M1 polarization induction by lead and amyloid peptides in microglial cells: Implications for neurodegeneration process.

Neurodegeneration in conditions like Alzheimer's and Parkinson's disease is influenced by genetic and environmental factors. This study explores the potential neurodegenerative effects of lead (Pb) toxicity and amyloid beta peptides (Aßp 1-40 and Aßp 25-35) by promoting M1 polarization in microglial cells. To this end, we investigated and observed that IC50 concentrations of Pb (22.8 µM) and Aßp 25-35(29.6 µM). Our results demonstrated significant Pb uptake (31.13% at 25 µM Pb) and increased intracellular ROS levels (77.1%) upon treatment with Pb in combination of both Aßp 1-40 and Aßp 25-35. Protein carbonylation significantly increased (73.12 nmol/mL) upon treatment with Pb in combination of both Aßp 1-40 and Aßp 25-35, indicating oxidative damage and compromised cellular defenses against oxidative stress along with elevated DNA oxidative damage (164.9 pg/mL of 8-OH-dG) upon treatment with Pb in combination with both Aßp 1-40 and Aßp 25-35. Microglial polarization showed elevated M1 markers (inducible nitric oxide synthase and cyclooxygenase 2) and reduced M2 markers (arginase-1 and cluster of differentiation 206), suggesting Pb's role in inducing neurodegenerative microglial polarization. These findings provide insights into the complex molecular events contributing to Pb-induced neurotoxicity and neurodegenerative diseases.

Heavy Metal Mediated Progressive Degeneration and Its Noxious Effects on Brain Microenvironment.

Heavy metals, including lead (Pb), cadmium (Cd), arsenic (As), cobalt (Co), copper (Cu), manganese (Mn), zinc (Zn), and others, have a significant impact on the development and progression of neurodegenerative diseases in the human brain. This comprehensive review aims to consolidate the recent research on the harmful effects of different metals on specific brain cells such as neurons, microglia, astrocytes, and oligodendrocytes. Understanding the potential influence of these metals in neurodegeneration is crucial for effectively combating the ongoing advancement of these diseases. Metal-induced neurodegeneration involves molecular mechanisms such as apoptosis induction, dysregulation of metabolic and signaling pathways, metal imbalance, oxidative stress, loss of synaptic transmission, pathogenic peptide aggregation, and neuroinflammation. This review provides valuable insights by compiling the supportive evidence from recent research findings. Additionally, we briefly discuss the modes of action of natural neuroprotective compounds. While this comprehensive review aims to consolidate the recent research on the harmful effects of various metals on specific brain cells, it may not cover all studies and findings related to metal-induced neurodegeneration. Studies that are done using bioinformatics tools, microRNAs, long non-coding RNAs, emerging disease models, and studies based on the modes of exposure to toxic metals are a future prospect to be explored.

Unveiling Potential Neurotoxic Mechansisms: Pb-Induced Activation of CDK5-p25 Signaling Axis in Alzheimer's Disease Development, Emphasizing CDK5 Inhibition and Formation of Toxic p25 Species.

Alzheimer's disease (AD) is a complex neurodegenerative disorder with an etiology influenced by various genetic and environmental factors. Heavy metals, such as lead (Pb), have been implicated in AD pathogenesis, but the underlying mechanisms remain poorly understood. This study investigates the potential neurodegenerative role of Pb and amyloid ß peptides (1-40 and 25-35) via their interaction with cyclin-dependent kinase 5 (CDK5) and its activator, p25, in an attempt to unravel the molecular basis of Pb-induced neurotoxicity in neuronal cells. To this end, a CDK5 inhibitor was utilized to selectively inhibit CDK5 activity and investigate its impact on neurodegeneration. The results revealed that Pb exposure led to elevated Pb uptake (56.7% at 15 µM Pb) and disturbances in intracellular calcium (19.6% increase upon Pb treatment). The results revealed a significant decrease in total antioxidant capacity (by 88.6% upon Pb treatment) and also elevation in protein carbonylation (by 26.2% upon Pb and Aßp's combination treatment), indicative of oxidative damage, suggesting an impaired cellular defence against oxidative stress and elevated DNA oxidative damage (178 pg/ml and 182 pg/ml of 8-OH-dG upon Pb and All treatment). Additionally, dysregulations in levels of calpain, p25-35 and CDK5 are observed and markers associated with antioxidant metabolism (phospho-Peroxiredoxin 1), DNA damage responses (phospho-ATM and phospho-p53), and nuclear membrane disruption (phospho-lamin A/C) were observed, supporting the role of Pb-induced CDK5-p25 signaling in AD pathogenesis. These findings shed light on the intricate molecular events underlying Pb-induced neurotoxicity and provide valuable insights into the mechanisms that contribute to AD development.

Exposure of combination of environmental pollutant, lead (Pb) and ß-amyloid peptides causes mitochondrial dysfunction and oxidative stress in human neuronal cells.

Exposure to the environmental pollutant lead (Pb) has been linked to Alzheimer's disease (AD), in which mitochondrial dysfunction is a pathological consequence of neuronal degeneration. The toxicity of Pb in combination with ß-amyloid peptides (1-40) and (25-35) causes selective death in neuronal cells. However, the precise mechanism through which Pb induces Alzheimer's disease, particularly mitochondrial damage, is unknown. Changes in mitochondrial mass, membrane potential, mitochondrial complex activities, mitochondrial DNA and oxidative stress were examined in neuronal cells of human origin exposed to Pb and ß-amyloid peptides (1-40) and (25-35) individually and in different combinations. The results showed depolarization of mitochondrial membrane potential, decrease in mitochondrial mass, ATP levels and mtDNA copy number in Pb and ß-amyloid peptides (1-40) and (25-35) exposed cells. Also, significant reductions in the expression of mitochondrial electron transport chain (ETC) complex proteins (ATP5A, COXIV, UQCRC2, SDHB, NDUFS3), as well as down regulation of ETC complex gene expressions such as COXIV, ATP5F1 and NDUFS3 and antioxidant gene expressions like MnSOD and Gpx4 were observed in exposed cells. Furthermore, Pb and ß-amyloid peptides exposure resulted in elevated mitochondrial malondialdehyde levels and a decrease in mitochondrial GSH levels. Our findings suggest that Pb toxicity could be one of the causative factors for the mitochondrial dysfunction and oxidative stress in Alzheimer's disease progression.

Defective mitophagy and induction of apoptosis by the depleted levels of PINK1 and Parkin in Pb and ß-amyloid peptide induced toxicity.

Exposure to lead (Pb), an environmental pollutant, is closely associated with the development of neurodegenerative disorders through oxidative stress induction and alterations in mitochondrial function. Damaged mitochondria could be one of the reasons for the progression of Alzheimer's Disease (AD). Mitophagy is vital in keeping the cell healthy. To know its role in Pb-induced AD, we investigated the PINK1/Parkin dependent pathway by studying specific mitophagy marker proteins such as PINK1 and Parkin in differentiated SH-SY5Y cells. Our data have indicated a significant reduction in the levels of PINK1 and Parkin in cells exposed to Pb and ß-amyloid peptides, both Aß (25-35) and Aß (1-40) individually and in different combinations, resulting in defective mitophagy. Also, the study unravels the status of mitochondrial permeability transition pore (MPTP), mitochondrial mass, mitochondrial membrane potential (MMP) and mitochondrial ROS production in cells treated with individual and different combination of Pb and Aß peptides. An increase in mitochondrial ROS production, enhanced MPTP opening, depolarization of membrane potential and reduced mitochondrial mass in the exposed groups were observed. Also, in the present study, we found that Pb and ß-amyloid peptides could trigger apoptosis by activating the Bak protein, which releases the cytochrome c from mitochondria through MPTP that further activates the AIF (apoptosis inducing factor) and caspase-3 proteins in the cytosol. The above findings reveal the potential role of mechanisms like PINK1/Parkin mediated mitophagy and dysfunctional mitochondria mediated apoptosis in Pb induced neurotoxicity.

Mechanisms associated with the dysregulation of mitochondrial function due to lead exposure and possible implications on the development of Alzheimer's disease.

Lead (Pb) is a multimedia contaminant with various pathophysiological consequences, including cognitive decline and neural abnormalities. Recent findings have reported an association of Pb toxicity with Alzheimer's disease (AD). Studies have revealed that mitochondrial dysfunction is a pathological characteristic of AD. According to toxicology reports, Pb promotes mitochondrial oxidative stress by lowering complex III activity in the electron transport chain, boosting reactive oxygen species formation, and reducing the cell's antioxidant defence system. Here, we review recent advances in the role of mitochondria in Pb-induced AD pathology, as well as the mechanisms associated with the mitochondrial dysfunction, such as the depolarisation of the mitochondrial membrane potential, mitochondrial permeability transition pore opening; mitochondrial biogenesis, bioenergetics and mitochondrial dynamics alterations; and mitophagy and apoptosis. We also discuss possible therapeutic options for mitochondrial-targeted neurodegenerative disease (AD).

Mitochondria-Mediated Moderation of Apoptosis by EGCG in Cytotoxic Neuronal Cells Induced by Lead (Pb) and Amyloid Peptides.

The developmental, epigenetic, and epidemiological studies on lead (Pb) toxicity have reported a strong connection between lead exposure and the progression of Alzheimer's disease (AD). The amyloid peptides were the main triggering elements, in the generation of extracellular plaques through which multiple cellular signaling events such as apoptosis and primarily oxidant-antioxidant balancing system will be affected, which leads to neuronal cell death. Our previous studies indicated that epigallocatechin gallate (EGCG), abundantly present in green tea, was found to be effective in alleviating the metal-induced neurotoxicity at the cellular level in terms of cell viability and apoptosis The aim of this study was to explore the protective mechanism of EGCG on the markers of oxidant-antioxidant system and mitochondria, which are involved in metal-induced neuronal cell death. Initially, the IC50 values for lead(Pb-5 µM), amyloid peptides (AP(1-40)-60 µM; AP(1-40)-8 µM), and EC50 value for EGCG(50 µM) were determined by both time- (12 h, 24 h, 48 h) and concentration-dependent manner and analyzed by MTT assay. The experimental groups were designed initially by treating with Pb and APs individually and in different combinations along with the presence of EGCG and are compared to the Pb and AP treated group without EGCG exposure. The cell lysates were used for analyzing oxidative stress markers by standardized laboratory protocol and the expression of mitochondrial markers such as VDAC and cytochrome C which were analyzed by both western blot and real-time PCR. Our results indicate that the EGCG-treated group has shown a significant increase in antioxidant marker expression levels (GSH, SOD, catalase, vitamin C) and a decrease in oxidative stress marker (NOS, MDA) levels when compared to the group without EGCG treatment (p < 0.05). Similarly, a significant decrease in expression levels of VDAC and cytochrome c were observed in the EGCG-treated group when compared to the group without EGCG treatment (p < 0.05). Our approach revealed that EGCG protects SH-SY5Y cells from Pb- and AP-induced cytotoxicity by regulating voltage-dependent anion channel (VDAC) expression and oxidant-antioxidant system and inhibits neuronal cell death.

Metallomic Biomarkers in Cerebrospinal fluid and Serum in patients with Parkinson's disease in Indian population.

Parkinson's disease (PD) is a neurodegenerative disease with the absence of markers for diagnosis. Several studies on PD reported the elements imbalance in biofluids as biomarkers. However, their results remained inconclusive. This study integrates metallomics, multivariate and artificial neural network (ANN) to understand element variations in CSF and serum of PD patients from the largest cohort of Indian population to solve the inconsistent results of previous studies. Also, this study is aimed to (1) ascertain a common element signature between CSF and serum. (2) Assess cross sectional element variation with clinical symptoms. (3) Develop ANN models for rapid diagnosis. A metallomic profile of 110 CSF and 530 serum samples showed significant variations in 10 elements of CSF and six in serum of patients compared to controls. Consistent variations in elements pattern were noticed for Calcium, Magnesium and Iron in both the fluids of PD, which provides feasible diagnosis from serum. Furthermore, implementing multivariate analyses showed clear classification between normal and PD in both the fluids. Also, ANN provides 99% accuracy in detection of disease from CSF and serum. Overall, our analyses demonstrate that elements profile in biofluids of PD will be useful in development of diagnostic markers for PD.

Hepatic histopathology and clinical characteristics associated with antiretroviral therapy in HIV patients without viral hepatitis.

BACKGROUND: All available ARV (antiretroviral) agents can cause hepatotoxicity. Many case reports of ARV-induced hepatotoxicity have been described in patients with confounding viral hepatitis. This case series is comprised 23 HIV-positive patients with hepatic enzyme abnormalities but without the evidence of viral hepatitis. The data available for these 23 patients were assessed with an effort to establish any correlation between ARV therapy and abnormal liver function tests (LFTs) as well as the histologic findings on liver biopsies. METHODS: The 23 participants included in this study were referred to a hepatology/gastrointestinal clinic that catered specifically to HIV patients. The patients were referred by their HIV providers for evaluation of elevated LFTs, gastrointestinal symptoms or cirrhosis. The data surveyed included variables associated with hepatotoxicity and HIV infection. RESULTS: Liver biopsies were obtained in 21 out of 23 participants. The remaining two participants had evidence of cirrhosis based on imaging studies. The LFT elevations were definitely or possibly attributed to ARV therapy in 17 out of 23 participants. Specifically, the biochemical hepatotoxicity was definitely related to ARV therapy in six and possibly related to ARV medications in 11 participants. Nine out of 17 participants had evidence of nonalcoholic steatohepatitis, whereas four out of 17 had clinical features of lipodystrophy. Six participants had elevated LFTs before starting ARV therapy. The participants with nonalcoholic fatty liver diseases had normal LFTs for many years after which a steep rise was noted. All participants with nonalcoholic fatty liver diseases were exposed to nucleoside reverse transcriptase inhibitors. CONCLUSION: ARV medications, particularly the nucleoside reverse transcriptase inhibitors, can cause a dose-dependent hepatotoxicity that occurs after several months of exposure and possibly result in increasing the adverse effects of alcohol and obesity. Owing to the overlap of ARV medications, the contribution of each class of drugs toward the observed hepatotoxicity is not entirely clear. Liver biopsies should be considered in patients receiving ARV therapy with elevated LFTs and/or evidence of fatty liver.