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Macrophages are the basic mediators and coordinators of various types of chronic inflammation and play a crucial role in the formation and development of atherosclerosis (AS). In the complex microenvironment of atherosclerotic plaques, macrophages of different sources are exposed to different signal stimuli and thus polarized into various subpopulations. Various types of macrophages with predominantly M1 and M2 phenotypes also play different regulatory roles in the initiation and progression of AS. Lipid-lowering drugs, mainly statins, are widely used in clinical practice, but the adverse reactions are obvious and there is a lack of personalized treatment. Emerging targeted macrophage and Traditional Chinese medicine (TCM)-related therapies can regulate the cellular microenvironment, inhibit the polarization of M1 macrophages, and promote the activation of M2 macrophages, providing new ideas for the prevention and treatment of AS.

Abstract This primary objective of our study was to investigate the relationship between serum calcium levels and the occurrence of sudden cardiac arrest (SCA) in stroke patients. We analyzed the clinical data of 10,423 acute stroke patients admitted to the intensive care unit. The association between serum calcium and SCA following an acute stroke was assessed through multivariate logistic regression. We explored the non-linear connection between serum calcium levels and SCA in stroke patients using a generalized additive model and smooth curve fitting. Our study uncovered that serum calcium serves as an independent risk factor for sudden cardiac arrest in stroke patients. Notably, we observed that the relationship between serum calcium levels upon admission and the occurrence of SCA in stroke patients within the hospital was non-linear. Furthermore, we identified inflection points in serum calcium levels at 8.2 and 10.4 mg/dL. These findings emphasize a non-linear relationship between serum calcium levels and the risk of SCA in stroke patients. Maintaining serum calcium within the range of 8.2–10.4 mg/dL could lead to a significant reduction in the incidence of cardiac arrest among stroke patients.

Abstract Chronic kidney disease (CKD) results mainly from diabetes, hypertension, and glomerulonephritis, which can develop into end‐stage renal disease and CKD‐related complications, thereby causing high morbidity and mortality. This progression is correlated with pathogenic alterations in the gut microbiota that generate uremic toxins, mainly including indoxyl sulfate, p‐cresol sulfate, and trimethylamine‐N‐oxide. The uremic toxins directly or indirectly induce CKD through oxidative stress, inflammatory response, and subsequently renal fibrosis. However, ongoing developments in CKD therapy still lack nutritional guidelines and new pharmacotherapies with significant effects. In this review, we discuss the modulatory effects of plant‐derived bioactive ingredients, such as dietary fiber (oligosaccharides and polysaccharides), polyphenols (e.g., curcumin, anthocyanins, catechins, and resveratrol), and peptides, on gut microbiota and CKD particularly from the view of the gut–kidney axis. We believe that a comprehensive understanding of the underlying mechanisms of CKD is necessary to develop new targeted therapy strategies that will benefit the prevention and treatment of CKD.

Scratching is a natural behavior in cats but can cause damage to household furnishings. In this work, we sought to identify potential semiochemicals in the urine and feces of domestic cats that may modify cat scratching behavior. Sex differences among adult, intact cats were examined for volatile molecules in their urine (n = 7 females, 7 males) and feces (n = 8 females, 10 males) using gas chromatography-mass spectrometry (GC-MS). Males had seven times more 3-Mercapto-3-Methyl Butanol (MMB, p < 0.001) in the urine and 98% more butanoic acid (p = 0.02) in the feces than females. One mL of mineral oil without (i.e., control) or with MMB (0.1 µg/mL) and butanoic acid (100 µg/mL; i.e., treatment), which corresponds to the estimated biological amount in a single elimination from a male cat, were evaluated for their effectiveness in modifying the use of scratching devices by cats. Two identical cardboard standing scratchers, treated with either the control or the solution containing both semiochemicals delivered through a hanging cotton sock were placed side by side in a home/shelter environment. The preference test consisted of exposing individual cats (n = 28) to both scratchers for 20 min and recording the duration and frequency they interacted or scratched each scratcher. The semiochemical solution significantly decreased scratching time (21.19 ± 3.8 vs. 6.08 ± 3.8 s; p < 0.001) and interaction time (31.54 ± 5.9 vs. 12.90 ± 5.9 s; p = 0.0001) and tended to reduce scratching frequency (1.49 ± 0.3 vs. 0.82 ± 0.3 times; p = 0.07) compared with the control solution. The male-representative solution of MMB and butanoic acid was aversive to cats and might have future applications in protecting furniture from the destructive scratching or in modifying behavior of domestic cats.

Methylsulfonylmethane (MSM) is a natural sulfur-containing organic substance that has many biological functions, such as antioxidant, anti-inflammatory, skin nourishing, and hair growth-promoting effects. This study was conducted to determine the effect of MSM supplementation on growth performance, antioxidant capacity, and hair quality in kittens. A total of 21 Ragdoll kittens were assigned to three diets by initial body weight and gender: basal diet supplemented with 0%, 0.2%, and 0.4% MSM (CON, LMSM, and HMSM groups) for 65 days. During the whole period, the food intake of kittens in the MSM-treated groups tended to be higher (P < 0.10) compared with the CON group, and the average daily gain (ADG) had no significant difference when compared to the kittens in the CON group (P > 0.05). Antioxidant capacity had no significant difference (P > 0.05) among the groups. The scale thickness of hair tended to be smaller in the LMSM group compared to the CON group (P < 0.10) and decreased significantly (P < 0.05) over time from d 0 to d 65 in the LMSM group, indicating the improvement of hair quality. Besides, supplementation with LMSM increased bacterial diversity. Kittens fed MSM had no significant differences in fecal genus at the end of the study. No significant differences in fecal short-chain fatty acids were observed among groups. Fecal metabolomics analysis further revealed that MSM hardly affected the metabolites. Overall, dietary supplementation with 0.2% MSM can improve the hair quality of kittens. Furthermore, 0.2∼0.4% of MSM had no detrimental effects on serum biochemistry, growth performance, gut microbiota, and metabolome, which supports the safety inclusion of MSM to a certain degree in feline diets. To the best of our knowledge, this is the first study to investigate the effects of MSM supplementation in cats.

Domestic cats are descended from solitary wild species and rely heavily on the olfaction system and chemical signals for daily activities. Cats kept as companion animals may experience stress due to a lack of predictability in their physical or social environment. The olfactory system is intimately connected to the brain regions controlling stress response, thus providing unique opportunities for olfactory strategies to modify stress and related behavioral problems in cats. However, the olfactory intervention of stress in cats has been mainly focused on several analog chemical signals and studies often provide inconsistent and non-replicable results. Supportive evidence in the literature for the potentially effective olfactory stimuli (e.g., cheek and mammary gland secretions, and plant attractants) in treating stress in cats was reviewed. Limitations with some of the work and critical considerations from studies with natural or negative results were discussed as well. Current findings sometimes constitute weak evidence of a reproducible effect of cat odor therapy for stress. The welfare application of an olfactory stimulus in stress alleviation requires a better understanding of its biological function in cats and the mechanisms at play, which may be achieved in future studies through methodological improvement (e.g., experiment pre-registration and appropriate control setting) and in-depth investigation with modern techniques that integrate multisource data. Contributions from individual and environmental differences should be considered for the stress response of a single cat and its sensitivity to olfactory manipulation. Olfactory strategies customized for specific contexts and individual cats can be more effective in improving the welfare of cats in various stressful conditions.

Dietary changes are inevitable for pets, yet little is known about the impact of different dietary change methods on the gastrointestinal response. The current comparative study evaluated the effects of different dietary changes on the diarrheal symptoms, fecal fermentation characteristics, microbiota, and metabolic profile of healthy puppies. A total of 13 beagle puppies were randomly divided into two groups; puppies in the abrupt change (AC) group were given 260 g of a chicken- and duck-based extruded diet (CD)daily for the one-week transition period, whereas puppies in the gradual transition (GT) group were fed according to a gradual transition ratio of a salmon-based extruded diet (SA) and a CD diets with a difference of 40 g per day for seven consecutive days. Serum samples were collected on D7, and fecal samples were collected on D0 and D7. The results indicated that GT reduced the incidence of diarrhea in puppies throughout the trial period. Dietary change methods had no influence on serum inflammatory factors or fecal SCFAs, but isovaleric acid was significantly reduced after GT. Meanwhile, 16S rRNA sequencing showed that the fecal microbiota was changed after different dietary changes. Compared with the bacterial changes after AC, the relative abundances of beneficial bacteria (i.e., Turicibacter and Faecalibacterium) in feces were increased after GT in puppies. Additionally, both GT and AC caused changes in amino acid metabolism, while AC also altered lipid metabolism. AC increased fecal histamine and spermine concentrations, but decreased concentrations of metabolites such as 5-hydroxyindoleacetic acid and serotonin. Our findings indicated that GT most likely reduced the diarrhea rate in puppies by modulating the composition and metabolism of the gut microbiota.

Early-life exposure to environmental stress disrupts the gut barrier and leads to inflammatory responses and changes in gut microbiota composition. Gallic acid (GA), a natural plant polyphenol, has received significant interest for its antioxidant, anti-inflammatory, and antimicrobial properties that support the maintenance of intestinal health. To assess whether dietary supplementation of GA alleviates environmental stress, a total of 19 puppies were randomly allocated to the following three dietary treatments for 2 weeks: 1) basal diet (control (CON)); 2) basal diet + transportation (TS); and 3) basal diet with the addition of 500 mg/kg of GA + transportation (TS+GA). After a 1-week supplementation period, puppies in the TS and TS+GA groups were transported from a stressful environment to another livable location, and puppies in the CON group were then left in the stressful environment. Results indicated that GA markedly reduced the diarrhea rate in puppies throughout the trial period and caused a moderate decline of serum cortisol and HSP-70 levels after transportation. Also, GA alleviated the oxidative stress and inflammatory response caused by multiple environmental stressors. Meanwhile, puppies fed GA had a higher abundance of fecal Firmicutes and Lactobacillus and lower Proteobacteria, Escherichia–Shigella, and Clostridium_sensu_stricto_1 after transportation. As a result, the TS+GA group had the highest total short-chain fatty acids and acetic acid. Also, the fecal and serum metabolomics analyses revealed that GA markedly reversed the abnormalities of amino acid metabolism, lipid metabolism, carbohydrate metabolism, and nucleotide metabolism caused by stresses. Finally, Spearman’s correlation analysis was carried out to explore the comprehensive microbiota and metabolite relationships. Overall, dietary supplementation of GA alleviates oxidative stress and inflammatory response in stressed puppies by causing beneficial shifts on gut microbiota and metabolites that may support gut and host health.

Transportation is common in cats and often causes stress and intestinal disorders. Antimicrobial peptides (AMPs) exhibit a broad spectrum of antibacterial activity, and they may have the capacity for antioxidant and immune regulation. The objective of this study was to investigate the effects of dietary supplementation with AMPs on stress response, gut microbiota and metabolites of cats that have undergone transport stress. A total of 14 Ragdoll cats were randomly allocated into 2 treatments: basal diet (CON) and a basal diet supplemented with 0.3% AMPs. After a 6-week feeding period, all cats were transported for 3 h and, then, fed for another week. The results show that the diarrhea rate of cats was markedly reduced by supplementation with AMPs throughout the trial period (p < 0.05). In addition, AMPs significantly reduced serum cortisol and serum amyloid A (p < 0.05) and increased apolipoprotein 1 after transportation (p < 0.05). Moreover, AMPs reduced the level of inflammatory factors in the serum caused by transportation stress, including tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) (p < 0.05). The AMPs enhanced the activities of glutathione peroxidase (p < 0.01) and superoxide dismutase (p < 0.05). Furthermore, cats fed AMPs had higher levels of branched chain fatty acids (BCFAs) and a relative abundance of Blautia and a lower relative abundance of Negativibacillus after transportation (p < 0.05). The serum metabolome analysis further revealed that AMPs markedly regulated lipid metabolism by upregulating cholic acid expression. In conclusion, AMP supplementation alleviated oxidative stress and inflammatory response in transportation by regulating the gut microbiota and metabolites, thereby relieving stress-induced diarrhea and supporting gut and host health in cats.

A variety of physical, emotional, and mental factors can induce a stress response in pet dogs and cats. During this process, hypothalamus–pituitary–adrenal (HPA) and sympathetic–adrenal medulla (SAM) axes are activated to produce a series of adaptive short-term reactions to the aversive situations. Meanwhile, oxidative stress is induced where there is an imbalance between the production and scavenging of reactive oxygen species (ROS). Oxidative damage is also incorporated in sustained stress response causing a series of chronic problems, such as cardiovascular and gastrointestinal diseases, immune dysfunction, and development of abnormal behaviors. In this review, the effects and mechanisms of dietary regulation strategies (e.g., antioxidants, anxiolytic agents, and probiotics) on relieving stress in pet dogs and cats are summarized and discussed. We aim to shed light on future studies in the field of pet food and nutrition.

Softening dry food with water is believed to be more beneficial to the intestinal health and nutrients absorption of dogs by some owners, but there appears to be little scientific basis for this belief. Thus, this study aimed to compare feeding dry food (DF) and water-softened dry food (SDF) on stress response, intestinal microbiome, and metabolic profile in dogs. Twenty healthy 5-month-old beagle dogs were selected and divided into two groups according to their gender and body weight using a completely randomized block design. Both groups were fed the same basal diet, with one group fed DF and the other fed SDF. The trial lasted for 21 days. The apparent total tract digestibility (ATTD) of nutrients, inflammatory cytokines, stress hormones, heat shock protein-70 (HSP-70), fecal microbiota, short-chain fatty acids (SCFAs), branch-chain fatty acids (BCFAs), and metabolomics were measured. Results showed that there was no significant difference in body weight, ATTD, and SCFAs between the DF and SDF groups (p > 0.05), whereas feeding with SDF caused a significant increase in serum cortisol level (p < 0.05) and tended to have higher interleukin-2 (p = 0.062) and HSP-70 (p = 0.097) levels. Fecal 16S rRNA gene sequencing found that the SDF group had higher alpha diversity indices (p < 0.05). Furthermore, the SDF group had higher levels of Streptococcus, Enterococcus, and Escherichia_Shigella, and lower levels of Faecalibacterium (p < 0.05). Serum and fecal metabolomics further showed that feeding with SDF significantly influenced the purine metabolism, riboflavin metabolism, and arginine and proline metabolism (p < 0.05). Overall, feeding with SDF caused higher cortisol level and generated effects of higher intestinal microbial diversity in dogs, but it caused an increase in some pathogenic bacteria, which may result in intestinal microbiome disturbance and metabolic disorder in dogs. In conclusion, feeding with SDF did not provide digestive benefits but caused some stress and posed a potential threat to the intestinal health of dogs. Thus, SDF is not recommended in the feeding of dogs.

Ubiquitin-like with plant homeodomain and really interesting new gene finger domains 1 (UHRF1) is a multi-domain nuclear protein that plays an important role in epigenetics and tumorigenesis, but its role in normal ovarian follicle development remains unknown. Thus, the present study evaluated if UHRF1 mRNA abundance in bovine follicular cells is developmentally and hormonally regulated, and if changes in UHRF1 are associated with changes in DNA methylation in follicular cells. Abundance of UHRF1 mRNA was greater in granulosa cells (GC) and theca cells (TC) from small (<6 mm) than large (≥8 mm) follicles and was greater in small-follicle GC than TC. In GC and TC, fibroblast growth factor 9 (FGF9) treatment increased (P < 0.05) UHRF1 expression by 2-fold. Also, luteinizing hormone (LH) and insulin-like growth factor 1 (IGF1) increased (P < 0.05) UHRF1 expression in TC by 2-fold, and forskolin (an adenylate cyclase inducer) alone or combined with IGF1 increased (P < 0.05) UHRF1 expression by 3-fold. An E2F transcription factor inhibitor (E2Fi) decreased (P < 0.05) UHRF1 expression by 44% in TC and by 99% in GC. Estradiol, progesterone, and dibutyryl-cAMP decreased (P < 0.05) UHRF1 mRNA abundance in GC. Treatment of GC with follicle-stimulating hormone (FSH) alone had no effect but when combined with IGF1 enhanced the UHRF1 mRNA abundance by 2.7-fold. Beauvericin (a mycotoxin) completely inhibited the FSH plus IGF1-induced UHRF1 expression in small-follicle GC. Treatments that increased UHRF1 mRNA (i.e., FGF9) in GC tended to decrease (by 63%; P < 0.10) global DNA methylation, and those that decreased UHRF1 mRNA (i.e., E2Fi) in GC tended to increase (by 2.4-fold; P < 0.10) global DNA methylation. Collectively, these results suggest that UHRF1 expression in both GC and TC is developmentally and hormonally regulated, and that UHRF1 may play a role in follicular growth and development as well as be involved in ovarian epigenetic processes. [ABSTRACT FROM AUTHOR]

Tight junctions (TJ) are protein structures that control the transport of water, ions and macromolecules across cell layers. Functions of the transmembrane TJ protein, occluding (OCLN) and the cytoplasmic TJ proteins, tight junction protein 1 (TJP1; also known as zona occludens protein-1), cingulin (CGN) and claudins (CLDN) are reviewed, and current evidence of their role in the ovarian function is reviewed. Abundance of OCLN, CLDNs and TJP1 mRNA changed during follicular growth. In vitro treatment with various growth factors known to affect ovarian folliculogenesis indicated that CGN, OCLN and TJP1 are hormonally regulated. The summarized studies indicate that expression of TJ proteins (i.e., OCLN, CLDN, TJP1 and CGN) changes with follicle size in a variety of vertebrate species but whether these changes in TJ proteins are increased or decreased depends on species and cell type. Evidence indicates that autocrine, paracrine and endocrine regulators, such as fibroblast growth factor-9, epidermal growth factor, androgens, tumor necrosis factor-a and glucocorticoids may modulate these TJ proteins. Additional evidence presented indicates that TJ proteins may be involved in ovarian cancer development in addition to normal follicular and luteal development. A model is proposed suggesting that hormonal downregulation of TJ proteins during ovarian follicular development could reduce barrier function (i.e., selective permeability of molecules between theca and granulosa cells) and allow for an increase in the volume of follicular fluid as well as allow additional serum factors into the follicle that may directly impact granulosa cell functions. [ABSTRACT FROM AUTHOR]

Mitotic catastrophe is the response of mammalian cells to mitotic DNA damage. It produces tetraploid cells with a range of different nuclear morphologies from binucleated to multimicronucleated. In response to DNA damage, checkpoints are activated to delay cell cycle progression and to coordinate repair. Cells in different cell cycle phases use different mechanisms to arrest their cell cycle progression. It has remained unclear whether the termination of mitosis in a mitotic catastrophe is regulated by DNA damage checkpoints. Here, we report the presence of a mitotic exit DNA damage checkpoint in mammalian cells. This checkpoint delays mitotic exit and prevents cytokinesis and, thereby, is responsible for mitotic catastrophe. The DNA damage-induced mitotic exit delay correlates with the inhibition of Cdh1 activation and the attenuated degradation of cyclin B1. We demonstrate that the checkpoint is Chk1-dependent. [ABSTRACT FROM AUTHOR]

The size of an organ must be tightly controlled so that it fits within an organism. The mammalian lens is a relatively simple organ composed of terminally differentiated, amitotic lens fiber cells capped on the anterior surface by a layer of immature, mitotic epithelial cells. The proliferation of lens epithelial cells fuels the growth of the lens, thus controling the size of the lens. We report that the Notch signaling pathway defines the boundary between proliferation and differentiation in the developing lens. The loss of Notch signaling results in the loss of epithelial cells to differentiation and a much smaller lens. We found that the Notch effector Herp2 is expressed in lens epithelium and directly suppresses p57Kip2 expression, providing a molecular link between Notch signaling and the cell cycle control machinery during lens development. [ABSTRACT FROM AUTHOR]

Ribonucleotide reductase (RR) catalyzes the reduction of ribonucleotides to deoxyribonucleotides for DNA synthesis. Human RR small subunit M2 exists in a homodimer form. However, the importance of the dimer form to the enzyme and the related mechanism remain unclear. In this study, we tried to identify the interfacial residues that may mediate the assembly of M2 homodimer by computational alanine scanning based on the x-ray crystal structure. Co-immunoprecipitation, size exclusion chromatography, and RR activity assays showed that the K95E mutation in M2 resulted in dimer disassembly and enzyme activity inhibition. In comparison, the charge-exchanging double mutation of K95E and E98K recovered the dimerization and activity. Structural comparisons suggested that a conserved cluster of charged residues, including Lys-95, Glu-98, Glu-105, and Glu-174, at the interface may function as an ionic lock for M2 homodimer. Although the measurements of the radical and iron contents showed that the monomer (the K95E mutant) was capable of generating the diiron and tyrosyl radical cofactor, co-immunoprecipitation and competitive enzyme inhibition assays indicated that the disassembly of M2 dimer reduced its interaction with the large subunit M1. In addition, the immunofluorescent and fusion protein-fluorescent imaging analyses showed that the dissociation of M2 dimer altered its subcellular localization. Finally, the transfection of the wild-type M2 but not the K95E mutant rescued the G1/S phase cell cycle arrest and cell growth inhibition caused by the siRNA knockdown of M2. Thus, the conserved Lys-95 charged residue cluster is critical for human RR M2 homodimerization, which is indispensable to constitute an active holoenzyme and function in cells. [ABSTRACT FROM AUTHOR]