Androgenetic alopecia (AGA) is the most common form of progressive hair loss, marked by a multifaceted pathogenesis and a lack of effective pharmacological treatments to arrest its progression. Flavonoids have drawn considerable research attention for their potential in fostering hair regeneration, yet kaempferol (Kae), a well-researched flavone, remains unexplored as a therapeutic agent for AGA. This study delves into the mechanisms and efficacy of Kae in AGA treatment, employing a blend of in vivo and in vitro experiments, complemented by transcriptome sequencing and molecular docking techniques. In vitro, Kae exhibited no significant toxicity to dermal papilla cells (DPCs); instead, it enhanced DPCs proliferation and migration in a dose-dependent manner, and significantly mitigated dihydrotestosterone (DHT)-induced cellular damage. Transcriptomic analysis and RT-qPCR indicated that Kae modulates the Wnt/β-catenin signaling pathway. Molecular docking studies indicated that Kae has binding potential to β-catenin and Cyclin D1, pivotal proteins within this pathway. Subsequent immunofluorescence experiments and Western blot confirmed Kae's ability to promote β-catenin nuclear translocation and inhibit DHT-induced downregulation of β-catenin and Cyclin D1. In vivo, oral Kae administration substantially promoted hair regeneration in an AGA mouse model, with efficacy on par with oral finasteride. In conclusion, this study presents robust evidence that Kae effectively stimulates hair growth by bolstering DPCs function and counteracting DHT-induced damage, thus holding promising therapeutic potential for AGA sufferers.

The mammary gland undergoes continuous growth, differentiation, and cyclical remodeling throughout the whole life, with morphogenesis from the embryonic stage to adulthood being crucial and highly sensitive to nutritional supply. While moderate nutritional restriction in early life and subsequent restore can promote the tissues development such as muscle, its effects on the mammary remain largely unexplored and appear to depend critically on the development stage. Thus, the effects of moderated nutritional restriction in early life including embryonic (ER), suckling (SR), or pubertal (PR) periods on mammary development and subsequent lactation performance in mice were investigated in the present study. In this study, we imposed nutritional restriction on mice during either a single period or two periods. Mammary gland and serum samples were collected at maturity (56 days) and on lactation day 15 for hormonal, histological, and transcriptomic analyses. Our results demonstrate that ER enhances mammary development and adult lactation capacity by boosting proliferative activity and increasing the mammary stem cell content. In contrast, postnatal nutritional restrictions (SR and PR) disrupt normal gland morphogenesis by attenuating hormonal signaling responses and reducing stromal tissue remodeling. Notably, the adverse effects of SR on mammary morphology are reversible upon nutritional repletion, with no subsequent impact on milk production, whereas PR leads to a significant impairment in adult lactation. These findings reveal distinct regulatory mechanisms of nutritional intervention at various development stages and provide a foundational basis for optimizing lactational outcomes through targeted nutritional strategies.

Intestinal microorganisms affect the pathogenesis of Parkinson's disease (PD) and, therefore, are a new research focus of PD treatment. Type 3 resistant starch from Canna edulis (Ce-RS3) regulates gut microbes and has prebiotic properties. The effects include decreased blood lipids, weight, and inflammation, as well as increased glycolipid metabolism. There are few reports on the use of prebiotics alone in the treatment of Parkinson's. In this study, based on the gut-brain axis, the pharmacological effects and related mechanisms of Ce-RS3 on PD were studied by analyzing intestinal bacteria and brain transcriptomics. Ce-RS3 improved motor function in PD model rats over a defined period and repaired PD-induced inflammation-related organ and neural damage. In addition, Ce-RS3 increased the number of short-chain fatty acid-producing, and other beneficial, bacteria. Transcriptomics showed that Ce-RS3 decreased inflammatory gene expression, upregulated the expression of the protein homeostasis-related gene Hspb1 and downregulated the expression levels of the protein aggregation-related genes Hdac6 and Ubd. Therefore, we hypothesized that Ce-RS3 plays a role in the treatment of PD by regulating the α-synuclein-related pathway through the brain-gut axis and protecting the neural tissues. This study provides a new intervention plan for the prevention and treatment of PD.

Astaxanthin, a natural carotenoid predominantly synthesized by marine microorganisms, has shown promise in attenuating inflammatory diseases, yet its role in colitis remains unclear. Here, we evaluated the therapeutic effects of astaxanthin in dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. Our findings revealed that astaxanthin significantly ameliorated colitis symptoms, notably at the dose of 100 mg/kg, demonstrated by reduced Disease Activity Index (DAI), increased colon length, diminished colon histopathological damage, and enhanced goblet cell population. Mechanistically, astaxanthin decreased proinflammatory cytokines and malondialdehyde (MDA) levels, suppressed Keap1 expression, activated phosphorylated Nuclear factor erythroid 2-related factor 2 (Nrf2), and increased downstream protein expression of HO-1 and GPX4, ultimately inhibiting ferroptosis. Although astaxanthin altered gut microbiota composition, antibiotic treatment and fecal microbiota transplantation confirmed that its anti-colitis effects were independent of microbiota changes. These findings suggest that astaxanthin alleviates colitis associated with Nrf2 pathway mediated ferroptosis, rather than through gut microbiota modulation.

Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease characterized by aberrant epithelial-mesenchymal transition (EMT) and extracellular matrix deposition. Dietary fiber, fermented by gut microbiota into butyrate, exerts anti-fibrotic effects, yet the underlying mechanisms are not fully elucidated. YBX1 plays a crucial role in the regulation of fibrosis and EMT. However, its function in PF remains unclear. This study aims to investigate the role of dietary fiber in PF and whether YBX1 mediates the anti-fibrotic effect of butyrate in PF. The roles of the high fiber (HF) diet and butyrate in PF and the changes in butyrate content were evaluated using RT-qPCR, Western blotting, immunofluorescence (IF) and GC-MS. RNA sequencing was used to analyze the downstream action sites of butyrate. The function of YBX1 in PF was elucidated through overexpression of YBX1, RNA sequencing, and KEGG pathway analysis. The interaction between YBX1 and butyrate was examined using ubiquitination and CHX assays. The results showed that the HF diet increased butyrate levels, thereby ameliorating PF by inhibiting EMT. The expression of YBX1 was downregulated in PF and overexpression of YBX1 inhibited EMT by regulating CYP1A1 / NF-κB signaling pathway, thereby improving the progression of PF. Butyrate upregulated YBX1 protein expression by reducing its ubiquitination. This work provides new insights and promising strategies for the prevention and treatment of PF through dietary interventions.

Spermidine (SPD), a microbiota‑derived polyamine, exerts potent anti‑inflammatory effects in colitis. This study investigated how SPD mitigates dextran sulfate sodium (DSS)-induced ferroptosis and explored the association between gut microbiota composition and polyamine metabolites in patients with ulcerative colitis (UC). DSS‑induced UC models were established in mice and HT‑29 cells, followed by SPD treatment. RNA sequencing was used to profile transcriptomic changes in HT‑29 cells, and the effects of SPD on NCOA4 and Ferritin were evaluated both in vivo and in vitro. NCOA4 silencing was performed to clarify its role in SPD‑mediated protection against ferroptosis. Fecal polyamines and gut microbiota profiles from UC patients and healthy controls were analyzed using UHPLC‑MS/MS and 16S rRNA sequencing. SPD significantly alleviated DSS‑induced colitis. Gene set enrichment analysis (GSEA) of differentially expressed genes in HT‑29 cells highlighted iron‑metabolism pathways as prominently affected. SPD mitigated DSS‑induced ferroptosis in vitro and in vivo, likely by limiting NCOA4‑dependent ferritin turnover and maintaining iron balance. In UC patients, disturbances in fecal polyamine levels corresponded closely with shifts in gut microbial composition, with 27 genera showing significant correlations with polyamine metabolites. Together, these findings position SPD as a modulator of ferroptosis via the NCOA4-ferritin axis and point to a potential therapeutic avenue. In UC, disrupted polyamine metabolites are closely linked to microbial alterations, implicating microbe-polyamine interactions in disease pathogenesis.

Acute pancreatitis (AP) is a self-limiting inflammatory disorder, but severe cases can lead to persistent organ failure with high mortality. Metabolic dysregulation and inflammatory activation play critical roles in AP pathogenesis, highlighting the metabolic-inflammation crosstalk as a potential therapeutic target. Although riboflavin, an essential water-soluble vitamin, has been implicated in modulating disease processes, its role in AP remains unclear. In this study, untargeted metabolomics identified significant riboflavin downregulation in an AP mouse model. Subsequent in vivo experiments demonstrated that riboflavin intervention (25, 50, and 100 mg/kg) ameliorated pancreatic injury and systemic inflammation, with 50 mg/kg exhibiting optimal efficacy. Targeted metabolomics revealed elevated acetate levels following riboflavin supplementation. At the same time, transcriptomic and molecular biology assays showed riboflavin-mediated downregulation of HDAC3, a key acetate downstream target, and suppression of NF-κB pathway activation. In vitro, riboflavin and acetate mitigated pancreatic acinar cell damage, including apoptosis and necrosis, and inhibited NF-κB signaling. Rescue experiments using the HDAC3 inhibitor RGFP966 further provided pharmacological evidence for a mechanistic link between the acetate-HDAC3 axis and riboflavin's protective effects. Collectively, these findings reveal that riboflavin alleviates AP, and its effect is associated with the modulation of the acetate-HDAC3 axis, offering a novel therapeutic strategy for this condition.

Nucleotides play a crucial role in the growth and development of infants. Studying the dynamics of nucleotides variation in human milk and the influencing factors can provide insights to guide the diets of lactating mothers.

Vitamin D deficiency (VDD) is a pressing global health concern, with pregnant women being identified as a high-risk population for VDD. Our previous study demonstrated that maternal VDD diet impaired placental development. Here, we aimed to investigate the effects of maternal VDD diet during pregnancy on offspring's spatial learning and memory ability. Our results showed that maternal VDD diet resulted in a decreased vitamin D levels in dams and their offspring, reduced offspring's body length and body weight, delayed offspring's nerve reflex behavior and impaired offspring's spatial learning and memory ability in Y maze and Morris water maze tests. Moreover, maternal VDD diet caused offspring's neuronal damage and loss, decreased the expressions of neurotrophic factors. While, maternal vitamin D supplementation during pregnancy has positive improvement on the above indexes, and with the most obvious in first trimester supplement group. Moreover, proteomic analysis of the offspring's hippocampal tissues was conducted to explore relative molecular mechanisms. Results showed that maternal VDD diet overactivated CaMKK2/AMPK/FoxO3a signaling pathway. While, CaMKK2 inhibitor STO-609 attenuated VDD-induced neuronal apoptosis and necrosis in vitro. Consistantly, maternal vitamin D supplementation during pregnancy also inhibited the overactivation of CaMKK2/AMPK/FoxO3a pathway. In conclusion, the present study provided novel insights into the mechanisms of maternal VDD on offspring's spatial learning and memory ability.

Iron overload is a common phenomenon in patients undergoing transfusions or organ transplantation. Clinical studies indicate that iron overload interferes with immune function. Baseless supplementation of iron leads to higher morbidity and mortality. In iron overload T-cell differentiation is skewed towards a Th2 response, with lower levels of interferon (IFN)-γ. Zinc is known for its immune balancing abilities, e.g. by induction of regulatory T cells. This study aims to investigate the interaction of iron and zinc in mixed lymphocyte cultures (MLC).

The gut-brain axis represents a complex bidirectional communication network connecting the central nervous and gastrointestinal systems. Fermented foods and their phenolic compounds, which increase their bioavailability due to microbial transformation in their contents, have the potential to affect the gut microbiota and therefore the gut-brain axis positively. Fermented foods such as kefir, yogurt, miso, natto, tempeh, kombucha, and their polyphenols have an effect on the gut microbiota and on the provision of neurological activities through neuroactive components that affect the nervous system. Phenolic compounds appear to have direct or indirect effects on brain tissue through various mechanisms such as reducing neuronal oxidative stress, suppressing microglial activation, supporting synaptic plasticity, and slowing down neurodegenerative processes such as Alzheimer's and Parkinson's. In addition, the polyphenol content enriched in fermented foods has been shown to exhibit psychobiotic effects in depression and anxiety models; It has been shown in clinical studies that it improves systemic inflammation and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. Current data support the inclusion of fermented, polyphenol-rich foods as a noninvasive strategy to enhance neuroprotection and mental health. However, enhanced clinical studies are needed where heterogeneity in the fermentation process and dosage adjustment are standardized. This article reviews the current literature on the effects of fermented foods and polyphenols on brain health via the microbiota and gut-brain axis.

Obesity and type 2 diabetes (T2D) are among the most common metabolic diseases that are associated with increased risk of noncommunicable diseases globally. Elenolic acid (EA), derived from olives, was shown to possess potent acute effects on obesity and diabetes that were associated with increased gut hormone secretion. Here, we investigate the longer-term effects of EA in two mouse models of obesity and diabetes. In diet-induced obese mice, oral administration of EA (50 mg/kg/day) for 7 weeks, normalized fasting blood glucose (from 176.6± 4.5 mg/dl to 120.8± 4.0 mg/dl), and restored glucose tolerance and insulin sensitivity to levels comparable to lean mice. These improvements were associated with increased circulating peptide YY and gastric inhibitory polypeptide concentrations, downregulation of hypothalamic agouti-related peptide (AgRP), reduced food intake (∼20%), and weight loss. Acutely, EA slowed gastric emptying rate by about 50% and increased glucagon like peptide-1 levels. In db/db mice, EA reduced non-fasting blood glucose from 459.0± 51.1 mg/dl to 208.9 ± 10.3 mg/dl, an effect comparable to liraglutide and greater than metformin. EA also lowered fasting blood glucose levels similar to liraglutide and significantly below those observed with metformin. Moreover, EA-treated mice exhibited less weight gain than those receiving either drug. These effects were accompanied by decreased hypothalamic AgRP expression and increased c-fos activation. These results suggest that EA is a novel, multi-target agent with therapeutic potential for treating T2D and obesity.

The ketogenic diet (KD) has shown therapeutic potential for epilepsy, neuroprotective effects, and, more recently, metabolic complications. In this study, we explored the impact of the KD on the promotion of ketometabolism and the improvement of dyslipidemia. To this end, we investigated the outcomes of two different diets, eucaloric KD and low-calorie diet (LCD), on ketogenesis, circulating intact lipids, bile acids, and neuro and pancreatic peptides. Based on our results, the concentration of ketone bodies, namely 3-hydroxybutyric acid, increased significantly by an average of 10 and 2 times for KD and LCD, respectively. Additionally, the concentration of several triglyceride (TAG) species decreased up to 98.3% and 99.1% for KD and LCD, respectively, while these reductions were only significant for LCD. Moreover, our results showed that three days of KD led to an increase in the baseline concentration of pancreatic polypeptide 3-36, which suggests that short-term KD has the potential to suppress the appetite. Finally, no significant change in the baseline and kinetic postprandial concentration of bile acid species was observed during the KD. In conclusion, our findings suggest that the ketogenic diet, being less restrictive than the low-calorie diet, has a greater impact on ketometabolism. However, while KD reduces TAG species, this reduction is not statistically significant, unlike the significant decrease observed with LCD.

Estrogen deficiency caused by menopause leads to obesity in women. In obesity, excessive visceral fat accumulation induces a chronic, low-grade inflammatory response, thereby increasing the risk of cardiovascular disease, insulin resistance, and type 2 diabetes mellitus. Browning of white adipose tissue (WAT) has emerged as a promising strategy to counteract obesity and related metabolic disorders. Coenzyme Q10 (CoQ10) has been reported to reduce oxidative stress, enhance mitochondria function and improve metabolic syndrome in obese and diabetic animals and patients. In this study, we evaluated whether long-term CoQ10 supplementation could induce WAT browning to ameliorate obesity in ovariectomized (OVX) rats fed a high-fat diet (HFD), and explored the underlying mechanisms. Supplementation with CoQ10 (20 and 40 mg/kg, once daily by gavage) for 12 weeks in OVX rats significantly reduced weight gain, excessive visceral fat accumulation, white adipocyte hypertrophy, plasma triglyceride levels, and glucose intolerance, while increasing energy expenditure compared to OVX rats treated with vehicle (p < 0.05). High dose CoQ10 (40 mg/kg) significantly lowered plasma insulin levels, reduced HIF-1α, MCP-1 and IL-6 protein expression, and increased phosphorylated AKT in retroperitoneal WAT (p < 0.05). In inguinal WAT (iWAT), CoQ10 enhanced the expression of browning-related proteins including UCP-1, CIDEA, PRDM16, PGC-1α, and phosphorylated AMPK, and elevated plasma irisin levels (p < 0.05). CoQ10 also regulated mitochondria dynamics of iWAT, as evidenced by increased MFN1, MFN2, and OPA1, and decreased FIS1 protein expression compared with the OVX group (p < 0.05). In 3T3-L1 adipocytes, CoQ10-induced expression of browning markers (UCP-1, TBX1 and PRDM16) was significantly suppressed by dorsomorphin, an AMPK inhibitor, and by AMPK knockdown (p < 0.05). In conclusion, long-term CoQ10 supplementation ameliorates weight gain, white adipocyte hypertrophy and inflammation in WAT, and metabolic disorders caused by combined estrogen deficiency and HFD, likely through its WAT browning effect. AMPK activation is suggested to contribute to the browning effect and enhance the expression of proteins involved in mitochondrial dynamics. Therefore, CoQ10 supplementation could be an effective intervention for preventing postmenopausal obesity.

Combination chemotherapy, irinotecan+5-fluorouracil, treats advanced colorectal cancer but causes intestinal toxicity mediated by cytokines and oxylipins. The objective of this study is to determine the effect of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on cytokines and the balance of oxylipins in colon tissue after chemotherapy. Ward colon tumours were implanted into female Fischer 344 rats (13-14 weeks old, n=56) and grew for two weeks before initiating chemotherapy (day 0). Subsequently, rats were maintained on the control diet (n=32) or switched to the EPA+DHA diet (n=24), an isocaloric diet that differed mainly in EPA and DHA content. Rats were euthanized on day 0 (baseline), 2, 4 and 8. The reference (no tumour, n=8) and baseline D0 (with tumour, n=8) groups did not receive chemotherapy. Cytokines, phospholipid fatty acids, and oxylipins in colon tissue were compared between the diets and over days post-chemotherapy. Feeding EPA+DHA resulted in a 9- and 2-fold increase in colon phospholipid by day 8 mirrored by a 10- and 2-fold increase in total oxylipins derived from EPA and DHA, respectively. Incorporation of EPA and DHA by day 2 prevented an increase in proinflammatory arachidonic acid (AA)-derived oxylipins after chemotherapy, including prostaglandin (PG) D, PGE, 6-keto-PGF, thromboxane B, and 5-hydroxyeicosatetraenoic acid. Displacement of AA by EPA and DHA in colonic membrane attenuates early inflammatory lipid oxylipins. Dietary EPA+DHA may mitigate intestinal perturbations in colorectal cancer patients receiving irinotecan+5-fluorouracil.

Replacing part of dietary glucose with galactose in the early post-weaning diet of mice, mimicking extended breastfeeding, improves both short- and long-term physiological and metabolic health parameters. As the primary organ for nutrient absorption, the small intestine was hypothesized to play a key role in these effects. Young, weaned mice underwent a three-week dietary intervention comparing isocaloric diets with a monosaccharide fraction of galactose+glucose versus glucose. Physiological parameters were assessed in both sexes, while metabolic analyses, transcriptomics, and immunohistochemistry of the proximal small intestine were conducted in fed female mice. Dietary galactose increased whole-body 24-hour fatty acid oxidation (FAO), both absolute and relative to carbohydrate oxidation, without changes in body weight or energy expenditure. Contrasting, the small intestine showed lower expression of transcripts involved in FAO, along with reduced enterocytic lipid droplets. Carbohydrate metabolism remained unaffected, while reduced expression of NADPH-dependent and -independent antioxidant enzymes and the pentose phosphate pathway suggested a shift in local metabolism. Despite these intestinal changes, the liver showed no alterations in lipid catabolism, implicating other organs in the observed systemic FAO increase. In addition, Ppargc1a, central regulator of mitochondrial biogenesis was upregulated, which is in line with the known role of galactose in upregulating mitochondrial oxidative phosphorylation. In conclusion, replacing half of post-weaning dietary glucose with galactose, mimicking prolonged lactose intake, profoundly affects substrate metabolism at both systemic and intestinal levels. We propose that reduced intestinal FAO redirects fatty acid oxidation to extra-intestinal, extra-hepatic tissues, driving the observed systemic metabolic benefits.

Eucommiae Cortex (EC), a Traditional Chinese health food product, is known for its anti-inflammatory, antioxidant, and hepatoprotective effects, with promising potential in treating rheumatoid arthritis (RA). This study used liquid chromatography-tandem mass spectrometry (LC-MS) to profile the bioactive compounds of ginger-processed EC (G-EC), focusing on its absorbed constituents and metabolic fate in vivo. Network pharmacology identified geniposidic acid (GPA) as a key bioavailable compound in G-EC, potentially alleviating RA. In vivo, GPA significantly improved RA symptoms. Additionally, exosomes from inflammatory fibroblast-like synoviocytes (FLSs) (LPS-exo) promoted M1 macrophage polarization, glycolytic activation, and synovial inflammation. GPA inhibited glycolysis, reduced M1 polarization induced by LPS-exo, and downregulated H3K56la histone lactylation. Mechanistic analysis suggested these effects involve the regulation of ATP-citrate lyase (ACLY) and Histone deacetylase 6 (HDAC6) expression. This study supports the therapeutic potential of GPA in RA and provides a foundation for further clinical research.

This study investigated the effects of Isoliquiritigenin (ISL) on adiposity in Wistar rats fed a high-fat diet (HFD), positing that ISL mitigates adiposity by inhibiting adipogenesis and promoting lipolysis via AMPK activation. Adult male Wistar rats were divided into six groups (n=8): Control (vehicle), Control + ISL (40 mg/kg), HFD (vehicle), HFD + ISL (20 mg/kg), HFD + ISL (40 mg/kg), and HFD + ISL (40 mg/kg) + Dorsomorphin (0.2 mg/kg) for 12 weeks. In a dose-dependent manner, ISL (thrice a week) significantly attenuated the increase in body weight and adipocyte size, improving glucose and insulin tolerance, HbA1c, and HOMA-IR without affecting food intake in HFD rats. Particularly, the higher dose of ISL (40 mg/kg) significantly increased the phosphorylation of AMPK (+193.3%), resulting in a p-AMPK/AMPK activity ratio increase of 191.0% in the white adipose tissue (WAT) of HFD rats. This dose also reduces body weight (24.6%), weight gain (28.7), fat deposit weight (-39.2% %), HOMA-IR (-67.62%), and serum triglycerides (-62.4%), cholesterol (56.7%), IL-6 (-66.1%) and TNF-α (-79.5%) in these HFD rats. It also increased p-ACC levels (+86.7%), Nrf2 mRNA (+392.7%), and PPARα mRNA (+255.0%), as well as the levels of HSL (+149.7 %) and ATGL (139.62%). ISL (40 mg/kg) also decreased WAT levels of IL-6 (-57.86%), TNF-α (-74.96%), mRNA of SREBP1 (-38/8%), FAS (-50%) & NF-kB (58.8%), and levels of PLIN1 (-50.1) in these HFD rats. Dorsomorphin treatment reversed these effects in ISL + HFD rats. In conclusion, ISL demonstrates anti-obesity effects in HFD-induced rats through AMPK activation.

Our previous research demonstrated that exogenous serine ameliorates insulin resistance in C57BL/6 mice fed a diet containing 0.8mg/kg selenium, likely by serving as a methyl donor for SAM biosynthesis. This study aims to investigate whether betaine, an alternative methyl donor, can similarly mitigate high Se-induced IR in mice.

Folate deficiency in pregnancy is strongly associated with fetal growth restriction (FGR). Fetal folate availability is determined by maternal folate intake and the capacity of the placenta to transport folate. However, the mechanisms regulating placental folate transport remain poorly understood. The mechanistic target of rapamycin (mTOR) regulates placental function and fetal growth, but it is unknown if mTOR regulates folate transport in vivo. We hypothesized that trophoblast-specific mTOR knockdown inhibits placental folate transport in mice. We generated transgenic mice with a doxycycline-inducible, trophoblast-specific Mtor knockdown using PiggyBac transposase-enhanced pronuclear injection. Doxycycline administration on embryonic day (E) 14.5 induced placental-specific Mtor knockdown, resulting in reduced fetal weight, placental weight, and fetal-to-placental weight ratio. Functionally, mTOR knockdown reduced folate uptake in isolated trophoblast plasma membranes (TPM), decreased the TPM protein expression of the three main placental folate transporters (FRα, RFC, and PCFT) without affecting protein expression of theses transporters in placental homogenates, and lowered fetal plasma folate concentration. In conclusion, mTOR signaling is a positive regulator of the three main placental folate transporters in vivo mediated by posttranslational mechanisms, likely involving effects of plasma membrane trafficking. Trophoblast mTOR signaling is essential for maintaining adequate fetal folate supply and we propose that the inhibition of placental mTOR signaling reported in FGR contributes to fetal folate deficiency and decreased fetal growth in this pregnancy complication. Our data supports the potential to target placental mTOR signaling as a novel intervention in pregnancies affected by abnormal fetal growth.

This study investigates the therapeutic potential of g-glutamyl valine (g-EV) in four-week-old male db/db mice, a well-established model for type 2 diabetes. Mice were fed an AIN-93G diet and administered g-EV (500 mg/kg body weight) via drinking water for three weeks. Blood, liver, muscle, and intestinal tissues were collected to assess blood glucose, peptide bioavailability, liver function, glycogen levels, protein expression, and transcriptomic changes. g-EV was bioavailable in circulation (2.07 ± 1.59 μM) and significantly improved food efficiency (+79%, P < 0.0001), despite reduced calorie intake (-27%, P < 0.0001). Treated mice exhibited markedly reduced polyuria and water intake (-80%, P < 0.0001), and showed substantial reductions in blood glucose under both fasted (-76%, P < 0.0001) and non-fasted (-29%, P = 0.0054) conditions. Although g-EV increased the hepatosomatic index (+66%, P < 0.0001), serum ALT levels remained unchanged (P = 0.0765), indicating no hepatotoxicity. RNA-Seq revealed 1308 differentially expressed genes in the liver and 147 in the jejunum, with 26 genes overlapping between the two. Key upregulated GO terms included fatty acid metabolism (jejunum) and oxidoreductase activity (liver). Hepatic p-AMPKα levels increased (+86%, P = 0.0137) alongside decreased liver glycogen (-79%, P < 0.0001), suggesting g-EV induces beneficial catabolic signaling. Overall, g-EV shows promise as an anti-diabetic peptide.