Alterations in Lysosome Homeostasis in Lipid-Related Disorders: Impact on Metabolic Tissues and Immune Cells

Lipid-related disorders, which primarily affect metabolic tissues, including adipose tissue and the liver are associated with alterations in lysosome homeostasis. Obesity is one of the more prevalent diseases, which results in energy imbalance within metabolic tissues and lysosome dysfunction. Less frequent diseases include Niemann-Pick type C (NPC) and Gaucher diseases, both of which are known as Lysosomal Storage Diseases (LSDs), where lysosomal dysfunction within metabolic tissues remains to be fully characterized. Adipocytes and hepatocytes share common pathways involved in the lysosome-autophagic axis, which are regulated by the function of cathepsins and CD36, an immuno-metabolic receptor and display alterations in lipid diseases, and thereby impacting metabolic functions. In addition to intrinsic defects observed in metabolic tissues, cells of the immune system, such as B cells can infiltrate adipose and liver tissues, during metabolic imbalance favoring inflammation. Moreover, B cells rely on lysosomes to promote the processing and presentation of extracellular antigens and thus could also present lysosome dysfunction, consequently affecting such functions. On the other hand, growing evidence suggests that cells accumulating lipids display defective inter-organelle membrane contact sites (MCSs) established by lysosomes and other compartments, which contribute to metabolic dysfunctions at the cellular level. Overall, in this review we will discuss recent findings addressing common mechanisms that are involved in lysosome dysregulation in adipocytes and hepatocytes during obesity, NPC, and Gaucher diseases. We will discuss whether these mechanisms may modulate the function of B cells and how inter-organelle contacts, emerging as relevant cellular mechanisms in the control of lipid homeostasis, have an impact on these diseases.

Untargeted Metabolomics on Skin Mucus Extract of Channa argus against Staphylococcus aureus: Antimicrobial Activity and Mechanism

Microbial contamination is one of the most common food safety issues that lead to food spoilage and foodborne illness, which readily affects the health of the masses as well as gives rise to huge economic losses. In this study, Channa argus was used as a source of antimicrobial agent that was then analyzed by untargeted metabolomics for its antibacterial mechanism against Staphylococcus aureus. The results indicated that the skin mucus extract of C. argus had great inhibitory action on the growth of S. aureus, and the morphology of S. aureus cells treated with the skin mucus extract exhibited severe morphological damage under scanning electron microscopy. In addition, metabolomics analysis revealed that skin mucus extract stress inhibited the primary metabolic pathways of S. aureus by inducing the tricarboxylic acid cycle and amino acid biosynthesis, which further affected the normal physiological functions of biofilms. In conclusion, the antimicrobial effect of the skin mucus extract is achieved by disrupting cell membrane functions to induce an intracellular metabolic imbalance. Hence, these results conduce to amass novel insights into the antimicrobial mechanism of the skin mucus extract of C. argus against S. aureus.

Metabolomics Insights into Inflammatory Bowel Disease: A Comprehensive Review

Inflammatory bowel disease (IBD) is a chronic, complex relapsing disorder characterised by immune dysregulation, gut microbiota alteration, and disturbed intestinal permeability. The diagnosis and the management of IBD are challenging due to the recurrent nature and complex evolution of the disease. Furthermore, the molecular mechanism underlying the aetiology and pathogenesis of IBD is still poorly understood. There is an unmet need for novel, reliable, and noninvasive tools for diagnosing and monitoring IBD. In addition, metabolomic profiles may provide a priori determination of optimal therapeutics and reveal novel targets for therapies. This review tries to gather scientific evidence to summarise the emerging contribution of metabolomics to elucidate the mechanisms underlying IBD and changes associated with disease phenotype and therapies, as well as to identify biomarkers with metabolic imbalance in those patients. Metabolite changes during health and disease could provide insights into the disease pathogenesis and the discovery of novel indicators for the diagnosis and prognosis assessment of IBD. Metabolomic studies in IBD have shown changes in tricarboxylic acid cycle intermediates, amino-acid and fatty-acid metabolism, and oxidative pathways. Metabolomics has made progress towards identifying metabolic alterations that may provide clinically useful biomarkers and a deeper understanding of the disease. However, at present, there is insufficient evidence evaluating the predictive accuracy of these molecular signatures and their diagnostic ability, which is necessary before metabolomic data can be translated into clinical practice.

An hourglass mechanism controls torpor bout length in hibernating garden dormice

Hibernating mammals drastically lower their rate of oxygen consumption and body temperature (Tb) for up to several weeks, but regularly rewarm and stay euthermic for brief periods (< 30 h). It has been hypothesized that these periodic arousals are driven by the development of a metabolic imbalance during torpor, that is, the accumulation or the depletion of metabolites or the accrual of cellular damage that can be eliminated only in the euthermic state. We obtained oxygen consumption (as a proxy of metabolic rate) and Tb at 7-minute intervals over entire torpor-arousal cycles in the garden dormouse (Eliomys quercinus). Torpor bout duration was highly dependent on mean oxygen consumption during the torpor bout. Oxygen consumption during torpor, in turn, was elevated by Tb, which fluctuated only slightly in dormice kept at∼3-8°C. This corresponds to a well-known effect of higher Tb on shortening torpor bout lengths in hibernators. Arousal duration was independent from prior torpor length, but arousal mean oxygen consumption increased with prior torpor Tb. These results, particularly the effect of torpor oxygen consumption on torpor bout length, point to an hourglass mechanism of torpor control, i.e., the correction of a metabolic imbalance during arousal. This conclusion is in line with previous comparative studies providing evidence for significant interspecific inverse relationships between the duration of torpor bouts and metabolism in torpor. Thus, a simple hourglass mechanism is sufficient to explain torpor/arousal cycles, without the need to involve non-temperature-compensated circadian rhythms.

Photosystem II Repair Cycle in Faba Bean May Play a Role in Its Resistance to Botrytis fabae Infection

Chocolate spot, which is caused by the necrotrophic fungus Botrytis fabae, is a major foliar disease occurring worldwide and dramatically reducing crop yields in faba bean (Vicia faba). Although chemical control of this disease is an option, it has serious economic and environmental drawbacks that make resistant cultivars a more sensible choice. The molecular mechanisms behind the defense against B. fabae are poorly understood. In this work, we studied the leave proteome in two faba bean genotypes that respond differently to B. fabae in order to expand the available knowledge on such mechanisms. For this purpose, we used two-dimensional gel electrophoresis (2DE) in combination with Matrix-Assisted Laser Desorption/Ionization (MALDI-TOF/TOF). Univariate statistical analysis of the gels revealed 194 differential protein spots, 102 of which were identified by mass spectrometry. Most of the spots belonged to proteins in the energy and primary metabolism, degradation, redox or response to stress functional groups. The MS results were validated with assays of protease activity in gels. Overall, they suggest that the two genotypes may respond to B. fabae with a different PSII protein repair cycle mechanism in the chloroplast. The differences in resistance to B. fabae may be the result of a metabolic imbalance in the susceptible genotype and of a more efficient chloroplast detoxification system in the resistant genotype at the early stages of infection.

Infection and Immunometabolism in the Central Nervous System: A Possible Mechanistic Link Between Metabolic Imbalance and Dementia

Metabolic syndromes are frequently associated with dementia, suggesting that the dysregulation of energy metabolism can increase the risk of neurodegeneration and cognitive impairment. In addition, growing evidence suggests the link between infections and brain disorders, including Alzheimer’s disease. The immune system and energy metabolism are in an intricate relationship. Infection triggers immune responses, which are accompanied by imbalance in cellular and organismal energy metabolism, while metabolic disorders can lead to immune dysregulation and higher infection susceptibility. In the brain, the activities of brain-resident immune cells, including microglia, are associated with their metabolic signatures, which may be affected by central nervous system (CNS) infection. Conversely, metabolic dysregulation can compromise innate immunity in the brain, leading to enhanced CNS infection susceptibility. Thus, infection and metabolic imbalance can be intertwined to each other in the etiology of brain disorders, including dementia. Insulin and leptin play pivotal roles in the regulation of immunometabolism in the CNS and periphery, and dysfunction of these signaling pathways are associated with cognitive impairment. Meanwhile, infectious complications are often comorbid with diabetes and obesity, which are characterized by insulin resistance and leptin signaling deficiency. Examples include human immunodeficiency virus (HIV) infection and periodontal disease caused by an oral pathogen Porphyromonas gingivalis. This review explores potential interactions between infectious agents and insulin and leptin signaling pathways, and discuss possible mechanisms underlying the relationship between infection, metabolic dysregulation, and brain disorders, particularly focusing on the roles of insulin and leptin.

Frequency of CYP1A1*2A polymorphisms and deletion of the GSMT1 gene in a Peruvian mestizo population

The polymorphic variants of CYP1A1 and the deletion of GSTM1 are present in the Peruvian mestizo population. Wild type and mutated genotypes (WT/*2A and *2A/ *2A) were identified, whose allele frequencies are 0.31 (T allele) and 0.69 (C allele), respectively; 53% with wild type GSTM1 (+) and 47% with null GSTM1. The frequency in Iquiteño emigrants was 0.72 CYP1A1*2A and 25% GSTM1 (-); from Lima 0.67 CYP1A1*2A and 33% of GSTM1 (-). The Hardy-Weinberg equilibrium test for the studied population showed that both frequencies are out of balance, p > .05. The presence of the risk allele of the CYP1A1*2A polymorphism and the deletion in the GSTM1 gene are high, which could be indicative of a phase I and II metabolic imbalance in this group of Peruvian populations, with potential risks of activating agents procarcinogens thus affecting the incidence of tumor pathologies with an environmental component.

Immunohistochemical Markers of Apoptotic and Hypoxic Damage Facilitate Evidence-Based Assessment in Pups with Neurological Disorders

Seizures in puppies often present a diagnostic challenge in terms of identifying and treating the underlying cause. Dog breeds with mutations of the MDR1-gene are known to show adverse reactions to certain drugs, yet metabolic imbalance exacerbated by physiologically immature organs and other contributing pathologies require consideration before arriving at a diagnosis. This study analysed the brains of two male, 5-week-old Australian Shepherd siblings that died after displaying severe neurological symptoms upon administration of MilproVet® to treat severe intestinal helminth infection. Despite the initial symptoms being similar, their case histories varied in terms of the symptom duration, access to supportive therapy and post-mortem interval. Histopathology and immunohistochemistry were used to obtain more information about the phase of the pathological processes in the brain, employing protein markers associated with acute hypoxic damage (β-amyloid precursor protein/APP) and apoptosis (diacylglycerolkinase-ζ/DGK-ζ, apoptotic protease activating factor 1/Apaf1, and B-cell lymphoma related protein 2/Bcl-2). The results seem to reflect the course of the animals’ clinical deterioration, implicating that the hypoxic damage to the brains was incompatible with life, and suggesting the usefulness of the mentioned immunohistochemical markers in clarifying the cause of death in animals with acute neurological deficits.