Environmental risk scores of persistent organic pollutants associate with higher ALS risk and shorter survival in a new Michigan case/control cohort.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurogenerative disease caused by combined genetic susceptibilities and environmental exposures. Identifying and validating these exposures are of paramount importance to modify disease risk. We previously reported that persistent organic pollutants (POPs) associate with ALS risk and survival and aimed to replicate these findings in a new cohort. METHOD: Participants with and without ALS recruited in Michigan provided plasma samples for POPs analysis by isotope dilution with triple quadrupole mass spectrometry. ORs for risk models and hazard ratios for survival models were calculated for individual POPs. POP mixtures were represented by environmental risk scores (ERS), a summation of total exposures, to evaluate the association with risk (ERSrisk) and survival (ERSsurvival). RESULTS: Samples from 164 ALS and 105 control participants were analysed. Several individual POPs significantly associated with ALS, including 8 of 22 polychlorinated biphenyls and 7 of 10 organochlorine pesticides (OCPs). ALS risk was most strongly represented by the mixture effects of OCPs alpha-hexachlorocyclohexane, hexachlorobenzene, trans-nonachlor and cis-nonachlor and an interquartile increase in ERSrisk enhanced ALS risk 2.58 times (p<0.001). ALS survival was represented by the combined mixture of all POPs and an interquartile increase in ERSsurvival enhanced ALS mortality rate 1.65 times (p=0.008). CONCLUSIONS: These data continue to support POPs as important factors for ALS risk and progression and replicate findings in a new cohort. The assessments of POPs in non-Michigan ALS cohorts are encouraged to better understand the global effect and the need for targeted disease risk reduction strategies.

Non-invasive in vivo measurements of metabolic alterations in the type 2 diabetic brain by 1 H magnetic resonance spectroscopy.

Type 2 diabetes (T2D) is a complex chronic metabolic disorder characterized by hyperglycemia because of insulin resistance. Diabetes with chronic hyperglycemia may alter brain metabolism, including brain glucose and neurotransmitter levels; however, detailed, longitudinal studies of metabolic alterations in T2D are lacking. To shed insight, here, we characterized the consequences of poorly controlled hyperglycemia on neurochemical profiles that reflect metabolic alterations of the brain in both humans and animal models of T2D. Using in vivo 1 H magnetic resonance spectroscopy, we quantified 12 metabolites cross-sectionally in T2D patients and 20 metabolites longitudinally in T2D db/db mice versus db+ controls. We found significantly elevated brain glucose (91%, p < 0.001), taurine (22%, p = 0.02), glucose+taurine (56%, p < 0.001), myo-inositol (12%, p = 0.02), and choline-containing compounds (10%, p = 0.01) in T2D patients versus age- and sex-matched controls, findings consistent with measures in T2D db/db versus control db+ littermates. In mice, hippocampal and striatal neurochemical alterations in brain glucose, ascorbate, creatine, phosphocreatine, γ-aminobutyric acid, glutamate, glutamine, glutathione, glycerophosphoryl-choline, lactate, myo-inositol, and taurine persisted in db/db mice with chronic disease progression from 16 to 48 weeks of age, which were distinct from control db+ mice. Overall, our study demonstrates the utility of 1 H magnetic resonance spectroscopy as a non-invasive tool for characterizing and monitoring brain metabolic changes with T2D progression.

Transcriptomic analysis of diabetic kidney disease and neuropathy in mouse models of type 1 and type 2 diabetes.

Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are common complications of type 1 (T1D) and type 2 (T2D) diabetes. However, the mechanisms underlying pathogenesis of these complications are unclear. In this study, we optimized a streptozotocin-induced db/+ murine model of T1D and compared it to our established db/db T2D mouse model of the same C57BLKS/J background. Glomeruli and sciatic nerve transcriptomic data from T1D and T2D mice were analyzed by self-organizing map and differential gene expression analysis. Consistent with prior literature, pathways related to immune function and inflammation were dysregulated in both complications in T1D and T2D mice. Gene-level analysis identified a high degree of concordance in shared differentially expressed genes (DEGs) in both complications and across diabetes type when using mice from the same cohort and genetic background. As we have previously shown a low concordance of shared DEGs in DPN when using mice from different cohorts and genetic backgrounds, this suggests that genetic background may influence diabetic complications. Collectively, these findings support the role of inflammation and indicate that genetic background is important in complications of both T1D and T2D.

Ecdysone-induced microRNA miR-276a-3p controls developmental growth by targeting the insulin-like receptor in Drosophila.

Animal growth is controlled by a variety of external and internal factors during development. The steroid hormone ecdysone plays a critical role in insect development by regulating the expression of various genes. In this study, we found that fat body-specific expression of miR-276a, an ecdysone-responsive microRNA (miRNA), led to a decrease in the total mass of the larval fat body, resulting in significant growth reduction in Drosophila. Changes in miR-276a expression also affected the proliferation of Drosophila S2 cells. Furthermore, we found that the insulin-like receptor (InR) is a biologically relevant target gene regulated by miR-276a-3p. In addition, we found that miR-276a-3p is upregulated by the canonical ecdysone signalling pathway involving the ecdysone receptor and broad complex. A reduction in cell proliferation caused by ecdysone was compromised by blocking miR-276a-3p activity. Thus, our results suggest that miR-276a-3p is involved in ecdysone-mediated growth reduction by controlling InR expression in the insulin signalling pathway.

The amyotrophic lateral sclerosis exposome: recent advances and future directions.

Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration with typical survival of only 2-5 years from diagnosis. The causes of ALS are multifactorial: known genetic mutations account for only around 70% of cases of familial ALS and 15% of sporadic cases, and heritability estimates range from 8% to 61%, indicating additional causes beyond genetics. Consequently, interest has grown in environmental contributions to ALS risk and progression. The gene-time-environment hypothesis posits that ALS onset occurs through an interaction of genes with environmental exposures during ageing. An alternative hypothesis, the multistep model of ALS, suggests that several hits, at least some of which could be environmental, are required to trigger disease onset, even in the presence of highly penetrant ALS-associated mutations. Studies have sought to characterize the ALS exposome - the lifetime accumulation of environmental exposures that increase disease risk and affect progression. Identifying the full scope of environmental toxicants that enhance ALS risk raises the prospect of preventing disease by eliminating or mitigating exposures. In this Review, we summarize the evidence for an ALS exposome, discussing the strengths and limitations of epidemiological studies that have identified contributions from various sources. We also consider potential mechanisms of exposure-mediated toxicity and suggest future directions for ALS exposome research.

MicroRNA miR-274-5p Suppresses Found-in-Neurons Associated with Melanotic Mass Formation and Developmental Growth in Drosophila.

The hematopoietic system plays a crucial role in immune defense response and normal development, and it is regulated by various factors from other tissues. The dysregulation of hematopoiesis is associated with melanotic mass formation; however, the molecular mechanisms underlying this process are poorly understood. Here, we observed that the overexpression of miR-274 in the fat body resulted in the formation of melanotic masses. Moreover, abnormal activation of the JNK and JAK/STAT signaling pathways was linked to these consequences. In addition to this defect, miR-274 overexpression in the larval fat body decreased the total tissue size, leading to a reduction in body weight. miR-274-5p was found to directly suppress the expression of found-in-neurons (fne), which encodes an RNA-binding protein. Similar to the effects of miR-274 overexpression, fne depletion led to melanotic mass formation and growth reduction. Collectively, miR-274 plays a regulatory role in the fne-JNK signaling axis in melanotic mass formation and growth control.

MicroRNA miR-263b-5p Regulates Developmental Growth and Cell Association by Suppressing Laminin A in Drosophila.

Basement membranes (BMs) play important roles under various physiological conditions in animals, including ecdysozoans. During development, BMs undergo alterations through diverse intrinsic and extrinsic regulatory mechanisms; however, the full complement of pathways controlling these changes remain unclear. Here, we found that fat body-overexpression of Drosophila miR-263b, which is highly expressed during the larval-to-pupal transition, resulted in a decrease in the overall size of the larval fat body, and ultimately, in a severe growth defect accompanied by a reduction in cell proliferation and cell size. Interestingly, we further observed that a large proportion of the larval fat body cells were prematurely disassociated from each other. Moreover, we present evidence that miR-263b-5p suppresses the main component of BMs, Laminin A (LanA). Through experiments using RNA interference (RNAi) of LanA, we found that its depletion phenocopied the effects in miR-263b-overexpressing flies. Overall, our findings suggest a potential role for miR-263b in developmental growth and cell association by suppressing LanA expression in the Drosophila fat body.

Dietary interventions improve diabetic kidney disease, but not peripheral neuropathy, in a db/db mouse model of type 2 diabetes.

Patients with type 2 diabetes often develop the microvascular complications of diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN), which decrease quality of life and increase mortality. Unfortunately, treatment options for DKD and DPN are limited. Lifestyle interventions, such as changes to diet, have been proposed as non-pharmacological treatment options for preventing or improving DKD and DPN. However, there are no reported studies simultaneously evaluating the therapeutic efficacy of varying dietary interventions in a type 2 diabetes mouse model of both DKD and DPN. Therefore, we compared the efficacy of a 12-week regimen of three dietary interventions, low carbohydrate, caloric restriction, and alternate day fasting, for preventing complications in a db/db type 2 diabetes mouse model by performing metabolic, DKD, and DPN phenotyping. All three dietary interventions promoted weight loss, ameliorated glycemic status, and improved DKD, but did not impact percent fat mass and DPN. Multiple regression analysis identified a negative correlation between fat mass and motor nerve conduction velocity. Collectively, our data indicate that these three dietary interventions improved weight and glycemic status and alleviated DKD but not DPN. Moreover, diets that decrease fat mass may be a promising non-pharmacological approach to improve DPN in type 2 diabetes given the negative correlation between fat mass and motor nerve conduction velocity.

Absence of pain in subjects with advanced radiographic knee osteoarthritis.

BACKGROUND: To investigate the frequency of pain among subjects with advanced radiographic knee osteoarthritis (OA) defined as Kellgren-Lawrence (KL) grade 4 and clinical features associated with pain. METHODS: Subjects from the Hallym Aging Study (HAS), the Korean National Health and Nutrition Examination Survey (KNHANES), and the Osteoarthritis Initiative (OAI) were included. Participants were asked knee-specific questions regarding the presence of knee pain. Clinical characteristics associated with the presence of pain were evaluated with multivariable logistic regression analysis. RESULTS: The study population consisted of 504, 10,152 and 4796 subjects from HAS, KNHANES, and OAI, respectively. KL grade 4 OA was identified in 9.3, 7.6, and 11.5% of subjects, while pain was absent in 23.5, 31.2, and 5.9% of subjects in KL grade 4 knee OA, respectively. After multivariable analysis, female gender showed a significant association with pain in the KNHANES group, while in the OAI group, younger age did. Advanced knee OA patients without pain did not differ from non-OA subjects in most items of SF-12 in both Korean and OAI subjects. Total WOMAC score was not significantly different between non-OA and advanced knee OA subjects without pain in the OAI. CONCLUSIONS: Our study showed that a considerable number of subjects with KL grade 4 OA did not report pain. In patients whose pain arises from causes other than structural damage of the joint, therapeutic decision based on knee X-ray would lead to suboptimal result. In addition, treatment options focusing solely on cartilage engineering, should be viewed with caution.

Algal Growth Potential of Microcystis aeruginosa from Reclaimed Water.

Algal growth potential (AGP) of the cyanobacterium Microcystis aeruginosa (M. aeruginosa, NIES-298) using reclaimed water from various wastewater reclamation pilot plants was investigated to evaluate the feasibility of the reclaimed water usage for recreational purposes. After completing the coagulation and ultrafiltration processes, the concentrations of most contaminants in the reclaimed water were lower than the reuse guidelines for recreational water. However, M. aeruginosa successfully adapted to low levels of soluble reactive phosphorus (PO(3-)(4)) concentrations. The AGP values of M. aeruginosa decreased with the progression of treatment processes, and with the increases in the dilution volume. Also, both the AGP and chlorophyll-a values can be estimated a priori without conducting the AGP tests. Therefore, aquatic ecosystems in locations prone to environmental conditions favorable for the growth of M. aeruginosa require more rigorous nutrient management plans (e.g., reverse osmosis and dilution with clean water resources) to reduce the nutrient availability.