Metabolic Rewiring by Human Placenta-Derived Mesenchymal Stem Cell Therapy Promotes Rejuvenation in Aged Female Rats

Aging is a degenerative process involving cell function deterioration, leading to altered metabolic pathways, increased metabolite diversity, and dysregulated metabolism. Previously, we reported that human placenta-derived mesenchymal stem cells (hPD-MSCs) have therapeutic effects on ovarian aging. This study aimed to identify hPD-MSC therapy-induced responses at the metabolite and protein levels and serum biomarker(s) of aging and/or rejuvenation. We observed weight loss after hPD-MSC therapy. Importantly, insulin-like growth factor-I (IGF-I), known prolongs healthy life spans, were markedly elevated in serum. Capillary electrophoresis-time-of-flight mass spectrometry (CE-TOF/MS) analysis identified 176 metabolites, among which the levels of 3-hydroxybutyric acid, glycocholic acid, and taurine, which are associated with health and longevity, were enhanced after hPD-MSC stimulation. Furthermore, after hPD-MSC therapy, the levels of vitamin B6 and its metabolite pyridoxal 5′-phosphate were markedly increased in the serum and liver, respectively. Interestingly, hPD-MSC therapy promoted serotonin production due to increased vitamin B6 metabolism rates. Increased liver serotonin levels after multiple-injection therapy altered the expression of mRNAs and proteins associated with hepatocyte proliferation and mitochondrial biogenesis. Changes in metabolites in circulation after hPD-MSC therapy can be used to identify biomarker(s) of aging and/or rejuvenation. In addition, serotonin is a valuable therapeutic target for reversing aging-associated liver degeneration.

Protein-synthesizing, bile-forming, urea-forming and carbohydrate functions in cows with fatty degeneration of the liver

In dairy farms of Ukraine, where highly productive dairy cows are kept, liver lesions are often diagnosed in the postpartum period. Postmortem studies of the liver of cows that were forcibly slaughtered showed that in mostly animals were diagnosed with fatty degeneration of the liver. The main causes of fatty hepatosis were violations of the structure of rations, imbalance of feeding on essential nutrients and biologically active substances, low content of easily digestible carbohydrates and high protein content. The study was performed on cows aged 4–5 years with productivity for the previous lactation of 5.600–7.500 L of milk, in a winter-stall period of keeping, 2–3 weeks after calving. According to clinical and biochemical blood tests, two groups of cows were formed – 50 clinically healthy and 50 cows with fatty liver disease. In cows diagnosed with fatty liver degeneration, the disease was manifested by decreased productivity and fatness, loss of appetite, oppression, hypotony of the rumen, reticulum and omasum. In some cows, there was pain at the liver area, increasing boundaries of hepatic dullness, jaundice of the visible mucous membranes and sclera. The blood serum of all cows with fatty liver disease established a decrease in albumin content, indicating impaired protein synthesis function of the liver. In some cows, the content of total protein in the serum increased due to globulin fractions, mainly gamma globulins. The ratio between the content of albumins and globulins decreased, which indicates the development in the blood of sick animals dysproteinemia. The development of fatty infiltration of the liver caused an increase in the concentration of bile acids in the serum of all sick cows. This is due to reduced conjugation and excretion of cholates by affected hepatocytes from the bile capillaries. The formation, absorption, conjugation, and excretion of bilirubin in the bile is disturbed, which causes the accumulation of total and conjugated bilirubin in the serum of sick animals. The cholesterol content in the blood of cows decreased, caused a violation of the esterification of its esters by hepatocytes. The established changes in the content of bile acids, total and conjugated bilirubin, and cholesterol in the blood of sick cows indicate a violation of bile secretion, bile production, and cholestasis development. In some cows with fatty liver degeneration, urea formation function and carbohydrate function are impaired, leading to a decrease in blood urea content and glucose.

Performance of Co-Housed Neon Tetras (Paracheirodon innesi) and Glowlight Rasboras (Trigonostigma hengeli) Fed Commercial Flakes and Lyophilized Natural Food

Little to no research has been conducted thus far regarding aquarium fish nutrition. In order to ensure the welfare of house-kept ornamentals, such studies should take into account that there are distinct biological differences occurring between different fish species/taxa, especially in regard to the structure of their digestive organs. Accordingly, a 12-week trial was executed to assess the effects of two commercial flakes and a mix of lyophilized natural food on the condition of co-reared neon tetras, Paracheirodon innesi (Characidae), and glowlight rasboras, Trigonostigma hengeli (Danionidae). The four feeding groups were as follows: (T)—Tetra flakes; (O)—Omega flakes; (TO)—Tetra + Omega; (TOL)—Tetra + Omega + Lyophilizate (twice a week). There were no differences in final body weight (FBW) between the feeding groups of either species, but in the case of neon tetras, FBW increased significantly from the initial value only for the T group. However, histological observations and measurements of digestive organs (livers, intestines) showed pronounced differences between the two species. The supplementation with natural food in group TOL caused lipoid hepatic degeneration only in the rasboras. The healthiest histological structure of livers and longest intestinal folds were found in group T of the tetras and group TO of the rasboras. Whole-mount staining for bone and cartilage did not reveal any significant deformities or differences in terms of bone mineralization. In conclusion, it was outlined that concurrent feeding of co-housed, anatomically diverse ornamental fish species is a highly ambiguous task, because the nutritional strategy applied for a community tank may yield radically divergent effects, most of which may remain unnoticed when depending only on external body observations and measurements. Most emphatically, this was highlighted in regard to the dietary supplementation with natural food—although no significant effects were observed in neon tetras, severe lipoid liver degeneration occurred in glowlight rasboras.

Fatty Liver Degeneration in Cardiovascular Diseases

Research relevance: fatty liver disease is one of the common worldwide disorders and is a public health problem, with obesity and other metabolic disorders. Research methods and materials: article is based on the publications review concerning fatty liver degeneration in cardiovascular diseases. Research objectives: to identify the course, etiology, and clinical picture of metabolic and immune changes in fatty liver degeneration. Research results: pathogenic factors associated with fatty liver disease are multifactorial and include inflammation, adipokines, intestinal dysbiosis, oxidative stress, which are established signs of cardiovascular disease. Conclusions: The accumulation of fat in the liver may be associated with ectopic adipose tissue, including myocardial fat and adipose tissue surrounding the heart, which is a central aspect.

Novel regulation of the transcription factor ZHX2 by N-terminal methylation

N-terminal methylation (Nα-methylation) by the methyltransferase NRMT1 is an important post-translational modification that regulates protein-DNA interactions. Accordingly, its loss impairs functions that are reliant on such interactions, including DNA repair and transcriptional regulation. Global loss of Nα-methylation results in severe developmental and premature aging phenotypes, but given over 300 predicted substrates, it is hard to discern which physiological substrates contribute to each phenotype. One of the most striking phenotypes in NRMT1 knockout (Nrmt1-/-) mice is early liver degeneration. To identify the disrupted signaling pathways leading to this phenotype and the NRMT1 substrates involved, we performed RNA-sequencing analysis of control and Nrmt1-/- adult mouse livers. We found both a significant upregulation of transcripts in the cytochrome P450 (CYP) family and downregulation of transcripts in the major urinary protein (MUP) family. Interestingly, transcription of both families is inversely regulated by the transcription factor zinc fingers and homeoboxes 2 (ZHX2). ZHX2 contains a non-canonical NRMT1 consensus sequence, indicating its function could be directly regulated by Nα-methylation. We confirmed misregulation of CYP and MUP mRNA and protein levels in Nrmt1-/- livers and verified NRMT1 can methylate ZHX2 in vitro. In addition, we used mutants of ZHX2 that cannot be methylated to directly demonstrate Nα-methylation promotes ZHX2 transcription factor activity. Finally, we show Nrmt1-/- mice also exhibit early postnatal de-repression of ZHX2 targets involved in fetal liver development. Taken together, these data implicate continual ZHX2 misregulation as a driving force behind the liver phenotype seen in Nrmt1-/- mice.

How Does Pikeperch Sander lucioperca Respond to Dietary Insect Meal Hermetia illucens? Investigation on Gut Microbiota, Histomorphology, and Antioxidant Biomarkers

Effects of feeding dietary defatted black soldier fly (Hermetia illucens) larvae meal (HI) on intestine microbiota, and on histomorphology, oxidative enzyme activities in liver and intestine of pikeperch (Sander lucioperca) were investigated. Four isoproteic (45% crude protein) and isolipidic (18% ether extract) diets were formulated to include 0% (CO), 9% (HI9), 18% (HI18) and 36% (HI36) of HI as replacement for fishmeal at 0, 25, 50, and 100%, respectively, and were fed to triplicate groups of juvenile pikeperch (initial body weight, 68.7 ± 7.1 g) for 84 days. No adverse effects were detected on the intestine of pikeperch fed diet groups, in terms of histomorphology (P > 0.05), while fish fed free or low levels of HI (≤ 9% in diet) showed significant liver degeneration (P < 0.05). Dietary HI significantly affected the oxidative enzyme activities of catalase and glutathione peroxidase in the liver, and glutathione S-transferase in the intestine (P < 0.05), while activity of superoxide dismutase in both liver and intestine was HI-dose independent (P > 0.05). Feeding HI-containing diets positively modulated the richness and diversity of intestinal microbiota, especially for HI18 group (P < 0.05). Inclusion HI up to 18% (50% fishmeal replacement) in pikeperch diets increased abundance of Clostridium, Oceanobacillus, Bacteroides, and Faecalibacterium genera, whereas the predominant bacterium, Cetobacterium was found in control and HI36 groups. This study reveals the potential of HI as an immune and health booster for juvenile pikeperch.

NON-TRADITIONAL VIEW ON TRADITIONAL RISK FACTORS OF CARDIOVASCULAR DISEASES IN SENIORS

В статье раскрываются малоизвестные врачебному сообществу научные данные о традиционных факторах сердечно-сосудистого риска применительно к социальной группе пожилых, старых людей и долгожителей. Рассматриваются связанные с метаболизмом признаки старения организма. Оцениваются особенности показателей липидного спектра, уровня мочевой кислоты, мочевины, креатинина, факторов системы свертывания крови. Приводятся данные о характере стенозирования коронарных артерий у пожилых и старых пациентов с ИБС; о взаимосвязи ИБС и жировой дегенерации печени; об особенностях липидного спектра у больных старших возрастных групп с различными заболеваниями сердца; о различных психологических особенностях и поведенческих типах личности стареющих людей, имеющих кардиологическую патологию. Обращается внимание на «профилактический парадокс», который наблюдается у мужчин 60 лет и старше с различными формами ИБС, когда влияние «традиционных» факторов риска на увеличение смертности от сердечнососудистых заболеваний практически нивелируется, а в качестве прогностически неблагоприятных факторов значимую роль играют низкий уровень холестерина ЛПВП, пониженный уровень апо- А 1, увеличение соотношения апо- В /апо- А 1 и низкая физическая активность. Дополнительную ценность обзору придает факт, что в современной литературе, как отечественной так и зарубежной, имеется незначительное количество публикаций, посвященных особенностям факторов риска развития кардиологических заболеваний у людей старших возрастных групп, а также у пациентов, чей возраст превышает 100 лет. The article reveals little-known scientific data on the traditional risk factors of cardiovascular diseases in relation to social groups of the elderly, old people and centenarians. Some of metabolism associated signs of ageing are considering. In the article some biochemical markers in seniors are evaluated (lipids, fibrinogen, uric acid etc.). Some particularities about atherosclerotic lesions of coronary arteries in seniors are discovering, as well as relationships between coronary heart disease (CHD) and fatty liver degeneration. One more topic of the article is the lipid spectrum characteristics in senior patients with different types of heart diseases and psychological features and behavioral personality types of the seniors with cardiovascular pathology. Special attention payed on so-called preventive paradox in men older than 60 years with different forms of CHD, when the influence of traditional risk factors is critically decreased, and as important prognostic factors low levels of high-density lipoprotein cholesterol, reduced APO-A1, an increasing of APO-B/APO-A1 ratio and low physical activity play a significant role.

Gut Barrier Proteins Mediate Liver Regulation by the Effects of Serotonin on the Non-Alcoholic Fatty Liver Disease

: Serotonin (5-hydroxytryptamine, 5-HT) has been recognized as a potent pro-inflammatory mediator. Increasing the bioavailability and preventing the formation of 5-HT can reduce the inflammatory response in the body. Moreover, 5-HT is considered as an important central physiologic mediator of intestinal function by regulating intestinal motility, permeability, and other functions. The dysfunction of intestinal serotonergic system causes intestinal barrier damage and further leads to the increase of bacterial endotoxin (LPS) translocation into the liver, which contributes to the development of non-alcoholic fatty liver disease (NAFLD). In addition, increasing the expression of serotonin reuptake transporter (SERT) and decreasing the expression of tryptophan hydroxylase1 (TPH1) can relieve the symptoms of NAFLD. Tryptophan (TRP), as a precursor of 5-HT synthesis, plays an important role in gut homeostasis and energy metabolism. Previous studies have found that TRP supplementation aggravates fatty liver degeneration by producing 5-HT, which activates mTOR signaling pathway in mice fed a high fat and high fructose diet. However, recent researches reveal that TRP supplementation stabilizes the intestinal barrier damage by increasing the expression of occludin and reduces the accumulation of fatty acids in liver. Although the effects of TRP supplementation on NAFLD are not clear and the specific mechanism needs to be further explored. A better understanding of the mechanisms of 5-HT on the liver and gut may open new therapeutic strategies in NAFLD.