavenged aged Aβ42 oligomers in the healthy fibroblast line. Gene and protein expression analyses revealed reduced APP expression and mature/immature APP expression ratio, BACE1 and presenilin 1 downregulation, and ADAM10 upregulation. Protein quantification revealed a significant reduction in C-terminal fragment beta, soluble APP (sAPP)β, and Aβ42/40 ratio in the amyloidogenic pathway and elevated sAPPα in the non-amyloidogenic pathway. Moreover, reactive oxygen species detection indicated that THICAPA reduced ROS production in fibroblasts from patients with fAD by 41.63%, although its intrinsic antioxidant properties were modest. THICAPA attenuates amyloidogenesis and upregulates the non-amyloidogenic pathway while alleviating ROS production. These findings suggest that THICAPA is a potential therapeutic candidate for treating fAD. Show less

Microglia-mediated neuroinflammation plays a crucial role in memory and cognitive deficits and the development of early mild cognitive impairment (MCI) associated with Alzheimer's disease (AD). Paeoniflorin (PF) has been established as an effective antioxidant and anti-apoptotic agent. This study investigated the protective effects of PF on neuroinflammation, amyloidogenesis, and memory impairments in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a C57BL/6 J amnesic mouse model. In BV-2 microglial cells, PF treatment inhibited LPS-stimulated nitric oxide (NO) production, attenuated microglial overactivation, and suppressed the excessive release of inflammatory mediators (iNOS and COX-2) in a concentration-dependent manner. More crucially, PF regulated the LPS-stimulated phosphorylation of mitogen-activated protein kinases (MAPKs)-including p38, ERK, and JNK-while also suppressing NF-κB nuclear transport and inhibiting IκB-α phosphorylation. In the in vivo study, PF (10 or 20 mg/kg) treatment significantly improved spatial learning memory and cognitive function and ameliorated memory deficits. Furthermore, PF administration upregulated BDNF, p-CREB, Nrf2, and HO-1 expression, which are biomarkers of neuroprotective and antioxidant effects. This was accompanied by a reduction in markers of neuroinflammation (iNOS and COX-2), the inhibition of microglia and astrocytes overactivation, and decreased expression of amyloidogenic protein markers APP and BACE-1 in the hippocampus and cerebral cortex. Further, PF inhibited the LPS-promoted phosphorylation of MAPK signaling, thereby reducing the phosphorylation level of IκB-α and inhibiting NF-κB activation in the hippocampus and cerebral cortex. Our results suggest that PF confers neuroprotective effects in an LPS model of Alzheimer-associated MCI by regulating the Nrf2/HO-1/BDNF/CREB and APP/BACE-1/NF-κB/MAPK signaling pathways. Show less

Physical activity has been considered an important non-medication intervention in preserving mnemonic processes during aging. However, how aerobic exercise promotes such benefits for human health remains unclear. In this study, we aimed to explore the neuroprotective and anti-inflammatory effects of aerobic exercise against lipopolysaccharide (LPS)-induced amnesic C57BL/6J mice and BV-2 microglial cell models. In the in vivo experiment, the aerobic exercise training groups were allowed to run on a motorized treadmill 5 days/week for 4 weeks at a speed of 10 rpm/min, with LPS (0.1 mg/kg) intraperitoneally injected once a week for 4 weeks. We found that aerobic exercise ameliorated memory impairment and cognitive deficits among the amnesic mice. Correspondingly, aerobic exercise significantly increased the protein expressions of FNDC5, which activates target neuroprotective markers BDNF and CREB, and antioxidant markers Nrf2/HO-1, leading to inhibiting microglial-mediated neuroinflammation and reduced the expression of BACE-1 in the hippocampus and cerebral cortex of amnesic mice. We estimated that aerobic exercise inhibited neuroinflammation in part through the action of FNDC5/irisin on microglial cells. Therefore, we explored the anti-inflammatory effects of irisin on LPS-stimulated BV-2 microglial cells. In the in vitro experiment, irisin treatment blocked NF-κB/MAPK/IRF3 signaling activation concomitantly with the significantly lowered levels of the LPS-induced iNOS and COX-2 elevations and promotes the Nrf2/HO-1 expression in the LPS-stimulated BV-2 microglial cells. Together, our findings suggest that aerobic exercise can improve the spatial learning ability and cognitive functions of LPS-treated mice by inhibiting microglia-mediated neuroinflammation through its effect on the expression of BDNF/FNDC5/irisin. Show less

Biodegradation of organic compounds would reveal important information on the final fate of a chemical in the environment. However, establishing biodegradability and fate of a chemical is cumbersome. In this scenario, the use of multimedia models help in predicting the fate and half-life of any compound to establish biodegradability. The study commenced with collection of wastewater samples, after primary and secondary treatment, from a Common Effluent Treatment Plant (CETP) treating tannery wastewater. The samples were subjected to gas chromatography-mass spectrometry (GC-MS) analysis. The GC-MS analysis identified that polyphenolic compounds were detected after biological treatment. The identified compounds emanated from tanning, dyeing, and fatliquoring process of leather making. Estimation Program Interface (EPI) Suite BIOWIN 3 and BIOWIN 4 model prediction revealed that while the primary biodegradation time-frame ranged from days to weeks, the ultimate biodegradation took weeks in the case of all the detected compounds. This study established that BIOWIN model could be used as a screening tool to determine biodegradability of complex chemicals used in tanneries and help to design better treatment facility with enhanced efficiency for removal of polyphenolic compounds. This methodology can also be applied to other industrial wastewaters containing recalcitrant chemicals, and with the help of BIOWIN model, information on biodegradability of chemicals present in the wastewater can be obtained. Show less

Retinopathy of prematurity (ROP) is a neurovascular complication in preterm babies, leading to severe visual impairment, but the underlying mechanisms are yet unclear. The present study aimed at unraveling the molecular mechanisms underlying the pathogenesis of ROP. A comprehensive screening of candidate genes in preterms with ROP ( Show less