The health benefits of tomato consumption may derive from bioactive compounds other than lycopene in tomatoes. 15-Cis-phytoene, a colorless precursor of lycopene abundant in tomatoes, has not been well studied for its biological activity. We investigated whether dietary 15-cis-phytoene protects against metabolic dysfunction-associated steatotic liver disease (MASLD) and whether this protection depends on the carotenoid cleavage enzymes, beta-carotene-15,15'-oxygenase 1 (BCO1) and beta-carotene-9',10'-oxygenase (BCO2). Wild-type (WT) and BCO1-/-/BCO2-/- double knock-out (DKO) mice were fed a high-refined carbohydrate diet (HRCD) with or without 15-cis-phytoene supplementation for 24 weeks. 15-Cis-phytoene supplementation markedly increased 15-cis and all-trans phytoene concentrations in intestine, liver, and serum, and significantly attenuated HRCD-induced MASLD in WT mice. The protective effects of phytoene on MASLD in WT mice were associated with increased hepatic mRNA and protein levels of SIRT1, PGC1α, and PPARα; enhanced AMPK and ACC phosphorylation; and upregulated fatty acid oxidation genes, but not with the gut microbiota composition. Despite much higher phytoene accumulation in the liver and serum, phytoene did not exhibit protection against HRCD-induced MASLD in DKO mice. Phytoene is a biologically active compound that contributes to the benefits of tomato consumption against MASLD. Its protective effects are likely mediated by cleavage metabolites through BCO1/BCO2.

Natural polyphenols have strong antioxidant and anti-inflammatory potential, but their low oral bioavailability means gut-mediated protective mechanisms need further clarification. Dendrobium officinale leaves are rich in polyphenols, and previous studies have suggested that their extracts may improve inflammation or metabolic disorders by regulating gut microbiota and short-chain fatty acid (SCFA) metabolism. However, the in vivo effects of purified Dendrobium officinale leaf polyphenols (DOLP) in a D-galactose-induced oxidative-inflammatory imbalance model remain insufficiently studied. This study characterized DOLP and investigated their effects on oxidative damage, inflammation, SCFA metabolism, and gut microbiota via in vitro assays and a D-gal-induced mouse model. DOLP was enriched in flavonoids and phenolic acids, mainly rutin and protocatechuic acid, with total polyphenols enriched from 3.82% to 69.2%, and exhibited stronger free radical-scavenging and α-glucosidase inhibitory activities than crude polyphenols. In vivo, DOLP partially restored normal body-weight gain, improved dyslipidemia and liver-function indices, reversed D-gal-induced reductions in acetate, propionate, butyrate, and valerate, increased Dubosiella, Faecalibacterium, Agathobacter, and Lactobacillus crispatus, and decreased Streptococcus, Bacillus, Clostridium sensu stricto 1, and Dolosigranulum. Integrative correlation analysis and random forest screening linked gut microbiota, SCFAs, and oxidative-inflammatory phenotypes, while GEO transcriptomic mining, network analysis, molecular docking, and ADMET prediction suggested interactions of rutin, vitexin, and quercetin-3-O-glucoside with SOD1 and GPX4. This study provides an integrated framework for understanding the gut-associated effects of DOLP, supporting development as food-derived functional ingredients. However, as causal validation experiments (e.g., fecal microbiota transplantation, antibiotic depletion, or SCFA intervention) were not performed, the microbiota-SCFA-host axis remains correlative, not causal.

Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder cancer (BC) occurrence and invasion, however, remains unclear. Large-scale cohorts’ analyses were performed to assess the association between dietary PEA and BC occurrence and invasion. In vitro and in vivo experiments, including EJ and T24 BC cell assays and a BBN-induced mouse model, were conducted to experimentally assess the impact of PEA on BC. Serum proteomics, gut microbiome, and targeted fecal lipidomics analyses were employed to explore the underlying mechanisms. Dietary PEA was negatively associated with BC occurrence and invasion in cohort analyses. PEA suppressed EJ and T24 BC cell migration, invasion, and proliferation, while inhibiting BC development in a BBN-induced mouse model. In vivo serum proteomics identified differentially expressed lipid-related proteins (e.g., Apoe and Apob) following PEA treatment, implicating its modulation of lipid metabolism pathways. Considering the essential role of the gut-bladder axis, the gut microbiome analysis exhibited that PEA markedly altered bacteria (e.g., g_Alistipes) and fungi (e.g., o_Erysiphales, g_Teberdinia, and g_Gibberella), with concomitant lipid metabolism changes. Furthermore, targeted fecal lipidomics demonstrated the shifts in key lipids, such as phosphatidylethanolamines (PE) involved in essential lipid clusters, suggesting regulation by gut microbiome linked to BC development. Collectively, our findings demonstrate that PEA mitigates BC by reshaping the gut microbiome and modulating lipid metabolism, providing new insights into its molecular and therapeutic potential. This study aims to investigate the effects of PEA on BC occurrence and invasion using multi-dimensional approaches. We found PEA showing the protective effect on BC based on large-scale cohorts, in vitro and in vivo experiments. This observation may be mediated by the gut microbiome’s involvement in the lipid-metabolism pathway, potentially highlighting a gut-bladder axis in BC. Abbreviations: PEA, pentadecanoic acid; BC, bladder cancer; BCPP, Bladder Cancer Prognosis Programme; CCK-8, Cell Counting Kit-8; DIA MS, Data-Independent Acquisition Mass Spectrometry; 16S rRNA, 16S ribosomal RNA; ITS, Internal Transcribed Spacer; LC-MS/MS, Liquid Chromatography-Tandem Mass Spectrometry; PE, phosphatidylethanolamine.

BACKGROUND:Exposure to brominated flame retardants (BFRs) may negatively impact human health. The association of BFRs with nonalcoholic fatty liver disease (NAFLD) in the general population is unclear. Meanwhile, limited studies have investigated the potential role of oxidative stress and inflammation in this link. METHODS:We included 4110 adults from the 2009-2014 National Health and Nutrition Examination Survey (NHANES). NAFLD was diagnosed by serum alanine aminotransferase (ALT), hepatic steatosis index (HSI), and United States fatty liver index (USFLI). The link between a single BFR exposure and NAFLD was estimated using weighted logistic regression and restricted cubic splines (RCS). The quantile-based g-computation (QGC), weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) were applied to evaluate the overall correlation of BFRs mixtures with NAFLD and identify significant compounds. Furthermore, we investigated the potential mediation function of oxidative stress and inflammation. RESULTS:Our study demonstrated that specific concentrations of BFRs are related to an increased risk of NAFLD, both individually and when combined. PBB153, PBDE28, PBDE209, and PBDE153 exhibited the highest importance for NAFLD and were potential risk factors worthy of concern. Additionally, mediation analysis showed that absolute neutrophil cell count (ANC) and lymphocyte count (LC) (inflammation markers) have significantly mediated influences on the correlations of PBB153, PBDE85, and PBDE28 with N AFLD risk. Albumin (ALB) (oxidative stress marker) has notably mediated influences on the correlations of PBDE99, PBDE154, and PBDE85 with NAFLD risk. Men had higher serum BFRs concentrations than women, and the association between BFRs and NAFLD was also more prominent in men, which may be related to physiological differences between the sexes. CONCLUSIONS:Our findings offer evidence for single and mixed associations of BFRs and NAFLD in ordinary US adults. Furthermore, oxidative stress and chronic inflammation may mediate the effects of BFR exposure on NAFLD development.

Objectives: Sirtuin 1 (SIRT1) is a highly conserved NAD+-dependent protein deacetylase that modulates lipid metabolism, oxidative stress, and inflammation. We have previously shown that whole tomato (tomato powder, TP) and lycopene inhibited high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) by modulating SIRT1 activity in animal models. Whether dietary TP inhibits NAFLD and HCC dependent on SIRT1 activity remains unknown. Methods: Mice with homozygous ablation in catalytic activity of SIRT1 (MT) and their corresponding wild type littermates (WT) were injected with the carcinogen diethylnitrosamine at two weeks of age. At six weeks of age, mice were fed with a HFD (60% total calories from fat) with or without TP (containing lycopene 100 mg/kg diet or equivalent to dietary lycopene intake of 8.1 mg per day in humans) for 34 weeks. Pathological and biochemical variables were assessed in the liver, mesenteric adipose tissue, and plasma. Results: TP feeding significantly reduced plasma levels of triglycerides, hepatic steatosis score, and inflammatory foci in HFD-fed WT and MT mice at comparable hepatic lycopene concentrations (7.7 ± 1.7 and 7.4 ± 2.0 nmol/g liver, respectively). However, the beneficial effects of TP feeding were achieved through different molecular mechanisms: In WT mice, the protective effect of TP was associated with increased hepatic SIRT1 protein expression and activity, along with decreased mRNA expressions of caspase-1 and fatty acid-binding protein 1. Moreover, TP feeding lowered the concentration of hepatic IL-1β protein; In MT mice, TP feeding decreased hepatic levels of malondialdehyde, acetylated-p53, and acetyl-CoA carboxylase, and increased mRNA expressions of glutathione peroxidase-1 and AMP-kinase phosphorylation. Furthermore, TP feeding significantly lowered the mRNA expression of IL-6 in mesenteric adipose tissue and the protein concentration of IL-6 in both plasma and the liver. Neither the lack of SIRT1 activity nor TP feeding altered the incidence, multiplicity, and volume of HCC in both WT and MT mice. Conclusions: The present study demonstrates that dietary TP, independent of SIRT1 activity, ameliorates HFD-induced NAFLD, oxidative stress, and inflammatory responses in the liver and mesenteric adipose tissue. Funding Sources: Supported by USDA/NIFA/AFRI and USDA/ARS.

Metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), has become the leading cause of chronic liver disease worldwide. Optimal dietary intervention strategies for MAFLD are not standardized. This study aimed to achieve consensus on prevention of MAFLD through dietary modification. A multidisciplinary panel of 55 international experts, including specialists in hepatology, gastroenterology, dietetics, endocrinology and other medical specialties from six continents collaborated in a Delphi-based consensus development process. The consensus statements covered aspects ranging from epidemiology to mechanisms, management, and dietary recommendations for MAFLD. The recommended dietary strategies emphasize adherence to a balanced diet with controlled energy intake and personalized nutritional interventions, such as calorie restriction, high-protein, or low-carbohydrate diets. Specific dietary advice encouraged increasing the consumption of whole grains, plant-based proteins, fish, seafood, low-fat or fat-free dairy products, liquid plant oils, and deeply colored fruits and vegetables. Concurrently, it advised reducing the intake of red and processed meats, saturated and trans fats, ultra-processed foods, added sugars, and alcohol. Additionally, maintaining the Mediterranean or DASH diet, minimizing sedentary behavior, and engaging in regular physical activity are recommended. These consensus statements lay the foundation for customized dietary guidelines and proposing avenues for further research on nutrition and MAFLD.

Objective: To evaluate the efficacy and safety of Jiawei Simiao powder (JWSMP) combined with celecoxib for the treatment of acute gouty arthritis by conducting a meta-analysis of randomized controlled trials (RCTs). Methods: The Chinese National Knowledge Infrastructure Databases, Chinese Scientific Journal Database, Wanfang, Cochrane Library, EMBASE, PubMed, and Web of Science databases were searched from inception until December 2023. Continuous variables were analyzed using the mean difference (MD) for analysis, and dichotomous variables were used as risk ratios. Data with similar characteristics were pooled for meta-analysis, and heterogeneity was assessed using I2. The Cochrane Handbook was used to assess the risk of bias and quality. RevMan 5.3 software was used to perform the meta-analysis. Results: Thirteen RCTs involving 1007 patients were included in the study. The quality of the included studies was low (unclear randomization processes and insufficient blinding reporting). The group receiving JWSMP combined with celecoxib showed significantly lower levels of serum uric acid (SUA, MD = −66.32, 95% confidence interval (CI): −80.97 to −51.67, P < .001), erythrocyte sedimentation rate (ESR, MD = −6.05, 95% CI: −8.29 to −3.82, P < .001), C-reactive protein (CRP, MD = −7.39, 95% CI: −11.15, −3.63, P < .001), and joint pain score (VAS score, MD = −2.14, 95% CI: −2.4 to −1.88, P < .001) compared to celecoxib alone. Additionally, the JWSMP combined group had a higher total effective rate (risk ratio = 1.22, 95% CI: 1.14 to 1.29, P < .001) and fewer adverse compared to celecoxib alone. Conclusions: JWSMP combined with celecoxib is more effective than celecoxib alone in improving the total efficacy rate, alleviating joint pain, and improving SUA, ESR, and CRP levels. JWSMP also reduced the occurrence of adverse events caused by celecoxib. However, the quality of the included studies was low, highlighting the need for further high-quality research with larger sample sizes and robust methodologies, such as double-blind randomization, to confirm these findings.

Terminalia chebula Retz., known for its dried fruit, namely Chebulae Fructus, is a medicinal plant with a long-standing global reputation, which was initially recognized for its therapeutic properties during the Jin Dynasty. This review consolidates current knowledge on the traditional uses, phytochemistry, pharmacological properties, toxicity, and pharmacokinetics of Chebulae Fructus, highlighting its clinical significance and the promising therapeutic potential of its compounds. To date, studies have identified approximately 149 compounds within the plant, including tannins, phenolic acids, lignans, triterpenes, flavonoids, and volatiles. These compounds confer a broad spectrum of biological activities in vitro and in vivo, such as antioxidant, anti-inflammatory, antiviral, anticancer, antibacterial, hepatoprotective, nephroprotective, neuroprotective, and anti-diabetic, some of which are already integrated into clinical practice. However, despite substantial advancements, considerable gaps remain in understanding the complete mechanisms of action, pharmacokinetics, and safety profiles of its extracts and compounds. This paper advocates for enhanced focus on these areas to fully elucidate the therapeutic capacities and facilitate the clinical application of Chebulae Fructus. This comprehensive analysis not only reinforces the ethnopharmacological significance of Chebulae Fructus but also lays a foundation for future pharmacological explorations.

When subject to damage or stress, cells develop responses in order to maintain tissue homeostasis. Two such decisions are ferroptosis and cellular senescence, but how cells decide between these outcomes remains unclear. Here we show that senescent cells increase levels of multiple membrane bound polyunsaturated fatty acids (PUFAs), but a specific PUFA, dihomo−gamma−linolenic acid (DGLA, 20:3−ω3) is reduced. Exogenous repletion of DGLA or inhibition of the enzyme that metabolizes DGLA, delta−5−desaturase, instead results in cell death by ferroptosis. Senescent cells also show elevated levels of other ferroptosis sensitizers, including labile iron and expression of lipoxygenases − but also increase Gpx4 levels. Oral administration of exogenous DGLA lowers senescent cell burden in aged mice and improves age−related functional outcomes. Finally, obese humans with lowered DGLA desaturation rates showed lower markers of adipose tissue senescence. Together, our data implicate DGLA and its desaturation as a major driver of decisions between senescence and ferroptosis. ### Competing Interest Statement CW is an inventor on patents related to the elimination of senescent cells using DGLA, D5D inhibitors, and other ferroptosis inducers. The content is the sole responsibility of the authors and does not necessarily represent the official views of the USDA.

PDF file - 78K, Means body weight of mice

PDF file - 30K, Supplementary Table S1. High-fat diet composition.

Supplementary Figure S1. Reduction of mRNA expressions of α7-nachr by BCX supplementation, not α3-, α5-, and β4-nachr, was associated with lung tumor multiplicity. Upper panel: The statistically significant correlation between lung tumor multiplicity (tumor number) and the expression of nachr-α7 mRNA (P = 0.03, r = 0.394, Pearson's correlation) and α7-nAChR protein (P < 0.01, r = 0.355, Pearson's correlation). Bottom panel: There were no significant differences in the nachr-α3, nachr-α5, and nachr-β4 mRNA levels among all the groups. The mRNA levels were measured with quantitative reverse transcription polymerase chain reaction (qRT-PCR) and were normalized to the levels of GAPDH mRNA levels. The columns represent the mean {plus minus} sem. Abbreviation: BCX(1): β-cryptoxanthin 1 mg/kg diet; BCX(10): β-cryptoxanthin 10 mg/kg diet; NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Supplementary Figure S2. BCX supplementation was associated with reduced early growth response-1 (Egr1) mRNA in the NNK-treated mice. The mRNA levels of egr1 were measured with quantitative reverse transcription polymerase chain reaction (qRT-PCR) and were normalized to the levels of GAPDH mRNA levels. The columns represent the mean {plus minus} sem. * P = 0.04. Dotted lines indicated significant decreasing levels in a BCX-dose dependent manner (P-linear trend = 0.05). Abbreviation: BCX (1): β-cryptoxanthin 1 mg/kg diet; BCX (10): β-cryptoxanthin 10 mg/kg diet; egr1: early growth response-1; NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Supplementary Figure S3. PI3K downstream Rac1 and ARF6 contribute to lamellipodia suppression by BCX. BEAS-2B cells were transfected with wild type Rac1 or ARF6. Then cells were treated with BCX (1.0, 2.0, 4.0 μM) or MG624 (1.0 μM) for 12 hr. Cells were stained with TRITC-labeled phalloidin and analyzed using fluorescent microscopy. The representative fluorescent images are shown (A, the lamellipodia are indicated by arrowheads). The number of cells with significant lamellipodia was counted in five random fields (C). The representative fluorescent images of BEAS-2B cells were transfected with Rac1-Q61L or ARF6-Q67L are shown (B, the lamellipodia are indicated by arrowheads). The number of cells with significant lamellipodia was counted in five random fields (D). Results of Scratch wound are displayed in (E). *P = 0.04, **P = 0.01 compared with control group.

Supplementary Table S1: Primers sequences for RT-PCR analysis of liver tissue.

PDF file - 61K, Supplementary Figure S2. Inhibition of carcinogen-initiated (DEN), HFD-promoted glucose intolerance by APO10LA. Glucose tolerance test was conducted on 6-8 mice/group and calculated for AUC.

PDF file - 69K, The primer sequences for quantitative real-time PCR

PDF file - 48K, Supplementary Figure S1. Chemical structure of lycopene, APO10LA, acyclic retinoic acid and all-trans retinoic acid.

The inflammation of the pancreatic islets triggers β cell dysfunction and type 2 diabetes mellitus (T2DM) onset. While dietary lycopene consumption contributes to protection against T2DM in animal studies, the potential mechanism of this compound in the regulation of islet function in T2DM remains largely unclear. In this study, by using anti-diabetic metformin as a positive control, we demonstrated that lycopene treatment suppressed islet inflammation and apoptosis in both high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice and in Min6 cells exposed to high glucose/palmitic acid (HG/PA)-RAW264.7 conditioned medium. Lycopene intervention resulted in M1/M2 macrophage polarization homeostasis, which is associated with increased insulin secretion, decreased fasting blood glucose levels, and improved lipid profiles in diabetic mice. Furthermore, the protective actions of lycopene were associated with the down-regulation of the TLR4/MyD88/NF-κB signaling pathway, which is positively related to inflammation in both diabetic mice and Min6 cells. Collectively, our findings indicated that lycopene ameliorates islet function and apoptosis and attenuates hyperglycemia and dyslipidemia by the regulation of the TLR4/MyD88/NF-κB signaling pathway. This study highlights dietary lycopene consumption as a novel strategy for the management of patients with diabetes.