Sleep matters: Neurodegeneration spectrum heterogeneity, combustion and friction ultrafine particles, industrial nanoparticle pollution, and sleep disorders-Denial is not an option.

Sustained exposures to ubiquitous outdoor/indoor fine particulate matter (PM2.5), including combustion and friction ultrafine PM (UFPM) and industrial nanoparticles (NPs) starting in utero, are linked to early pediatric and young adulthood aberrant neural protein accumulation, including hyperphosphorylated tau (p-tau), beta-amyloid (Aß1 - 42), α-synuclein (α syn) and TAR DNA-binding protein 43 (TDP-43), hallmarks of Alzheimer's (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). UFPM from anthropogenic and natural sources and NPs enter the brain through the nasal/olfactory pathway, lung, gastrointestinal (GI) tract, skin, and placental barriers. On a global scale, the most important sources of outdoor UFPM are motor traffic emissions. This study focuses on the neuropathology heterogeneity and overlap of AD, PD, FTLD, and ALS in older adults, their similarities with the neuropathology of young, highly exposed urbanites, and their strong link with sleep disorders. Critical information includes how this UFPM and NPs cross all biological barriers, interact with brain soluble proteins and key organelles, and result in the oxidative, endoplasmic reticulum, and mitochondrial stress, neuroinflammation, DNA damage, protein aggregation and misfolding, and faulty complex protein quality control. The brain toxicity of UFPM and NPs makes them powerful candidates for early development and progression of fatal common neurodegenerative diseases, all having sleep disturbances. A detailed residential history, proximity to high-traffic roads, occupational histories, exposures to high-emission sources (i.e., factories, burning pits, forest fires, and airports), indoor PM sources (tobacco, wood burning in winter, cooking fumes, and microplastics in house dust), and consumption of industrial NPs, along with neurocognitive and neuropsychiatric histories, are critical. Environmental pollution is a ubiquitous, early, and cumulative risk factor for neurodegeneration and sleep disorders. Prevention of deadly neurological diseases associated with air pollution should be a public health priority.

Alzheimer and Parkinson diseases, frontotemporal lobar degeneration and amyotrophic lateral sclerosis overlapping neuropathology start in the first two decades of life in pollution exposed urbanites and brain ultrafine particulate matter and industrial nanoparticles, including Fe, Ti, Al, V, Ni, Hg, Co, Cu, Zn, Ag, Pt, Ce, La, Pr and W are key players. Metropolitan Mexico City health crisis is in progress.

The neuropathological hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) are present in urban children exposed to fine particulate matter (PM2.5), combustion and friction ultrafine PM (UFPM), and industrial nanoparticles (NPs). Metropolitan Mexico City (MMC) forensic autopsies strongly suggest that anthropogenic UFPM and industrial NPs reach the brain through the nasal/olfactory, lung, gastrointestinal tract, skin, and placental barriers. Diesel-heavy unregulated vehicles are a key UFPM source for 21.8 million MMC residents. We found that hyperphosphorylated tau, beta amyloid1-42, α-synuclein, and TAR DNA-binding protein-43 were associated with NPs in 186 forensic autopsies (mean age 27.45 ± 11.89 years). The neurovascular unit is an early NPs anatomical target, and the first two decades of life are critical: 100% of 57 children aged 14.8 ± 5.2 years had AD pathology; 25 (43.9%) AD+TDP-43; 11 (19.3%) AD + PD + TDP-43; and 2 (3.56%) AD +PD. Fe, Ti, Hg, Ni, Co, Cu, Zn, Cd, Al, Mg, Ag, Ce, La, Pr, W, Ca, Cl, K, Si, S, Na, and C NPs are seen in frontal and temporal lobes, olfactory bulb, caudate, substantia nigra, locus coeruleus, medulla, cerebellum, and/or motor cortical and spinal regions. Endothelial, neuronal, and glial damages are extensive, with NPs in mitochondria, rough endoplasmic reticulum, the Golgi apparatus, and lysosomes. Autophagy, cell and nuclear membrane damage, disruption of nuclear pores and heterochromatin, and cell death are present. Metals associated with abrasion and deterioration of automobile catalysts and electronic waste and rare earth elements, i.e., lanthanum, cerium, and praseodymium, are entering young brains. Exposure to environmental UFPM and industrial NPs in the first two decades of life are prime candidates for initiating the early stages of fatal neurodegenerative diseases. MMC children and young adults-surrogates for children in polluted areas around the world-exhibit early AD, PD, FTLD, and ALS neuropathological hallmarks forecasting serious health, social, economic, academic, and judicial societal detrimental impact. Neurodegeneration prevention should be a public health priority as the problem of human exposure to particle pollution is solvable. We are knowledgeable of the main emission sources and the technological options to control them. What are we waiting for?

TDP-43 CSF Concentrations Increase Exponentially with Age in Metropolitan Mexico City Young Urbanites Highly Exposed to PM2.5 and Ultrafine Particles and Historically Showing Alzheimer and Parkinson's Hallmarks. Brain TDP-43 Pathology in MMC Residents Is Associated with High Cisternal CSF TDP-43 Concentrations.

Environmental exposures to fine particulate matter (PM2.5) and ultrafine particle matter (UFPM) are associated with overlapping Alzheimer's, Parkinson's and TAR DNA-binding protein 43 (TDP-43) hallmark protein pathologies in young Metropolitan Mexico City (MMC) urbanites. We measured CSF concentrations of TDP-43 in 194 urban residents, including 92 MMC children aged 10.2 ± 4.7 y exposed to PM2.5 levels above the USEPA annual standard and to high UFPM and 26 low pollution controls (11.5 ± 4.4 y); 43 MMC adults (42.3 ± 15.9 y) and 14 low pollution adult controls (33.1 ± 12.0 y); and 19 amyotrophic lateral sclerosis (ALS) patients (52.4 ± 14.1 y). TDP-43 neuropathology and cisternal CSF data from 20 subjects­15 MMC (41.1 ± 18.9 y) and 5 low pollution controls (46 ± 16.01 y)­were included. CSF TDP-43 exponentially increased with age (p < 0.0001) and it was higher for MMC residents. TDP-43 cisternal CSF levels of 572 ± 208 pg/mL in 6/15 MMC autopsy cases forecasted TDP-43 in the olfactory bulb, medulla and pons, reticular formation and motor nuclei neurons. A 16 y old with TDP-43 cisternal levels of 1030 pg/mL exhibited TDP-43 pathology and all 15 MMC autopsy cases exhibited AD and PD hallmarks. Overlapping TDP-43, AD and PD pathologies start in childhood in urbanites with high exposures to PM2.5 and UFPM. Early, sustained exposures to PM air pollution represent a high risk for developing brains and MMC UFPM emissions sources ought to be clearly identified, regulated, monitored and controlled. Prevention of deadly neurologic diseases associated with air pollution ought to be a public health priority and preventive medicine is key.

Environmentally Toxic Solid Nanoparticles in Noradrenergic and Dopaminergic Nuclei and Cerebellum of Metropolitan Mexico City Children and Young Adults with Neural Quadruple Misfolded Protein Pathologies and High Exposures to Nano Particulate Matter.

Quadruple aberrant hyperphosphorylated tau, beta-amyloid, α-synuclein and TDP-43 neuropathology and metal solid nanoparticles (NPs) are documented in the brains of children and young adults exposed to Metropolitan Mexico City (MMC) pollution. We investigated environmental NPs reaching noradrenergic and dopaminergic nuclei and the cerebellum and their associated ultrastructural alterations. Here, we identify NPs in the locus coeruleus (LC), substantia nigrae (SN) and cerebellum by transmission electron microscopy (TEM) and energy-dispersive X-ray spectrometry (EDX) in 197 samples from 179 MMC residents, aged 25.9 ± 9.2 years and seven older adults aged 63 ± 14.5 years. Fe, Ti, Hg, W, Al and Zn spherical and acicular NPs were identified in the SN, LC and cerebellar neural and vascular mitochondria, endoplasmic reticulum, Golgi, neuromelanin, heterochromatin and nuclear pore complexes (NPCs) along with early and progressive neurovascular damage and cerebellar endothelial erythrophagocytosis. Strikingly, FeNPs 4 ± 1 nm and Hg NPs 8 ± 2 nm were seen predominantly in the LC and SN. Nanoparticles could serve as a common denominator for misfolded proteins and could play a role in altering and obstructing NPCs. The NPs/carbon monoxide correlation is potentially useful for evaluating early neurodegeneration risk in urbanites. Early life NP exposures pose high risk to brains for development of lethal neurologic outcomes. NP emissions sources ought to be clearly recognized, regulated, and monitored; future generations are at stake.

Environmental Nanoparticles Reach Human Fetal Brains.

Anthropogenic ultrafine particulate matter (UFPM) and industrial and natural nanoparticles (NPs) are ubiquitous. Normal term, preeclamptic, and postconceptional weeks(PCW) 8-15 human placentas and brains from polluted Mexican cities were analyzed by TEM and energy-dispersive X-ray spectroscopy. We documented NPs in maternal erythrocytes, early syncytiotrophoblast, Hofbauer cells, and fetal endothelium (ECs). Fetal ECs exhibited caveolar NP activity and widespread erythroblast contact. Brain ECs displayed micropodial extensions reaching luminal NP-loaded erythroblasts. Neurons and primitive glia displayed nuclear, organelle, and cytoplasmic NPs in both singles and conglomerates. Nanoscale Fe, Ti, and Al alloys, Hg, Cu, Ca, Sn, and Si were detected in placentas and fetal brains. Preeclamptic fetal blood NP vesicles are prospective neonate UFPM exposure biomarkers. NPs are reaching brain tissues at the early developmental PCW 8-15 stage, and NPs in maternal and fetal placental tissue compartments strongly suggests the placental barrier is not limiting the access of environmental NPs. Erythroblasts are the main early NP carriers to fetal tissues. The passage of UFPM/NPs from mothers to fetuses is documented and fingerprinting placental single particle composition could be useful for postnatal risk assessments. Fetal brain combustion and industrial NPs raise medical concerns about prenatal and postnatal health, including neurological and neurodegenerative lifelong consequences.

Environmental Fe, Ti, Al, Cu, Hg, Bi, and Si Nanoparticles in the Atrioventricular Conduction Axis and the Associated Ultrastructural Damage in Young Urbanites: Cardiac Arrhythmias Caused by Anthropogenic, Industrial, E-Waste, and Indoor Nanoparticles.

Air pollution exposure is a risk factor for arrhythmia. The atrioventricular (AV) conduction axis is key for the passage of electrical signals to ventricles. We investigated whether environmental nanoparticles (NPs) reach the AV axis and whether they are associated with ultrastructural cell damage. Here, we demonstrate the detection of the shape, size, and composition of NPs by transmission electron microscopy (TEM) and energy-dispersive X-ray spectrometry (EDX) in 10 subjects from Metropolitan Mexico City (MMC) with a mean age of 25.3 ± 5.9 and a 71-year-old subject without cardiac pathology. We found that in every case, Fe, Ti, Al, Hg, Cu, Bi, and/or Si spherical or acicular NPs with a mean size of 36 ± 17 nm were present in the AV axis in situ, freely and as conglomerates, within the mitochondria, sarcomeres, lysosomes, lipofuscin, and/or intercalated disks and gap junctions of Purkinje and transitional cells, telocytes, macrophages, endothelium, and adjacent atrial and ventricular fibers. Erythrocytes were found to transfer NPs to the endothelium. Purkinje fibers with increased lysosomal activity and totally disordered myofilaments and fragmented Z-disks exhibited NP conglomerates in association with gap junctions and intercalated disks. AV conduction axis pathology caused by environmental NPs is a plausible and modifiable risk factor for understanding common arrhythmias and reentrant tachycardia. Anthropogenic, industrial, e-waste, and indoor NPs reach pacemaker regions, thereby increasing potential mechanisms that disrupt the electrical impulse pathways of the heart. The cardiotoxic, oxidative, and abnormal electric performance effects of NPs in pacemaker locations warrant extensive research. Cardiac arrhythmias associated with nanoparticle effects could be preventable.

Environmental Nanoparticles, SARS-CoV-2 Brain Involvement, and Potential Acceleration of Alzheimer's and Parkinson's Diseases in Young Urbanites Exposed to Air Pollution.

Alzheimer's and Parkinson's diseases (AD, PD) have a pediatric and young adult onset in Metropolitan Mexico City (MMC). The SARS-CoV-2 neurotropic RNA virus is triggering neurological complications and deep concern regarding acceleration of neuroinflammatory and neurodegenerative processes already in progress. This review, based on our MMC experience, will discuss two major issues: 1) why residents chronically exposed to air pollution are likely to be more susceptible to SARS-CoV-2 systemic and brain effects and 2) why young people with AD and PD already in progress will accelerate neurodegenerative processes. Secondary mental consequences of social distancing and isolation, fear, financial insecurity, violence, poor health support, and lack of understanding of the complex crisis are expected in MMC residents infected or free of SARS-CoV-2. MMC residents with pre-SARS-CoV-2 accumulation of misfolded proteins diagnostic of AD and PD and metal-rich, magnetic nanoparticles damaging key neural organelles are an ideal host for neurotropic SARS-CoV-2 RNA virus invading the body through the same portals damaged by nanoparticles: nasal olfactory epithelium, the gastrointestinal tract, and the alveolar-capillary portal. We urgently need MMC multicenter retrospective-prospective neurological and psychiatric population follow-up and intervention strategies in place in case of acceleration of neurodegenerative processes, increased risk of suicide, and mental disease worsening. Identification of vulnerable populations and continuous effort to lower air pollution ought to be critical steps.

Quadruple abnormal protein aggregates in brainstem pathology and exogenous metal-rich magnetic nanoparticles (and engineered Ti-rich nanorods). The substantia nigrae is a very early target in young urbanites and the gastrointestinal tract a key brainstem portal.

Fine particulate air pollution (PM2.5) exposures are linked with Alzheimer's and Parkinson's diseases (AD,PD). AD and PD neuropathological hallmarks are documented in children and young adults exposed lifelong to Metropolitan Mexico City air pollution; together with high frontal metal concentrations (especially iron)-rich nanoparticles (NP), matching air pollution combustion- and friction-derived particles. Here, we identify aberrant hyperphosphorylated tau, ɑ synuclein and TDP-43 in the brainstem of 186 Mexico City 27.29 ± 11.8y old residents. Critically, substantia nigrae (SN) pathology seen in mitochondria, endoplasmic reticulum and neuromelanin (NM) is co-associated with the abundant presence of exogenous, Fe-, Al- and Ti-rich NPs.The SN exhibits early and progressive neurovascular unit damage and mitochondria and NM are associated with metal-rich NPs including exogenous engineered Ti-rich nanorods, also identified in neuroenteric neurons. Such reactive, cytotoxic and magnetic NPs may act as catalysts for reactive oxygen species formation, altered cell signaling, and protein misfolding, aggregation and fibril formation. Hence, pervasive, airborne and environmental, metal-rich and magnetic nanoparticles may be a common denominator for quadruple misfolded protein neurodegenerative pathologies affecting urbanites from earliest childhood. The substantia nigrae is a very early target and the gastrointestinal tract (and the neuroenteric system) key brainstem portals. The ultimate neural damage and neuropathology (Alzheimer's, Parkinson's and TDP-43 pathology included) could depend on NP characteristics and the differential access and targets achieved via their portals of entry. Thus where you live, what air pollutants you are exposed to, what you are inhaling and swallowing from the air you breathe,what you eat, how you travel, and your occupational longlife history are key. Control of NP sources becomes critical.

Alzheimer disease starts in childhood in polluted Metropolitan Mexico City. A major health crisis in progress.

Exposures to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards are associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) youth have life time exposures to PM2.5 and O3 above standards. We focused on MMC residents ≤30 years and reviewed 134 consecutive autopsies of subjects age 20.03 ± 6.38 y (range 11 months to 30 y), the staging of Htau and ß amyloid, the lifetime cumulative PM2.5 (CPM 2.5) and the impact of the Apolipoprotein E (APOE) 4 allele, the most prevalent genetic risk for AD. We also reviewed the results of the Montreal Cognitive Assessment (MoCA) and the brainstem auditory evoked potentials (BAEPs) in clinically healthy young cohorts. Mobile sources, particularly from non-regulated diesel vehicles dominate the MMC pollutant emissions exposing the population to PM2.5 concentrations above WHO and EPA standards. Iron-rich,magnetic, highly oxidative, combustion and friction-derived nanoparticles (CFDNPs) are measured in the brain of every MMC resident. Progressive development of Alzheimer starts in childhood and in 99.25% of 134 consecutive autopsies ≤30 years we can stage the disease and its progression; 66% of ≤30 years urbanites have cognitive impairment and involvement of the brainstem is reflected by auditory central dysfunction in every subject studied. The average age for dementia using MoCA is 20.6 ± 3.4 y. APOE4 vs 3 carriers have 1.26 higher odds of committing suicide. PM2.5 and CFDNPs play a key role in the development of neuroinflammation and neurodegeneration in young urbanites. A serious health crisis is in progress with social, educational, judicial, economic and overall negative health impact for 25 million residents. Understanding the neural circuitry associated with the earliest cognitive and behavioral manifestations of AD is needed. Air pollution control should be prioritised-including the regulation of diesel vehicles- and the first two decades of life ought to be targeted for neuroprotective interventions. Defining paediatric environmental, nutritional, metabolic and genetic risk factor interactions is a multidisciplinary task of paramount importance to prevent Alzheimer's disease. Current and future generations are at risk.

Reduced repressive epigenetic marks, increased DNA damage and Alzheimer's disease hallmarks in the brain of humans and mice exposed to particulate urban air pollution.

Exposure to air pollutants is associated with an increased risk of developing Alzheimer's disease (AD). AD pathological hallmarks and cognitive deficits are documented in children and young adults in polluted cities (e.g. Metropolitan Mexico City, MMC). Iron-rich combustion- and friction-derived nanoparticles (CFDNPs) that are abundantly present in airborne particulate matter pollution have been detected in abundance in the brains of young urbanites. Epigenetic gene regulation has emerged as a candidate mechanism linking exposure to air pollution and brain diseases. A global decrease of the repressive histone post-translational modifications (HPTMs) H3K9me2 and H3K9me3 (H3K9me2/me3) has been described both in AD patients and animal models. Here, we evaluated nuclear levels of H3K9me2/me3 and the DNA double-strand-break marker γ-H2AX by immunostaining in post-mortem prefrontal white matter samples from 23 young adults (age 29 ± 6 years) who resided in MMC (n = 13) versus low-pollution areas (n = 10). Lower H3K9me2/me3 and higher γ-H2A.X staining were present in MMC urbanites, who also displayed the presence of hyperphosphorylated tau and amyloid-ß (Aß) plaques. Transmission electron microscopy revealed abundant CFDNPs in neuronal, glial and endothelial nuclei in MMC residents' frontal samples. In addition, mice exposed to particulate air pollution (for 7 months) in urban Santiago (Chile) displayed similar brain impacts; reduced H3K9me2/me3 and increased γ-H2A.X staining, together with increased levels of AD-related tau phosphorylation. Together, these findings suggest that particulate air pollution, including metal-rich CFDNPs, impairs brain chromatin silencing and reduces DNA integrity, increasing the risk of developing AD in young individuals exposed to high levels of particulate air pollution.

High-glucose diets induce mitochondrial dysfunction in Caenorhabditis elegans.

Glucose is an important nutrient that dictates the development, fertility and lifespan of all organisms. In humans, a deficit in its homeostatic control might lead to hyperglucemia and the development of obesity and type 2 diabetes, which show a decreased ability to respond to and metabolize glucose. Previously, we have reported that high-glucose diets (HGD) induce alterations in triglyceride content, body size, progeny, and the mRNA accumulation of key regulators of carbohydrate and lipid metabolism, and longevity in Caenorhabditis elegans (PLoS ONE 13(7): e0199888). Herein, we show that increasing amounts of glucose in the diet induce the swelling of both mitochondria in germ and muscle cells. Additionally, HGD alter the enzymatic activities of the different respiratory complexes in an intricate pattern. Finally, we observed a downregulation of ceramide synthases (hyl-1 and hyl-2) and antioxidant genes (gcs-1 and gst-4), while mitophagy genes (pink-1 and dct-1) were upregulated, probably as part of a mitohormetic mechanism in response to glucose toxicity.

Evaluation of New Benzimidazole Derivatives as Cysticidal Agents: In Vitro, in Vivo and Docking Studies.

Based on our previous research on cysticidal drugs, we report the synthesis and evaluation of three new benzimidazole derivatives. In these compounds, the amido group was used as a bioisosteric replacement of the ester group. The molecular docking on ß-tubulin revealed that the derivatives interacted through hydrogen bonding with N165, E198 and V236. All compounds showed in vitro activity against Taenia crassiceps cysts. Among them, benzimidazole 3 was found to be the most potent of the series (EC50 0.86 µM). This compound also exhibited the highest probability of binding and the lowest binding free energy score and was therefore selected for in vivo evaluation. Results indicated that the efficacy of compound 3 was comparable to that of the reference drug, albendazole (50.39 vs. 47.16% parasite reduction). Animals treated with compound 3 seemed to tolerate this benzimidazole well, with no changes in behavior, or food and water consumption. These findings are consistent with the in silico prediction results, which indicated low toxicity risks. The pharmacokinetic study showed that the half-life and mean residence time (6.06 and 11.9 h, respectively) were long after oral administration. Together, these results indicate that this new benzimidazole derivative represents a promising structure with cysticidal activity.

Combustion and friction-derived nanoparticles and industrial-sourced nanoparticles: The culprit of Alzheimer and Parkinson's diseases.

Redox-active, strongly magnetic, combustion and friction-derived nanoparticles (CFDNPs) are abundant in particulate matter air pollution. Urban children and young adults with Alzheimer disease Continuum have higher numbers of brain CFDNPs versus clean air controls. CFDNPs surface charge, dynamic magnetic susceptibility, iron content and redox activity contribute to ROS generation, neurovascular unit (NVU), mitochondria, and endoplasmic reticulum (ER) damage, and are catalysts for protein misfolding, aggregation and fibrillation. CFDNPs respond to external magnetic fields and are involved in cell damage by agglomeration/clustering, magnetic rotation and/or hyperthermia. This review focus in the interaction of CFDNPs, nanomedicine and industrial NPs with biological systems and the impact of portals of entry, particle sizes, surface charge, biomolecular corona, biodistribution, mitochondrial dysfunction, cellular toxicity, anterograde and retrograde axonal transport, brain dysfunction and pathology. NPs toxicity information come from researchers synthetizing particles and improving their performance for drug delivery, drug targeting, magnetic resonance imaging and heat mediators for cancer therapy. Critical information includes how these NPs overcome all barriers, the NPs protein corona changes as they cross the NVU and the complexity of NPs interaction with soluble proteins and key organelles. Oxidative, ER and mitochondrial stress, and a faulty complex protein quality control are at the core of Alzheimer and Parkinson's diseases and NPs mechanisms of action and toxicity are strong candidates for early development and progression of both fatal diseases. Nanoparticle exposure regardless of sources carries a high risk for the developing brain homeostasis and ought to be included in the AD and PD research framework.

Combustion- and friction-derived magnetic air pollution nanoparticles in human hearts.

Air pollution is a risk factor for cardiovascular and Alzheimer's disease (AD). Iron-rich, strongly magnetic, combustion- and friction-derived nanoparticles (CFDNPs) are abundant in particulate air pollution. Metropolitan Mexico City (MMC) young residents have abundant brain CFDNPs associated with AD pathology. We aimed to identify if magnetic CFDNPs are present in urbanites' hearts and associated with cell damage. We used magnetic analysis and transmission electron microscopy (TEM) to identify heart CFDNPs and measured oxidative stress (cellular prion protein, PrPC), and endoplasmic reticulum (ER) stress (glucose regulated protein, GRP78) in 72 subjects age 23.8 ±â€¯9.4y: 63 MMC residents, with Alzheimer Continuum vs 9 controls. Magnetite/maghemite nanoparticles displaying the typical rounded crystal morphologies and fused surface textures of CFDNPs were more abundant in MMC residents' hearts. NPs, ∼2-10 × more abundant in exposed vs controls, were present inside mitochondria in ventricular cardiomyocytes, in ER, at mitochondria-ER contact sites (MERCs), intercalated disks, endothelial and mast cells. Erythrocytes were identified transferring 'hitchhiking' NPs to activated endothelium. Magnetic CFDNP concentrations and particle numbers ranged from 0.2 to 1.7 µg/g and ∼2 to 22 × 109/g, respectively. Co-occurring with cardiomyocyte NPs were abnormal mitochondria and MERCs, dilated ER, and lipofuscin. MMC residents had strong left ventricular PrPC and bi-ventricular GRP78 up-regulation. The health impact of up to ∼22 billion magnetic NPs/g of ventricular tissue are likely reflecting the combination of surface charge, ferrimagnetism, and redox activity, and includes their potential for disruption of the heart's electrical impulse pathways, hyperthermia and alignment and/or rotation in response to magnetic fields. Exposure to solid NPs appears to be directly associated with early and significant cardiac damage. Identification of strongly magnetic CFDNPs in the hearts of children and young adults provides an important novel layer of information for understanding CVD pathogenesis emphasizing the urgent need for prioritization of particulate air pollution control.

Air Pollution, Combustion and Friction Derived Nanoparticles, and Alzheimer's Disease in Urban Children and Young Adults.

Exposures to fine particulate matter (PM2.5) and ozone (O3) ≥US EPA standards are associated with Alzheimer's disease (AD) risk. The projection of 13.8 million AD cases in the US by the year 2050 obligate us to explore early environmental exposures as contributors to AD risk and pathogenesis. Metropolitan Mexico City children and young adults have lifetime exposures to PM2.5 and O3, and AD starting in the brainstem and olfactory bulb is relentlessly progressing in the first two decades of life. Magnetite combustion and friction-derived nanoparticles reach the brain and are associated with early and progressive damage to the neurovascular unit and to brain cells. In this review: 1) we highlight the interplay environment/genetics in the AD development in young populations; 2) comment upon ApoE ɛ4 and the rapid progression of neurofibrillary tangle stages and higher suicide risk in youth; and 3) discuss the role of combustion-derived nanoparticles and brain damage. A key aspect of this review is to show the reader that air pollution is complex and that profiles change from city to city with common denominators across countries. We explore and compare particulate matter profiles in Mexico City, Paris, and Santiago in Chile and make the point of why we should invest in decreasing PM2.5 to at least our current US EPA standard. Multidisciplinary intervention strategies are critical for prevention or amelioration of cognitive deficits and AD progression and risk of suicide in young individuals. AD pathology evolving from childhood is threating the wellbeing of future generations.

On the molecular and cellular effects of omeprazole to further support its effectiveness as an antigiardial drug.

Research on Giardia lamblia has accumulated large information about its molecular cell biology and infection biology. However, giardiasis is still one of the commonest parasitic diarrheal diseases affecting humans. Additionally, an alarming increase in cases refractory to conventional treatment has been reported in low prevalence settings. Consequently, efforts directed toward supporting the efficient use of alternative drugs, and the study of their molecular targets appears promising. Repurposing of proton pump inhibitors is effective in vitro against the parasite and the toxic activity is associated with the inhibition of the G. lamblia triosephosphate isomerase (GlTIM) via the formation of covalent adducts with cysteine residue at position 222. Herein, we evaluate the effectiveness of omeprazole in vitro and in situ on GlTIM mutants lacking the most superficial cysteines. We studied the influence on the glycolysis of Giardia trophozoites treated with omeprazole and characterized, for the first time, the morphological effect caused by this drug on the parasite. Our results support the effectiveness of omeprazole against GlTIM despite of the possibility to mutate the druggable amino acid targets as an adaptive response. Also, we further characterized the effect of omeprazole on trophozoites and discuss the possible mechanism involved in its antigiardial effect.

Antigiardiasic activity of Cu(II) coordination compounds: Redox imbalance and membrane damage after a short exposure time.

Giardiasis is a widespread illness that affects inhabitants of underdeveloped countries, being children and seniors the highest risk population. The several adverse effects produced by current therapies besides its increasing ineffectiveness due to the appearance of resistant strains evidence the urgent need for new therapeutic approaches. We present the antigiardiasic effect of eight Cu(II) coordination compounds, which belong to the family Casiopeínas. Two of them, 4,7-diphenyl-1,10-phenanthroline(acetylacetonato)copper(II) nitrate (CasIII-Ha,36 µM) and 4,7-diphenyl-1,10-phenanthroline(glycinato)copper(II) nitrate (CasI-gly,36 µM) have shown the best antiproliferative effect in Giardia intestinalis trophozoite cultures, both with the higher lipophilic character of the series. The antiproliferative effect of these coordination compounds is attributable to its capacity to interact with the cellular membrane and to increase reactive oxygen species (ROS) concentration within the parasite since the first hours of exposure, (2-6 h). We found that these compounds mainly induced the cell death of trophozoites by apoptosis, contrary to metronidazole, which induces apoptosis and necrosis in the same ratio. The cytotoxic effects on lymphocytes and macrophages isolated from human peripheral blood allowed us to establish a selectivity index and in turn, identify and propose the best candidates to continue with the assays in animal models. The selected molecules do not include the most active compounds against trophozoites, instead of that, we propose the compounds 4',4'-dimethyl-2,2'-bipyridine(acetylacetonato)copper(II) nitrate (CasIII-ia,IC50 = 156 µM) and 4,7-dimethyl-1,10-phenanthroline(acetylacetonato) copper(II) nitrate (CasIII-Ea,IC50 = 125 µM), which possess an antiproliferative efficacy comparable with Metronidazole but also are those that produce the lowest effect on the viability of human lymphocytes and macrophages.

Mild Cognitive Impairment and Dementia Involving Multiple Cognitive Domains in Mexican Urbanites.

Exposures to fine particulate matter PM2.5 and ozone O3 are associated with Alzheimer's disease (AD) risk. Mexico City residents have lifetime exposures to PM2.5 and O3 above annual USEPA standards and their brains contain high redox, combustion, and friction-derived magnetite nanoparticles. AD pathological changes with subcortical pre-tangle stages in infancy and cortical tau pre-tangles, NFT Stages I-II, and amyloid phases 1-2 are identified by the 2nd decade. Given their AD continuum, a reliable identification of cognitive impairment is of utmost importance. The Montreal Cognitive Assessment (MoCA) was administered to 517 urbanites, age 21.60±5.88 years, with 13.69±1.28 formal education years, in Mexican PM2.5 polluted cities. MoCA score was 23.92±2.82, and 24.7% and 30.3% scored ≤24 and ≤22, respectively (MCI≤24, AD≤22). Cognitive deficits progressively targeted Visuospatial, Executive, Language, and Memory domains, body mass index (BMI) impacting total scores negatively (p = 0.0008), aging driving down Executive, Visuospatial, and Language index scores (p < 0.0001, 0.0037, and 0.0045), and males performing better in Executive tasks. Average age for AD MoCA scores was 22.38±7.7 years. Residency in polluted cities is associated with progression of multi-domain cognitive impairment affecting 55% of Mexican seemingly healthy youth. Normal BMI ought to be a neuroprotection goal. MoCA provides guidance for further mandatory neuropsychological testing in young populations. Identifying and lowering key neurotoxicants impacting neural risk trajectories in the developing brain and monitoring cognitive performance would greatly facilitate multidisciplinary early diagnosis and prevention of AD in high risk young populations. Cognitive deficits hinder development of those representing the force moving the country in future years.

Non-Phosphorylated Tau in Cerebrospinal Fluid is a Marker of Alzheimer's Disease Continuum in Young Urbanites Exposed to Air Pollution.

Long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards is associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) children exhibit subcortical pretangles in infancy and cortical tau pre-tangles, NFTs, and amyloid phases 1-2 by the 2nd decade. Given their AD continuum, we measured in 507 normal cerebrospinal fluid (CSF) samples (MMC 354, controls 153, 12.82±6.73 y), a high affinity monoclonal non-phosphorylated tau antibody (non-P-Tau), as a potential biomarker of AD and axonal damage. In 81 samples, we also measured total tau (T-Tau), tau phosphorylated at threonine 181 (P-Tau), amyloid-ß1-42, BDNF, and vitamin D. We documented by electron microscopy myelinated axonal size and the pathology associated with combustion-derived nanoparticles (CDNPs) in anterior cingulate cortex white matter in 6 young residents (16.25±3.34 y). Non-P-Tau showed a strong increase with age significantly faster among MMC versus controls (p = 0.0055). Aß1 - 42 and BDNF concentrations were lower in MMC children (p = 0.002 and 0.03, respectively). Anterior cingulate cortex showed a significant decrease (p = <0.0001) in the average axonal size and CDNPs were associated with organelle pathology. Significant age increases in non-P-Tau support tau changes early in a population with axonal pathology and evolving AD hallmarks in the first two decades of life. Non-P-Tau is an early biomarker of axonal damage and potentially valuable to monitor progressive longitudinal changes along with AD multianalyte classical CSF markers. Neuroprotection of young urbanites with PM2.5 and CDNPs exposures ought to be a public health priority to halt the development of AD in the first two decades of life.

Alzheimer's disease and alpha-synuclein pathology in the olfactory bulbs of infants, children, teens and adults ≤ 40 years in Metropolitan Mexico City. APOE4 carriers at higher risk of suicide accelerate their olfactory bulb pathology.

There is growing evidence that air pollution is a risk factor for a number of neurodegenerative diseases, most notably Alzheimer's (AD) and Parkinson's (PD). It is generally assumed that the pathology of these diseases arises only later in life and commonly begins within olfactory eloquent pathways prior to the onset of the classical clinical symptoms. The present study demonstrates that chronic exposure to high levels of air pollution results in AD- and PD-related pathology within the olfactory bulbs of children and relatively young adults ages 11 months to 40 years. The olfactory bulbs (OBs) of 179 residents of highly polluted Metropolitan Mexico City (MMC) were evaluated for AD- and alpha-synuclein-related pathology. Even in toddlers, hyperphosphorylated tau (hTau) and Lewy neurites (LN) were identified in the OBs. By the second decade, 84% of the bulbs exhibited hTau (48/57), 68% LNs and vascular amyloid (39/57) and 36% (21/57) diffuse amyloid plaques. OB active endothelial phagocytosis of red blood cell fragments containing combustion-derived nanoparticles (CDNPs) and the neurovascular unit damage were associated with myelinated and unmyelinated axonal damage. OB hTau neurites were associated mostly with pretangle stages 1a and 1b in subjects ≤ 20 years of age, strongly suggesting olfactory deficits could potentially be an early guide of AD pretangle subcortical and cortical hTau. APOE4 versus APOE3 carriers were 6-13 times more likely to exhibit OB vascular amyloid, neuronal amyloid accumulation, alpha-synuclein aggregates, hTau neurofibrillary tangles, and neurites. Remarkably, APOE4 carriers were 4.57 times more likely than non-carriers to die by suicide. The present findings, along with previous data that over a third of clinically healthy MMC teens and young adults exhibit low scores on an odor identification test, support the concept that olfactory testing may aid in identifying young people at high risk for neurodegenerative diseases. Moreover, results strongly support early neuroprotective interventions in fine particulate matter (PM2.5) and CDNP's exposed individuals ≤ 20 years of age, and the critical need for air pollution control.