Accumulation Of Metabolic By-products Research Articles

The Effects of Different Doses of Canthaxanthin in the Diet of Laying Hens on Egg Quality, Physical Characteristics, Metabolic Mechanism, and Offspring Health.

Currently, there is a dearth of in-depth analysis and research on the impact of canthaxanthin on the production performance, egg quality, physical characteristics, and offspring health of laying hens. Furthermore, the metabolic mechanism of cantharidin in the body remains unclear. Therefore, to solve the above issues in detail, our study was conducted with a control group (C group), a low-dose canthaxanthin group (L group), and a high-dose canthaxanthin group (H group), each fed for a period of 40 days. Production performance was monitored during the experiment, in which L and H groups showed a significant increase in ADFI. Eggs were collected for quality analysis, revealing no significant differences in qualities except for yolk color (YC). The YC of the C group almost did not change, ranging from 6.08 to 6.20; however, the trend in YC change in other groups showed an initial intense increase, followed by a decrease, and eventually reached dynamic equilibrium. By detecting the content of canthaxanthin in the yolk, the YC change trend was found to be correlated with canthaxanthin levels in the yolk. The content of unsaturated fatty acid increased slightly in L and H groups. Following the incubation period, the physical characteristics and blood biochemical indices of chicks were evaluated. It was observed that the shank color of chicks in the L and H groups was significantly higher than that in the C group at birth. However, by the 35th day, there were no significant differences in shank color among the three groups. Further investigation into the metabolic mechanism involving canthaxanthin revealed that the substance underwent incomplete metabolism upon entering the body, resulting in its accumulation as well as metabolic by-product accumulation in the yolk. In summary, this study highlighted the importance of understanding canthaxanthin's role in production performance, egg quality, and offspring health, providing valuable insights for breeders to optimize feeding strategies.

Exploring metabolic responses and pathway changes in CHO-K1 cells under varied aeration conditions and copper supplementations using 1 H NMR-based metabolomics.

The optimization of bioprocess for CHO cell culture involves careful consideration of factors such as nutrient consumption, metabolic byproduct accumulation, cell growth, and monoclonal antibody (mAb) production. Valuable insights can be obtained by understanding cellular physiology to ensure robust and efficient bioprocess. This study aims to improve our understanding of the CHO-K1 cell metabolism using 1 H NMR-based metabolomics. Initially, the variations in culture performance and metabolic profiles under varied aeration conditions and copper supplementations were thoroughly examined. Furthermore, a comprehensive metabolic pathway analysis was performed to assess the impact of these conditions on the implicated pathways. The results revealed substantial alterations in the pyruvate metabolism, histidine metabolism, as well as phenylalanine, tyrosine and tryptophan biosynthesis, which were especially evident in cultures subjected to copper deficiency conditions. Conclusively, significant metabolites governing cell growth and mAb titer were identified through orthogonal partial least square-discriminant analysis (OPLS-DA). Metabolites, including glycerol, alanine, formate, glutamate, phenylalanine, and valine, exhibited strong associations with distinct cell growth phases. Additionally, glycerol, acetate, lactate, formate, glycine, histidine, and aspartate emerged as metabolites influencing cell productivity. This study demonstrates the potential of employing 1 H NMR-based metabolomics technology in bioprocess research. It provides valuable guidance for feed medium development, feeding strategy design, bioprocess parameter adjustments, and ultimately the enhancement of cell proliferation and mAb yield.

Psychobiotics for Mitigation of Neuro-Degenerative Diseases: Recent Advancements.

Ageing is inevitable and poses a universal challenge for all living organisms, including humans. The human body experiences rapid cell division and metabolism until approximately 25 years of age, after which the accumulation of metabolic by-products and cellular damage leads to age-related diseases. Neurodegenerative diseases are of concern due to their irreversible nature, lack of effective treatment, and impact on society and the economy. Researchers are interested in finding drugs that can effectively alleviate ageing and age-related diseases without side-effects. Psychobiotics are a novel class of probiotic organisms and prebiotic interventions that confer mental health benefits to the host when taken appropriately. Psychobiotic strains affect functions related to the central nervous system (CNS) and behaviors mediated by the Gut-Brain-Axis (GBA) through various pathways. There is an increasing interest in researchers of these microbial-based psychopharmaceuticals. Psychobiotics have been reported to reduce neuronal ageing, inflammation, oxidative stress, and cortisol levels; increase synaptic plasticity and levels of neurotransmitters and antioxidants. The present review focuses on the manifestation of elderly neurodegenerative and mental disorders, particularly Alzheimer's disease (AD), Parkinson's disease (PD), and depression, and the current status of their potential alleviation through psychobiotic interventions, highlighting their possible mechanisms of action.

Concurrent metaboreflex activation increases chronotropic and ventilatory responses to passive leg movement without sex-related differences

Previous studies in animal models showed that exercise-induced metabolites accumulation may sensitize the mechanoreflex-induced response. The aim of this study was to assess whether the magnitude of the central hemodynamic and ventilatory adjustments evoked by isolated stimulation of the mechanoreceptors in humans are influenced by the prior accumulation of metabolic byproducts in the muscle. 10 males and 10 females performed two exercise bouts consisting of 5-min of intermittent isometric knee-extensions performed 10% above the previously determined critical force. Post-exercise, the subjects recovered for 5 min either with a suprasystolic circulatory occlusion applied to the exercised quadriceps (PECO) or under freely-perfused conditions (CON). Afterwards, 1-min of continuous passive leg movement was performed. Central hemodynamics, pulmonary data, and electromyography from exercising/passively-moved leg were recorded throughout the trial. Root mean square of successive differences (RMSSD, index of vagal tone) was also calculated. Δpeak responses of heart rate (ΔHR) and ventilation (Delta dot{V}_{{text{E}}}) to passive leg movement were higher in PECO compared to CON (ΔHR: 6 ± 5 vs 2 ± 4 bpm, p = 0.01; 3.9 ± 3.4 vs 1.9 ± 1.7 L min−1, p = 0.02). Δpeak of mean arterial pressure (ΔMAP) was significantly different between conditions (5 ± 3 vs − 3 ± 3 mmHg, p < 0.01). Changes in RMSSD with passive leg movement were different between PECO and CON (p < 0.01), with a decrease only in the former (39 ± 18 to 32 ± 15 ms, p = 0.04). No difference was found in all the other measured variables between conditions (p > 0.05). These findings suggest that mechanoreflex-mediated increases in HR and dot{V}_{{text{E}}} are sensitized by metabolites accumulation. These responses were not influenced by biological sex.

The Involvement of Glucose and Lipid Metabolism Alteration in Rheumatoid Arthritis and Its Clinical Implication.

Obviously, immune cells like T cells and macrophages play a major role in rheumatoid arthritis (RA). On one hand, the breakdown of immune homeostasis directly induces systemic inflammation; on the other hand, these cells initiate and perpetuate synovitis and tissue damages through the interaction with fibroblast-like synoviocytes (FLS). In recent years, the pathological link between metabolic disorders and immune imbalance has received increasing attention. High energy demand of immune cells leads to the accumulation of metabolic byproducts and inflammatory mediators. They act on various metabolism-sensitive signal pathways as well as relevant transcription factors, such as HIF-1α, and STATs. These molecular events will impact RA-related effectors like circulating immune cells and joint-resident cells in return, allowing the continuous progression of systemic inflammation, arthritic manifestations, and life-threatening complications. In other words, metabolic complications are secondary pathological factors for the progression of RA. Therefore, the status of energy metabolism may be an important indicator to evaluate RA severity, and in-depth explorations of the mechanisms underlying the mystery of how RA-related metabolic disorders develop will provide useful clues to further clarify the etiology of RA, and inspire the discovery of new anti-rheumatic targets. This article reviews the latest research progress on the interactions between immune and metabolism systems in the context of RA. Great importance is attached to the changes in certain pathways controlling both immune and metabolism functions during RA progression.

Glutaric aciduria type 1: Typical aspects in imaging

Glutaric aciduria type 1 is an autosomal recessive lysine and tryptophan disorder characterized by glutamic acid and other metabolic by-product accumulation. This disease can be diagnosed in the postnatal period, supported by magnetic resonance imaging (MRI) and confirmed by biochemistry. This article aims to highlight the typical features of this disease in brain MRI which connects frontotemporal atrophy with bilateral and symmetrical signal abnormalities of the brainstem, periventricular white matter, and basal ganglia. As a result, we use two cases to show how this rare disease manifests itself in imaging.

Response to Moderate and Vigorous Aerobic/Resistance Exercise in a Woman With Long-COVID

Response to Moderate and Vigorous Aerobic/Resistance Exercise in a Woman With Long-COVID

Is there Evidence for the Suggestion that Fatigue Accumulates Following Resistance Exercise?

It has been suggested that improper post-exercise recovery or improper sequence of training may result in an 'accumulation' of fatigue. Despite this suggestion, there is a lack of clarity regarding which physiological mechanisms may be proposed to contribute to fatigue accumulation. The present paper explores the time course of the changes in various fatigue-related measures in order to understand how they may accumulate or lessen over time following an exercise bout or in the context of an exercise program. Regarding peripheral fatigue, the depletion of energy substrates and accumulation of metabolic byproducts has been demonstrated to occur following an acute bout of resistance training; however, peripheral accumulation and depletion appear unlikely candidates to accumulate over time. A number of mechanisms may contribute to the development of central fatigue, postulating the need for prolonged periods of recovery; however, a time course is difficult to determine and is dependent on which measurement is examined. In addition, it has not been demonstrated that central fatigue measures accumulate over time. A potential candidate that may be interpreted as accumulated fatigue is muscle damage, which shares similar characteristics (i.e., prolonged strength loss). Due to the delayed appearance of muscle damage, it may be interpreted as accumulated fatigue. Overall, evidence for the presence of fatigue accumulation with resistance training is equivocal, making it difficult to draw the conclusion that fatigue accumulates. Considerable work remains as to whether fatigue can accumulate over time. Future studies are warranted to elucidate potential mechanisms underlying the concept of fatigue accumulation.

Fermented Deer Blood Ameliorates Intense Exercise-Induced Fatigue via Modulating Small Intestine Microbiota and Metabolites in Mice.

Intense and excessive exercise-induced fatigue has become an important health issue and can damage intestinal health. Deer blood, as a food byproduct with nutritional value, has been found to restore physical strength. However, little is known about the antifatigue effect of fermented deer blood (FDB) on intense exercise mice. The purpose of the present study is to investigate the antifatigue effect of FDB, and whether this effect is correlated with the altered small intestinal microbiota and metabolites in exercise mice. In this study, 5-week-old male C57BL/6J mice are given treadmill exercise with or without FDB supplementation (30 and 150 mg/kg/d) for 3 weeks. FDB significantly reduces metabolic byproduct accumulation, liver and intestinal damage, and enhances glycogen storage and antioxidant capacity in intense exercise mice. Moreover, FDB restructures the small intestinal microbiota by increasing the abundance of probiotics and butyric acid producing bacteria and decreasing the abundance of pathogenic bacteria. FDB also regulates the levels of metabolites involved in TCA cycle and amino acid metabolism in urine and small intestine content. Correlation analysis shows that FDB-modulated microbiota is highly associated with its antifatigue effect. FDB may ameliorate fatigue and intestinal injury through targeting small intestinal microbiota.

Use of metabolomics to identify strategies to improve and prolong ex vivo lung perfusion for lung transplants

Normothermic ex vivo lung perfusion (EVLP) allows for functional assessment of donor lungs; thus has increased the use of marginal lungs for transplantation. To extend EVLP for advanced organ reconditioning and regenerative interventions, cellular metabolic changes need to be understood. We sought to comprehensively characterize the dynamic metabolic changes of the lungs during EVLP, and to identify strategies to improve EVLP. Human donor lungs (n = 50) were assessed under a 4-hour Toronto EVLP protocol. EVLP perfusate was sampled at first (EVLP-1h) and fourth hour (EVLP-4h) of perfusion and were submitted for mass spectrometry-based untargeted metabolic profiling. Differentially expressed metabolites between the 2 timepoints were identified and analyzed from the samples of lungs transplanted post-EVLP (n = 42) to determine the underlying molecular mechanisms. Of the total 312 detected metabolites, 84 were up-regulated and 103 were down-regulated at EVLP-4h relative to 1h (FDR adjusted p < .05, fold change ≥ |1.1|). At EVLP-4h, markedly decreased energy substrates were observed, accompanied by the increase in fatty acid β-oxidation. Concurrently, accumulation of amino acids and nucleic acids was evident, indicative of increased protein and nucleotide catabolism. The uniform decrease in free lysophospholipids and polyunsaturated fatty acids at EVLP-4h suggests cell membrane remodeling. Untargeted metabolomics revealed signs of energy substrate consumption and metabolic by-product accumulation under current EVLP protocols. Strategies to supplement nutrients and to maintain homeostasis will be vital in improving the current clinical practice and prolonging organ perfusion for therapeutic application to further enhance donor lung utilization.

Reduced Scattering Coefficient During Incremental Exercise Is Constant Without Being Affected by Changes in Muscle Oxygenation or Hemodynamics.

Previous studies have reported that the reduced scattering coefficient (μs') in the vastus lateralis changes during ramp-incremental exercise due to blood volume changes or accumulation of metabolic by-products. We aimed to clarify the influences of deoxygenation and blood volume changes during exercise on μs' dynamics in subjects with various aerobic capacities. Twenty-three healthy young men participated in this study. All subjects performed a ramp-incremental cycling exercise until exhaustion and were divided into two groups: lower (Low: n=12; peak pulmonary oxygen uptake per kg of fat-free mass (VO2peak), 54.2±5.3mL/kg/min) and higher aerobic capacity group (High: n=11; VO2peak, 69.7±5.2mL/kg/min) by median of VO2peak. Deoxygenated hemoglobin and myoglobin concentrations (deoxy[Hb+Mb]) and total [Hb+Mb] (total[Hb+Mb]) in the vastus lateralis were monitored during the exercise by three-wavelength (760, 800, and 830nm) time-resolved NIRS. Similarly, μs' at each wavelength was continuously monitored. With increasing exercise intensity, deoxy[Hb+Mb] and total[Hb+Mb] significantly increased in both groups, and the average values of the peak amplitudes of deoxy[Hb+Mb] and total[Hb+Mb] during exercise showed a 106.4% increase and a 17.9% increase from the start of the exercise, respectively. Furthermore, the peak amplitude of total[Hb+Mb] was significantly greater in High. Conversely, there were no changes in μs' at any wavelength during exercise and no differences between two groups, suggesting that the great deoxygenation and blood volume changes during incremental exercise have little effect on μs' dynamics.

Hydroxychloroquine and Chloroquine Induced Cardiomyopathy: A Concise Review

Hydroxychloroquine and Chloroquine are commonly used for the treatment of malaria and autoimmune conditions. Most recently, hydroxychloroquine has been implicated in the treatment armamentarium of Severe acute respiratory syndrome (SARS) caused by SARS-associated coronavirus-2. A rare, underreported side effect of hydroxychloroquine and chloroquine is cardiotoxicity. The cardiomyopathy occurs as a result of inhibition of lysosomal enzymes causing lysosomal dysfunction and intra-cellular accumulation of metabolic byproducts in the myocardium, leading to hypertrophy with or without restrictive physiology and resultant conduction abnormalities. Based on our review of 57 reported cases of hydroxychloroquine or chloroquine induced cardiomyopathy, dyspnea was the most common associated symptom. The most common rhythms seen on EKG were as follows: complete heart block (18.75%), right bundle branch block (RBBB) (18.75%). The most common findings on echocardiography were left ventricular hypertrophy (LVH) (54%), systolic dysfunction (48%) and diastolic dysfunction (32%). A definitive diagnosis is established by endomyocardial biopsy which demonstrates the presence of curvilinear inclusion bodies. The outcome following cessation of the offending agent ranges from complete reversal in 45% of the cases to continued progression with need for cardiac transplantation or even death in 17.5% of the cases.

Sympathetic reactivity and inflammation: another joint problem in rheumatoid arthritis?

Sympathetic reactivity and inflammation: another joint problem in rheumatoid arthritis?

The Effect of Aspartate and Sodium Bicarbonate Supplementation on Muscle Contractile Properties Among Trained Men.

Farney, TM, MacLellan, MJ, Hearon, CM, Johannsen, NM, and Nelson, AG. The effect of aspartate and sodium bicarbonate supplementation on muscle contractile properties among trained men. J Strength Cond Res 34(3): 763-770, 2020-The focus of this investigation was to examine the effects of aspartate and NaHCO3 supplementation on muscle contractile properties within trained men. Eleven men (21.9 ± 1.5 years) ingested supplementation as 4 conditions all separated by 1 week and included the following: placebo (PLA), L-aspartate (12.5 mg) (ASP), NaHCO3 (0.3 g·kg) (SBC), or combination of ASP and SBC (CBO). For each day of testing, participants performed 1 high-intensity exercise session along with a pre- and postexercise (pre- or postex) isometric mid thigh pull test to measure peak force (PF) production and rate of force development (RFD). Blood was collected for all testing sessions before and after the high-intensity exercise to determine ammonia accumulation (AMM). Exercise sessions consisted of 4 exercises: barbell thrusters, squat jumps, lunge jumps, and forward jumps, with the total amount of work being equated for all 4 exercises across all 4 testing sessions. Participants performed the exercises in the aforementioned order, which was designated as 1 round. Each participant performed 3 rounds, with the work-to-rest ratio being 20-second work, 30-second rest. A 1-minute rest was given between the rounds. There were no treatment effects (p > 0.05) for PF, RFD, or AMM. However, there was a significant main effect for supplement consumption for the total time of work with the ASP, SBC, and CBO treatments having a lower time to completion compared with the PLA treatment. Ammonia was significantly elevated postexercise (p = 0.004), whereas there were no differences from preexercise to postexercise for PF or RFD (p > 0.05). The only significant treatment × time interaction was for RFD (p = 0.03) with CBO increasing postexercise, with the other 3 treatments all decreasing postexercise. The combination of ASP and SBC together may have the potential to reduce fatigue by mitigating the effects of metabolic by-product accumulation.

Exploring the role of fatigue-related metabolite activity during high-intensity exercise using a simplified whole-body mathematical model

Intense exercise leads to muscle fatigue, a contractile and metabolic failure of contracting muscle to sustain desired work. It is widely accepted that the close relationship between intense exercise and the accumulation of metabolic by-products is the major cause of skeletal muscle fatigue. High-intensity exercise activates ATPase activity and strongly promotes ATP production, leading to an alteration of metabolic by-products. However, the complex mechanisms underlying the development of muscle fatigue are not fully understood. In this study, we developed a novel mathematical model for whole-body mechanisms that can reproduce the key biological processes of metabolic fatigue during high-intensity exercise. Five vital compartments are represented: skeletal muscle, liver, lungs, blood vessels and other organs. These compartments capture the key mechanisms involved, including the buffering role of creatine kinase, the bicarbonate buffer system in the regulation of blood pH, and the accumulation of metabolic by-products. The simulation results provide the essential evidence for a better understanding of muscle fatigue such as increases in blood lactate and muscle inorganic phosphate, and drop in blood pH level. Moreover, we revised our previous contraction model by introducing the inhibitory effect of metabolic by-products based on structural and experimental data. The accumulation of metabolic by-products reduces the number of strongly bound cross-bridges, leading to a reduction in maximal contraction. In conclusion, our simplified model reliably reflects metabolic fluxes and concentrations that are in good agreement with experimental findings, yielding a better understanding of metabolic fatigue during high-intensity exercise. • Whole-body mathematical model quantitatively estimates the key metabolic fluxes and concentrations during intense exercise. • The constant workload expressed as percentage of maximum oxygen uptake is used as an input parameter for this novel model. • The model has several parameters that can be modified to analyze the effect of individual differences.

GBA1-associated parkinsonism: new insights and therapeutic opportunities.

GBA1 mutations, which result in the lysosomal disorder Gaucher disease, are the most common known genetic risk factor for Parkinson disease and Dementia with Lewy Bodies (DLB). The pathogenesis of this association is not fully understood, but further elucidation of this link could lead to new therapeutic options. The characteristic clinical phenotype of GBA1-PD resembles sporadic Parkinson disease, but with an earlier onset and more severe course. Many different GBA1 mutations increase the risk of Parkinson disease, some primarily detected in specific populations. Glucocerebrosidase deficiency appears to be associated with increased α-synuclein aggregation and accumulation, mitochondrial dysfunction because of impaired autophagy, and increased endoplasmic reticulum stress. As our understanding of GBA1-associated Parkinson disease increases, new treatment opportunities emerge. MicroRNA profiles are providing examples of both up-regulated and down-regulated proteins related to GBA1 and may provide new therapeutic targets. Chaperone therapy, directed at either misfolded glucocerebrosidase or α-synuclein aggregation, is currently under development and there are several early clinical trials ongoing. Substrate reduction therapy, aimed at lowering the accumulation of metabolic by-products, especially glucosylsphingosine, is also being explored. Basic science insights from the rare disorder Gaucher disease are serving to catapult drug discovery for parkinsonism.

Results of economic activity and problems of aquaculture development in the Possiet Bay (Japan Sea) in 2000–2015

The Possiet Bay in the western Japan Sea is crucially important for marine aquaculture of Primorye because of the environments favorable for cultivation of many aquatic species. The local marine farms cultivate sea cucumber and several bivalve species, including the most valuable yesso scallop, which output production is counted in hundreds of tons. The number of farms in the Possiet Bay increases recently, as well as their production of seeding materials and marketable output of seafood. Cultivation of 3 bivalve species (yesso scallop, pacifc blue mussel, and pacifc oyster) and 1 holothurian species (japanese spiky sea cucumber) is considered. The seeding material is collected by the farms located in the Possiet Bay, which prefer to collect more valuable spat of the scallop and sea cucumber, while the mussel and oyster are collected in smaller amounts. In total, more than 640 million of the scallop juveniles and about 1.2 million of the sea cucumber juveniles were collected by local farms in the period from 2000 to 2015, including both the spat collected on their own collectors or bought from other vendors. Dynamics of the output is presented for these species. The greatest harvest of the marketable scallop (over 1800 t) was produced in 2006–2010, with the highest annual output over 510 t. The summary production of all marine farms in the Possiet Bay within the 15-year period (2001–2015) is estimated as 4,300 t, that exceeds the registered catch of scallop in this area in the whole history of its fshery (that was banned in the middle of 1980s). Even before the fshery opening in the early XX century, the yeaso scallop biomass in this area did not exceed 1,000 t. Dynamics of anthropogenic pressure to the Possiet Bay waters is analyzed, as well. There is concluded that yesso scallop has natural ability to considerable growth of its biomass because of high fecundity, though this potential is limited by lack of substrate for the spat settling that is successfully compensated with artifcial substrata provided by marine farms. However, the growth of scallop biomass and production causes higher phytoplankton consumption, increasing of water pollution by dissolved and particulate organic matter, and accumulation of metabolic by-products in marine organisms. Rapid development of aquaculture causes some social and ecological risks, as well, as territorial disputes, legislative problems (with harvesting permits, etc.), starfsh expansion, grazing of farmed mollusks by marine birds, destruction of aquaculture facilities in new areas located in the insuffciently closed bights by typhoons, and epizootics (most dangerous for the sea cucumbers).

Matrix Production and Sporulation in Bacillus subtilis Biofilms Localize to Propagating Wave Fronts

Bacterial biofilms are surface-attached microbial communities encased in self-produced extracellular polymeric substances. Here we demonstrate that during the development of Bacillus subtilis biofilms, matrix production is localized to an annular front propagating at the periphery and sporulation to a second front at a fixed distance at the interior. We show that within these fronts, cells switch off matrix production and transition to sporulation after a set time delay of ∼100 min. Correlation analyses of fluctuations in fluorescence reporter activity reveal that the fronts emerge from a pair of gene-expression waves of matrix production and sporulation. The localized expression waves travel across cells that are immobilized in the biofilm matrix in contrast to active cell migration or horizontal colony spreading. Our results suggest that front propagation arises via a local developmental program occurring at the level of individual bacterial cells, likely driven by nutrient depletion and metabolic by-product accumulation. A single-length scale and timescale couples the spatiotemporal propagation of both fronts throughout development. As a result, gene expression patterns within the advancing fronts collapse to self-similar expression profiles. Our findings highlight the key role of the localized cellular developmental program associated with the propagating front in describing biofilm growth.

Ultrastructure of neurovascular changes in human diabetic retinopathy.

The previous concept regarding diabetic retinopathy assigned a primary role to hyperglycemia-induced microvascular alterations, while neuronal and glial abnormalities were considered to be secondary to either ischemia or exudation. The aim of this study was to reveal the potential role of neuronal and glial cells in initial and advanced alterations of the retinopathy in human type 2 diabetes. Electron microscopy and histochemical studies were performed on 38 surgically removed human eyes (28 obtained from diabetic patients and 10 from non-diabetic patients). Morphometric analysis of basement membrane material and lipids was performed. An accumulation of metabolic by-products was found in the capillary wall with aging: this aspect was significantly more pronounced in diabetics. Müller glial cells were found to contribute to alterations of the capillary wall and to occlusion, as well as to the development of proliferative retinopathy and cystoid degeneration of the retina. Our results showed morphological evidence regarding the role of neuronal and glial cells in the pathology of diabetic retinopathy, prior and in addition to microangiopathy. These morphological findings support a neurovascular pathogenesis at the origin of diabetic retinopathy, thus the current treatment approach should be completed by neuroprotective measures.

How regularities of mortality statistics explain why we age despite having potentially ageless somatic stem cells.

Researchers working in the area of ageing have found numerous manifestations of this process at the molecular biological level, including DNA and protein damage, accumulation of metabolic by-products, lipids peroxidation, macromolecular cross-linking, non-enzymatic glycosylation, anti-oxidant/pro-oxidant misbalance, rising of pro-inflammatory cytokines, etc. This results in an increase in the proportion of cells in growth arrest, reduction of the rate of information processing, metabolic rate decrease, and decrease in rates of other processes characterizing dynamic aspects of the organism's interaction with its environment. Such staggering multilevel diversity in manifestation of senescence precludes (without methodology of systems biology) development of a correct understanding of its primary causes and does not allow for developing approaches capable of postponing ageing or reducing organisms' ageing rate to attain health preservation. Moreover, it turns out that damage production and damage elimination processes, the misbalance of which results in the ageing process, can to a large extent be regulated by external signals. The purpose of this report is to provide evidence supporting this view and its compatibility with the regularities of mortality statistics, because the main idea is very simple. Even potentially a non-senescent but certainly not immortal body must start to age under inadequate conditions (like a non-melting piece of ice taken out from the deepfreeze inevitably start to melt at the temperatures above zero Celsius). This conclusion is totally consistent with existing patterns of mortality and with agelessness potential of somatic stem cells. Therefore, there is no need to build up and explore too complicated, computational and sophisticated systems models of intrinsic ageing to understand the origin of this mainly extrinsic root cause of natural ageing, which is controlled by environmental signals. In our case, a simple phenomenological black-box approach with Input-Output analysis is ample. Here Input refers to the environmentally dependent initial force of mortality, whereas Output is a rate of age-related increase of mortality force.