Air pollution & the brain: Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease

Background Increasing evidence links diverse forms of air pollution to neuroinflammation and neuropathology in both human and animal models, but the effects of long-term exposures are poorly understood. Objective We explored the central nervous system consequences of subchronic exposure to diesel exhaust (DE) and addressed the minimum levels necessary to elicit neuroinflammation and markers of early neuropathology. Methods Male Fischer 344 rats were exposed to DE (992, 311, 100, 35 and 0 μg PM/m3) by inhalation over 6 months. Results DE exposure resulted in elevated levels of TNFα at high concentrations in all regions tested, with the exception of the cerebellum. The midbrain region was the most sensitive, where exposures as low as 100 μg PM/m3 significantly increased brain TNFα levels. However, this sensitivity to DE was not conferred to all markers of neuroinflammation, as the midbrain showed no increase in IL-6 expression at any concentration tested, an increase in IL-1β at only high concentrations, and a decrease in MIP-1α expression, supporting that compensatory mechanisms may occur with subchronic exposure. Aβ42 levels were the highest in the frontal lobe of mice exposed to 992 μg PM/m3 and tau [pS199] levels were elevated at the higher DE concentrations (992 and 311 μg PM/m3) in both the temporal lobe and frontal lobe, indicating that proteins linked to preclinical Alzheimer\u27s disease were affected. α Synuclein levels were elevated in the midbrain in response to the 992 μg PM/m3 exposure, supporting that air pollution may be associated with early Parkinson\u27s disease-like pathology. Conclusions Together, the data support that the midbrain may be more sensitive to the neuroinflammatory effects of subchronic air pollution exposure. However, the DE-induced elevation of proteins associated with neurodegenerative diseases was limited to only the higher exposures, suggesting that air pollution-induced neuroinflammation may precede preclinical markers of neurodegenerative disease in the midbrain

Diesel Exhaust Activates & Primes Microglia: Air Pollution, Neuroinflammation, & Regulation of Dopaminergic Neurotoxicity

BACKGROUND: Air pollution is linked to central nervous system disease, but the mechanisms responsible are poorly understood. OBJECTIVES: Here, we sought to address the brain-region-specific effects of diesel exhaust (DE) and key cellular mechanisms underlying DE-induced microglia activation, neuroinflammation, and dopaminergic (DA) neurotoxicity. METHODS: Rats were exposed to DE (2.0, 0.5, and 0 mg/m3) by inhalation over 4 weeks or as a single intratracheal administration of DE particles (DEP; 20 mg/kg). Primary neuron-glia cultures and the HAPI (highly aggressively proliferating immortalized) microglial cell line were used to explore cellular mechanisms. RESULTS: Rats exposed to DE by inhalation demonstrated elevated levels of whole-brain IL-6 (interleukin-6) protein, nitrated proteins, and IBA-1 (ionized calcium-binding adaptor molecule 1) protein (microglial marker), indicating generalized neuroinflammation. Analysis by brain region revealed that DE increased TNFα (tumor necrosis factor-α), IL-1β, IL-6, MIP-1α (macrophage inflammatory protein-1α) RAGE (receptor for advanced glycation end products), fractalkine, and the IBA-1 microglial marker in most regions tested, with the midbrain showing the greatest DE response. Intratracheal administration of DEP increased microglial IBA-1 staining in the substantia nigra and elevated both serum and whole-brain TNFα at 6 hr posttreatment. Although DEP alone failed to cause the production of cytokines and chemokines, DEP (5 μg/mL) pretreatment followed by lipopolysaccharide (2.5 ng/mL) in vitro synergistically amplified nitric oxide production, TNFα release, and DA neurotoxicity. Pretreatment with fractalkine (50 pg/mL) in vitro ameliorated DEP (50 μg/mL)-induced microglial hydrogen peroxide production and DA neurotoxicity. CONCLUSIONS: Together, these findings reveal complex, interacting mechanisms responsible for how air pollution may cause neuroinflammation and DA neurotoxicity

Atypical microglial response to biodiesel exhaust in healthy and hypertensive rats

Accumulating evidence suggests a deleterious role for urban air pollution in central nervous system (CNS) diseases and neurodevelopmental disorders. Microglia, the resident innate immune cells and sentinels in the brain, are a common source of neuroinflammation and are implicated in how air pollution may exert CNS effects. While renewable energy, such as soy-based biofuel, is of increasing public interest, there is little information on how soy biofuel may affect the brain. To address this, male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were exposed to 100% Soy Biodiesel Exhaust (100SBDE; 0, 50, 150 and 500 μg/m3) by inhalation for 4 h/day for 4 weeks (5 days/week). IBA-1 staining of microglia in the substantia nigra revealed significant changes in morphology with 100SBDE exposure in rats from both genotypes, where the SHR were less sensitive. Further analysis failed to show consistent changes in pro-inflammatory cytokine expression, nitrated protein, and arginase1 expression in brain tissue from either rat strain exposed to 100SBDE. CX3CR1 and fractalkine mRNA expression were lower in the striatum of all 100SBDE exposed rats, but greater SBDE exposure was required for loss of fractalkine expression in the SHR. Together, these data support that month-long 100SBDE exposure impacts the basal ganglia with changes in microglia morphology, an impaired fractalkine axis, and an atypical activation response without traditional markers of M1 or M2 activation, where the SHR may be less sensitive to these effects

Diesel Exhaust Activates and Primes Microglia: Air Pollution, Neuroinflammation, and Regulation of Dopaminergic Neurotoxicity

Background: Air pollution is linked to central nervous system disease, but the mechanisms responsible are poorly understood

Recommendations for change in infection prevention programs and practice

Fifty years of evolution in infection prevention and control programs have involved significant accomplishments related to clinical practices, methodologies, and technology. However, regulatory mandates, and resource and research limitations, coupled with emerging infection threats such as the COVID-19 pandemic, present considerable challenges for infection preventionists. This article provides guidance and recommendations in 14 key areas. These interventions should be considered for implementation by United States health care facilities in the near future

Prophage induction reduces Shiga toxin producing \u3ci\u3eEscherichia coli\u3c/i\u3e (STEC) and Salmonella enterica on tomatoes and spinach: A model study

Fresh produce is increasingly implicated in foodborne outbreaks and most fresh produce is consumed raw, emphasizing the need to develop non-thermal methods to control foodborne pathogens. This study investigates bacterial cell lysis through induction of prophages as a novel approach to control foodborne bacterial pathogens on fresh produce. Shiga toxin producing Escherichia coli (STEC) and Salmonella enterica isolates were exposed to different prophage inducers (i.e. mitomycin C or streptonigrin) and growth of the cells was monitored by measuring the optical density (OD600) during incubation at 37C. Beginning at three hours after addition of the inducer, all concentrations (0.5, 1, 2 mg/mL) of mitomycin C, or 2 mg/mL streptonigrin significantly reduced the OD600 in broth cultures, in a concentration dependent manner, relative to cultures where no inducer was added. PCR confirmed bacterial release of induced bacteriophages and demonstrated that a single compound could successfully induce multiple types of prophages. The ability of mitomycin C to induce prophages in STEC O157:H7 and in S. enterica (serovars Typhimurium and Newport) on fresh produce was evaluated by inoculating red greenhouse tomatoes or spinach leaves with 5 x 107 and 5 x 108 colony forming units, respectively. After allowing time for the inoculum to dry on the fresh produce samples, 6 mg/mL mitomycin C was sprayed onto each sample, while control samples were sprayed with water. Following overnight incubation at 4C, the bacterial cells were recovered and plate counts were performed. A 3 log reduction in STEC O157:H7 cells was observed on tomatoes sprayed with mitomycin C compared to those sprayed with water, while a 1 log reduction was obtained on spinach. Similarly, spraying mitomycin C on tomatoes and spinach inoculated with S. enterica isolates resulted in a 1-1.5 log and 2 log reduction, respectively. These findings serve as a proof of concept that prophage induction can effectively control bacterial foodborne pathogens on fresh produce

Tissue regeneration in dentistry: can salamanders provide insight?

The ability to regenerate damaged tissues would be of tremendous benefit for medicine and dentistry. Unfortunately, humans are unable to regenerate tissues such teeth, fingers or to repair injured spinal cord. With an aging population, health problems are more prominent and dentistry is no exception as loss of bone tissue in the orofacial sphere from periodontal disease is on the rise. Humans can repair oral soft tissues exceptionally well, however hard tissues, like bone and teeth, are devoid of the ability to repair well or at all. Fortunately, Mother Nature has solved nearly every problem that we would like to solve for our own benefit and tissue regeneration is no exception. By studying animals that can regenerate, like Axolotls (Mexican salamander), we hope to find ways to stimulate regeneration in humans. We will discuss the role of the transforming growth factor beta cytokines as they are central to wound healing in humans and regeneration in Axolotls. We will also compare wound healing in humans (skin and oral mucosa) to Axolotl skin wound healing and limb regeneration. Finally, we will address the problem of bone regeneration and present results in salamanders which indicate that in order to regenerate bone you need to recruit non-bone cells. Fundamental research, such as the work being done in animals that can regenerate, offers insight to help understand why some treatments are successful while others fail when it comes to specific tissues such as bones

Coordination of meristem and boundary functions by transcription factors in the SHOOT MERISTEMLESS regulatory network

The Arabidopsis homeodomain transcription factor SHOOT MERISTEMLESS (STM) is crucial for shoot apical meristem (SAM) function, yet the components and structure of the STMgene regulatory network (GRN) are largely unknown. Here, we show that transcriptional regulators are overrepresented among STM-regulated genes and, using these as GRN components in Bayesian network analysis, we infer STM GRN associations and reveal regulatory relationships between STM and factors involved in multiple aspects of SAM function. These include hormone regulation, TCP-mediated control of cell differentiation, AIL/PLT-mediated regulation of pluripotency and phyllotaxis, and specification of meristem-organ boundary zones via CUC1. We demonstrate a direct positive transcriptional feedback loop between STM and CUC1, despite their distinct expression patterns in the meristem and organ boundary, respectively. Our further finding that STM activates expression of the CUC1-targeting microRNA miR164c combined with mathematical modelling provides a potential solution for this apparent contradiction, demonstrating that these proposed regulatory interactions coupled with STM mobility could be sufficient to provide a mechanism for CUC1 localisation at the meristem-organ boundary. Our findings highlight the central role for the STM GRN in coordinating SAM functions

Chronic Apocynin Treatment Attenuates Beta Amyloid Plaque Size and Microglial Number in hAPP(751)SL Mice

Background: NADPH oxidase is implicated in neurotoxic microglial activation and the progressive nature of Alzheimer’s Disease (AD). Here, we test the ability of two NADPH oxidase inhibitors, apocynin and dextromethorphan (DM), to reduce learning deficits and neuropathology in transgenic mice overexpressing human amyloid precursor protein with the Swedish and London mutations (hAPP(751)SL). Methods: Four month old hAPP(751)SL mice were treated daily with saline, 15 mg/kg DM, 7.5 mg/kg DM, or 10 mg/kg apocynin by gavage for four months. Results: Only hAPP(751)SL mice treated with apocynin showed reduced plaque size and a reduction in the number of cortical microglia, when compared to the saline treated group. Analysis of whole brain homogenates from all treatments tested (saline, DM, and apocynin) demonstrated low levels of TNFa, protein nitration, lipid peroxidation, and NADPH oxidase activation, indicating a low level of neuroinflammation and oxidative stress in hAPP(751)SL mice at 8 months of age that was not significantly affected by any drug treatment. Despite in vitro analyses demonstrating that apocynin and DM ameliorate Ab-induced extracellular superoxide production and neurotoxicity, both DM and apocynin failed to significantly affect learning and memory tasks or synaptic density in hAPP(751)SL mice. To discern how apocynin was affecting plaque levels (plaque load) and microglial number in vivo, in vitro analysis of microglia was performed, revealing no apocynin effects on beta-amyloid (Ab) phagocytosis, microglial proliferation, or microglial survival. Conclusions: Together, this study suggests that while hAPP(751)SL mice show increases in microglial number and plaque load, they fail to exhibit elevated markers of neuroinflammation consistent with AD at 8 months of age, which may be a limitation of this animal model. Despite absence of clear neuroinflammation, apocynin was still able to reduce both plaque size and microglial number, suggesting that apocynin may have additional therapeutic effects independent of anti-inflammatory characteristics