Affect Body Weight Research Articles

Effect of Dietary Supplementation of Durvillaea Antarctica Meal on Production and Meat Quality Traits of Lambs

Worldwide, there are reports indicating that sheep raised in insular systems spontaneously consume seaweed. In the southern hemisphere, there exists Durvillaea antarctica, a brown seaweed that possesses minerals and fatty acids that could improve some aspects of sheep production and meat quality, respectively. However, the consumption of this algae in lambs has been scarcely studied. The objective of this study was to evaluate the effects of dietary inclusion of Durvillaea antarctica meal on the growth performance, blood profile, and meat quality of fattening lambs. Thirty Araucana Creole lambs were housed and allocated to three pens. One pen served as a control, while the remaining two were supplemented with diets containing 5% and 10% Durvillaea antarctica meal. After 9 weeks, the animals were slaughtered. The dietary treatments did not significantly affect body weight and blood biochemical parameters. However, changes were observed in meat quality traits, including increased redness and reduced luminosity in the loin for the high inclusion treatment, in addition to slight alterations in pH and lower lipid oxidation in lambs’ meat fed Durvillaea antarctica. Furthermore, the meat from lambs supplemented with Durvillaea antarctica exhibited increased levels of linoleic acid and arachidonic acid, along with higher monounsaturated fatty acid content and a reduced omega-3/omega-6 ratio. This study shows that Durvillaea antarctica can be used to feed lambs without impairing growth or production parameters, which has been little studied. It is possible that this brown seaweed could be considered a natural additive to improve the quality and nutritional value of lamb meat. The effect of this seaweed on other ruminant models could be addressed in future studies.

Exploring the role of Bisphenol A in obesity-driven colorectal cancer progression: network toxicology and multi-organ pathology in animal models.

Bisphenol A (BPA), an endocrine disruptor, is linked to cancer progression in estrogen-responsive tissues, but its role in promoting colorectal cancer (CRC) progression in the context of obesity remains underexplored. This study examines BPA's influence on CRC in obese Sprague-Dawley rats using network toxicology and experimental models. Computational analysis using the Database for Annotation, Visualization, and Integrated Discovery identified pathways such as "CRC" and "chemical carcinogenesis-receptor activation", implicating the PI3K-AKT pathway in IL-1 beta upregulation and BPA's role in CRC during obesity. Thirty male rats were grouped (n = 6) as follows: N (normal diet), NC (normal diet + CRC), HC (high-fat diet + CRC), NCB (normal diet + CRC + BPA), and HCB (high-fat diet + CRC + BPA). CRC was induced with 1,2-dimethylhydrazine (40 mg/kg), and BPA (25 mg/kg) was administered for 19 weeks. Although BPA exposure did not affect body weight or biochemical parameters, the HCB group exhibited significant histopathological changes in the colon, including lymphoid hyperplasia, liver damage, and increased IL-1β levels. Furthermore, diet influenced adipocyte size, exacerbating BPA's effects on CRC progression. Findings suggest BPA may worsen CRC progression in obese rats through identified pathways, promoting multi-organ pathology and underscoring the need for stricter regulations, especially for vulnerable populations. ENVIRONMENTAL IMPLICATION: Bisphenol A (BPA), a widespread environmental contaminant, is increasingly linked to serious health issues, including cancer, in susceptible populations. Our study highlights BPA's role in promoting obesity-driven colorectal cancer (CRC) progression, demonstrating its carcinogenic potential in high-risk contexts. These findings emphasize the urgent need for regulatory scrutiny of BPA exposure, particularly in obese individuals, and support the development of safer alternatives. Addressing BPA's impact can contribute to preventive health strategies and inform policies aimed at reducing environmental and public health risks associated with endocrine-disrupting chemicals.

Preventive and therapeutic effects of genistein and daidzein on anxiety-like behaviors in ovariectomized rats.

Estrogen has demonstrated beneficial effects; however, it can also have unfavorable effects. Phytoestrogens are present in many consumable products and commonly used as supplements. These are of interest as they may have beneficial effects on mood with fewer undesirable effects on reproductive tissues. This study investigated the anxiolytic-like effects of the phytoestrogens genistein and daidzein on ovariectomized (Ovx) rats and their effects on the expression of uterine estrogen receptors (ER) and brain monoamines. In experiment 1, Ovx rats received either vehicle, 17β-estradiol, or 0.25-1 mg/kg of genistein or daidzein for 4weeks before behavioral tests of anxiety. In experiment 2, we assessed the therapeutic effects of genistein and daidzein. The ovariectomies were used to induce anxiety, so the treatments were started 3weeks post-ovariectomy. The Ovx rats received vehicle, 17β-estradiol, or 0.25mg/kg of genistein or daidzein daily for 4weeks before behavioral tests. We found daidzein and genistein comparable to 17β-estradiol in their anxiolytic-like effects. Further, while 17β-estradiol decreased body weight gain, increased uterine weight, and increased the uterine ERα/ERβ ratio, neither genistein nor daidzein had these undesirable effects. The alterations in brain monoamines following genistein or daidzein treatments were somewhat different from those seen after 17β-estradiol treatment. In conclusion, daily daidzein or genistein administration for 4weeks did not negatively affect body weight, food intake, uterine tissue, uterine ER expressions, or ERα/ERβ ratio but demonstrated anxiolytic-like effects on Ovx rats. We conclude that low-dose (0.25mg/kg) genistein or daidzein can alleviate anxiety in a female anxious rat model.

Selenium-Enriched Aspergillus oryzae A02 Enhances Testicular Antioxidant Capacity in Mice by Regulating Intestinal Microbiota and Serum Metabolite.

Selenium (Se) is a trace element that is essential for health. Organic Se created by Se-enriched microorganisms has the characteristics of low toxicity, high bioavailability, and regulation of physiological functions. Here, the regulatory effect of Se-enriched Aspergillus oryzae A02 on the reproductive function of male mice and its potential molecular mechanism was studied. Specifically, twenty-four male mice were randomly divided into a control group and a Se-enriched A. oryzae A02 (Nano-Se) (daily gavage of 0.5mg/kg, dissolved in saline) for an 8-week experiment. The results showed that Nano-Se intervention did not affect body weight and testicular index, but increased sperm concentration and seminiferous epithelium height in experimental mice, indicating that Nano-Se has the potential to improve the reproductive performance of male mice. Mechanistically, Nano-Se intervention increased the levels of antioxidant-related indicators catalase (CAT) and glutathione peroxidase (GSH-Px) in mouse serum, and increased the relative mRNA expression of GSH-Px, heme oxygenase-1 (HO-1), and NADPH quinine oxidoreductase-1 (NQO-1) in testicular tissues. We identified 9,10,13-trihydroxyoctadecenoic acids (TriHOMEs), stearidonic acid and selenomethionine linked with alpha-linolenic acid metabolism, selenocompound metabolism, folate biosynthesis, ubiquinone, and other terpenoid-quinone biosynthesis and biosynthesis of cofactors. In addition, Nano-Se did not influence the fecal bacterial alpha and beta diversity (P > 0.05), but increased the abundance of the Actinobacteriota and Proteobacteria phyla and the Staphylococcus and Corynebacterium genera, and lowered the abundance of the Bacteroidota phylum and the Lactobacillus and norank_f_Muribaculaceae genera. Nano-Se is considered a novel and promising nutritional regulator to improve reproductive function.

Haplotype analysis incorporating ancestral origins identified novel genetic loci associated with chicken body weight using an advanced intercross line

BackgroundThe genome-wide association study (GWAS) is a powerful method for mapping quantitative trait loci (QTL). However, standard GWAS can detect only QTL that segregate in the mapping population. Crossing populations with different characteristics increases genetic variability but F2 or back-crosses lack mapping resolution due to the limited number of recombination events. This drawback can be overcome with advanced intercross line (AIL) populations, which increase the number recombination events and provide a more accurate mapping resolution. Recent studies in humans have revealed ancestry-dependent genetic architecture and shown the effectiveness of admixture mapping in admixed populations.ResultsThrough the incorporation of line-of-origin effects and GWAS on an F9 AIL population, we identified genes that affect body weight at eight weeks of age (BW8) in chickens. The proposed ancestral-haplotype-based GWAS (testing only the origin regardless of the alleles) revealed three new QTLs on GGA12, GGA15, and GGA20. By using the concepts of ancestral homozygotes (individuals that carry two haplotypes of the same origin) and ancestral heterozygotes (carrying one haplotype of each origin), we identified 632 loci that exhibited high-parent (the heterozygote is better than both parents) and mid-parent (the heterozygote is better than the median of the parents) dominance across 12 chromosomes. Out of the 199 genes associated with BW8, EYA1, PDE1C, and MYC were identified as the best candidate genes for further validation.ConclusionsIn addition to the candidate genes reported in this study, our research demonstrates the effectiveness of incorporating ancestral information in population genetic analyses, which can be broadly applicable for genetic mapping in populations generated by ancestors with distinct phenotypes and genetic backgrounds. Our methods can benefit both geneticists and biologists interested in the genetic determinism of complex traits.

Digging deep for nutrients and metabolites derived from high dietary protein intake and their potential functions in metabolic health.

Intake of high quantities of dietary proteins sourced from dairy, meat or plants can affect body weight and metabolic health in humans. To improve our understanding of how this may be achieved, we reviewed the data related to the availability of nutrients and metabolites in the faeces, circulation and urine. All protein sources (≥20% by energy) increased faecal levels of branched chain fatty acids and ammonia, and decreased the levels of butyrate. There were metabolites responding to dairy and meat proteins (branch chain amino acids) as well as dairy and plant proteins (p-cresol), which were increased in faecal matter. Specific to dairy protein intake, the faecal levels of acetate, indole and phenol were increased, whereas plant protein intake specifically increased the levels of kynurenine and tyramine. Meat protein intake increased the faecal levels of methionine, cysteine and alanine, and decreased the levels of propionate and acetate. The metabolite profile in the faecal matter following dairy protein intake mirrored availability in circulation or urine. These findings provide an understanding of the contrasting gut versus systemic effects of different dietary proteins, which we know to show different physiological effects. In this regard, we provide directions to determining the mechanisms for the effects of different dietary proteins.

Expression of p53 in human adipose tissue correlates positively with FAS and BMI.

Activation of Fas (CD95) in adipocytes inhibits browning and may contribute to body weight gain in mice. Moreover, Fas expression in white adipose tissue (WAT) correlates positively with body mass index (BMI) in humans. However, molecular pathways involved in the inhibitory effect of Fas on energy metabolism remain incompletely understood. Herein, we report that protein levels of the tumor suppressor p53 were reduced in primary white adipocytes of adipocyte-specific Fas-knockout mice. Moreover, Fas ligand (FasL) treatment increased p53 concentrations in cultured adipocytes and decreased mitochondrial oxygen consumption in control but not in p53-depleted cells, indicating that Fas activation reduces energy expenditure in a p53-dependent manner. In line, in differentiated human mesenchymal stem cells and WAT derived from different anatomical depots, FAS expression was positively associated with p53. Furthermore, p53 expression in human subcutaneous and visceral WAT correlated positively with BMI, whereas its expression in visceral WAT was inversely associated with insulin sensitivity (as assessed by hyperinsulinemic-euglycemic clamp). Taken together, our data suggest that Fas regulates p53 expression in adipocytes, and may thereby affect body weight gain and insulin sensitivity.

Effect of Feeding Sugarcane Bagasse-Extracted Polyphenolic Mixture on the Growth Performance, Meat Quality, and Oxidative and Inflammatory Status of Chronic Heat-Stressed Broiler Chickens.

This study aimed to evaluate the effects of sugarcane bagasse-extracted polyphenolic mixture (SBPM) supplementation on the harmful effects of chronic heat stress (HS) in broiler chickens. Two hundred and eighty-eight day-old male Ross 308 chicks were fed an SBPM in 0, 75, 150, or 300 ppm-supplemented diets and reared under thermoneutral (TN, 22.1-24.8 °C) or chronic HS (28.3-36.2 °C) conditions from 11 d to 42 d. The chronic HS treatment negatively affected body weight, feed intake, and feed conversion ratio (p < 0.05), and these changes were partially attenuated by the SBPM supplementation (p < 0.05). Plasma lipid peroxidation content, inflammatory cytokines [interleukin (IL)-6, IL-β], corticosterone, and uric acid concentrations were significantly increased by HS, and these increases were attenuated by the SBPM supplementation (p < 0.05). Intestinal permeability indicator and serum fluorescein isothiocyanate-dextran levels after oral gavage were increased by HS and were also suppressed by the supplementation (p < 0.05). The HS-decreased muscle drip loss, lipid peroxidation, and glutathione content were also suppressed by the SBPM supplementation. The abovementioned alleviating effects of the SBPM were of a dose-dependent manner in most cases. This study demonstrated that SBPM supplementation can improve the growth performance, meat quality, inflammation, and intestinal permeability of chronic HS-treated broiler chickens.

Intermittent breaking of isolation may ameliorate decrease in physical activity caused by isolation.

Social isolation affects physical functioning owing to psychological stress. We constructed a rat model to clarify the unexplored effects of social isolation and to determine whether environmental changes as an intervention against social isolation can reduce the stress-inducing effects of social isolation on physiological factors. Eight-week-old male rats were divided into three groups: group-housed, isolated, and intervention. Group-housed rats were kept 2 animals per cage. Isolated rats were kept 1 rat per cage. The intervention group alternated between the isolation and group-housed conditions. All rats were euthanized after 21 days. Their plasma, masseter muscles, and lower limb muscles were collected. Body weight, food intake, locomotor activity, muscle weight, and plasma corticosterone, ghrelin, and myostatin levels were measured. The results indicated that there were no significant differences between the group-housed and intervention groups for all outcomes. However, weight gain, food intake, and plasma corticosterone levels were higher in the isolated group than in the group-housed group. Plasma myostatin levels were higher in the isolated group than in the intervention group. Plasma ghrelin concentrations were lower in the isolated group than in the group-housed or intervention groups. In the isolated group, locomotor activity decreased compared to that in the intervention group. The lower limb muscle weight ratio also decreased in the isolated group compared to that in the group-housed and intervention groups. In conclusion, isolation decreased physical activity and affected body weight, food intake, and muscle weight; these changes were associated with corticosterone as a stress marker, ghrelin as an appetite-related factor, and myostatin, which is a growth inhibitor of skeletal muscles. Moreover, these changes were suppressed when the isolation time was reduced in the intervention group. The present study suggests that intermittent breaking of isolation may reduce the physical effects of isolation.

Genome-Wide Association Study of Body Weight Traits in Texel and Kazakh Crossbred Sheep.

Background: Originating from the cold and arid regions of northwestern China, Kazakh sheep are dual-purpose breeds optimized for both meat and fat production. In contrast, Texel sheep are internationally recognized for their high-quality meat and exceptional flavor. Previous studies have indicated that the hybrids of Texel and Kazakh sheep exhibit significant quality advantages. Additionally, body weight is a crucial indicator of sheep production performance, directly correlating with meat yield and economic returns. Objective: This study aims to identify genetic variations and related genes associated with the body weight traits of hybrid lambs, thereby revealing their genetic mechanisms. Methods: This study genotyped hybrid lambs using a 50K chip and performed rigorous quality control on both genotypic and phenotypic data. The traits examined include body weight traits of lambs at various stages such as birth, pre-weaning, and post-weaning. Various genome-wide association study (GWAS) models were utilized to analyze the association between lamb body weight traits and genetic markers. The study then employed an Ensemble-like GWAS (E-GWAS) strategy to integrate these models, achieving a stable list of SNPs, rather than a mere aggregation. Multiple annotation databases were consulted to further investigate the mechanisms by which genetic markers affect body weight traits. All study results were validated through an extensive literature review. Results: Analyses with multiple statistical models revealed that 48 SNPs were significantly associated with body weight traits. The annotation process identified 24 related genes (including 4 unknown genes) and 9 quantitative trait loci (QTLs). Additionally, 6 Gene Ontology (GO) terms and 22 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were determined. Conclusions: This study identified key genes and pathways in the body weight traits of hybrids between Texel and Kazakh sheep, enhancing our understanding of their genetic mechanisms.

Effects of COVID-19 virus-like particles on the behavioral and cognitive performance of human apolipoprotein E targeted replacement mice.

The effects of viral infections might be apolipoprotein E (apoE) isoform-dependent. In humans, there are three major apoE isoforms, E2, E3, and E4. E4 is associated with the enhanced entry of several viruses into the brain and their disease progression. A concern of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the development of post-acute COVID-19 syndrome, also known as long COVID. Genetic risk factors for developing long COVID were reported. In this study, we used virus-like particles (VLPs) that include expression of the SARS-CoV-2 nucleocapsid (N), membrane (M), and envelope (E) structural proteins together with S. In the current study, we used human E2, E3, and E4 targeted replacement mice to assess whether these VLPs affect body weight, behavioral and cognitive performance, and circadian body temperatures. Using VLPs allow working outside an ABSL-3 facility. The effects of VLPs on some behavioral measures were apoE isoform-dependent, with the E2 mice being more affected than E3 or E4 mice. The overall decreased activity in the open field containing objects in week 2 indicate that VLPs can also reduce activity levels in an apoE isoform-independent fashion. The results of the current study indicate that even in the absence of viral replication, detrimental effects of VLPs on behavioral measures and circadian body temperatures are seen.

Gut Microbiota Modulates Fgf21 Expression and Metabolic Phenotypes Induced by Ketogenic Diet.

The ketogenic diet (KD) is a widely used intervention for obesity and diabetes, effectively reducing body weight and blood glucose levels. However, the molecular mechanisms by which the KD influences body weight and glucose metabolism are not fully understood. While previous research has shown that the KD affects the gut microbiota, the exact role of microbiota in mediating its metabolic effects remains unclear. In this study, we used antibiotics to eliminate the gut microbiota, confirming its necessity for the KD's impact on weight loss and glucose metabolism. We also demonstrated the significant role of FGF21 in these processes, through antibiotics intervention in Fgf21-deficient mice. Furthermore, we revealed that the KD alters serum valine levels via the gut microbiota, which in turn regulates hepatic Fgf21 expression and circulating FGF21 levels through the GCN2-eIF2α-ATF5 signaling pathway. Additionally, we demonstrated that valine supplementation inhibits the elevated expression of FGF21, leading to the reduced body weight and improved glucose metabolism of the KD-fed mice. Overall, we found that the gut microbiota from the KD regulates Fgf21 transcription via the GCN2-eIF2α-ATF5 signaling pathway. ultimately affecting body weight and glucose metabolism. Our findings highlight a complex regulatory network linking the KD, Fgf21 expression, and gut microbiota, offering a theoretical foundation for targeted therapies to enhance the metabolic benefits of the KD.

Effects of High-Dose Vitamin D3 Supplementation on Pig Performance, Vitamin D Content in Meat, and Muscle Transcriptome in Pigs.

Vitamin D is known for its role in calcium homeostasis, bone health, and immune function. Recent research has explored its effects on muscle functionality and meat quality in pigs. This study examined high-dose vitamin D3 supplementation in pigs, focusing on growth, blood and tissue vitamin D3 levels, and muscle transcriptome changes. Thirty pigs were divided into three groups, given different amounts of oral supplementation: control, 5000 IU/kg and 10,000 IU/kg vitamin D3. Biochemical and haematological blood parameters, vitamin D content in blood and muscle, and kidney calcium content were evaluated. RNA-seq and qPCR analysed muscle transcriptome changes, while gene set enrichment analysis (GSEA) identified gene expression enrichments. Results showed that 5000 IU/kg vitamin D3 supplementation altered blood parameters like platelet anisocytosis and glucose levels but did not affect body weight, weight gain, or feed intake. Kidney calcium content increased with supplementation. The muscle (longissimus dorsi) vitamin D content increased, suggesting the potential for biofortified pork, although still not optimal as a dietary vitamin D source. Transcriptome analysis revealed minimal gene expression changes, with only the interferon-gamma receptor 2 (IFNGR2) gene differentially expressed at the highest dose. GSEA indicated enrichment in ATP metabolic processes and electron transport chain genes in the 5000 IU/kg group, and immune system, cholesterol, steroid, and fatty acid metabolism genes in the 10,000 IU/kg group. Despite literature suggesting a role for vitamin D in muscle gene expression and growth improvement, this study found its effects limited.

Positive Changes in Body Composition and Profiles of Individuals with Diabetes 3 Years Following Laparoscopic Sleeve Gastrectomy in Japanese Patients with Obesity.

We analyzed the changes in obesity, glucose metabolism, and body composition over a 3-year period in Japanese patients with obesity following laparoscopic sleeve gastrectomy (LSG). Body weight, parameters related to diabetes such as glycated hemoglobin (HbA1c), and electrical impedance analysis were used to assess body composition in forty-eight Japanese patients with obesity before surgery and 6 months, 1 year, 2 years, and 3 years after LSG. At 6 months, 1, 2, and 3 years post-LSG, there were significant reductions in body weight, body mass index, blood pressure, fasting plasma glucose, triglyceride, and HbA1c levels. Six months after LSG, fat mass (FM), muscle mass (MM), and %FM all showed a decrease compared to pre-treatment values (all p < 0.05). FM and %FM remained in a decreased state until 3 years had passed. In contrast, %MM increased at 6 months post-LSG and was maintained up to 3 years post-LSG (all p < 0.05). Furthermore, changes in FM and %FM were associated with changes in body weight and A1C. In contrast, change in %MM exhibited a negative correlation with body weight and A1C following LSG. Finally, multivariate regression analyses demonstrated that alterations in FM were independent factors affecting body weight in patients with obesity 3 years after LSG. We observed improvements in FM, fasting plasma glucose, and HbA1c levels over a 3-year period in Japanese patients after LSG. The reduction in FM and maintenance of %MM after LSG were suggested as possible links between the effects of LSG on obesity and diabetes over 3 years.

The Bioavailability of Solid-State Fermented Feather Meal Using a Novel Feather-Degrading Bacterium Bacillus velezensis PN1 in Broilers.

In this study, an effective feather-degrading bacterium was isolated and the solid-state fermentation condition for feather degradation was optimized. The resulting fermented feather meal (FFM) was evaluated for its bioavailability in broilers. Four Bacillus strains were examined for feather degradation rates, with Bacillus velezensis PN1 exhibiting the highest rate (83.24%, p < 0.05). A 3 × 3 × 3 factorial design was used to test substrate moisture content (45%, 55%, 65%), temperature (27 °C, 37 °C, 47 °C), and incubation time (24, 48, 72 h) for optimized fermentation conditions. In vitro pepsin digestibility (IVPD) revealed a significant interaction between temperature and time (p < 0.05), and the optimal performance was achieved at 37 °C for 72 h, followed by 37 °C for 48 h. Considering production time and cost, FFM2 (produced with 65% moisture at 37 °C for 48 h) was further compared with FFM1 (produced under the same conditions but at a lower temperature of 27 °C), and commercial hydrolyzed feather meal (HFM). IVPD did not differ significantly between FFM1, FFM2, and HFM, as they all showed significantly higher digestibility compared to raw feathers (RFs). FFM1, as well as FFM2, had significantly higher histidine and lysine concentrations than RF (p < 0.05), while FFM2 had a significantly lower cysteine content (p < 0.05). Based on fermentation conditions and amino acid composition, FFM2 was considered more suitable for large-scale production and was used in a broiler growth trial. The inclusion of 5% FFM2 in the broiler diet did not significantly affect body weight at 35 days compared to the 5% HFM group (p > 0.05), although both groups showed significantly lower weight gain than the 5% fish meal (FM) group (p < 0.05). The feed conversion ratio and performance efficiency factor did not differ significantly between the FFM2, HFM, and FM groups (p > 0.05). In groups fed diets without supplemental crystalline amino acids, growth performance did not significantly differ between the HFM and FFM2 groups (p > 0.05), although both performed significantly worse than groups with amino acid supplementation. In conclusion, FFM produced by B. velezensis PN1 through solid-state fermentation enhances feather bioavailability in poultry and can completely replace HFM when included at 5% in broiler diets, offering a potential sustainable alternative for poultry nutrition on a commercial scale.

Levamisole Ameliorates Rheumatoid Arthritis by Downregulating the PI3K/Akt Pathway in SD Rats.

Background/Objectives: Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease characterized by a protracted course, high rates of morbidity, and disability yet lacks effective therapeutic modalities. Levamisole (LVM), an immunomodulatory drug, has been clinically reported for its potential in RA treatment, while its therapeutic mechanism toward RA remains to be elucidated. Hence, this study provides theoretical support for the application of LVM in the treatment of RA. Methods: This study employed male Sprague-Dawley (SD) rats to construct the adjuvant-induced arthritis (AIA) model, administering LVM orally (5 mg/kg, 15 mg/kg, and 45 mg/kg) for 25 days. An evaluation of LVM's therapeutic effects on RA was conducted through arthritis index scores, paw pad thickness, paw volume, hematoxylin and eosin (H&E) staining, 3D microcomputed tomography (micro-CT) scans, serum levels of pro-/anti-inflammatory cytokines, and serum biochemical indicators. Western blotting and immunohistochemistry staining were utilized to measure the expression levels of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) proteins in synovial and ankle joint tissues. Results: Treatment with the median dose of LVM (15 mg/kg, M-LVM) significantly reduced the arthritis index (p < 0.01), paw pad thickness (p < 0.001), and paw volume (p < 0.01) without affecting body weight. Additionally, M-LVM alleviated inflammatory lesions in the synovium and ankle joints and also normalized serum levels of interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β). The Model group exhibited significant increases in serum levels of alkaline phosphatase (ALP) (p < 0.01), creatine kinase (CK) (p < 0.05), and glucose (GLU) (p < 0.001) compared with the Control group; however, M-LVM effectively regulated these parameters to normal levels. Western blotting and immunohistochemistry staining revealed that PI3K-/Akt-related proteins were highly expressed in the synovial and ankle joint tissues of rats in the Model group, while treatment with M-LVM significantly reduced the expression of these proteins. Furthermore, histological examination of major organs (heart, liver, lungs, kidneys, and thymus) showed no significant pathological changes, with the exception of the spleen, where M-LVM ameliorated splenic lesions. Conclusions: We demonstrate that LVM at an optimal dose substantially relieves synovitis and bone erosion in AIA rats by inhibiting the PI3K/Akt signaling pathway.

Construction of a Myeloid Gene Signature Revealing Novel Therapeutic Targets for Myeloid Malignancies

FH, SL and BG equal contributors Myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML) exhibit shared hallmarks of hyperinflammation and aberrant clonal expansion. Chronic MPNs exhibit a propensity for transformation to secondary AML (sAML), which imparts a dismal prognosis with limited treatment options. However, the pathogenesis of leukemia transition for MPN and the bidirectional relationship between MPN and AML remain incompletely understood. In this study, we investigated commonly-featured genes and pathways of these two diseases to explore novel therapeutic strategies. To dissect the causal association between MPN and AML, we first performed two-sample bidirectional mendelian randomization (MR) analysis which revealed that MPN predicts the risk of AML across multiple statistical methods with consistent directionality and significance. Heterogeneity, pleiotropy, or outlier effects were ruled out by sensitivity analyses with no reverse causality from AML to MPN. To identify a potential myeloid signature, we estimated causal effects of 2,940 plasma proteins on MPN via a two-sample MR framework and identified 55 candidates significantly associated with increased risk of MPN (P &amp;lt; 0.05, OR &amp;gt; 1). Utilizing data from the BEAT-AML cohort, we further screened the prognostic value of these candidates using Cox and log-rank test survival analyses and identified a 4-gene myeloid signature comprising MPO, CDCP1, CRISP3 and DXCR, with each conferring prognostic significance individually. Our scRNA-seq results confirmed enrichment of myeloid signature genes in myeloid progenitor cells, with further elevation in MPN. Of note, expression of myeloid signature genes was induced by Jak2V617F and MPLW515L in Ba/F3 cells. We then investigated the combined prognostic significance of these four genes by constructing a risk score via LASSO regression modeling and divided patients into high- and low-risk groups accordingly. Cox analysis validated the risk score as an independent prognostic factor (HR: 3.01 (1.2 - 7.6), P = 0.019) and Kaplan-Meier survival analysis demonstrated that low-risk AML patients had a significantly better survival than high-risk AML patients with median survival of 21.9 months vs. 11.9 months (P &amp;lt; 0.0001). The prediction accuracy of the myeloid signature was successfully validated in the TCGA-LAML cohort. The risk score significantly correlated with several key clinical parameters, including age, platelet count, ELN2017 staging, monocyte percentage and bone marrow cellularity. To interrogate the underlying mechanism of the myeloid signature, we performed gene set enrichment analysis (GSEA) and observed enrichment of several inflammatory pathways in high-risk AML patients. A similar enrichment of inflammatory pathways in MPN samples compared to healthy donors observed in our previous scRNA-seq results reinforced hyperinflammation as a shared etiology of myeloid malignancies. To explore potential therapeutic strategies, we performed in silico drug sensitivity screening which predicted specific vulnerability of high-risk AML to compounds targeting PI3K/AKT/mTOR pathway signaling. Activation of PI3K/AKT/mTOR signaling in both MPN and AML samples observed across multiple single cell and bulk RNA-seq datasets further prompted us to evaluate targeted therapies against this pathway in myeloid malignancies. MPN and AML cells exhibited sensitivity to mTOR inhibitors as indicated by suppression of cellular proliferation, metabolism, colony formation, and inflammatory cytokine secretion in conjunction with induction of apoptosis. We further evaluated the therapeutic effects of mTOR inhibition in vivo via administration of omipalisib, a potent dual PI3K/mTOR inhibitor, to JAK2V617F knock-in mice. Omipalisib treatment significantly ameliorated features of myeloid malignancies including splenomegaly and leukocytosis which were both significantly reduced following 4 weeks of treatment, without affecting body weight. In summary, our MR analyses reveal that MPN predicts the risk of AML and enabled the construction of a novel myeloid signature which risk stratified AML patients across two different cohorts. We further demonstrate shared activation of PI3K/AKT/mTOR pathway across myeloid malignancies, with in vitro and in vivo data providing a rationale for therapeutic targeting of PI3K/AKT/mTOR pathway in these diseases.

Factors affecting body weight fluctuation in free-ranging Asian black bears

Factors affecting body weight fluctuation in free-ranging Asian black bears

Effects of branched-chain amino acid imbalance and dietary valine and isoleucine supplementation in modified corn-soybean meal diets with corn distillers dried grains with solubles on growth performance, carcass quality, intestinal health, and cecal microbiome in Cobb 500

One important feature of corn distillers dried grains with solubles (DDGS) is its high leucine:lysine ratio, which can inhibit chicken growth by causing branched-chain amino acid (BCAA) antagonism. The current study was conducted to investigate the effects of BCAA imbalance of inclusion of DDGS and whether additional dietary valine and isoleucine could alleviate the negative effects in broilers. A total of 640 0-d-old male Cobb 500 broilers were allocated into 4 treatments with 8 replicates and reared until d 42. The four different dietary groups were as follows: 1) control (CON) group (corn-soybean meal-based diet); 2) 30% DDGS (30D) group (replacing soybean meal with 30% DDGS); 3) 30D + additional valine and isoleucine (30DB) group; and 4) the group of 30DB + additional valine and isoleucine to provide the same leucine:valine and leucine:isoleucine ratios as the CON group (30DBB). The analyzed leucine:lysine ratios of the CON group were 1.36/1.41/1.46 (starter/grower/finisher phase), whereas the average leucine:lysine ratios of the 30% DDGS groups were 1.61/1.70/1.78 (starter/grower/finisher phase). The 30% DDGS groups (30D, 30DB, and 30DBB) negatively affected body weight (BW) from d 7 to 42 and BW gain (BWG), feed intake, carcass weight, breast muscle weight, and jejunal and ileal villus height:crypt depth during the overall period (d 0 to 42) (P < 0.05). Furthermore, the 30% DDGS groups significantly altered expression levels of jejunal tight junction proteins, breast muscle mechanistic target of rapamycin (mTOR) pathway-related genes, BCAA catabolism genes, and AA transporters compared to the CON (P < 0.01). The 30% DDGS groups showed differences in beta-diversity indices compared to the CON group (P < 0.05). The 30DBB group showing the lowest d 21 and 42 BW and overall BWG had the largest differences compared to the CON group in most measurements. In conclusion, excessive replacement of soybean meal with DDGS can significantly increase leucine levels, which may negatively affect chicken growth. Additionally, inappropriate ratios of valine and isoleucine can further decrease growth performance.

Hydrogen sulfide alleviates neural degeneration probably by reducing oxidative stress and aldose reductase expression.

We investigated the potential role of hydrogen sulfide (H2S) as a novel therapy for diabetic peripheral neuropathy in diabetic rats. A single dose of streptozotocin (60 mg/kg) was applied to the rats for the diabetic rat models. Sodium bisulfide (50 μmol/kg/d) was injected intraperitoneally daily for 2 weeks as H2S treatment. Electromyogram, haematoxylin eosin staining, transmission electron microscopy, western blotting and enzyme-linked immunosorbent assay were then performed. H2S treatment did not affect body weights, blood glucose levels or liver function of diabetic rats, while the creatine levels of the H2S-treated diabetic rats decreased compared with the diabetic control rats. H2S treatment for 2 weeks did not affect the sciatic nerve conduction velocity of the diabetic rats. However, H2S treatment relieved neurons loss and cell atrophy of dorsal root ganglion, and axon degeneration of sciatic nerve in diabetic rats. Serum super oxide dismutase (SOD) levels and SOD2 levels in the sciatic nerve of diabetic rats were lower than the non-diabetic rats but were restored after H2S treatment. Serum and sciatic nerve homogenate malondialdehyde and aldose reductase expression were higher in diabetic rats but decreased significantly after H2S treatment. Our study revealed that H2S alleviates neural degeneration in diabetic rats probably by reducing oxidative stress and downregulating aldose reductase expression.