Design, synthesis, and biological evaluation of novel 8-substituted quercetin derivatives targeting the ß­catenin/B-cell lymphoma 9 interaction.

The ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for aberrantly active Wnt/ß-catenin signaling which actively participates in initiating and progressing of many cancers. Herein, we discovered novel 8-substituted quercetin derivatives with potential inhibitory activities targeting ß-catenin/BCL9 PPI. Among all the derivatives, compound B4 displayed the most promising PPI inhibitory activity with an IC50 value of 2.25 µM in a competitive fluorescence polarization assay and a KD value of 1.44 µM for the ß-catenin protein. Furthermore, B4 selectively inhibited the growth of colorectal cancer (CRC) cells, suppressed the transactivation of Wnt signaling, and downregulated the expression of oncogenic Wnt target gene. Especially, B4 showed potent anti-CRC activity in vivo with the tumor growth inhibition (TGI) of 75.99 % and regulated the tumor immune microenvironment.

Core-shell-structured magnetic covalent organic frameworks for effective extraction of parabens prior to their determination by HPLC.

Covalent organic framework (COF)-decorated magnetic nanoparticles (Fe3O4@DhaTab) with core-shell structure have been synthesized by one-pot method. The prepared Fe3O4@DhaTab was well characterized, and parameters of magnetic solid-phase extraction (MSPE) for parabens were also investigated in detail. Under optimized conditions, the adsorbent dosage was only 3 mg and extraction time was 10 min. The developed Fe3O4@DhaTab-based MSPE-HPLC analysis method offered good linearity (0.01-20 µg mL-1) with R2 (0.999) and low limits of detection (3.3-6.5 µg L-1) using UV detector at 254 nm. The proposed method was applied to determine four parabens in environmental water samples with recoveries in the range 64.0-105% and relative standard deviations of 0.16-7.8%. The adsorption mechanism was explored and indicated that porous DhaTab shell provided π-π, hydrophobic, and hydrogen bonding interactions in the MSPE process. The results revealed the potential of magnetic-functionalized COFs in determination of environmental contaminants.

SERS and MALDI-TOF MS based plasma exosome profiling for rapid detection of osteosarcoma.

Osteosarcoma is the most frequent primary bone cancer, particularly among children and adolescents. The early diagnosis of osteosarcoma is significant for timely clinical treatment to reduce the mortality of patients. Exosomes play a significant role in intercellular communication and serve as promising biomarkers in liquid biopsy for the diagnosis and monitoring of tumors. Herein, we report the utility of surface-enhanced Raman scattering (SERS) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for rapid identification of osteosarcoma. We firstly profiled the intrinsic SERS signals and MALDI-TOF mass fingerprints of different subgroups of extracellular vesicles (EVs) and the corresponding cells, demonstrating that the SERS signals and MALDI-TOF mass spectra of exosomes from different types of cells were more discriminative compared to those of large and medium EVs and the cells themselves. Then, we characterized plasma-derived exosomes of 15 osteosarcoma patients and 15 healthy volunteers using SERS and MALDI-TOF MS, revealing distinctive biochemical differences in the spectra. We further utilized a data fusion approach to combine the two types of spectroscopic techniques, differentiating osteosarcoma patients from healthy controls with higher precision than either technique. The results reveal that the non-invasive liquid biopsy method using SERS and MALDI-TOF MS fingerprinting of exosomes has great potential for rapid diagnosis of osteosarcoma.

Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities.

A series of quinazolinyl-containing benzamide derivatives were designed, synthesized and evaluated for their in vitro histone deacetylase 1 (HDAC1) inhibitory activities. Compounds 11a surpassed the known class I selective HDAC inhibitor MS-275 in both HDAC1 enzymatic inhibitory activity and cellular anti-proliferative activity against a selected set of cancer cell types (Hut78, K562, Hep3B and HCT116 cells) with no observed effects on human normal cells. In particular, compound 11a inhibited HDAC1 over the other tested HDACs isoforms (HDAC2, HDAC6 and HDAC8) with acceptable safety profiles. Moreover, compound 11a displayed favorable oral pharmacokinetic properties and showed significant antitumor activity in the A549 tumor xenograft model in vivo.

Curcumin Attenuates on Carbon Tetrachloride-Induced Acute Liver Injury in Mice via Modulation of the Nrf2/HO-1 and TGF-ß1/Smad3 Pathway.

This study aimed to investigate the protective effect of curcumin against carbon tetrachloride (CCl4)-induced acute liver injury in a mouse model, and to explain the underlying mechanism. Curcumin at doses of 50, 100 and 200 mg/kg/day were administered orally once daily for seven days prior to CCl4 exposure. At 24 h, curcumin-attenuated CCl4 induced elevated serum transaminase activities and histopathological damage in the mouse's liver. Curcumin pre-treatment at 50, 100 and 200 mg/kg significantly ameliorated CCl4-induced oxidative stress, characterized by decreased malondialdehyde (MDA) formations, and increased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) content, followed by a decrease in caspase-9 and -3 activities. Curcumin pre-treatment significantly decreased CCl4-induced inflammation. Furthermore, curcumin pre-treatment significantly down-regulated the expression of TGF-ß1 and Smad3 mRNAs (both p < 0.01), and up-regulated the expression of nuclear-factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both p < 0.01) in the liver. Inhibition of HO-1 attenuated the protective effect of curcumin on CCl4-induced acute liver injury. Given these outcomes, curcumin could protect against CCl4-induced acute liver injury by inhibiting oxidative stress and inflammation, which may partly involve the activation of Nrf2/HO-1 and inhibition of TGF-ß1/Smad3 pathways.

Thymol as a Potential Neuroprotective Agent: Mechanisms, Efficacy, and Future Prospects.

Neurodegenerative diseases pose a growing global health challenge, with limited effective therapeutic options. Mitochondrial dysfunction, oxidative stress, neuroinflammation, apoptosis, and autophagy are common underlying mechanisms in these diseases. Thymol is a phenolic monoterpene compound that has gained attention for its diverse biological properties, including antioxidant, anti-inflammatory, and immunomodulatory activities. Thymol supplementation could provide potential neuroprotection and improve cognitive deficits, depressant-like effects, learning, and memory impairments in rodents. Mechanistic investigations reveal that the neuroprotective effects of thymol involve the improvement of oxidative stress, mitochondrial dysfunction, and inflammatory response. Several signaling pathways, including mitochondrial apoptotic, NF-κB, AKT, Nrf2, and CREB/BDNF pathways are also involved. In this review, the neuroprotective effects of thymol, the potential molecular mechanisms, safety, applications, and current challenges toward development as a neuroprotective agent were summarized and discussed. We hope that this review provides valuable insights for the further development of this promising natural product as a promising neuroprotective agent.

Evaluation of the Improvement Effect of Whey Protein Poly-Peptides on Quality Characteristics of Repeated Freeze-Thawed Spanish Mackerel Surimi Balls.

This investigation aimed to assess the effects of whey protein hydrolysate (WPH) on the oxidative stability of protein and the ability of Scomberomorus niphoniu surimi balls to retain water after repeated freeze-thaw (F-T) cycles. Ten percent natural whey peptides (NWP), 5% WPH, 10% WPH, 15% WPH, 0.02% butyl hydroxyl anisole (BHA), and a control group that did not receive any treatment were the six groups that were employed in the experiment. The cooking loss, water retention, total sulfhydryl content, and carbonyl content of each group were all measured. Notably, it was found that the surimi balls' capacity to hold onto water and fend off oxidation was enhanced in a dose-dependent manner by the addition of WPH. Furthermore, the results showed that the 15% WPH added to the surimi balls effectively decreased protein oxidation in the F-T cycles and ameliorated the texture deterioration of surimi balls induced by repeated F-T, laying a theoretical foundation for the industrial application of WPH in surimi products.

Identification, characterization, and insights into the mechanism of novel dipeptidyl peptidase-IV inhibitory peptides from yak hemoglobin by in silico exploration, molecular docking, and in vitro assessment.

Dipeptidyl peptidase IV (DPP-IV) inhibitory peptides were screened and identified from yak hemoglobin for the first time by in silico analysis, molecular docking, and in vitro evaluation. Results showed that yak hemoglobin had a high potential to produce DPP-IV inhibitory peptides based on the sequence alignment and bioactive potential evaluation. Furthermore, "pancreatic elastase + stem bromelain" was the optimal combined-enzymatic strategy by simulated proteolysis. Additionally, 25 novel peptides were found from its simulated hydrolysate, among which 10 peptides had high binding affinities with DPP-IV by molecular docking. Most of these peptides were also in silico characterized with favorable physicochemical properties and biological potentials, including relatively low molecular weight, high hydrophobicity, several net charges, good water solubility, nontoxicity, acceptable sensory quality, and good human intestinal absorption. Finally, six novel DPP-IV inhibitory peptides were identified via in vitro assessment, among which EEKA (IC50 = 235.26 µM), DEV (IC50 = 339.45 µM), and HCDKL (IC50 = 632.93 µM) showed the strongest capacities. The hydrogen bonds and electrostatic attractions formed with core residues within the S2 pocket of DPP-IV could be mainly responsible for their inhibition performances. This work provided a time-saving method and broadened application for yak by-products development as sources of functional foods.

Effects of catechin on the stability of myofibrillar protein-soybean oil emulsion and the adsorbed properties of myosin at the oil-water interface.

The effects of different concentrations of catechin on the stability of myofibrillar protein-soybean oil emulsions and the related mechanisms were investigated. Adding 10 µmol/g catechin had no obvious effects on the emulsion stability and myosin structure, but 50, 100 and 200 µmol/g catechin decreased the emulsion stability. The microstructure observations showed that 10 µmol/g catechin caused a dense and uniform emulsion to form, whereas 50, 100 and 200 µmol/g catechin induced the merging of oil droplets. The addition of 50, 100 and 200 µmol/g catechin caused a decline in both the total sulfhydryl content and surface hydrophobicity, suggesting protein aggregation, which decreased the adsorption capacity of myosin and the elasticity of interfacial film. These results suggested that higher concentrations of catechin were detrimental to the emulsifying properties of myosin and that the dose should be considered when it is used as an antioxidant.

Lycopene as a Therapeutic Agent against Aflatoxin B1-Related Toxicity: Mechanistic Insights and Future Directions.

Aflatoxin (AFT) contamination poses a significant global public health and safety concern, prompting widespread apprehension. Of the various AFTs, aflatoxin B1 (AFB1) stands out for its pronounced toxicity and its association with a spectrum of chronic ailments, including cardiovascular disease, neurodegenerative disorders, and cancer. Lycopene, a lipid-soluble natural carotenoid, has emerged as a potential mitigator of the deleterious effects induced by AFB1 exposure, spanning cardiac injury, hepatotoxicity, nephrotoxicity, intestinal damage, and reproductive impairment. This protective mechanism operates by reducing oxidative stress, inflammation, and lipid peroxidation, and activating the mitochondrial apoptotic pathway, facilitating the activation of mitochondrial biogenesis, the endogenous antioxidant system, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/kelch-like ECH-associated protein 1 (KEAP1) and peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) pathways, as well as regulating the activities of cytochrome P450 (CYP450) enzymes. This review provides an overview of the protective effects of lycopene against AFB1 exposure-induced toxicity and the underlying molecular mechanisms. Furthermore, it explores the safety profile and potential clinical applications of lycopene. The present review underscores lycopene's potential as a promising detoxification agent against AFB1 exposure, with the intent to stimulate further research and practical utilization in this domain.

Mechanistic Study of Novel Dipeptidyl Peptidase IV Inhibitory Peptides from Goat's Milk Based on Peptidomics and In Silico Analysis.

Two novel dipeptidyl peptidase IV (DPP-IV) inhibitory peptides (YPF and LLLP) were discovered from goat milk protein by peptidomics, in silico analysis, and in vitro assessment. A total of 698 peptides (<23 AA) were successfully identified by LC-MS/MS from goat milk hydrolysates (hydrolyzed by papaian plus proteinase K). Then, 105 potential DPP-IV inhibitory peptides were screened using PeptideRanker, the ToxinPred tool, Libdock, iDPPIV-SCM, and sequence characteristics. After ADME, physicochemical property evaluation, and a literature search, 12 candidates were efficiently selected and synthesized in vitro for functional validation. Two peptides (YPF and LLLP) were found to exert relatively high in vitro chemical system (IC50 = 368.54 ± 12.97 µM and 213.99 ± 0.64 µM) and in situ (IC50 = 159.46 ± 17.40 µM and 154.96 ± 8.41 µM) DPP-IV inhibitory capacities, and their inhibitory mechanisms were further explored by molecular docking. Our study showed that the formation of strong non-bonding interactions with the core residues from the pocket of DPP-IV (such as ARG358, PHE357, GLU205, TYR662, TYR547, and TYR666) might primarily account for the DPP-IV inhibitory activity of two identified peptides. Overall, the two novel DPP-IV inhibitory peptides rapidly identified in this study can be used as functional food ingredients for the control of diabetes.

Chitosan nanoparticles effectively improved quality stability of pork patties subjected to multiple freeze-thaw cycles.

The potential of chitosan nanoparticles (CHNPs) for improving the quality stability of pork patties under freeze-thaw (F-T) cycles was studied. Chitosan nanoparticles were successfully produced by the ionotropic gelation method. Pork patties were incorporated with 0%, 0.5% chitosan, 1% chitosan, 0.5% CHNPs, and 1% CHNPs and then subjected to repeated F-T cycles. Results showed that CHNPs were able to inhibit lipid and protein oxidation with a significant decrease in the lipid malondialdehyde and protein carbonyl formation in the patties after seven F-T cycles. Low-field nuclear magnetic resonance (LF-NMR) results indicated that CHNPs effectively restrained water mobility of samples. In addition, CHNPs exhibited a distinguishable improvement in the textural properties and water holding capacity in the stored patties during F-T cycles. Thus, CHNPs could be used as a natural ingredient to protect frozen patties from quality degradation caused by temperature fluctuations.

Whey Protein Hydrolysate Improved the Structure and Function of Myofibrillar Protein in Ground Pork during Repeated Freeze-Thaw Cycles.

Whey protein hydrolysate (WPH) has made a breakthrough in inhibiting oxidative deterioration and improving the quality of meat products during storage. Based on our previous study of extracting the most antioxidant active fraction I (FI, the molecular weight < 1 kDa) from whey protein hydrolysates of different molecular weights, the present study continued to delve into the effects of WPH with fraction I on the structure and function of myofibrillar proteins (MP) in ground pork during the freeze-thaw (F-T) cycles. With the number of F-T cycles raised, the total sulfhydryl content, the relative contents of α-helix, Ca2+-ATPase activity, K+-ATPase activity, solubility, emulsion activity index (EAI), and emulsion stability index (ESI) of MP gradually decreased. Conversely, the carbonyl content and the relative content of random curl showed an increasing trend. In particular, the damage to the structure and the function of MP became more pronounced after three F-T cycles. But, during F-T cycles, FI stabilized the structure of MP. Compared to the control group, the 10% FI group showed a remarkable improvement (p < 0.05) in the total sulfhydryl content, Ca2+-ATPase activity, K+-ATPase activity, solubility, EAI and ESI after multiple F-T cycles, suggesting that 10% FI could effectively inhibit protein oxidation and had the influence of preserving MP function properties. In conclusion, WPH with fraction I can be used as a potential natural antioxidant peptide for maintaining the quality of frozen processed meat products.

Effects of Whey Peptides on the Quality of Pork Ball Preprepared Dishes during Repeated Freezing-Thawing.

This study evaluated the effect of FI (Fraction I, molecular weight < 1 kDa), which is separated from natural whey protein, on the antioxidant activity, sensory quality, color, texture characteristics, and microbial growth of pork balls during repeated freeze-thaw cycles (F-T cycles). The results indicated that pork balls mixed with FI significantly improved in quality after repeating the F-T cycle, especially with the addition of 10% FI. The quality was improved significantly after repeated F-T cycles by adding 10% FI, and the antioxidant activity after seven F-T cycles decreased by 40.78%, a similar result to that obtained with the addition of 0.02% BHA. In addition, FI effectively reduced the sensory damage of pork balls caused by repeated freezing-thawing and also significantly inhibited the growth of microorganisms. In summary, FI not only has excellent antioxidant capacity under repeated freeze-thaw conditions but also has significant antibacterial and quality preservation effects and is expected to be quantified as a kind of natural food additive with antibacterial and antioxidant properties. This paper not only explores the effect of FI on the quality characteristics of frozen and thawed pork balls in prepared dishes but also provides a theoretical basis for the application of whey polypeptides in prepared meat.

Protection of Whey Polypeptide on the Lipid Oxidation, Color, and Textural Stability of Frozen-Thawed Spanish Mackerel Surimi.

Repeated freeze-thaw (FT) cycles can have an impact on surimi quality. In this study, we used 0.02% BHA as a positive control group. We examined the effects of different concentrations (0%, 5%, 10%, and 15%) of whey protein hydrolysate (WPH) on surimi, focusing on alterations in color metrics (L* for brightness, a* for red-green, b* for yellow-blue, and overall whiteness), textural characteristics, and antioxidant capacity during various freeze-thaw (FT) cycles. The results showed that the lipid oxidant values of surimi, as well as its a* and b* values, rose as the number of FT cycles increased; whereas the adhesiveness, resilience, gumminess, and shear force dropped, as did L* and the whiteness values, leading to an overall darkening of color and gloss. By contrast, the study found that the addition of WPH could effectively slow down the decrease of surimi textural stability after repeated freeze-thawing, with the textural stability of the group with 15% WPH being significantly superior to those of the other groups (p < 0.05). Under the same number of cycles, adding 15% WPH to the experimental group could successfully lower total volatile basic nitrogen (TVB-N) and effectively increase the antioxidant activity of surimi. This finding suggested that 15% WPH had the greatest effect on increasing surimi FT stability. To conclude, it was proved that WPH can be added to frozen surimi and improve its quality.

Effects of carboxymethyl chitosan on the oxidation stability and gel properties of myofibrillar protein from frozen pork patties.

The effect of carboxymethyl chitosan (CMCH) on the oxidation stability and gel properties of myofibrillar protein (MP) from frozen pork patties was investigated. The results showed that CMCH could inhibit the denaturation of MP induced by freezing. Compared with the control group, the protein solubility was significantly (P < 0.05) increased, while the carbonyl content, the loss of sulfhydryl groups, and the surface hydrophobicity were decreased, respectively. Meanwhile, the incorporation of CMCH could alleviate the influence of frozen storage on water mobility and reduce the water loss. With the increased concentration of CMCH, the whiteness, strength, and water-holding capacity (WHC) of MP gels were significantly improved, in which the maximum value was at addition level of 1 %. In addition, CMCH inhibited the decrease in the maximum elastic (G') value and loss factor (tan δ) value of samples. By scanning electron microscopy (SEM) observation, CMCH stabilized the microstructure of the gel and maintained the relative integrity of the gel tissue. These findings suggest that CMCH could be used as a cryoprotectant to maintain the structural stability of MP in pork patty during frozen storage.

Catechins affect the oil-holding capacity of meat batters by changing the structure and emulsifying properties of surface proteins at the fat globules.

The effects of different concentrations of catechins on the oil-holding capacity, myofibrillar proteins (MPs) structure and adsorbed properties of interfacial proteins in meat batters were investigated. The addition of 100 mg/kg catechin had no negative effects on the physicochemical properties of meat batter. However, 500 and 1500 mg/kg catechin caused an increase in drip loss and deterioration of dynamic rheological properties; the total sulfhydryl content, surface hydrophobicity and α-helix ratio of MPs decreased significantly (p < 0.05); in meat emulsions, the emulsifying property was reduced, the particle size increased, and less interfacial protein was absorbed on the fat globules. All concentrations of catechins significantly (p < 0.05) inhibited lipid oxidation in meat batters. Medium and high concentrations of catechins induced aggregation of MPs via covalent and noncovalent interactions between MPs and MPs or MPs and catechins, which destroyed the gel and emulsifying property of protein and eventually decrease the oil-holding capacity of meat batters.

The Effects and Regulatory Mechanism of Casein-Derived Peptide VLPVPQK in Alleviating Insulin Resistance of HepG2 Cells.

The liver plays a key role in keeping the homeostasis of glucose and lipid metabolism. Insulin resistance of the liver induced by extra glucose and lipid ingestion contributes greatly to chronic metabolic disease, which is greatly threatening to human health. The small peptide, VLPVPQK, originating from casein hydrolysates of milk, shows various health-promoting functions. However, the effects of VLPVPQK on metabolic disorders of the liver are still not fully understood. Therefore, in the present study, the effects and regulatory mechanism of VLPVPQK on insulin-resistant HepG2 cells was further investigated. The results showed that VLPVPQK exerted strong scavenging capacities against various free radicals, including oxygen radicals, hydroxyl radicals, and cellular reactive oxygen species. In addition, supplementation of VLPVPQK (62.5, 125, and 250 µM) significantly reversed the high glucose and fat (30 mM glucose and 0.2 mM palmitic acid) induced decrement of glucose uptake in HepG2 cells without affecting cell viability. Furthermore, VLPVPQK intervention affected the transcriptomic profiling of the cells. The differentially expressed (DE) genes (FDR < 0.05, and absolute fold change (FC) > 1.5) between VLPVPQK and the model group were mostly enriched in the carbohydrate metabolism-related KEGG pathways. Interestingly, the expression of two core genes (HKDC1 and G6PC1) involved in the above pathways was dramatically elevated after VLPVPQK intervention, which played a key role in regulating glucose metabolism. Furthermore, supplementation of VLPVPQK reversed the high glucose and fat-induced depression of AKR1B10. Overall, VLPVPQK could alleviate the metabolic disorder of hepatocytes by elevating the glucose uptake and eliminating the ROS, while the HKDC1 and AKR1B10 genes might be the potential target genes and play important roles in the process.

Design, synthesis and biological evaluation of quercetin derivatives as novel ß-catenin/B-cell lymphoma 9 protein-protein interaction inhibitors.

The ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for the suppression of hyperactive Wnt/ß-catenin signaling that is vigorously involved in cancer initiation and development. Herein, we first described quercetin and its derivatives had potential inhibitory effects on ß-catenin/BCL9 PPI. The most potent compound, quercetin-3'-O-(4-methylpiperazine-1-yl) propyl (C1), directly binded with ß-catenin and disrupted the ß-catenin/BCL9 interaction in both the protein level and the cellular context. C1 also effectively inhibited colorectal cancer in vitro and showed better selectivity in inhibiting hyperactive Wnt/ß-catenin signaling cells like CT26 and HCT116. And we further confirmed that C1 could inhibit CT26 tumor growth in vivo and regulate the tumor immune microenvironment. This study provides a good chemical probe to explore ß-catenin-related biology and a drug-like quercetin derivative as novel ß-catenin/BCL9 PPI inhibitors for further drug development.

Insights into the Protein Differentiation Mechanism between Jinhua Fatty Ham and Lean Ham through Label-Free Proteomics.

Jinhua lean ham (LH), a dry-cured ham made from the defatted hind legs of pigs, has become increasingly popular among consumers with health concerns. However, the influence of fat removal on the quality of Jinhua ham is still not fully understood. Therefore, a label-free proteomics strategy was used to explore the protein differential profile between Jinhua fatty ham (FH) and lean ham (LH). Results showed that 179 differential proteins (DPs) were detected, including 82 up-regulated and 97 down-regulated DPs in LH vs. FH, among which actin, myosin, tropomyosin, aspartate aminotransferase, pyruvate carboxylase, and glucose-6-phosphate isomerase were considered the key DPs. GO analysis suggested that DPs were mainly involved in binding, catalytic activity, cellular process, and metabolic process, among which catalytic activity was significantly up-regulated in LH. Moreover, the main KEGG-enriched pathways of FH focused on glycogen metabolism, mainly including the TCA cycle, pyruvate metabolism, and glycolysis/gluconeogenesis. However, amino acid metabolism and oxidative phosphorylation were the main metabolic pathways in LH. From the protein differentiation perspective, fat removal significantly promoted protein degradation, amino acid metabolism, and the oxidative phosphorylation process. These findings could help us to understand the effects of fat removal on the nutritional metabolism of Jinhua hams and provide theoretical supports for developing healthier low-fat meat products.