Prolactin Signaling Pathway Research Articles

Effect of Rhei Radix Et Rhizome on treatment of polycystic ovary syndrome by regulating PI3K/AKT pathway and targeting EGFR/ALB in rats

Ethnopharmacological relevanceAbnormal endocrine metabolism caused by polycystic ovary syndrome (PCOS) poses a serious risk to reproductive health in females. According to Traditional Chinese Medicine (TCM) theories, the leading causes of PCOS include turbid phlegm, blood stasis and stagnation of liver Qi. Rhei Radix Et Rhizome is widely used in TCM to attack stagnation, clear damp heat, relieve fire. Rhei Radix Et Rhizome is an important part of the TCM formulas for the treatment of PCOS, which has a long history of medicinal use. However, the specific effect and mechanisms of Rhei Radix Et Rhizome on PCOS have yet to be elucidated. Aim of the studyThe object of this study aimed to investigate the effect and its pharmacological mechanism of Rhei Radix Et Rhizome on the treatment of polycystic ovary syndrome. MethodsPCOS was induced in female Sprague Dawley (SD) rats by administering letrozole (1 mg/kg, per orally, p.o.) for 21 days, then treated with Rhei Radix Et Rhizome at doses of 0.6 g/kg or 1.2 g/kg. Rats weight, blood glucose and estrus period are measured, and serum hormone include free testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and ovarian lesions were observed to determine the effects of Rhei Radix Et Rhizome. Network pharmacology and molecular docking predicted the targets of Rhei Radix Et Rhizome on PCOS. Epidermal growth factor receptor (EGFR), albumin (ALB), PI3K and P-AKT/AKT protein expression levels in ovarian tissues were assessed by Western blot. ResultsRhei Radix Et Rhizome reduce abnormal weight and fasting blood glucose induced by letrozole (n = 5, p < 0.01), and improve the disturbed estrus cycle, reduce T, LH levels and LH/FSH ratio of PCOS rats (n = 4, p < 0.01). In addition, it alleviates the polycystic changes of ovaries in PCOS rats and reduces ovarian histopathological damage (n = 4, p < 0.01). Additionally, the core active components of Rhei Radix Et Rhizome for PCOS include Sennoside D_qt, Procyanidin B-5,3′-O-gallate, and Mutatochrome, which strongly bind to core therapeutic targets ALB and EGFR. Furthermore, the treatment reduces the increase of EGFR and ALB induced by letrozole (n = 4, p < 0.01). KEGG pathway enrichment analysis highlights endocrine resistance and prolactin signaling pathway, in both of which the PI3K/AKT pathway plays a crucial role. Our results show Rhei Radix Et Rhizome rescue the abnormal expression of PI3K/AKT pathway in PCOS rats (n = 4, p < 0.01). However, no significant dose-dependent relationship was observed in the tested dose range for the above experiments. ConclusionThese findings suggest that Rhei Radix Et Rhizome can regulate the PI3K/AKT pathway and target EGFR and ALB to treat polycystic ovary syndrome in rats. This study provides a scientific basis for the use of Rhei Radix Et Rhizome in the treatment of PCOS and highlights its potential mechanism through modulation of the PI3K/AKT pathway.

Exploring the potential mechanisms of polysaccharides against gastric ulcer: Network pharmacology analysis and molecular docking validation

AbstractGastric ulcer is a common peptic ulcer that affects human health and life quality seriously. As anti‐gastric ulcer drugs usually cause side‐effects, polysaccharides may be the potential alternatives because of better effectiveness and less toxicity. Although the anti‐gastric ulcer activities of polysaccharides have been widely reported, the mechanisms have not yet been well‐disclosed. In this study, network pharmacology analysis was performed to explore the potential mechanisms of polysaccharides against gastric ulcer, and the results were validated by molecular docking. Results indicated that β‐glucan, arabinogalactan, xylan, and arabinan were the key structures, and ABL1, AKT1, androgen receptor, epidermal growth factor receptor, v‐Ha‐ras Harvey rat sarcoma viral oncogene homolog, HSP90AA1, mitogen‐activated protein kinase 8 (MAPK8), MAPK14, NOS2, PIK3R1, RAC1, ras homolog gene family member A, and proto‐oncogene tyrosine‐protein kinase Src were the core targets for polysaccharides in treating gastric ulcer. Polysaccharides have influences on 1958 GO items and 199 KEGG pathways, and their anti‐gastric ulcer activities are related to MAPK, Ras, PI3K‐Akt, vascular endothelial growth factor, prolactin, FoxO and Rap1 signaling pathways, etc. Molecular docking validation showed that the results of network pharmacology analysis were credible, and interactions between polysaccharide structures and core targets were observed. This study contributes to understanding the mechanisms of polysaccharides in treating gastric ulcer and provides references for future activity screening and mechanism research in anti‐gastric ulcer.

The molecular basis of hypoprolactinaemia.

Hypoprolactinaemia is an endocrinopathy which is typically encountered as part of a combined pituitary hormone deficiency picture. The vast majority of genetic causes identified to date have been in the context of congenital hypopituitarism with multiple co-existent endocrinopathies. This is primarily with its closest hormonal relation, namely growth hormone. Acquired hypoprolactinaemia is generally rare in paediatric patients, and usually occurs together with other hormonal deficiencies. Congenital hypopituitarism occurs with an incidence of 1:4,000-10,000 cases and mutations in the following transcription factors account for the majority of documented genetic causes: PROP-1, POU1F1, LHX3/4 as well as documented case reports for a smaller subset of transcription factors and other molecules implicated in lactotroph development and prolactin secretion. Isolated prolactin deficiency has been described in a number of sporadic case reports in the literature, but no cases of mutations in the gene have been described to date. A range of genetic polymorphisms affecting multiple components of the prolactin signalling pathway have been identified in the literature, ranging from RNA spliceosome mutations (RNPC3) to loss of function mutations in IGSF-1. As paediatricians gain a greater understanding of the long-term ramifications of hypoprolactinaemia in terms of metabolic syndrome, type 2 diabetes mellitus and impaired fertility, the expectation is that clinicians will measure prolactin more frequently over time. Ultimately, we will encounter further reports of hypoprolactinaemia-related clinical presentations with further genetic mutations, in turn leading to a greater insight into the molecular basis of hypoprolactinaemia in terms of signalling pathways and downstream mediators. In the interim, the greatest untapped reserve of genetic causes remains within the phenotypic spectrum of congenital hypopituitarism.

Network pharmacology combined with molecular docking and molecular dynamics to verify the therapeutic potential of mung beans (Vigna radiata) against prostate cancer

BackgroundProstate cancer is the most common oncological disease in men and one of leading causes of death worldwide. Growing evidence has demonstrated the effectiveness of mung bean bioactive compounds in suppressing various cancer cells. However, their effects and underlying mechanisms on prostate cancer have not been verified. The present study aimed to investigate the therapeutical effects and underlying mechanisms of mung bean compounds against prostate cancer.ResultsThe results revealed that 56 proteins related to prostate cancer could be modulated by mung bean, including several vital proteins of SRC (Sarcoma), Mitogen-Activated Protein Kinase 8 (MAPK8), Heat shock protein 90 kDa alpha member A1 (HSP90AA1), and Harvey Rat sarcoma virus (HRAS). It was also found that the potential pathways associated with prostate cancer pathogenesis comprising pyrimidine metabolism, nitrogen metabolism, and prolactin signaling pathways. Of 19 mung bean compounds docked to four key proteins reveal three promising compound (dulcinoside, peonidin-3-glucoside, and chlorogenic acid) with lower binding affinity score of − 7.7, − 12.2, − 9.0, and − 6.5 kcal/mol against SRC, MAPK8, HSP90AA1, and HRAS, respectively in their site of action. Dynamic simulation results also showed values of − 36.52 ± 2.93, − 35.93 ± 1.67, and − 35.77 ± 1.17 kJ/mol for Dulcinoside-SRC, Dulcinoside-MAPK8, and P3G-HSP90AA1 complexes, respectively. The binding of the compound occur in stable and flexible with the proteins. Moreover, all mung bean compounds predicted to have good ADMET properties.ConclusionsThe study concluded that dulcinoside, peonidin-3-glucoside, and chlorogenic acid potentially exhibited anticancer activity against prostate cancer in silico. Nevertheless, further studies such as in vitro and in vivo are needed to optimize and prove the efficacy of the mung brand and its compounds against prostate cancer.Graphical abstract

Identification of candidate genes and pathways involved in the establishment of sexual size dimorphism in the olive flounder (Paralichthys olivaceus) using RNA-seq

Olive flounder (Paralichthys olivaceus) is a valuable mariculture fish that shows female-biased sexual size dimorphism (SSD), yet the molecular mechanisms responsible for this phenomenon remain poorly understood. In this study, the growth differences between females and males were compared, and comparative transcriptome analyses of brains/pituitaries, livers, muscles, and gonads from 13-month-old females and males were performed. The critical time window for SSD was from 13- to 14-month-old, with females reaching significantly larger sizes than males. Muscle cell size and plasma growth hormone (GH), insulin-like growth factor 1 and 2 (IGF1, IGF2), 11-ketotestosterone (11-KT), and 17β-estradiol (E2) levels had no significant differences between the sexes of 13- and 14-month-old flounders. Furthermore, the RNA-seq data revealed differential expression in the genes encoding the receptors for these hormones, suggesting that regulation may occur at the receptor level, potentially leading to SSD during the critical window. RNA-seq analysis identified 88, 645, 414, and 15,833 differentially expressed genes between females and males in brains/pituitaries, livers, muscles, and gonads, respectively. KEGG (Kyoto Encyclopedia of Genes and Genomes) and GSEA-based KEGG analyses revealed that some pathways associated with growth and development, including “prolactin signaling pathway” in brains/pituitaries, “cell cycle”, “oocyte meiosis”, and “DNA replication” in livers, “focal adhesion”, “ECM-receptor interaction”, “protein digestion and absorption”, “arginine and proline metabolism”, and “cysteine and methionine metabolism” in muscles, and “Hippo signaling pathway” and “JAK-STAT signaling pathway” in gonads may be involved in the establishment of sexual growth differences. Notably, females had lower steroid hormone synthesis abilities than males in brains/pituitaries, livers, and gonads, indicating the importance of sex steroid hormones in the establishment of SSD. Moreover, genes including frizzled3 (fzd3) and prolactin (prl) in brains/pituitaries, and growth hormone receptor (ghr), estrogen receptor (esr1), insulin-like growth factor binding protein-3 (igfbp3), bone morphogenetic protein 8A-like (bmp8a), leptin receptor (lepr), and lipoprotein lipase-like (lpl) in livers emerge as potential candidates for the establishment of SSD. In conclusion, this study may help clarify the molecular mechanisms involved in SSD-related growth traits in flounder and provide basic data for genetic breeding of flounder.

Mechanisms of Selected Cassipourea Metabolites for Melasma Treatment: Network Pharmacology and Molecular Dynamics Study

Background Melasma is a common dyschromia, mainly found in women with darker skin types. Although asymptomatic, melasma significantly impacts patients’ quality of life. Due to this complex pathogenesis, melasma is difficult to treat. Plant and plant-derived products have been explored as alternatives for the treatment of melasma. Methods This study utilized network pharmacology coupled with molecular docking and molecular dynamics simulations to investigate the molecular mechanisms of three selected Cassipourea metabolites in the treatment of melasma. Results Of the 202 genes obtained from the 14 profiled metabolites, only PTGS2, TYR, ESR2, and ESR1 were common among metabolites and targets implicated in melasma. From this, The gene ontology highlighted the intracellular steroid hormone receptor, signalling pathway, macromolecular complex, and estrogen receptor activity as the top enriched functional annotations, while the KEGG pathway analysis identified five signalling pathways, from which the prolactin signalling pathway, endocrine resistance, and estrogen signalling pathway were implicated in the pathogenesis of melasma. These pathways were further connected by their linkage to ESR2 and ESR1., Of all Cassipourea metabolites and standards, with afzelechin having the highest docking score for both gens. Further binding interaction analysis showed that ESR2-bound tamoxifen had the highest binding free energy of -47.68 kcal/mol, however, among the interacting Cassipourea metabolites, sitosterol-glycoside exhibited the highest negative binding affinity for both ESR2 (-40.50 kcal/mol) and ESR1 (-78.97 kcal/mol) over 150 ns simulation, suggesting its potential as a dual modulator. Altogether, the metabolites presented remarkable binding stability and thermodynamic compactness with the apo-genes. Conclusion The finding that the selected Cassipourea metabolites are associated with the genes and enzymes implicated in melasma pathogenesis, together with their significant binding effects on the enriched genes, suggests their regulatory potential on the profiled targets and, consequently, in the treatment of melasma.

Dissection of potential anti-osteoporosis mechanism of isopsoralen - a quality control marker in Psoraleae Fructus - by metabolite profiling and network pharmacology.

Isopsoralen (ISO), a quality control marker (Q-marker) in Psoraleae Fructus, is proven to present an obvious anti-osteoporosis effect. Until now, the metabolism and anti-osteoporosis mechanisms of ISO have not been fully elucidated, greatly restricting its drug development. The metabolites of ISO in rats were profiled by using ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry. The potential anti-osteoporosis mechanism of ISO in vivo was predicted by using network pharmacology. A total of 15 metabolites were characterized in rats after ingestion of ISO (20 mg/kg/day, by gavage), including 2 in plasma, 12 in urine, 6 in feces, 1 in heart, 3 in liver, 1 in spleen, 1 in lung, 3 in kidney, and 2 in brain. The pharmacology network results showed that ISO and its metabolites could regulate AKT1, SRC, NFKB1, EGFR, MAPK3, etc., involved in the prolactin signaling pathway, ErbB signaling pathway, thyroid hormone pathway, and PI3K-Akt signaling pathway. This is the first time for revealing the in vivo metabolism features and potential anti-osteoporosis mechanism of ISO by metabolite profiling and network pharmacology, providing data for further verification of pharmacological mechanism.

Comprehensive analysis of the prognostic and immunological signature of TNFAIP8 family genes in human glioma

TNFAIP8 family molecules have been recognized for their involvement in the progression of tumors across a range of cancer types. Emerging experimental data suggests a role for certain TNFAIP8 family molecules in the development of glioma. Nonetheless, the comprehensive understanding of the genomic alterations, prognostic significance, and immunological profiles of TNFAIP8 family molecules in glioma remains incomplete. In the study, using the comprehensive bioinformatics tools, we explored the unique functions of 4 TNFAIP8 members including TNFAIP8, TNFAIP8L1, TNFAIP8L2 and TNFAIP8L3 in glioma. The expressions of TNFAIP8, TNFAIP8L1, TNFAIP8L2, and TNFAIP8L3 were notably upregulated in glioma tissues compared to normal tissues. Furthermore, survival analysis indicated that elevated expression levels of TNFAIP8, TNFAIP8L1 and TNFAIP8L2 were correlated with unfavorable outcomes in terms of overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) among glioma patients. Genetic modifications, such as mutations and copy number alterations, within the TNFAIP8 family exhibited a significant association with extended OS, DSS and PFS in individuals diagnosed with glioma. The findings suggest a noteworthy correlation between TNFAIP8 family members and the age and 1p/19q codeletion status of glioma patients. We also found that there were significant relationships between TNFAIP8 family expression and tumor immunity in glioma. Furthermore, functional annotation of TNFAIP8 family members and their co-expressed genes in gliomas was carried out using GO and KEGG pathway analysis. The GO analysis revealed that the primary biological processes influenced by the TNFAIP8 family co-expressed genes included cell chemotaxis, temperature homeostasis, and endocytic vesicle formation. Additionally, the KEGG analysis demonstrated that TNFAIP8 family co-expressed genes are involved in regulating various pathways such as inflammatory mediator regulation of TRP channels, pathways in cancer, prolactin signaling pathway, and Fc gamma R-mediated phagocytosis. Overall, the findings suggest that TNFAIP8 family members may play a significant role in the development of glioma and have the potential to serve as prognostic indicators and therapeutic targets for individuals with glioma.

Microbial and Metabolic Profiling of Obese and Lean Luchuan Pigs: Implications for Phenotypic Divergence.

Luchuan (LC) pigs are a Chinese breed renowned for their distinctive black and white coloring, superior meat quality and rapid reproduction, but their growth rate is slow. Over the course of approximately two decades of controlled breeding, the LC pigs maintained at the Shanghai Academy of Agricultural Sciences (Shanghai, China) have diverged into two phenotypes: one characterized by obesity (FLC) and the other by leanness (LLC). Recent studies indicate a correlation between microorganisms and the differentiation of host phenotypes. In this study, we examined the fecal microbiota profiles and serum metabolites of FLC and LLC pigs. The body weight, chest circumference, and alanine aminotransferase and aspartate aminotransferase enzyme activities were increased in the FLC pigs compared to the LLC pigs. Conversely, the levels of the Fusobacterium and Streptococcus genera were lower in the FLC pigs, while the number of Firmicutes, Lactobacillus, Phascolartobacterium, and Rikenellaceae_RC9_gut_group members were higher. A total of 52 metabolites were altered between the two groups, with many playing crucial roles in prolactin signaling, oocyte meiosis, and aldosterone-regulated sodium reabsorption pathways. The correlation analyses demonstrated a significant association between the modified microbiota and metabolites and the phenotypic variations observed in the LC pigs. Specifically, Jeotgalicoccus was positively correlated with the body weight and chest circumference, but was negatively correlated with metabolites such as 2-mercaptobenzothiazole and N1-pyrazin-2-yl-4-chlorobenzamide, which were positively associated with Bacteroides. These results provide compelling evidence for a novel relationship between the gut microbiome and metabolome in the phenotypic differentiation of LC pigs.

The potential role of hippo pathway effector yap1/yap1b in female-biased sexual size dimorphism of Chinese tongue sole (Cynoglossus semilaevis)

One fundamental question in biology is how animals control their proper body size. Hippo signaling pathway has emerged as an evolutionarily conserved network to regulate organ size from Drosophila to mammals. Interestingly, our previous study has also implied the roles of hippo signaling in Chinese tongue sole (Cynoglossus semilaevis), a flatfish exhibiting female-biased sexual size dimorphism (SSD). Specifically, two yes-associated protein 1 (yap1) homologs, key effectors within hippo signaling, exhibited the opposite expression pattern in the female and male gonads of C. semilaevis. Whether and how these two yap1 genes participate in female-biased SSD is unknown. In the present study, phylogenetic tree analysis firstly designated these two yap1 genes as yap1 and yap1b, with no taz gene available in C. semilaevis. Subsequent quantitative PCR analysis demonstrated that yap1 exhibited the highest expression levels within the male gonad at three-month-old, while the predominant expression of yap1b was detected in the female gonad at two-year-old. The co-localization of yap1 and yap1b was observed in the cytoplasm of oocyte and sperm. Cebpα, a negative regulator for dmrt1, exhibited positive and negative regulation on the yap1 and yap1b, respectively. Myog, a crucial transcription factor for myogenesis, specifically binded and activated yap1b promoter, not yap1. Furthermore, DAP-seq revealed the regulatory networks of yap1 and yap1b in C. semilaevis. Importantly, many growth and reproduction-related pathways, including the JAK-STAT signaling pathway, prolactin signaling pathway, axonal regeneration, and steroid hormone synthesis, were included in the common peaks of yap1 and yap1b. Moreover, the application of verteporfin reagents into testis and ovary cells resulted in a decrease in yap1 and yap1b levels. Consequently, the expression of growth hormone receptor (ghr), growth hormone actin α (smtla), estrogen receptor (esr2b), and 17β-hydroxysteroid dehydrogenase type 7 (hsd17b7), were also affected. In addition, the administration of verteporfin on C. semilaevis caused a significant reduction in growth rate. These findings provided insights into the role of the hippo signaling pathway in regulating SSD of C. semilaevis.

The role of transcription factor FOXA1/C2/M1/O3/P1/Q1 in breast cancer.

Breast cancer is a common malignancy with the highest mortality rate among women worldwide. Its incidence is on the rise year after year, accounting for more than one-tenth of new cancers worldwide. Increasing evidence suggests that forkhead box (FOX) transcription factors play an important role in the occurrence and development of breast cancer. However, little is known about the relationship between the expression, prognostic value, function, and immune infiltration of FOX transcription factors in tumor microenvironment. We used bioinformatics to investigate expression and function of FOX factor in breast cancer. Our results revealed the expression levels of FOXA1 and FOXM1 were significantly higher in breast cancer tissues than in normal tissues. The high expression of mRNA in FOXA1 (P < .05), FOXM1 (P < .01), and FOXP1 (P < .05) groups was related to tumor stage. Survival analysis results showed that increased FOXP1 mRNA levels were significantly associated with overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) in all patients with breast cancer (P < .05). Patients with the FOXA1 high-expression group had better RFS and DMFS than the low-expression group (P < .05), while patients with FOXM1 high-expression group had worse RFS, OS, and DMFS than the low-expression group (P < .05). Meanwhile, mutation analysis showed that genetic alterations in FOX transcription factors were significantly associated with shorter OS and progression-free survival (P < .05), but not with disease-free survival (P = .710) in patients with breast cancer. FOXP1, FOXA1, and FOXM1 may be used as potential biomarkers to predict the prognosis of patients with breast cancer. Functional enrichment indicated that FOX was mainly involved in cell division, cell senescence, cell cycle, and prolactin signaling pathway. In patients with breast cancer, FOXC2 expression was negatively correlated with the infiltration of B cells and positively correlated with the infiltration of neutrophils and dendritic cells. However, FOXM1 was negatively correlated with the infiltration of CD8 + T cells and macrophages and positively correlated with the infiltration of neutrophils and dendritic cells. These findings provided novel insights into the screening of prognostic biomarkers of the FOX family in breast cancer and laid a foundation for further research on the immune infiltration of the FOX transcription factor family members in tumors.

Rectal microbiomes and serum metabolomics reveal the improved effect of Artemisia ordosica crude polysaccharides on the lactation performance, antioxidant status, and immune responses of lactating donkeys

This study is aimed at investigating the effects of dietary supplementation with Artemisia ordosica crude polysaccharides (AOCP) on lactation performance, antioxidant status, and immune status of lactating donkeys and analyzing rectal microbiomes and serum metabolomes. Fourteen lactating Dezhou donkeys with similar age (6.16 ± 0.67 yr of BW ± SD), weight (250.06 ± 25.18 kg), DIM (39.11 ± 7.42 d), and average parity of 3 were randomly allocated into 2 treatments: a control group (CON, basal diet) and an AOCP group (AOCP, basal diet with 1.0 g/kg DM AOCP). Ten weeks were allotted for the experiment, 2 wk for adaptation, and 8 wk for collecting data and samples. The results showed that supplementation of donkey diets with AOCP increased lactation performance, including DMI, milking yield, estimated milk yield, solids-corrected milk, ECM, milk fat yield, milk protein yield, milk lactose yield, milk TS yield, and milk SNF yield. The digestibility of DM, CP, ADF, and NDF was increased in the AOCP group compared with the CON group. The AOCP group increased the concentrations of IgA, IgG, and IgM, the activities of the superoxide dismutase, catalase, and total antioxidant capacity in the serum. Artemisia ordosica crude polysaccharides decreased the concentrations of tumor necrosis factor-α, nitric oxide, reactive oxygen species, and malondialdehyde in the serum. Compared with the CON group, AOCP increased propionate, butyrate, isovalerate, and total VFA concentrations in rectal feces (P < 0.05). The addition of AOCP to increased diversity (Shannon index) and altered structure of the rectal microflora. As a result of AOCP supplementation, there has been a significant improvement in the colonization of beneficial bacteria, including Lactobacillus, Unclassified_f_Prevotellacea, Ruminococcus, and Fibrobacter genera. In contrast, a decrease in the colonization of the Clostridium_sensu_stricto_1 bacterial genus and other pathogenic bacteria was observed. Meanwhile, metabolomics analysis found that AOCP supplementation upregulated metabolites l-tyrosine content while downregulating 9(S)-HODE, choline, sucrose, lysophosphatidylcholine (LysoPC) (18:0), LysoPC (18:1(9Z)), and LysoPC (20:2(11Z,14Z)) concentrations. These altered metabolites were involved in the PPAR signaling pathway, prolactin signaling pathway, glycerophospholipid metabolism, carbohydrate digestion and absorption, and tyrosine metabolism pathways, which were mainly related to antioxidant capacity, immune responses, and protein metabolism in the lactating donkeys. As a consequence of feeding AOCP diets, beneficial bacteria were abundant, and antioxidant and protein metabolism-related pathways were enriched, which may enhance lactation performance in donkeys. Therefore, supplementing AOCP diets is a desirable dietary strategy to improve donkey health and lactation performance.

Characterization and Comparative Analysis of Whole-Transcriptome Sequencing in High- and Low-Fecundity Chongming White Goat Ovaries during the Estrus Phase.

Reproductive performance is one of the most important economic traits in the goat industry. Increasing the number of goats is an effective measure to improve production efficiency and reduce production costs. Ovaries are important reproductive organs in female mammals that directly affect the estrous cycle and reproductive abilities. Understanding the complex transcription network of non-coding RNAs (lncRNAs, circRNAs, and miRNAs) and messenger RNA (mRNA) could lead to significant insights into the ovarian regulation of the reproductive processes of animals. However, the whole-transcriptome analysis of the non-coding RNAs and mRNA of the ovaries in Chongming white goats between high-fecundity (HP) and low-fecundity (LP) groups is limited. In this study, a whole-transcriptome sequencing approach was used to identify lncRNA, circRNA, miRNA, and mRNA expression in the ovaries of Chongming white goats during the estrus phase using RNA-Seq technology. More than 20,000 messenger RNAs (mRNAs), 10,000 long non-coding RNAs (lncRNAs), 3500 circular RNAs (circRNAs), and 1000 micro RNAs (miRNAs) were identified. A total of 1024 differential transcripts (724 mRNAs, 112 lncRNAs, 178 circRNAs, and 10 miRNAs) existing between the HP and the LP groups were revealed through a bioinformatics analysis. They were enriched in the prolactin signaling pathway, the Jak-STAT signaling pathway, and the GnRH signaling pathway, as well as various metabolic pathways. Differentially expressed mRNAs (such as LYPD6, VEGFA, NOS3, TNXB, and EPHA2) and miRNAs (such as miR-10a-5p) play key roles in the regulation of goat ovaries during the estrus phase. The enrichment of pathways related to reproduction, such as the Hippo, Hedgehog, PI3K-AKT, and MAPK signaling pathways, suggests that they might be involved in the prolificacy of goat ovaries. Overall, we identified several gene modules associated with goat fecundity and provided a basis for a molecular mechanism in the ovaries of Chongming white goats.

Alcohol extract of Rubia yunnanensis: Metabolic alterations and preventive effects against OGD/R‑induced oxidative damage in HT22 cells.

The present study investigated the inhibitory and neuroprotective effects of Rubia yunnanensis alcohol extract (RY-A) on oxidative stress induced by oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 cells. In vitro cultured HT22 cells were randomly divided into control, OGD/R, OGD/R + 100 µmol/l edaravone and OGD/R + 10, 20 and 40 µg/ml RY-A groups. Oxygen-sugar deprivation was performed with 10 mmol/l sodium dithionite combined with sugar-free DMEM medium for 2 h, followed by re-glycolization and reoxygenation for 2 h to establish an in vitro OGD/R model. Cell morphology was observed under a phase contrast microscope. Cell survival rate was detected by thiazolyl blue and lactate dehydrogenase and oxidative stress-related indexes were detected by commercial kits. The effects and metabolic alterations of RY-A treatment after OGD/R were evaluated using ultra-high performance liquid chromatography and mass spectrometry. Protein levels were further examined by western blotting. The results showed that cells in the OGD/R group were swollen and lacked protrusions, had significantly reduced viability and had significantly elevated oxidative stress-related indexes of reactive oxygen species, nitric oxide levels and malondialdehyde content and significantly reduced activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase, compared with controls. Compared with the OGD/R group, the RY-A group had significantly improved cell morphology and significantly increased cell viability and in terms of oxidative stress, exhibited significantly reduced reactive oxygen species, nitric oxide levels and malondialdehyde content, as well as significantly increased superoxide dismutase and glutathione peroxidase activities. Metabolomic analysis identified changes in 20 metabolites, including L-tryptophan, ornithine, eicosapentaenoic acid-d5, isosafrole and xanthine. Metabolomics analysis showed that the pathways affected included those related to phenylalanine, tyrosine and tryptophan biosynthesis, the prolactin signaling pathway and amphetamine addiction. These results suggested that RY-A had significant preventive effects on an in vitro model of cerebral ischemia-reperfusion injury simulated by OGD/R and the mechanism may be related to increased tryptophan content, activation of indoleamine 2,3-dioxygenase enzymes and inhibition of oxidative stress.

Comparative Analysis of the Ovary Transcriptome among Wanyue Black and Yorkshire Gilts Using RNA-Seq.

Pubertal genetic variations between the indigenous Chinese Wanyue Black pig breed and the imported Yorkshire breed significantly impact their reproductive capacity. In order to identify the differentially expressed genes, gene networks, and metabolic pathways in ovary transcriptome of gilts, the serum hormone levels were analyzed by ELISA, and RNA-seq was performed to analyze ovarian genes. Our results reveal higher estradiol (E2) levels in Wanyue black gilts compared to Yorkshire gilts, while Yorkshire gilts exhibit elevated progesterone (P4) and GnRH levels. We identified a total of 154 differentially expressed genes (DEGs), with 87 up-regulated and 67 down-regulated genes in the Wanyue black gilts ovaries compared to the Yorkshire gilts. GO enrichment analysis unveiled the participation of DEGs in processes such as "Reproduction", "Reproductive system development", and "Ovarian follicle development". Moreover, KEGG enrichment analysis revealed the involvement of DEGs in multiple signaling pathways associated with hormone biosynthesis and puberty, encompassing "Steroid hormone biosynthesis", "Estrogen signaling pathway", and "Prolactin signaling pathway". The subsequent bioinformatics analysis identified nine functional genes that potentially contribute to the disparity in ovaries between Wanyue black gilts and Yorkshire gilts. This study offers significant insights into the endocrine and genetic aspects of pubertal development in gilts.

Current Insights in Prolactin Signaling and Ovulatory Function.

Prolactin (PRL) is a pleiotropic hormone released from lactotrophic cells of the anterior pituitary gland that also originates from extrapituitary sources and plays an important role in regulating lactation in mammals, as well as other actions. Acting in an endocrine and paracrine/autocrine manner, PRL regulates the hypothalamic-pituitary-ovarian axis, thus influencing the maturation of ovarian follicles and ovulation. This review provides a detailed discussion of the current knowledge on the role of PRL in the context of ovulation and ovulatory disorders, particularly with regard to hyperprolactinemia, which is one of the most common causes of infertility in women. Much attention has been given to the PRL structure and the PRL receptor (PRLR), as well as the diverse functions of PRLR signaling under normal and pathological conditions. The hormonal regulation of the menstrual cycle in connection with folliculogenesis and ovulation, as well as the current classifications of ovulation disorders, are also described. Finally, the state of knowledge regarding the importance of TIDA (tuberoinfundibular dopamine), KNDγ (kisspeptin/neurokinin B/dynorphin), and GnRH (gonadotropin-releasing hormone) neurons in PRL- and kisspeptin (KP)-dependent regulation of the hypothalamic-pituitary-gonadal (HPG) axis in women is reviewed. Based on this review, a rationale for influencing PRL signaling pathways in therapeutic activities accompanying ovulation disorders is presented.

Advancing breastfeeding promotion: leveraging integrative natural galactagogues and unveiling their potential roles-Insights from a 19-year Taiwan nationwide registry to address lactation insufficiency in postpartum women.

Lactation insufficiency is a prevalent challenge for nursing mothers globally. There is a growing interest in the use of herbal galactagogues for enhancing lactation, but their therapeutic efficacy and underlying mechanisms need thorough investigation. This study aims to investigate the efficacy and mechanisms of action of herbal galactagogues in addressing lactation insufficiency by utilizing real-world data and employing a network analysis approach. Our retrospective study used Taiwan's Longitudinal Health Insurance Database 2000 (LHID2000) to identify 490 patients diagnosed with lactation insufficiency from 2000 to 2018. We analyzed demographic characteristics, co-existing diseases, and prescription patterns for both users and non-users of Chinese herbal products (CHP). Additionally, we utilized a network analysis approach to explore potential compounds and targets in the most frequently used CHP, the Wang Bu Liu Xing and Lu Lu Tong herb pair (WLHP) combination. Out of 490 patients, 81% were CHP users. There were no significant differences in demographic characteristics between CHP users and non-users, but we observed a notable divergence in the prevalence of co-existing diseases. A detailed examination of CHP prescriptions revealed the predominance of WLHP, prompting further investigation. Comprehensive analysis identified 29 major compounds in WLHP, which were associated with 215 unique targets. Intersection analysis revealed 101 overlapping targets between WLHP and lactation, suggesting their potential as therapeutic targets for lactation insufficiency treatment. Topological analysis of the protein-protein interaction (PPI) network identified 13 hub genes potentially crucial for the therapeutic effect of WLHP. Functional enrichment analysis showed that these targets were involved in critical lactation regulation pathways, including the PI3K-Akt signaling pathway, prolactin signaling pathway, estrogen signaling pathway, and AMPK signaling pathway. This study emphasizes the potential of CHP, specifically the WLHP combination, in managing lactation insufficiency. The multi-compound, multi-target approach of WLHP and its interaction with key biological processes and signaling pathways offer valuable insights into the underlying mechanisms of its therapeutic effects. These findings warrant further experimental validation and can guide future research and clinical applications of CHP in lactation insufficiency treatment.

The Dynamics of Bioactive Ingredients With Anti-Inflammatory and Anti-Breast Cancer Activity During Prunellae Spica Development

To investigate the scientific connotation of harvest period for Prunella vulgaris L. ( P vulgaris, known as Prunellae Spica), the triterpenoids and phenols of Prunellae Spica in developmental stages were quantified by high performance liquid chromatography, and the anti-inflammatory and anti-breast cancer properties of which were investigated. Furthermore, Grey correlation and Pearson correlation analysis were used to screen the anti-inflammatory and anti-breast cancer–related effective ingredients, and a multidimensional network of “ingredient-target-pathway” through network pharmacology was constructed. The results showed that the harvest time of Prunellae Spica was closely related to its chemical composition and pharmacological activity. Phenols, such as salvianic acid A, caffeic acid, and salviaflaside, mainly accumulated in late development, while rosmarinic acid showed the opposite. Triterpenes, such as oleanolic acid and ursolic acid, mainly accumulated in early development, while betulinic acid accumulated during ripening. The anti-breast cancer activity of Prunellae Spica in early development was stronger than that in the later, but the anti-inflammatory activity in late development was stronger than that in the early stage. Significantly associated with anti-inflammatory activity in Prunellae Spica was salviaflaside, which may regulate TNF and NOD-like receptor signaling pathways by acting on targets such as CASP7, CASP8, CASP3, NOD2, and CASP1. Significantly associated with anti-breast cancer activity were oleanolic acid and ursolic acid, which may regulate Ovarian steroidogenesis and Prolactin signaling pathways on targets such as PTGS2, CYP19A1, ESR2, CYP17A1, and MAPK3. These results suggest that P vulgaris could be harvested before ripening for its anti-breast cancer use, and after ripening for its anti-inflammatory use.

Revealing the Antiperspirant Components of Floating Wheat and Their Mechanisms of Action through Metabolomics and Network Pharmacology.

Floating wheat is a classical herbal with potential efficacy in the treatment of hyperhidrosis. Aiming at revealing the main components and potential mechanisms of floating wheat, a comprehensive and unique phytopharmacology profile study was carried out. First, common wheat was used as a control to look for chemical markers of floating wheat. In the screening analysis, a total of 180 shared compounds were characterized in common wheat and floating wheat, respectively. The results showed that floating wheat and common wheat contain similar types of compounds. In addition, in non-targeted metabolomic analysis, when taking the contents of the constituents into account, it was found that there indeed existed quite a difference between floating wheat and common wheat and 17 potential biomarkers for floating wheat. Meanwhile, a total of seven components targeted for hyperhidrosis were screened out based on network pharmacology. Seven key differential components were screened, among which kaempferol, asiatic acid, sclareol, enoxolone, and secoisolariciresinol had higher degree values than the others. The analysis of interacting genes revealed three key genes, namely, MAP2K1, ESR1, and ESR2. The Kyoto Encyclopaedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses showed that various signaling pathways were involved. Prolactin signaling, thyroid cancer, endocrine resistance, gonadotropin secretion, and estrogen signaling pathways were the main pathways of the intervention of floating wheat in excessive sweating, which was associated with the estrogenic response, hormone receptor binding, androgen metabolism, apoptosis, cancer, and many other biological processes. Molecular docking showed that the screened key components could form good bindings with the target proteins through intermolecular forces. This study reveals the active ingredients and potential molecular mechanism of floating wheat in the treatment of hyperhidrosis and provides a reference for subsequent basic research.

Causal relationship between multiple sclerosis and cortical structure: a Mendelian randomization study

BackgroundObservational studies have suggested an association between multiple sclerosis (MS) and cortical structure, but the results have been inconsistent.ObjectiveWe used two-sample Mendelian randomization (MR) to assess the causal relationship between MS and cortical structure.MethodsMS data as the exposure trait, including 14,498 cases and 24,091 controls, were obtained from the International Multiple Sclerosis Genetics Consortium. Genome-wide association study (GWAS) data for cortical surface area (SAw/nw) and thickness (THw/nw) in 51,665 individuals of European ancestry were obtained from the ENIGMA Consortium. The inverse-variance weighted (IVW) method was used as the primary analysis for MR. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. Enrichment analysis was performed on MR analyses filtered by sensitivity analysis.ResultsAfter IVW and sensitivity analysis filtering, only six surviving MR results provided suggestive evidence supporting a causal relationship between MS and cortical structure, including lingual SAw (p = .0342, beta (se) = 5.7127 (2.6969)), parahippocampal SAw (p = .0224, beta (se) = 1.5577 (0.6822)), rostral middle frontal SAw (p = .0154, beta (se) = − 9.0301 (3.7281)), cuneus THw (p = .0418, beta (se) = − 0.0020 (0.0010)), lateral orbitofrontal THw (p = .0281, beta (se) = 0.0025 (0.0010)), and lateral orbitofrontal THnw (p = .0417, beta (se) = 0.0029 (0.0014)). Enrichment analysis suggested that leukocyte cell-related pathways, JAK-STAT signaling pathway, NF-kappa B signaling pathway, cytokine-cytokine receptor interaction, and prolactin signaling pathway may be involved in the effect of MS on cortical morphology.ConclusionOur results provide evidence supporting a causal relationship between MS and cortical structure. Enrichment analysis suggests that the pathways mediating brain morphology abnormalities in MS patients are mainly related to immune and inflammation-driven pathways.