Gut brain axis: an insight into microbiota role in Parkinson's disease.

Parkinson's disease (PD) is one of the most common progressive neurodegenerative diseases. It is characterized neuropathologically by the presence of alpha-synuclein containing Lewy Bodies in the substantia nigra of the brain with loss of dopaminergic neurons in the pars compacta of the substantia nigra. The presence of alpha-synuclein aggregates in the substantia nigra and the enteric nervous system (ENS) drew attention to the possibility of a correlation between the gut microbiota and Parkinson's disease. The gut-brain axis is a two-way communication system, which explains how through the vagus nerve, the gut microbiota can affect the central nervous system (CNS), including brain functions related to the ENS, as well as how CNS can alter various gut secretions and immune responses. As a result, this dysbiosis or alteration in gut microbiota can be an early sign of PD with reported changes in short chain fatty acids, bile acids, and lipids. This gave rise to the use of probiotics and faecal microbiota transplantation as alternative approaches to improve the symptoms of patients with PD. The aim of this review is to discuss investigations that have been done to explore the gastrointestinal involvement in Parkinson's disease, the effect of dysbiosis, and potential therapeutic strategies for PD.

Effect of amphotericin B-deoxycholate (Fungizone) on the mitochondria of Wistar rats' renal proximal tubules cells.

Amphotericin B-deoxycholate (Fungizone [FZ]) is a widely used potent antimycotic drug in spite of its nephrotoxic effect via different mechanisms. The effect of FZ on renal cell bioenergetics is not clear. The current study evaluated the effect of FZ on the bioenergetics of albino rats' isolated renal proximal tubule cells (PTCs). The cytotoxic effect of FZ on the isolated renal cells was assessed by MTT and lactate dehydrogenase (LDH) assays. The effect of FZ on the PTCs uptake (OAT1 and OCT2) and efflux (P-gp and MRP2) transporters was evaluated. Then, the effect of FZ on mitochondria was assessed by studying complexes I-IV activities, lactate assay, oxygen consumption rates (OCR), and western blotting for all mitochondrial complexes. Moreover, the effect of FZ on mitochondrial membrane fluidity (MMF) and fatty acids composition was evaluated. Additionally, the protective effect of coenzyme q10 was studied. Outcomes showed that FZ was cytotoxic to the PTCs in a concentration and time-dependent patterns. FZ significantly inhibited the studied uptake and efflux tubular transporters with inhibition of the mitochondrial complexes activities and parallel increase in lactate production and decrease in OCRs. Finally, FZ significantly reduced the expression of all mitochondrial complexes in addition to significant increase in MMF and MMFA concentration. Coenzyme Q10 was found to significantly decrease FZ-induced cytotoxicity and transporters impairment in the PTC. FZ significantly inhibits bioenergetics of PTC, which may stimulate the cascade of cell death and clinical nephrotoxicity.

The role of oxidative stress in ovarian toxicity induced by haloperidol and clozapine-a histological and biochemical study in albino rats.

Oxidative stress has been implicated in reproductive toxicity induced by antipsychotics (APs). This study aims to further investigate the role of AP-induced oxidative stress in reproductive dysfunction. Thirty adult female albino rats were divided into three groups including a control group (n = 10) receiving distilled water, HAL group (n = 10) receiving haloperidol (HAL) (2 mg/kg/day), and CLZ group (n = 10) receiving clozapine (CLZ) (20 mg/kg/day). After 28 days, the rats were anesthetized, blood was withdrawn from their hearts, and ovaries were removed before they were sacrificed. Serum prolactin concentrations were measured. For each rat, one ovary was used for biochemical studies including mitochondrial complexes I and III activities and oxidative stress markers (lipid peroxidation, super oxide dismutase [SOD], catalase [CAT], and reduced glutathione [GSH]). The other ovary was used for histopathological examination and immunohistochemistry staining for p53 and Ki-67. HAL-treated rats showed significantly (p < 0.001) higher serum prolactin concentrations compared with other groups. HAL significantly inhibited complexes I (p < 0.001) and III activities (p < 0.05), while CLZ inhibited only complex I (p < 0.001). Lipid peroxidation was increased by HAL (p < 0.001) and CLZ (p < 0.01). HAL caused significant (p < 0.001) reductions in SOD, CAT, and GSH. CLZ caused a significant decrease in SOD (p < 0.001) and GSH (p < 0.01) with no effect on CAT. Histopathological studies of CLZ- and HAL-treated ovaries showed features suggestive of hyperprolactinemia and oxidative stress. Ki-67- and P53-immunostained sections were suggestive of disruption of cellular proliferation. These findings support the hypothesis that HAL and CLZ induce reproductive dysfunction through mechanisms involving ovarian mitochondrial dysfunction and oxidative stress.

Prevalence and pattern of refractive errors among Saudi adults.

BACKGROUND & OBJECTIVES: Refractive Errors (RE) are responsible for major portion of the treatable visual impairment and avoidable blindness in the world. The prevalence of RE varies with age, gender, ethnicity, geographical locations and also from time to time due to progresse in eye care services. We aimed to study the prevalence of RE and assess their patterns among Saudi adults of Arar city, the capital of Northern Border Region of Saudi Arabia. METHODS: This is a cross-sectional, population-based study. A total number of 966 Saudi adults aged 16 to 39 years were enrolled. The patterns of their RE were studied through auto-refraction evaluation. RESULTS: The prevalence of RE was 45.8%. The most frequent type of RE was myopia in 24.4%, followed by hyperopia 11.9% and astigmatism in 9.5% cases. Ages and genders significantly affect the prevalence of the different patterns of RE (0.033 and 0.012, respectively). CONCLUSION: The prevalence of RE in Arar city is slightly lower than that previously published in the same targeted age group. Myopia is the main RE. More awareness programs, especially among young adults are recommended for better outcomes.

Urinary biomarkers for early detection of platinum based drugs induced nephrotoxicity.

BACKGROUND: Nephrotoxicity is a major hazard complicating the use of platinum based drugs (PBD), which can hinder using higher doses protocols to maximize the therapeutic gain. Shortage of serum creatinine level as an accurate biomarker for acute kidney injuries (AKI) necessitates searching for novel biomarkers with better sensitivity and specificity in patients on PBD. METHODS: In a prospective cohort design, 132 patients receiving PBD were selected for the study. AKI was diagnosed by continuous follow up of serum creatinine level according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines 2012. Serum creatinine and urinary biomarkers (KIM-1, NGAL and cystatin C) was measured in the day of treatment and for 3 days after PBD cycle. RESULTS: AKI occurred in 35 patients (26.52% of patients). KIM-1, Cystatin C, and NGAL showed significant increase in samples collected in the day of AKI in comparison to their corresponding basal levels (P <  0.0001). In addition, significant increase in urinary levels of the biomarkers in samples collected 1 day before AKI in comparison to their basal levels (P <  0.0001, P <  0.0001, and P = 0.013 for KIM-1, NGAL and Cystatin C respectively). Furthermore KIM-1 data showed a significant increase 2 days before serum creatinine rise in comparison to the corresponding KIM-1 levels in patients who developed AKI (P = 0.001). CONCLUSIONS: Urinary KIM-1, Cystatin C and NGAL can predict PBD induced AKI in earlier stages than serum createnine. KIM-1 is the most sensitive biomarker for early detection of AKI in patients receiving PBD.

In vitro Anti-cholinesterase and Anti-oxidant Activity of Three Standardised Polyherbal Products Used for Memory Enhancing in Ethnomedicine of South-East Nigeria.

BACKGROUND: Polyherbal standardised extracts used in ethnomedicine of Eastern Nigeria for memory improvements were evaluated for anti-cholinesterases and anti-oxidant properties. METHODS: Anti-cholinesterase, anti-oxidant, and total phenolic and flavonoid contents were established using standard procedures. RESULTS: The three polyherbal extracts exhibited significant concentration dependent acetylcholinesterase (AChE) inhibitory activity (P = 0.001). The highest AChE inhibition was observed with the Neocare Herbal Tea (NHT) with 99.7% (IC50 = 324 µg/mL); whereas the Herbalin Complex Tea (HCT) and Phytoblis Herbal Tea (PHT) exhibited 73.8% (IC50 = 0.2 µg/mL) and 60.6% (IC50 = 0.7 µg/mL) inhibition, respectively, relative to eserine at 100% inhibition (IC50 = 0.9 µg/mL) at 200 µg/mL. The order of percentage increase in inhibition of AChE was NHT > HCT > PHT; while the order of decrease in potency was HCT > PHT > NHT.Radical scavenging activities of HCT, NHT and PHT were 82.13% (IC50 = 0.08 µg/mL), 77.43% (IC50 = 0.01 µg/mL) and 76.28% (IC50 = 0.3 µg/mL), respectively, at 1 mg/mL concentrations. The reducing power revealed a dose-dependent effect, with NHT > PHT > HCT. The order of total phenolics content in the extracts were PHT > HCT > NHT, and for total flavonoids content: PHT > NHT > HCT. CONCLUSION: The three polyherbal standardised products possess significant acetylcholinesterase inhibitory activity and secondary metabolites that could collectively contribute to their memory-enhancing effects.

Anti-acetylcholinesterase activity and antioxidant properties of extracts and fractions of Carpolobia lutea.

CONTEXT: There is an unmet need to discover new treatments for Alzheimer's disease. This study determined the anti-acetylcholinesterase (AChE) activity, DPPH free radical scavenging and antioxidant properties of Carpolobia lutea G. Don (Polygalaceae). OBJECTIVE: The objective of this study is to quantify C. lutea anti-AChE, DPPH free radical scavenging, and antioxidant activities and cell cytotoxicity. MATERIALS AND METHODS: Plant stem, leaves and roots were subjected to sequential solvent extractions, and screened for anti-AChE activity across a concentration range of 0.02-200 µg/mL. Plant DPPH radical scavenging activity, reducing power, and total phenolic and flavonoid contents were determined, and cytotoxicity evaluated using human hepatocytes. RESULTS: Carpolobia lutea exhibited concentration-dependent anti-AChE activity. The most potent inhibitory activity for the stem was the crude ethanol extract and hexane stem fraction oil (IC50 = 140 µg/mL); for the leaves, the chloroform leaf fraction (IC50 = 60 µg/mL); and for roots, the methanol, ethyl acetate and aqueous root fractions (IC50 = 0.3-3 µg/mL). Dose-dependent free radical scavenging activity and reducing power were observed with increasing stem, leaf or root concentration. Total phenolic contents were the highest in the stem: ∼632 mg gallic acid equivalents/g for a hexane stem fraction oil. Total flavonoid content was the highest in the leaves: ∼297 mg quercetin equivalents/g for a chloroform leaf fraction. At 1 µg/mL, only the crude ethanol extract oil was significantly cytotoxic to hepatocytes. DISCUSSION AND CONCLUSIONS: Carpolobia lutea possesses anti-AChE activity and beneficial antioxidant capacity indicative of its potential development as a treatment of Alzheimer's and other diseases characterized by a cholinergic deficit.

Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics.

Antipsychotics (APs) are widely used medications, however these are not without side effects such as disruption of blood brain barrier function (BBB). To investigate this further we have studied the chronic effects of the typical APs, chlorpromazine (CPZ) and haloperidol (HAL) and the atypical APs, risperidone (RIS) and clozapine (CLZ), on the bioenergetics of human micro-vascular endothelial cells (HBVECs) of the BBB. Alamar blue (AB) and ATP assays showed that these APs impair bioenergenesis in HBVECs in a concentration and time dependent manner. However since these effects were incomplete they suggest a population of cell bioenergetically heterogeneous, an idea supported by the bistable nature by which APs affected the mitochondrial transmembrane potential. CPZ, HAL and CLZ inhibited the activity of mitochondrial complexes I and III. Our data demonstrates that at therapeutic concentrations, APs can impair the bioenergetic status of HBVECs, an action that help explains the adverse side effects of these drugs when used clinically.

Nigella sativa, active principle thymoquinone, alleviates palmitate-induced cytotoxicity, inflammation and bioenergetic disruptions in macrophages: An invitro study model.

Thymoquinone (TQ) is one of the main phytochemical bioactive ingredients in Nigella sativa, with reported immunity-boosting properties. The current study evaluated the anti-inflammatory effect of TQ against inflammation brought on by free fatty acid Palmitate (PA) using macrophages raw 264.7 cell line. Data revealed that TQ significantly improved the viability of basal and PA stimulated Macrophages at concentrations of 50 and 100 µg/mL. Also, TQ significantly reduced nitric oxide and triglyceride levels in PA-stimulated macrophages at concentrations of 50 and 100 µg/mL. The pro-inflammatory cytokines studies revealed that PA significantly increased the release of the cytokines TNF-α, MHGB-1, IL-1ß, and IL-6. TQ at concentrations 25, 50, and 100 µg/ml significantly decreases the release of the studied cytokines in PA-stimulated macrophages to variable extents with parallel inhibition to their corresponding gene expression. Bioenergetic assays showed that PA significantly decreased cellular ATP, mitochondrial complexes I and III activities and mitochondrial membrane potential with a subsequent significant increase in lactate production. At the same time, TQ can alleviate the effect of PA on macrophages' bioenergetics parameters to variable extent based on TQ concentration. To conclude, TQ could mitigate palmitate-induced inflammation and cytotoxicity in macrophages by improving macrophage viability and controlling cytokine release with improved PA-induced bioenergetics disruption.

Awareness About Osteoporosis Among the General Population Based on the Osteoporosis Knowledge Assessment Tool (OKAT): A Cross-Sectional Study in the Northern Border Region of Saudi Arabia.

OBJECTIVE: Osteoporosis is a progressive systemic skeletal disease characterized by increasing susceptibility to fractures. The current study was conducted to assess the awareness about osteoporosis among the general population in the Northern Border region of Saudi Arabia to improve awareness and proper planning for public awareness about osteoporosis. METHODS: The study was conducted as a cross-sectional survey study, based on the online distribution of the Arabic-translated Osteoporosis Knowledge Assessment Tool (OKAT). The questionnaire questions cover the demographic characteristics of the participants, as well as symptoms, risk factors, prevention, and knowledge of treatment centers for osteoporosis in Saudi Arabia. RESULTS: 395 participants were enrolled in the study after their informed consenting. After scoring all correct answers for each participant, the mean score of all participants' answers was 12.5±3.4 (range 0-19). Participants with poor knowledge (0-7 scores), moderate knowledge (8-13 scores), and good knowledge (13-20 scores) represent 61 (15.4%), 213 (53.9%), and 121 (30.6%), respectively. The mean percentage of right answers to all the questions is 44.1%. The highest awareness level was shown in the area of osteoporosis symptoms and risk of fractures, while the lowest was recorded in the questions covering the risk factors. Ages, genders, jobs, and levels of education significantly affected the participants' levels of awareness. CONCLUSION: The public awareness among the population in the Northern Border region about osteoporosis is less than satisfactory. More awareness activities targeting the risky groups should be planned especially in the area of risk factors and preventive measures for osteoporosis.

The Evaluation of Artificial Intelligence Technology for the Differentiation of Fresh Human Blood Cells From Other Species' Blood in the Investigation of Crime Scenes.

OBJECTIVES: The current study used the deep machine learning approach to differentiate human blood specimens from cow, goat, and chicken blood stains based on cell morphology. METHODS: A total of 1,955 known Giemsa-stained digitized images were acquired from the blood of humans, cows, goats, and chickens. To train the deep learning models, the well-known VGG16, Resnet18, and Resnet34 algorithms were used. Based on the image analysis, confusion matrices were generated. RESULTS: Findings showed that the F1 score for the chicken, cow, goat, and human classes were all equal to 1.0 for each of the three algorithms. The Matthews correlation coefficient (MCC) was 1 for chickens, cows, and humans in all three algorithms, while the MCC score was 0.989 for goats by ResNet18, and it was 0.994 for both ResNet34 and VGG16 algorithms. The three algorithms showed 100% sensitivity, specificity, and positive and negative predictive values for the human, cow, and chicken cells. For the goat cells, the data showed 100% sensitivity and negative predictive values with specificity and positive predictive values ranging from 98.5% to 99.6%. CONCLUSION: These data showed the importance of deep learning as a potential tool for the differentiation of the species of origin of fresh crime scene blood stains.

Awareness and Attitude About Ototoxic Drugs Among Medical Doctors in Arar City, Saudi Arabia.

OBJECTIVES: The purpose of this study was to assess the awareness of ototoxicity among medical doctors in Arar City, Saudi Arabia. METHODS: This is a cross-sectional study based on a pre-formed validated questionnaire (Appendix) that included three sections covering participants' demographic data (three questions), their attitudes (five questions), and knowledge (13 questions) regarding drug-induced ototoxicity. RESULTS: After obtaining their informed consent, 213 physicians from government and private sector health facilities in Arar were enrolled in the study. Interns and general practitioners represented 57.8% of the participants; consultants represented 17.8%. Only 71.8% of participants were interested in drug-induced ototoxicity, while 26.3% considered ototoxicity a rare complication. Approximately 90% of the participants were knowledgeable about the adverse effects of drugs on the vestibulocochlear system, and 26.7% reported having experienced cases of drug-induced ototoxicity in their practice. Participants showed an overall knowledge score about ototoxicity of 9.3±3.27 (out of 14). The knowledge score was significantly higher (p-value=0.0007) for participants with more years of clinical experience. The most widely known ototoxic drug for participants was frusemide (72.3%), followed by aminoglycoside (68.5%), while acetaminophen (44.1%) ototoxicity was the least known among participants. CONCLUSION: Awareness of drug-induced ototoxicity is satisfactory among physicians in the Northern Borders region. However, workshops about all types of drugs with ototoxic effects and the main lines for the management of drug-induced ototoxicity are recommended to increase awareness.

Association of Screen Time Exposure With Autism Spectrum Disorder in Four to Six-Year-Old Children in Arar City, Saudi Arabia.

Background Autism spectrum disorder (ASD) is a psychopathologic disorder caused by several factors. The early signs include poor interaction and communication, delayed milestones, and repeated behavior patterns. This study aimed to assess the relationship between screen time and ASD severity and investigate the types of electronic devices associated with ASD in children aged four to six years in Arar City, Kingdom of Saudi Arabia (KSA). Methodology A cross-sectional study was conducted in primary healthcare centers (PHCs) in Arar City, KSA. The study enrolled all parents with children aged four to six years attending the PHCs in Arar City, KSA. Results The total sample size was 199 participants. Regarding the relationship between screen time exposure and ASD, there were variable screen time exposure durations, with 22.6% of children exposed for less than an hour, 30.7% for one to two hours, and 46.7% for more than two hours. Moreover, the type of electronic devices to which children were exposed varied, with smartphones being the most prevalent (68.3%). In terms of the age of children since exposure to electronic devices, the data indicated that 30.2% were exposed before the age of two, 35.2% between two and three years, and 34.7% after three years of age. Regarding the relationship with sociodemographic characteristics, there was a statistically significant relationship with the mother's age at birth (p = 0.050), mother's education level (p = 0.009), father's education level (p = 0.049), whether the child was suffering from any chronic or neurological disease (p = 0.008), age since the child was exposed to electronic devices (p = 0.049), and screen time exposure duration (p = 0.040). Conclusions The study highlights the significant association between screen time exposure and the development of ASD in children. Public awareness of this associated risk among caregivers is recommended to follow the protective guidelines. Further research and interventions are needed to better understand and address the impact of screen media use on children's neurodevelopment and overall well-being.

Role of mitochondrial disruption and oxidative stress in plasticizer phthalate-induced cytotoxicity to human bone osteoblasts.

Phthalates are frequently utilized in a wide range of products such as plasticizers with reported negative effects on bones. The current study evaluated the effect of butyl cyclohexyl phthalate on the human osteoblasts via different assays. MTT and lactate dehydrogenase assays were used to examine the in-vitro cytotoxic effect of butyl cyclohexyl phthalate on human bone osteoblasts in concentrations 0.1, 1, 10, and 100 µM for 12 to 72 h postexposures. Incubation of osteoblasts with butyl cyclohexyl phthalate significantly reduced cell viability based on its concentrations and durations of exposure. In parallel, osteoblast secretion of procollagen type 1, osteocalcin, as well as alkaline phosphatase was significantly decreased by butyl cyclohexyl phthalate in concentrations (1 or 2 µM). Butyl cyclohexyl phthalate decreased ATP synthesis and mitochondrial complexes I and III activities, with increased lactate production, all of which were detrimental to cellular bioenergetics. The cellular redox defense systems were significantly depleted by increased lipid peroxidation, elevated reactive oxygen species, decreased catalase and superoxide dismutase enzymes activities, and decreased intracellular reduced glutathione (GSH). Redox stress was also induced. Interestingly, preincubating osteoblasts with reduced GSH before exposing them to butyl cyclohexyl phthalate significantly lowered the cytotoxicity of the butyl cyclohexyl phthalate, suggesting that antioxidants may play a helpful protective effect.

Assessment of antipsychotic-induced cytotoxic effects on isolated CD1 mouse pancreatic beta cells.

Objectives: The study aims to assess apoptosis, oxidative stress, and inflammation as underlying diabetogenic mechanisms in isolated CD1 mouse beta-pancreatic cells of some prescribed Antipsychotics (APs). Methods: Three types of APs were tested in different concentrations (0.1, 1, 10, and 100 µM) on adult male CD1 mice. The cytotoxicity of the tested APs was determined using different assays including MTT and Lactate Dehydrogenase (LDH) assays. Oxidative stress was assessed by and measuring Reactive oxygen species (ROS) production, lipid peroxidation, and antioxidant enzyme activities. Moreover, the effect on the inflammatory cascade was also investigated. Results: The tested APs were cytotoxic to beta cells and showed patterns dependent on both concentration and exposure, with a parallel reduction in glucose-stimulated insulin secretion of the treated cells. The APs also showed induction of oxidative stress in the treated cells by significantly increasing the ROS, lipid peroxidation, and NRf2 gene expression, together with decreased antioxidant enzyme activities. Moreover, APs showed significant increases in cytokines levels to their estimated IC50 levels. The activities of caspases 3, 8, and 9 were also significantly increased in all treated samples at their IC50s and at 10 µM concentrations of all tested APs. However, the glutathione and inhibitors of caspase-3, IL-6, and TNF-α significantly improved GSIS and the viability of the AP-treated cells. Conclusion: The results suggest a significant role for apoptosis, oxidative stress, and inflammation, in the diabetogenic effect of APs, expected role of antioxidants and anti-inflammatory drugs as therapeutics for improving the outcome in cases of long-term prescribed APs.

Vaping, Environmental Toxicants Exposure, and Lung Cancer Risk.

Lung cancer (LC) is the second-most prevalent tumor worldwide. According to the most recent GLOBOCAN data, over 2.2 million LC cases were reported in 2020, with an estimated new death incident of 1,796,144 lung cancer cases. Genetic, lifestyle, and environmental exposure play an important role as risk factors for LC. E-cigarette, or vaping, products (EVPs) use has been dramatically increasing world-wide. There is growing concern that EVPs consumption may increase the risk of LC because EVPs contain several proven carcinogenic compounds. However, the relationship between EVPs and LC is not well established. E-cigarette contains nicotine derivatives (e.g., nitrosnornicotine, nitrosamine ketone), heavy metals (including organometal compounds), polycyclic aromatic hydrocarbons, and flavorings (aldehydes and complex organics). Several environmental toxicants have been proven to contribute to LC. Proven and plausible environmental carcinogens could be physical (ionizing and non-ionizing radiation), chemicals (such as asbestos, formaldehyde, and dioxins), and heavy metals (such as cobalt, arsenic, cadmium, chromium, and nickel). Air pollution, especially particulate matter (PM) emitted from vehicles and industrial exhausts, is linked with LC. Although extensive environmental exposure prevention policies and smoking reduction strategies have been adopted globally, the dangers remain. Combined, both EVPs and toxic environmental exposures may demonstrate significant synergistic oncogenicity. This review aims to analyze the current publications on the importance of the relationship between EVPs consumption and environmental toxicants in the pathogenesis of LC.

Differential Effects of Paraquat, Rotenone, and MPTP on Cellular Bioenergetics of Undifferentiated and Differentiated Human Neuroblastoma Cells.

Paraquat (PQ), rotenone (RO), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are neurotoxicants that can damage human health. Exposure to these neurotoxicants has been linked to neurodegeneration, particularly Parkinson's disease. However, their mechanisms of action have not been fully elucidated, nor has the relative vulnerability of neuronal subtypes to their exposures. To address this, the current study investigated the cytotoxic effects of PQ, RO, and MPTP and their relative effects on cellular bioenergetics and oxidative stress on undifferentiated human neuroblastoma (SH-SY5Y) cells and those differentiated to dopaminergic (DA) or cholinergic (CH) phenotypes. The tested neurotoxicants were all cytotoxic to the three cell phenotypes that correlated with both concentration and exposure duration. At half-maximal effective concentrations (EC50s), there were significant reductions in cellular ATP levels and reduced activity of the mitochondrial complexes I and III, with a parallel increase in lactate production. PQ at 10 µM significantly decreased ATP production and mitochondrial complex III activity only in DA cells. RO was the most potent inhibitor of mitochondrial complex 1 and did not inhibit mitochondrial complex III even at concentrations that induced a 50% loss of cell viability. MPTP was the most potent toxicant in undifferentiated cells. All neurotoxicants significantly increased reactive oxygen species, lipid peroxidation, and nuclear expression of Nrf2, with a corresponding inhibition of the antioxidant enzymes catalase and superoxide dismutase. At a 10 µM exposure to PQ or RO, oxidative stress biomarkers were significant in DA cells. Collectively, this study underscores the importance of mitochondrial dysfunction and oxidative stress in PQ, RO, and MPTP-induced cytotoxicity and that neuronal phenotypes display differential vulnerability to these neurotoxicants.

Cyclic AMP and calcium signaling are involved in antipsychotic-induced diabetogenic effects in isolated pancreatic ß cells of CD1 mice.

Objectives: Antipsychotics (APs) are medications used for different psychological disorders. They can introduce diabetogenic effects through different mechanisms, including cyclic adenosine monophosphate (cAMP) and calcium (Ca2+) signaling pathways. However, this effect is poorly understood. Therefore, this study aimed to evaluate the effect of three widely used APs (chlorpromazine, haloperidol, and clozapine) on cAMP and Ca2+ signaling. Methods: The local bioethics committee of Northern Border University approved the study. Pancreatic ß-cells were isolated from male CD1 mice, and three drug stock solutions were made in different concentrations (0.1, 1, 10, and 100 µM). The levels of glucose-stimulated insulin secretion (GSIS) and cAMP as well as the activities of adenylyl cyclase (AC), cAMP-dependent protein kinase (PKA), guanine-nucleotide exchange protein activated by cAMP (Epac 1 and 2), Ca2+ mobilization, and Ca2+/calmodulin kinase II (CaMKII) were then determined using different methods. Results: APs were found to be cytotoxic to pancreatic ß cells and caused a parallel and significant decrease in GSIS. APs significantly reduced the levels of cAMP in the treated cells, with an associated reduction in ATP production, CaMKII, PKA, and transmembrane AC activities as well as Ca2+ mobilization to variable extents. In addition, the gene expression results showed that APs significantly decreased the expression of both the active subunits AC1 and AC8, the PKA α and ß subunits, Epac1 and Epac2 as well as the four main subunits of CaMKII to variable extents. Conclusion: AP-induced alterations in the cAMP and Ca2+ signaling pathways can play a significant role in their diabetogenic potential.

Mitochondrial disruption in isolated human monocytes: an underlying mechanism for cadmium-induced immunotoxicity.

Cadmium (Cd) is an immunotoxic metal frequently found in the environment. The in vitro study undertaken here evaluated the immunotoxic effects of Cd in isolated human peripheral blood monocytes (hPBM). The results of the studies of exposures to varying doses of Cd (0, 0.1, 1, 10, and 100 µM, as cadmium dichloride [CdCl2]) for 3, 6, 12, 24, 48, and 72 hr showed the test agent was cytotoxic to the cells in time- and concentration-related manners. Thereafter, using only those doses found to not cause extreme cell lethality a 48-hr period, the impact of 0.1 or 1 µM CdCl2 on the cells was evaluated. Functionally, CdCl2 treatment led to time- and concentration-related decreases in hPBM phagocytic activities as well as in the ability of the cells to form/release cytokines (including tumor necrosis factor [TNF]-α and interleukin [IL]-6 and -8). The CdCl2 also led to significantly decreased ATP production (in part, via inhibition of mitochondrial complexes I and III) as well as in mitochondrial membrane potentials (MMP) and oxygen consumption rates (OCR; associated with parallel increases in cell lactate production) in the cells. In addition, CdCl2 treatment resulted in significant increases in mitochondrial membrane fluidity (MMF) and cell unsaturated fatty acid content. Based on the results here, one might conclude that some of the effects that arose during the CdCl2-induced dysfunction of the isolated hPBM (i.e. changes phagocytic activity, cytokine formation/secretion) could have evolved secondary to CdCl2-induced disruptions of hPBM cell bioenergetics - an effect that itself was a culmination of an overall toxicity from CdCl2 upon the mitochondria within these cells.

An Investigation of the Neurotoxic Effects of Malathion, Chlorpyrifos, and Paraquat to Different Brain Regions.

Acute or chronic exposures to pesticides have been linked to neurotoxicity and the potential development of neurodegenerative diseases (NDDs). This study aimed to consider the neurotoxicity of three widely utilized pesticides: malathion, chlorpyrifos, and paraquat within the hippocampus (HC), corpus striatum (CS), cerebellum (CER), and cerebral cortex (CC). Neurotoxicity was evaluated at relatively low, medium, and high pesticide dosages. All pesticides inhibited acetylcholinesterase (AChE) and neuropathy target esterase (NTE) in each of the brain regions, but esterase inhibition was greatest in the HC and CS. Each of the pesticides also induced greater disruption to cellular bioenergetics within the HC and CS, and this was monitored via inhibition of mitochondrial complex enzymes I and II, reduced ATP levels, and increased lactate production. Similarly, the HC and CS were more vulnerable to redox stress, with greater inhibition of the antioxidant enzymes catalase and superoxide dismutase and increased lipid peroxidation. All pesticides induced the production of nuclear Nrf2 in a dose-dependent manner. Collectively, these results show that pesticides disrupt cellular bioenergetics and that the HC and CS are more susceptible to pesticide effects than the CER and CC.