Antonisamy William James

Background: Engagement of the NF-κB signaling pathway is crucial for controlling immune and inflammatory gene expression within the central nervous system (CNS). Naringenin, a flavonoid derived from citrus fruits, is known for its anti-inflammatory and antioxidant effects; however, its impact on LPS-induced neuroinflammation in HMC3 (human microglial) and SH-SY5Y (neuronal) cell lines has not been thoroughly studied. Objectives: We sought to ascertain the neuroprotective role of Naringenin in LPS-induced neuroinflammation in microglia and neuronal cell lines with a focus on modulation of the NF-κB signaling pathway. Methods: LPS treatment was given to HMC3 cells to induce an inflammatory response, besides the secretome of HMC3 cells was transfered to SH-SY5Y cells with the administration of Naringenin. A cell viability assay, ROS level measurements, Western blotting, and immunocytochemistry were employed to quantify and localize NF-κB and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). Nuclear fractions of NF-κB were analyzed to screen its activation and translocation. Results: Naringenin treatment led to a dose-dependent decrease in LPS-induced reactive oxygen species (ROS) production. It significantly reduced the expression of pro-inflammatory cytokines and inhibited NF-κB activation in HMC3 cells. The nuclear translocation of NF-κB was notably diminished after treatment, as demonstrated by both Western blot and immunocytochemistry. These results suggest that Naringenin exerts an anti-inflammatory effect by suppressing the NF-κB signaling pathway. Conclusions: The findings suggest the potential therapeutic role of Naringenin using in vitro models in mitigating neuroinflammation through modulation of the NF-κB signaling pathway.

Background: Engagement of the NF-κB signaling pathway is crucial for controlling im-mune and inflammatory gene expression within the central nervous system (CNS). Naringenin, a flavonoid derived from citrus fruits, is known for its anti-inflammatory and antioxidant effects; however, its impact on LPS-induced neuroinflammation in HMC3 (human microglial) and SH-SY5Y (neuronal) cell lines has not been thoroughly studied. Objectives: To ascertain the neuroprotective role of Naringenin on LPS-induced neuroin-flammation in microglia and neuronal cell lines with focus on modulation of NF-κB sig-naling pathway. Methods: LPS treatment was given to HMC3 cells to induce an inflam-matory response and secretome of HMC3 cells to SH-SY5Y cells with the administration of Naringenin. The cell viability assay, ROS levels, Western blotting, immunocytochemis-try were employed to quantify and localize NF-κB and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). Nuclear and cytosolic fractions of NF-κB were analyzed to screen its activation and translocation. Results: Naringenin treatment led to a dose-dependent de-crease in LPS-induced reactive oxygen species (ROS) production. It significantly reduced the expression of pro-inflammatory cytokines and inhibited NF-κB activation in HMC3 cells. The nuclear translocation of NF-κB was notably diminished after treatment, as demonstrated by both western blot and immunocytochemistry. These results suggest that Naringenin exerts an anti-inflammatory effect by suppressing the NF-κB signaling path-way. Conclusion: The findings suggest the potential therapeutic role of Naringenin using in vitro models in mitigating neuroinflammation through modulation of NF-κB signaling pathway.

Neuroinflammation and neuronal death are direct consequences of persistent microglial activation, a phenomenon observed in many chronic neurological conditions. Activated microglia impact neuronal cells by releasing proinflammatory cytokines and inflammatory mediators, leading to neuronal damage and neurodegeneration. To investigate whether polyinosinic polycytidylic acid (poly I:C), a synthetic double-stranded RNA molecule, induces neuroinflammation and neuronal death, we exposed human microglia (HMC-3 cells) to poly I:C for 24 h, and performed inflammatory cytokine analysis. Additionally, to investigate whether poly (I:C) induces memory impairment and motor coordination deficits in mice, we conducted a behavioral assessment and also measured the expression of inflammatory cytokines in the brain. Poly (I:C) exposure significantly increased the mRNA and protein expression of inflammasome, proinflammatory cytokines (TNFα, IL-6, IL-1β, IL-8, IL-12, and IL-18) and chemokines in microglia. Poly (I:C) also significantly increased the translocation of NF-kB from the cytosol to the nucleus. Furthermore, the conditioned medium from poly (I:C)-treated cells markedly increased apoptosis in human neuronal cells (differentiated SHSY5Y cells) by activating pro-apoptotic markers, including Bax, Bad, cleaved caspase-3, cleaved PARP, and AIF. Mice exposed to poly (I:C) showed a significant increase in mRNA expression of inflammatory cytokines, such as IL-6 and TNF-α, in the hippocampus. A decrease in the percentage of alternation on the T-maze, reduced distance travelled, and average speed in the open field test indicate cognitive deficits as well as anxiety-like behavior in mice exposed to poly (I:C). These findings suggest that poly (I:C) induces neuroinflammation through the inflammasome and proinflammatory mediators via the NLRP3/NF-κB signaling pathway in vitro and in vivo.

Neuroinflammation and neuronal death are direct consequences of persistent microglial activation observed in many chronic neurological conditions. Activated microglia impact neuronal cells by releasing proinflammatory cytokines and inflammatory mediators, leading to neuronal damage and neurodegeneration. To investigate whether Polyinosinic polycytidylic acid (poly I:C), a synthetic double-stranded RNA molecule, induces neuroinflammation and neuronal death, we exposed microglia (HMC-3 cells) to poly I: C for 24 hrs, and assessed inflammatory cytokines. Additionally, to investigate whether poly(I:C) induces memory impairment and motor coordination deficits in C57BL/6 mice, we conducted a behavioural assessment and measured the expression of inflammatory cytokines in the brain. Poly (I:C) exposure significantly increased the mRNA and protein expression of inflammasome, proinflammatory cytokines (TNFα, IL-6, IL-1β, IL-8, IL-12, and IL-18) and chemokines in microglia. Poly (I: C) also significantly increased the translocation of NF-kB from the cytosol to the nucleus. Furthermore, the conditioned medium from poly(I:C)-treated cells markedly increased apoptosis in human neuronal cells (differentiated SHSY5Y cells) by activating pro-apoptotic markers, including Bax, Bad, cleaved caspase-3, cleaved PARP, and AIF. In mice, exposure to poly (I:C) significantly increased the mRNA expression of inflammatory cytokines, such as IL-6 and TNF-α, in the hippocampus. It also decreased the percentage of alternation in the T-maze test and reduced the distance travelled and average speed in the open field test, indicating motor and cognitive deficits. These findings suggest that poly (I:C) induces neuroinflammation through the inflammasome and proinflammatory mediators via the NLRP3/NF-κB signaling pathway in vitro and in vivo and induces motor and memory impairment in mice.

Vascular dementia (VaD) is a heterogeneous group of brain disorders caused by cerebrovascular pathologies and the second most common cause of dementia, accounting for over 20% of cases and posing an important global health concern. VaD can be caused by cerebral infarction or injury in critical brain regions, including the speech area of the dominant hemisphere or arcuate fasciculus of the dominant hemisphere, leading to notable cognitive impairment. Although the exact causes of dementia remain multifactorial and complex, oxidative stress (reactive oxygen species), neuroinflammation (TNFα, IL-6, and IL-1β), and inflammasomes are considered central mechanisms in its pathology. These conditions contribute to neuronal damage, synaptic dysfunction, and cognitive decline. Thus, antioxidants and anti-inflammatory agents have emerged as potential therapeutic targets in dementia. Recent studies emphasize that cerebrovascular disease plays a dual role: first, as a primary cause of cognitive impairment and then as a contributor to the manifestation of dementia driven by other factors, such as Alzheimer’s disease and other neurodegenerative conditions. This comprehensive review of VaD focuses on molecular mechanisms and their consequences. We provided up-to-date knowledge about epidemiology, pathophysiological mechanisms, and current therapeutic approaches for VaD.

Neuroinflammatory conditions linked to iron dysregulation pose significant challenges in neurodegenerative diseases. Iron‐loaded microglia are observed in the brains of patients with various neuroinflammatory conditions, yet how iron overload affects microglial function and contributes to various neuroinflammatory processes is poorly understood. This in vitro study elucidates the relationship between excess iron, cofilin activation, and microglial function, shedding light on potential therapeutic avenues. Iron overload was induced in Human Microglial Clone 3 cells using ferrous sulfate, and the expressions of ferritin heavy chain, ferritin light chain, divalent metal transporter 1, cofilin, p‐cofilin, nuclear factor‐κB (NF‐κB), and various inflammatory cytokines were analyzed using real‐time quantitative polymerase chain reaction, immunocytochemistry, Western blotting, and enzyme‐linked immunosorbent assay. Results revealed a notable increase in cofilin, NF‐κB, and inflammatory cytokine expression levels following excess iron exposure. Moreover, treatment with deferoxamine (DFX), a known iron chelator, and a novel cofilin inhibitor (CI) synthesized in our laboratory demonstrate a mitigating effect on iron‐induced cofilin expression. Furthermore, both DFX and CI exhibit promising outcomes in mitigating the inflammatory consequences of excess iron, including the expression of pro‐inflammatory cytokines and NF‐κB activation. These findings suggest that both DFX and CI can potentially alleviate microglia‐induced neuroinflammation by targeting both iron dysregulation and cofilin‐mediated pathways. Overall, this study provides valuable insights into iron‐induced cofilin activation and microglial activation, offering avenues for potential targeted therapies for neuroinflammatory conditions associated with iron and cofilin dysregulation in neurodegenerative diseases. image

Endoplasmic reticulum (ER) stress is a detrimental cellular phenomenon in the cells and is activated by the accumulation of unfolded or misfolded proteins in the ER. The unfolded protein accumulation activates the unfolded protein response (UPR), an adaptive mechanism designed to mitigate cellular stress by enhancing the ER’s protein-folding capacity and protecting cells from apoptotic stimuli in neuroinflammation and neurodegenerative diseases. However, chronic ER stress and prolonged activation of the UPR can have adverse effects, including the activation of pro-apoptotic and inflammatory signaling pathways, which contribute to the development and progression of neurodegenerative disorders. Neurodegenerative diseases are complex and devastating conditions with underlying pathogenesis that are not fully understood. Genetic mutations leading to the accumulation of misfolded or phosphorylated tau proteins and amyloid-beta in the ER can induce ER stress, resulting in neuroinflammation and neuronal death. Several studies have reported the involvement of increased ER stress and UPR signaling proteins in the pathogenesis and progression of neurodegenerative diseases. Thus, inhibiting ER stress and neuroinflammation and targeting their associated signaling pathways represent a significant area of research interest. This review discusses the critical signaling molecules involved in ER stress, their mechanisms in the progression of neurodegenerative diseases, and the latest developments in the available ER stress inhibitors. Despite the extensive development of ER stress inhibitors over the years, only a limited number have been approved as pharmaceutical drugs. There remains a critical need for effective ER stress inhibitors to provide efficient treatments for neurodegenerative diseases, including Alzheimer’s disease.

Traumatic brain injury (TBI) is a major healthcare problem and a common cause of mortality and morbidity. Clinical and preclinical research suggests sex-related differences in short- and longterm outcomes following TBI; however, males have been the main focus of TBI research. Females show a protective response against TBI. Female animals in preclinical studies and women in clinical trials have shown comparatively better outcomes against mild, moderate, or severe TBI. This reflects a favorable protective nature of the females compared to the males, primarily attributed to various protective mechanisms that provide better prognosis and recovery in the females after TBI. Understanding the sex difference in the TBI pathophysiology and the underlying mechanisms remains an elusive goal. In this review, we provide insights into various mechanisms related to the anatomical, physiological, hormonal, enzymatic, inflammatory, oxidative, genetic, or mitochondrial basis that support the protective nature of females compared to males. Furthermore, we sought to outline the evidence of multiple biomarkers that are highly potential in the investigation of TBI's prognosis, pathophysiology, and treatment and which can serve as objective measures and novel targets for individualized therapeutic interventions in TBI treatment. Implementations from this review are important for the understanding of the effect of sex on TBI outcomes and possible mechanisms behind the favorable response in females. It also emphasizes the critical need to include females as a biological variable and in sufficient numbers in future TBI studies.

The gut microbiota (GM) communicates with the brain via biochemical signaling constituting the gut–brain axis, which significantly regulates the body’s physiological processes. The GM dysbiosis can impact the digestive system and the functioning of the central nervous system (CNS) linked to the onset of neurodegenerative diseases. In this review, the scientific data compiled from diverse sources primarily emphasize the neuropathological characteristics linked to the accumulation of modified insoluble proteins (such as β-amyloid peptides and hyperphosphorylated tau proteins) in Alzheimer’s disease (AD) and the potential impact of gut microbiota (GM) on AD susceptibility or resilience. The specific GM profile of human beings may serve as an essential tool for preventing or progressing neurodegenerative diseases like AD. This review focuses mainly on the effect of gut microfauna on the gut–brain axis in the onset and progression of AD. The GM produces various bioactive molecules that may serve as proinflammatory or anti-inflammatory signaling, contributing directly or indirectly to the repression or progression of neurodegenerative disorders by modulating the response of the brain axis. Human studies must focus on further understanding the gut–brain axis and venture to clarify microbiota-based therapeutic strategies for AD.

The gut microbiota (GM) communicates with the brain via biochemical signaling constituting the gut-brain axis, which significantly regulates the body's physiological processes. The GM dysbiosis can impact the digestive system and the functioning of the central nervous system (CNS) linked to the onset of neurodegenerative diseases. In this review, the scientific data compiled from diverse sources primarily emphasizes the neuropathological characteristics linked to the accumulation of modified insoluble proteins (such as β-Amyloid peptides and hyperphosphorylated tau proteins) in Alzheimer’s Disease (AD) and the potential impact of gut microbiota (GM) on AD susceptibility or resilience. The specific GM profile of human beings may serve as an essential tool for preventing or progressing neurodegenerative diseases like AD. This review focuses mainly on the effect of gut microfauna on the gut-brain axis in the onset and progression of AD. The GM produces various bioactive molecules that may serve as proinflammatory or anti-inflammatory signaling, contributing directly or indirectly to the repression or progression of neurodegenerative disorders by modulating the response of the brain axis. Human studies must focus on further understanding the gut-brain axis and venture to clarify microbiota-based therapeutic strategies for AD.