Search Results (171)

Background: Several recent studies have documented an increased cardiovascular risk in patients with primary hyperparathyroidism (PHPT), thereby stimulating interest in the association with uric acid (UA), a metabolite linked to cardiovascular disease and chronic kidney disease (CKD) progression, whose role in these conditions is still the subject of study. The aim of this review is to summarize the underlying pathophysiological mechanisms of the PHPT-UA relation and discuss their potential clinical implications. Methods: We conducted a comprehensive literature review, with a focus on the physiological and clinical aspects of the relationship between PHPT and UA. Results: The evidence in the literature supports the association between PHPT and elevated UA levels, although the underlying mechanisms still need to be elucidated. Key mechanisms seem to involve tubular and intestinal transporters, particularly the ABCG2 transporter, as well as indirect effects mediated by hypercalcemia and inflammatory processes. Conclusions: The association between PHPT and UA, though recognized for years, highlights the existence of linked pathophysiological mechanisms between mineral and purine metabolism. However, the current knowledge does not clarify whether uric acid plays an active role in the development of complications related to hyperparathyroidism or if it just represents an indirect marker of metabolic dysfunction. In the absence of specific guidelines, measuring UA levels to screen for hyperuricemia, especially in patients with additional risk factors, should be considered to prevent related complications. Future studies could clarify the role of UA in PHPT, improving our understanding of the disease and potentially leading to new therapeutic strategies to prevent cardiovascular, renal and joint manifestations. Full article

Chronic kidney disease (CKD) is associated with the systemic accumulation of uremic toxins (UTs) due to impaired renal elimination. Among these, indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are particularly challenging because of their high protein binding and limited removal by dialysis. In addition to renal excretion, the transport of IS and PCS, and their microbiota-derived precursors, indole and p-cresol, across key physiological barriers—the intestinal barrier, blood–brain barrier, and renal proximal tubule—critically influences their distribution and elimination. This review provides an overview of transporter-mediated mechanisms involved in the disposition of IS, PCS, and their microbial precursors, indole and p-cresol. It also examines how these UTs may interact with commonly prescribed drugs in CKD, particularly those that share transporter pathways as substrates or inhibitors. These drug–toxin interactions may influence the pharmacokinetics and toxicity of IS and PCS, but remain poorly characterized and largely overlooked in clinical settings. A better understanding of these processes may guide future efforts to optimize pharmacotherapy and support more informed management of CKD patients, particularly in the context of polypharmacy. Full article

Zinc (Zn) is a crucial trace element in vertebrates, fulfilling a range of physiological functions, whose metabolism and homeostasis are manipulated by Zn transporter proteins. SUMOylation, a reversible post-translational modification (PTM), extensively participates in various biological processes in the body, yet its underlying mechanism in regulating Zn transporters remains unexplored. Our findings indicate that high dietary Zn substantially elevated intestinal Zn content and modulated the expression profiles of Zn transporter-related genes and proteins, including ZIP8 transporter. In addition, high Zn diet tended to inhibit the SUMOylation modification and upregulate deSUMOylation modification in the intestine and intestinal epithelial cells. Furthermore, we found that the ZIP8 protein undergoes SUMOylation modification; UBC9 upregulated but SENP1 and Zn downregulated the SUMOylation level of ZIP8, and the K24 and K222 positions are the primary SUMOylation modification sites of ZIP8 protein in yellow catfish. Mechanistically, SENP1 modulates the deSUMOylation modification of ZIP8 by sensing Zn-induced oxidative stress. In summary, for the first time, we have uncovered a unique regulatory mechanism of ZIP8 mediated by SUMOylation modification in vertebrates and demonstrate that SENP1 is capable of sensing oxidative stress to reduce the SUMOylation modification of ZIP8 at K24 and K222 sites. Full article

Lipid metabolism disorders represent a significant risk factor for the pathogenesis of Alzheimer’s disease (AD). Apolipoprotein E (APOE) has been regarded as a pivotal regulator of lipid homeostasis in the central nervous system (CNS), with polymorphic alleles identified as genetic risk factors for late-onset AD. Despite advances in APOE research and the development of numerous pharmaceutical approaches targeting distinct APOE isoforms, there remain limited treatment approaches for AD that focus on lipid metabolic homeostasis. Consequently, it is necessary to reevaluate the lipid metabolic process in the CNS. Apolipoprotein A1 (APOA-I), a major component of high-density lipoprotein (HDL), plays a crucial role in reverse cholesterol transport from tissues to the liver to maintain lipid homeostasis. Over the past few decades, numerous studies have suggested a connection between reduced APOA-I levels and a higher risk of AD. APOA-I is synthesized exclusively in the liver and intestines, and there is a lack of conclusive evidence supporting its functional significance within the central nervous system, in contrast to APOE, which is produced locally by glial cells and neurons within the CNS. Moreover, APOA-I’s ability to penetrate the blood-brain barrier (BBB) is still poorly understood, which causes its significance in central lipid metabolism and AD pathophysiology to be mainly disregarded. Recent advancements in tracing methodologies have underscored the essential role of APOA-I in regulating lipid metabolism in the CNS. This review aims to elucidate the physiological functions and metabolic pathways of APOA-I, integrating its associations with AD-related pathologies, risk factors, and potential therapeutic targets. Through this discourse, we aim to provide novel insights into the intricate relationship between AD and APOA-I, paving the way for future research in this field. Full article

The intestinal health and functionality of animals play pivotal roles in nutrient digestion and absorption, as well as in maintaining defense against pathogenic invasions. These biological processes are modulated by various determinants, including husbandry conditions, dietary composition, and gut microbial ecology. The excessive use of anthropogenic antibiotics may disrupt intestinal microbiota composition, potentially leading to dysbiosis that directly compromises host homeostasis. While Lactobacillus species are recognized for their immunomodulatory properties, their precise mechanisms in regulating host anti-inflammatory gene expression and influencing mucosal layer maturation, particularly regarding E. coli colonization resistance, require further elucidation. To investigate the regulatory mechanisms of Lactobacillus in relation to intestinal architecture and function during E. coli infection, we established a colonic infection model using Bal b/c mice, conducting systematic analyses of intestinal morphology, inflammatory mediator profiles, and microbial community dynamics. Our results demonstrate that Lactobacillus supplementation (Pediococcus acidilactici) effectively mitigated E. coli O78-induced enteritis, with co-administration during infection facilitating the restoration of physiological parameters, including body mass, intestinal histoarchitecture, and microbial metabolic functions. Microbiome profiling revealed that the Lactobacillus intervention significantly elevated Lactococcus abundance while reducing Weissella populations (p < 0.05), concurrently enhancing metabolic pathways related to nutrient assimilation and environmental signal processing (including translation mechanisms, ribosomal biogenesis, amino acid transport metabolism, and energy transduction systems; p < 0.05). Mechanistically, Lactobacillus administration attenuated E. coli-induced intestinal pathology through multiple pathways: downregulating pro-inflammatory cytokine expression (IL-1β, IL-1α, and TNF-α), upregulating epithelial junctional complexes (Occludin, Claudin-1, and ZO-1), and stimulating mucin biosynthesis (MUC1 and MUC2; p < 0.05). These modifications collectively enhanced mucosal barrier integrity and promoted epithelial maturation. This investigation advances our comprehension of microbiota–host crosstalk during enteropathogenic infections under probiotic intervention, offering valuable insights for developing novel nutritional strategies and microbial management protocols in animal husbandry. Full article

Objectives: The aim of this study was to investigate the effects of different stages of training on the intestinal microbial abundance of Yili horses. Methods: Ten Yili horses, all aged 2 years old and weighing 305 ± 20 kg, were selected and divided into a training group and an untrained group. The training group performed riding training 6 days a week, and the untrained group moved freely in the activity circle every day. Fecal samples were collected on days 30 and 60, and the intestinal microorganisms were detected and analyzed using metagenomics. Results: Compared with the 30-day untrained group, the relative abundances of Bacteroidetes were significantly increased in the 30-day training group (p < 0.01). Conversely, the abundances of Clostridiaceae, Clostridium, and Ruminococcus were significantly decreased (p < 0.01), whereas those of Prevotella, Bacteroideaceae, and Bacteroidetes were significantly increased (p < 0.05). Additionally, the relative abundances of Firmicutes and Actinomycetes were significantly decreased (p < 0.05). Compared with the 60-day untrained group, no significant differences in the phyla Bacteriaceae and Bacteriae of the 60-day training group (p > 0.05) were observed. In the linear discriminant analysis effect size analysis, seven significantly different bacteria were detected in the fecal flora of horses in the 30-day training group versus the untrained 30-day group, but only one significantly different bacterium was detected after 60 days. The Kyoto Encyclopedia of Genes and Genomes analysis showed that the differentially expressed genes were related to metabolism and the environmental information processing pathway, carbohydrate metabolism, and membrane transport pathways. Conclusions: Therefore, training seems to affect the diversity and composition of the gut microbiota of Yili horses, especially during the first 30 days of training. Full article

Background/Objectives: Alzheimer’s disease (AD) is the most common type of dementia, characterized by complex processes such as neuro-inflammation, oxidative damage, synaptic loss, and neuronal death. Carotenoids are among the potential therapeutic molecules that have attracted attention due to their neuroprotective properties, but their efficacy is limited mainly by their capacity to cross the blood–brain barrier (BBB). Results: The results showed that T. chuii extracts could protect neuronal cells from neurotoxic damage, especially against L-glutamate and H₂O₂. Moreover, the BBB permeability and the intestinal transport analyses revealed that fucoxanthinol, crocoxanthin, diatoxanthin, neoxanthin, violaxanthin, and prasinoxanthin have diverse permeabilities depending on the incubation time and the cell model used. Fucoxanthinol was the carotenoid with the highest and similar permeability in HBMEC cells (4.41%, 5.13%, and 18.94% at 2, 4, and 24 h, respectively) and Caco-2 cells (7.01%, 8.63%, and 18.36% at the same times), while crocoxanthin, diatoxanthin, and neoxanthin showed different kinetics. Methods: The neuroprotective potential of two extracts obtained from Tetraselmis chuii microalga were evaluated against Aβ1-42-, L-glutamate-, and H₂O₂-induced toxicities in SH-SY5Y cells. In addition, the BBB permeability and the intestinal transepithelial transport of the main carotenoids present in the extracts were evaluated and compared using two cell culture models, HBMEC and Caco-2 cells. For that aim, the transport of the bioactive molecules across the barriers was evaluated using UHPLC-q-TOF-MS after 2, 4, and 24 h of incubation. Conclusions: These findings indicate that T. chuii is a promising natural source of bioactive compounds to develop functional foods against neurodegenerative diseases. Full article

Hypercholesterolemia causes atherosclerosis by inducing immune cell migration and chronic inflammation in arterial walls. Recent single-cell analyses reveal the presence of lipid-enriched foamy macrophages, as well as other macrophage subtypes, neutrophils, T cells, and B cells, in atherosclerotic plaques in both animal models and humans. These cells interact with each other and other cells, including non-immune cells such as endothelial cells and smooth muscle cells. They thereby regulate metabolic, inflammatory, phagocytic, and cell death processes, thus affecting the progression and stability of atherosclerotic plaques. The nuclear receptors liver X receptor (LXR)α and LXRβ are transcription factors that are activated by oxysterols and regulate lipid metabolism and immune responses. LXRs regulate cholesterol homeostasis by controlling cholesterol’s transport, absorption, synthesis, and breakdown in the liver and intestine. LXRs are also highly expressed in tissue-resident and monocyte-derived macrophages and other immune cells, including both myeloid cells and lymphocytes, and they regulate both innate and adaptive immune responses. Interestingly, LXRs have immunosuppressive and immunoregulatory functions that are cell-type-dependent. In animal models of atherosclerosis, LXRs have been shown to be involved in both progression and regression phases. The pharmacological activation of LXR enhances cholesterol efflux from macrophages and promotes atherosclerosis progression. Deleting LXR in immune cells, especially myeloid cells, accelerates atherosclerosis by increasing monocyte migration, macrophage proliferation and activation, and neutrophil extracellular traps (NETs); furthermore, the deletion of hematopoietic LXRs impairs the regression of atherosclerotic plaques. Therefore, LXRs in immune cells may be a potent therapeutic target for atherosclerosis. Full article

Tetrodotoxin (TTX) is a potent marine neurotoxin found in pufferfish, causing severe poisoning or death if consumed improperly. Studies have indicated that intestinal symbiotic microbiota are associated with the production and accumulation of TTX in pufferfish. However, the specific symbiotic microorganisms involved in these processes and their respective functions remain unclear. This study explored differences in intestinal microbiota related to the TTX content between toxic and non-toxic tiger puffer Takifugu rubripes. We found that the dominant phyla exhibiting significant abundance differences between the two groups were Proteobacteria and Bacteroidota, with the core bacterial genera being Rikenella, Vibrio, Photobacterium, and Bacteroides. Moreover, the genera Marinimicrobium, Idomarina, Galbibacter, and Brumimicrobium were reported for the first time to be potentially associated with TTX bioaccumulation in T. rubripes. In addition, an integrated analysis with our previous study indicated that the “ABC transporters” pathway may play significant roles in the production and transport of TTX in both symbiotic microorganisms and T. rubripes. This study preliminarily investigated the intestinal symbiotic bacteria associated with the accumulation and metabolism of TTX in T. rubripes, as well as screening potential microbial biomarkers for assessing the safety of pufferfish. Full article

Over the last decades, a novel immunological function was established for the sodium–glucose co-transporter 1 (SGLT1), a protein involved in sugar absorption in the small intestine. High-glucose dosage and pharmacological concentrations of a C-glucoside analog showed a protective role in in vitro and in vivo models of severe inflammation states; experimental evidence suggests the engagement of SGLT1 in these processes. The mechanism of action underlying the protection is still unclear. To enhance our understanding of the molecular mechanisms responsible for this protection, we have developed a synthesis for the preparation of hydrogen isotope-labeled versions of the C-glucoside hit compound. Specifically, we report the synthesis of the deuterium-labeled derivative, which can be utilized for mass spectrometry-based research to examine the compound’s metabolic pathway, distribution, and cellular/tissue localization. The synthetic method developed can be extended to produce the tritiated analog, serving as a radioactive tracer. Full article

Exosomes can transport regulatory biomolecules and are mediators of cellular signaling among metabolic tissues through endocrine mechanisms. Understanding the pathways and processes underlying exosome-mediated inter-tissue communication is critical for elucidating the molecular pathophysiology of metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disorders. Consequently, these mechanisms represent novel and promising targets for pharmacological regulation. We examined the current knowledge regarding exosome physiology, the mechanisms of interaction with target tissues, and its role in metabolic tissue communication. We also analyzed the secretory profiles of exosomes in metabolic tissues, emphasizing their regulatory roles in adipose tissue, liver, pancreas, skeletal muscle, and the small intestine, while discussing their association with metabolic diseases. In this sense, we propose the exosomal pentad as a novel framework highlighting exosome-mediated inter-organ communication, where exosomes may regulate a metabolic axis involving these tissues. This model aligns with the ominous octet in type 2 diabetes but emphasizes exosomes as key regulators of metabolic homeostasis and potential therapeutic targets. The role of exosomes for the treatment of metabolic diseases emerges as a critical area of pharmacologic exploration. For instance, therapeutic strategies that prevent target tissue binding or expression of cargo molecules such as miRNAs could be designed, using antagomiRs or nanoparticles. Additionally, integrins like αvβ5 on the exosomal membrane can be blocked with monoclonal antibodies or engineered for targeted delivery of therapeutic molecules. Exosomes, critical mediators of inter-organ communication and metabolic regulation, hold potential to design precise molecular-level therapies while minimizing systemic side effects. Full article

Chronic enteropathy (CE) or chronic inflammatory enteropathy is a group of diseases with multiple and different etiologies characterized by chronic gastrointestinal signs such as vomiting, diarrhea, anorexia, weight loss for more than 3 weeks, and inflammatory cell infiltration, such as lymphoplasmacytic cells in the intestinal mucosal lamina propria. The diagnosis was histologically confirmed after excluding other diseases such as parasitic infections, tumors, pancreatitis, exocrine pancreatic insufficiency, metabolic diseases, and endocrine diseases, such as hypoadrenocorticism. Nutritional management depends on several important functions, such as digestion and absorption processes, digestive enzymes and nutritional transporters, and barrier functions. Intestinal dysbiosis may have been found to be involved in various functions. Recently, cobalamin (vitamin B₁₂) and vitamin D have been considered negative prognostic factors in dogs with CE. Cobalamin supplementation ameliorates clinical disease severity in dogs with CE, and vitamin D supplementation ameliorates hypocalcemia in dogs with CE and hypoalbuminemia. Therefore, the aim of this review is to provide an overview of CE and present treatment and nutritional management strategies for CE and prognostic vitamins. Full article

Background/Objectives: Previously, we found that caloric restriction (CR) in mice increases taurine levels by stimulating hepatic synthesis, secretion into the intestine and deconjugation of taurine-conjugated bile acids (BA). Subsequently, in the intestine, taurine conjugates various molecules, including glutathione (GSH). The current study explores the mechanisms behind forming taurine-GSH conjugate and its consequences for taurine, other taurine conjugates, and BA in order to improve understanding of their role in CR. Methods: The non-enzymatic conjugation of taurine and GSH was assessed and the uptake of taurine, GSH, and taurine-GSH was verified in five sections of the small intestine. Levels of taurine, gavaged ¹³C labeled taurine, taurine conjugates, taurine-GSH, and GSH were measured in various tissues of ad libitum and CR mice. Next, the taurine-related CR phenotype was challenged by applying the inhibitors of taurine transporter (SLC6A6) and GSH-S transferases (GST). Results: The CR-related increase in taurine in intestinal mucosa was accompanied by the uptake and distribution of taurine towards selected organs. A unique composition of taurine conjugates characterized each tissue. Although taurine-GSH conjugate could be formed in non-enzymatic reactions, GST activity contributed to taurine-related CR outcomes. Upon SLC6A6 and GST inhibition, the taurine-related parameters were affected mainly in the ileum rather than the liver. Meanwhile, BA levels were somewhat affected by GST inhibition in the ileum and in the liver by SLC6A6 inhibitor. Conclusions: The discovered CR phenotype involves a regulatory network that adjusts taurine and BA homeostasis. GSH supports these processes by conjugating taurine, impacting taurine uptake from the intestine and its availability to form other types of conjugates. Full article

Inflammation is associated with the pathophysiology of type 2 diabetes and COVID-19. Phytochemicals have the potential to modulate inflammation, expression of SARS-CoV-2 viral entry receptors (angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2)) and glucose transport in the gut. This study assessed the impact of phytochemicals on these processes. We screened 12 phytochemicals alongside 10 pharmaceuticals and three plant extracts, selected for known or hypothesised effects on the SARS-CoV-2 receptors and COVID-19 risk, for their effects on the expression of ACE2 or TMPRSS2 in differentiated Caco-2/TC7 human intestinal epithelial cells. Genistein, apigenin, artemisinin and sulforaphane were the most promising ones, as assessed by the downregulation of TMPRSS2, and thus they were used in subsequent experiments. The cells were then co-stimulated with pro-inflammatory cytokines interleukin-1 beta (IL-1β) and tumour necrosis factor-alpha (TNF-α) for ≤168 h to induce inflammation, which are known to induce multiple pathways, including the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Target gene expression (ACE2, TMPRSS2, SGLT1 (sodium-dependent glucose transporter 1) and GLUT2 (glucose transporter 2)) was measured by droplet digital PCR, while interleukin-1 (IL-6), interleukin-1 (IL-8) and ACE2 proteins were assessed using ELISA in both normal and inflamed cells. IL-1β and TNF-α treatment upregulated ACE2, TMPRSS2 and SGLT1 gene expression. ACE2 increased with the duration of cytokine exposure, coupled with a significant decrease in IL-8, SGLT1 and TMPRSS2 over time. Pearson correlation analysis revealed that the increase in ACE2 was strongly associated with a decrease in IL-8 (r = −0.77, p < 0.01). The regulation of SGLT1 gene expression followed the same pattern as TMPRSS2, implying a common mechanism. Although none of the phytochemicals decreased inflammation-induced IL-8 secretion, genistein normalised inflammation-induced increases in SGLT1 and TMPRSS2. The association between TMPRSS2 and SGLT1 gene expression, which is particularly evident in inflammatory conditions, suggests a common regulatory pathway. Genistein downregulated the inflammation-induced increase in SGLT1 and TMPRSS2, which may help lower the postprandial glycaemic response and COVID-19 risk or severity in healthy individuals and those with metabolic disorders. Full article

Multifilm mass transfer theory has been used in conjunction with developing a new in vitro starch digestion model and applied to assessing starch digestion kinetics. One significance of this research is that this in vitro model has similar dynamics, such as similar Reynolds numbers for both in vivo and in vitro systems. In the in vitro intestine model, when the flow rate changes from 5.9 × 10⁻⁶ m³ s⁻¹ to 1.0 × 10⁻⁵ m³ s⁻¹ inside the intestine wall (inside the sausage casing), the Re number changes from 362 to 615. An oral digestion model, a stomach model, and an intestine model have been built to quantitatively understand reaction rate kinetics and two-film (or multifilm) mass transfer for carbohydrate digestion. This in vitro digestion system represents the oral mastication process to reduce the length scale of the test food, amylase inhibition in the stomach, and glucose generation and transport through the intestine wall according to the various emptying rates from stomach. Another dimensionless group, the Damköhler number (Da), has been calculated based on glucose measurements from this in vitro model, which show similar glycemic responses of the hydrolysis for banana and carrot with in vivo results. Another significance of this research is to distinguish a low GI food from a high GI one in this in vitro system and the possibility to estimate the GI value based on the glucose measurements. Full article