This study aimed to evaluate the protective effects of sodium humate (HNa) alone and in combination with low-dose cefixime (CFM) in mice infected with enterotoxigenic Escherichia coli (ETEC). An ETEC infection mouse model was established to compare the effects of individual or combined interventions on physiological parameters, intestinal morphology, barrier function, levels of specific intestinal bacterial groups, cell proliferation/apoptosis, and inflammatory pathways. The results showed that the HNa + CFM combination significantly promoted body weight recovery, ameliorated damage to jejunal villus structure and ultrastructure, and increased the mRNA expression of mucins (MUC1/2/3) and tight junction proteins (ZO-1, Occludin, Claudin-1) compared to the ETEC group. Concurrently, the combined treatment significantly reduced fecal E. coli counts and increased the abundance of Lactobacillus and Bifidobacterium, promoted epithelial repair by upregulating proliferation-related genes (EGFR, PCNA, TGF-β1), and decreased the Bax/Bcl-2 ratio. Furthermore, the combined intervention significantly reduced serum LPS levels and consequently suppressed ETEC-induced activation of the TLR4/MyD88/NF-κB pathway, as evidenced by reduced protein expression of TLR4 and MyD88, decreased phosphorylation of IκBα and p65, and diminished nuclear accumulation of NF-κB p65, leading to downregulation of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and elevation of IL-10. In conclusion, the combined application of HNa and low-dose CFM showed additional protective benefits against ETEC infection. These effects were associated with multi-targeted repair of the intestinal barrier, modulation of measured bacterial levels, and suppression of excessive inflammatory responses. This strategy offers a potential approach for the clinical management of bacterial enteritis and reducing antibiotic dependence.

Microplastics (MPs), as widespread and increasingly prevalent environmental pollutants, pose a persistent threat to aquatic organisms and mammals, including humans. Sodium humate (HNa), a naturally derived humate salt that is widely available, low-cost, and has a favorable safety profile, exhibits multiple biological activities, including antimicrobial, anti-inflammatory, and antioxidant properties. This study was designed to evaluate whether HNa could protect against intestinal and hepatic injury caused by polystyrene microplastics (PS-MPs) exposure in mice and to clarify the involvement of the gut–liver axis. HNa intervention alleviated impairment of body weight gain and colonic pathological injury following PS-MPs exposure. HNa enhanced intestinal antioxidant capacity, suppressed pro-inflammatory mediator expression, and promoted anti-inflammatory factor expression. Furthermore, HNa upregulated the expression of mucins and adherens junction and tight junction proteins, thereby restoring intestinal barrier function and limiting endotoxin translocation. In the liver, HNa ameliorated histopathological lesions, improved biochemical injury markers, attenuated inflammatory responses, and suppressed excessive activation of the TLR4/NF-κB pathway. Collectively, HNa mitigated gut–liver axis injury following PS-MPs exposure in mice through coordinated protection of intestinal barrier integrity and attenuation of hepatic inflammatory signaling. This study provides the first experimental evidence that HNa mitigates PS-MPs toxicity by protecting the gut–liver axis, supporting its potential as a practical intervention strategy against MPs-related digestive system injury.

Neuroblastoma in children is commonly found as an extracranial solid tumor with poor prognosis in high-risk cases impeding successful treatment. While dysregulated cell death mechanisms and metabolic reprogramming are hallmarks of cancer progression, the interplay between fatty acid metabolism and cell death pathway regulation in neuroblastoma remains incompletely understood. Identifying molecular subtypes influenced by fatty acid metabolism were built by consensus clustering analysis. Independent prognostic genes were identified through random survival forest analysis, acquiring a novel risk signature. Risk signatures were validated internally and externally, and their independent prognostic value, immune landscape, and drug susceptibility were explored. The study systematically analyzed correlations between signature genes and seven major cell death pathways (apoptosis, pyroptosis, ferroptosis, autophagy, necroptosis, cuproptosis, and disulfidptosis), encompassing over 1,200 genes to comprehensively explore the intricate relationships between these molecular signatures and diverse cell death mechanisms. Gene Set Enrichment Analysis (GSEA) was performed to assess pathway-level associations. Utilizing a single-cell dataset of neuroblastoma samples, cells were categorized and labeled based on UMAP analysis. Feature map visualization was employed to display the expression level and allocation of specific genes across various cell populations. Validation of CHD5 expression in NB cells and tissues was confirmed through Western blotting and immunohistochemical staining. The study identified 42 fatty acid metabolism key enzyme genes whose expression was significantly different within high-risk and non-high-risk neuroblastoma patients, by which acquiring two distinct prognostic clusters associated with fatty acid metabolism. A machine learning approach was used to select 4 hub genes (CHD5, TP63, XKR4, and CTAG1A) for the establishment of a fatty acid metabolism prognostic risk model. Cell death pathway analysis revealed that TP63 exhibited the strongest correlations across multiple death pathways, particularly with necroptosis (r = 0.684, p = 2.80e-23) and pyroptosis (r = 0.647, p = 3.12e-20), while XKR4 showed moderate correlations with autophagy (r = 0.398, p = 2.09e-07) and CHD5 displayed selective associations. High risk score and low risk score groups displayed notable variations in the immune microenvironment, characterized by reduced immune cell infiltration in the high group leading to immune escape, and conversely, heightened responsiveness of the low group to immune checkpoint blockade therapy. Single-cell dataset analysis highlighted significant expression of CHD5 in specific cell populations, suggesting its potential as a marker gene for neuroblastoma. Immunohistochemical staining revealed varying levels of CHD5 expression across different clinical stages of neuroblastoma, with decreased deposition observed as staging advances. Functionally, CHD5 expression was found to inhibit proliferation, migration, and invasion of neuroblastoma cells. The developed fatty acid metabolism prognostic risk model underscores the significance of fatty acids in neuroblastoma prognosis and immune landscape, thereby facilitating the optimization of chemotherapy and immunotherapy strategies for this disease. The comprehensive analysis of cell death pathways revealed distinct regulatory mechanisms of signature genes, particularly highlighting TP63's central role in coordinating multiple cell death processes. CHD5, as an identified gene inhibiting the proliferation, invasion and metastasis of neuroblastoma cells, serves as a novel tumor biomarker.

This study aimed to investigate the beneficial effects of α-linolenic acid (ALA) on intestinal barrier function and antioxidant status in broilers, along with the associated molecular mechanisms. 320 one-day-old Arbor Acres broilers were randomly divided into four groups, each with eight replicates, and fed diets with 0 (control), 200, 400, and 600 mg of ALA/kg for 42 days. ALA supplementation did not significantly affect the broilers' overall growth performance. Supplementing diets with 400 and 600 mg/kg of ALA significantly enhanced (p < 0.05) jejunal and ileal villus height, the jejunal villus height to crypt depth ratio, and ileal mRNA expression and protein levels of Zonula occludens-1 (ZO-1) and occludin in broilers on Day 42. Broilers fed diets containing 600 mg/kg of ALA exhibited significantly increased (p < 0.05) serum catalase (CAT) activity, total antioxidant capacity (T-AOC), and jejunal and ileal activities of CAT and total superoxide dismutase (T-SOD), alongside reduced malondialdehyde (MDA) concentrations in serum, jejunum, and ileum on Days 21 and 42, compared to the control group. Supplementing 600 mg/kg of ALA significantly increased (p < 0.05) the mRNA expressions of CAT, SOD1, NRF2, and HO-1, along with the protein levels of cytoplasmic and nuclear NRF2 and HO-1 in the jejunum and ileum on Days 21 and 42. These findings demonstrate the protective effects of ALA in improving intestinal health in broilers. The underlying mechanisms may involve enhancing intestinal barrier integrity by increasing tight junction protein abundance and boosting intestinal antioxidant capacity by elevating antioxidant enzyme activity and activating the NRF2 pathway. In conclusion, our results showed that 600 mg/kg of ALA was identified as the optimal concentration for improving intestinal barrier function and antioxidant status in broilers, highlighting its potential for protecting intestinal health through ALA-based interventions.

Sorafenib (Sor), a first-line drug for advanced hepatocellular carcinoma (HCC), can potently induce tumor ferroptosis by inhibiting the cystine/glutamate countertransporter (System Xc-). However, tumors can upregulate the expression of ferritin to prevent its progression to ferroptosis, which induces Sor insensitivity. In this study, ultrasound (US) reaction nanoparticles (NPs) composed of ferritin-homing peptide (HKN15)-modified poly (lactic-coglycolic acid) and the acoustic droplet vaporization (ADV)-responsive material perfluorhexane (PFH) were fabricated. Owing to the positive feedback effects of HKN15 and ferritin overexpression, the NPs (HKN15@PLGA-PFH) specifically accumulate around ferritin in HCC cells. With US irradiation at pathological regions, the spatiotemporally ADV effect can influence the stability of the iron pool named ferritin, which releases cellular iron, leading to inevitable ferroptosis through the production of ROS and lipid peroxidation and a reduction in GSH and GPx4. Overall, the cytotoxic effect of the combined treatment group was 1.6 times greater than that of the Sor-only group against HCC cells, which highlights an innovative potential strategy for increasing the therapeutic efficacy of Sor through combined treatment to sensitize HCC cells to ferroptosis.

There is an urgent need for effective treatments targeting comorbidities of type 2 diabetes (T2DM) and obesity. Developing dual agonists of glucagon-like peptide 1 receptor (GLP-1R) and neuropeptide Y receptor type 2 (NPY2R) with combined PYY3-36 and GLP-1 bioactivity is promising. However, designing such dual agonists that effectively control glycemia and reduce weight while minimizing gastrointestinal side effects is challenging. In this study, we systematically evaluated the side effects induced by co-administering various GLP-1R agonists and PYY3-36 analogue. Our findings revealed that different GLP-1R agonist-PYY analogue combinations elicited gastrointestinal side effects of varying intensities. Among these, the co-administration of bullfrog GLP-1 analogue (bGLP-1) with PYY3-36 analogue resulted in lower gastrointestinal side effects. Thus, bGLP-1 was selected as the preferred candidate for designing dual GLP-1R/NPY2R agonists. Through stepwise structural design, optimization of linker arms, and durability enhancements, coupled with in vitro receptor screening, the novel peptide bGLP/PYY-19 emerged as the lead candidate. Notably, experimental results in mice and rats showed a significant reduction in emesis with bGLP/PYY-19 compared to semaglutide and bGLP-1 long-acting analogue (LAbGLP-1). Furthermore, bGLP/PYY-19 significantly outperformed semaglutide and LAbGLP-1 in reducing body weight in diet-induced obese (DIO) mice, without inducing nausea-associated behavior. These findings underscore the potential of dual-targeting single peptide conjugates as a promising strategy for developing glucoregulatory treatments that offer superior weight loss benefits and are better tolerated compared to treatments targeting GLP-1R alone.

Selenium (Se), an essential trace element, plays a critical role in protecting the toxicity of methylmercury (MeHg). However, its detoxification mechanism for alleviating MeHg-induced damage remains largely unexplored. This study focused on the antagonistic effects of Se supplementation on the toxic responses induced by MeHg pretreatment in Caenorhabditis elegans. Our results showed that following a 20 h pre-exposure to MeHg, 4 h exposure to Se effectively and rapidly antagonized the reproductive and neurological impairments induced by MeHg. Meanwhile, we found that the total Hg content decreased from 166 ± 46.0 to 109 ± 18.7 μg/g after the addition of Se. Apart from inhibiting the bioaccumulation of Hg, Se supplementation reduced MeHg-induced reactive oxygen species (ROS) and promoted mitochondrial fusion to improve mitochondrial quality. In addition, MeHg-induced autophagy could be alleviated by increasing lysosome activity after the addition of Se. Further studies revealed that Se supplementation modulated the expression of gss-1 and gst-4, regulating glutathione (GSH) synthesis and elevated MeHg-decreased GSH content from 45.5 % to 79.7 %. These findings suggested that Se recovered MeHg-induced reproductive and neurological damage by modulating mitochondrial function and GSH synthesis, providing valuable insights for developing novel therapeutic strategies against MeHg toxicity.

Although hyperlipidemia is a key factor in cardiovascular disease, there are limited safe and effective therapies for disorders of lipid metabolism. This study investigated the therapeutic potential of Ginkgolide B (GB), a bioactive component of Ginkgo biloba leaves, in ameliorating hyperlipidemia and explored its underlying mechanisms. Utilizing a high-fat diet-induced hyperlipidemic rat model and lipidomics analysis, the study showed that GB significantly decreased serum total cholesterol, triglyceride, and low-density lipoprotein levels. Lipidomics revealed that GB reversed dysregulated sphingolipid metabolism, notably decreasing ceramides levels and increasing sphingomyelins, which are implicated in metabolic inflammation and oxidative stress. Mechanistically, GB activated PPARα, thereby enhancing fatty acid oxidation and upregulating the Nrf2 pathway to mitigate oxidative damage. These dual effects were validated in vitro using HepG2 cells, where GB reduced lipid accumulation and improved antioxidant defenses. Overall, these findings highlight GB as a promising therapeutic agent for hyperlipidemia by restoring sphingolipid homeostasis and targeting the interplay between lipid metabolism and oxidative stress.

Postmenopausal women face an elevated risk of osteoporosis due to decreased estradiol secretion. Obesity is also a prevalent disease during menopause, but the impact on bone health is understudied. Genistein (GEN) is a soy-derived isoflavone that has beneficial effects on a variety of age-related diseases, but the exact role of GEN in bone health in hypoestrogenism and obesity-induced stress remains to be elucidated. This study employed an ovariectomized (OVX) mouse model subjected to a high-fat diet to simulate postmenopausal obesity and investigate the effects of GEN intake on bone metabolism. Bone mass alterations and metabolic function were evaluated using micro-CT imaging, biochemical markers, and histopathological staining. The homeostasis of the bone matrix was further assessed through primary bone marrow cell differentiation assays, western blotting, and quantitative real-time PCR (qRT-PCR). Additionally, intestinal barrier protein expression, 16S rRNA gene sequencing, and untargeted metabolomics were integrated to examine GEN's impact on gut structure, microbiota composition, and fecal metabolic profiles. Our findings indicated that diet-induced obesity (DIO) exacerbated OVX-induced osteopenia in mice, whereas GEN supplementation significantly mitigated bone loss and restored balanced differentiation among osteoblasts, adipocytes, and osteoclasts. Furthermore, GEN improved metabolic abnormalities associated with obesity. It also preserved intestinal barrier integrity by maintaining tight junction proteins and mucus levels, thereby reducing systemic inflammation. The results of 16s rDNA gene sequencing showed that GEN alleviated intestinal microbiota dysbiosis and increased the abundance of beneficial bacteria g-Dubosiella and g-Blautia in feces. Moreover, metabolomics analysis showed that GEN intervention could alleviate lipid peroxidation and promote primary bile acid biosynthesis. In conclusion, long-term intake of GEN can regulate gut microbiota composition and metabolism, maintain intestinal barrier function, ameliorate pathological metabolic abnormalities, and ultimately prevent obesity and estrogen hypoestrogenic-induced osteopenia. These findings provide novel insights into how GEN intake and soy diet prevent osteoporosis.

BACKGROUND/OBJECTIVES:Di-2-ethylhexyl phthalate (DEHP) is a universally used plasticizer and EDCs. Our previous studies verified that prolonged contact with DEHP induced detrimental impacts on reproductive physiology. Resveratrol (RES), a polyphenolic compound predominantly concentrated in Vitis vinifera epidermis, exhibits multifaceted pharmacological properties. The purpose of this study was to investigate whether RES can alleviate testicular injury caused by DEHP, and to investigate its possible mechanism. METHODS:The experimental design comprised 4 randomized groups of male SD rats: Control group: each animal was given corn oil and saline. DEHP group: the animals received DEHP (500 mg/kg/day) and saline. DEHP and RES group: the animals received DEHP (500 mg/kg/day) and RES (60 mg/kg/day). RES group: the animals received corn oil and RES (60 mg/kg/day). RESULTS:In vivo, RES alleviated DEHP-induced testicular ferroptosis by upregulating SIRT1 and enhancing its interaction with HIF-1α. This mechanism suppressed mitophagy, decreased Fe²⁺and ROS release, and inhibited lipid peroxidation. TM4 cell experiments confirmed these findings. Notably, SIRT1 knockdown inhibited the remission effect of RES on ferroptosis. CONCLUSIONS:In summary, we demonstrated that RES mitigated testicular damage caused by DEHP by inhibiting ferroptosis through the SIRT1-HIF-1α axis. This investigation delineates novel molecular targets and mechanistic frameworks for developing therapeutic interventions against DEHP toxicity.

The activation, injury, and dysfunction of endothelial cells are considered to be the initial key events in the development of atherosclerosis. Di (2-ethylhexyl) phthalate (DEHP), a prevalent organic pollutant, can cause damage to multiple organs. Polysaccharide of Atractylodes macrocephala Koidz (PAMK) is a bioactive compound extracted from A. macrocephala Koidz with various biological activities. This study investigates the protective effects of PAMK on porcine aortic valve endothelial cells (PAVEC) damaged by DEHP. PAVECs treated with DEHP alone or with PAMK showed reduced cell apoptosis and death in PAMK-pretreated cells. PAMK up-regulated Bcl-2 expression and down-regulated Bax protein, suppressing apoptosis. Flow cytometry analysis demonstrated that PAMK protected PAVECs from DEHP-induced damage. These findings suggest that PAMK inhibits cell apoptosis and protects against DEHP damage in endothelial cells.

Inorganic arsenic (iAs) is a well-recognized environmental pollutant that induces severe brain injury in humans and animals. The antioxidant, anti-inflammatory, and anti-ferroptotic effects of resveratrol (Res) were demonstrated in multiple animal experiments. In order to investigate the protective effect of Res on iAs-induced chicken brain injury, the 40 chickens (19-d-old, female) brain injury model was established by oral administration of iAs (30 mg/L NaAsO2) for 6 weeks. All chickens had free access to both food and water during the experiment. The biochemical indices, hematoxylin-eosin staining, and related protein levels of oxidative stress, inflammation and ferroptosis were then determined. Our results indicated that Res (1000 mg/kg) alleviated the iAs-induced brain injury after 6 weeks of oral administration, primarily by reducing the interleukin-1 beta mRNA expression and nuclear factor kappa B and malondialdehyde level, and increasing the antioxidant enzyme activity and the mRNA expression of nuclear factor erythroid 2-related factor 2 (Nrf2). Taken together, our study demonstrates that Res effectively inhibits iAs-induced oxidative stress and ferroptosis by mediating the Nrf2 signaling pathway, thereby alleviating iAs-induced brain injury in chickens. This is the first time that the amelioration effects of Res on the iAs-induced brain have been investigated from multiple perspectives.

The objective of this study was to investigate the protective effects and mechanisms of dietary administration of sodium humate (HNa) and its zinc and selenium chelate (Zn/Se-HNa) in mitigating Salmonella Typhimurium (S. Typhi) induced intestinal injury in broiler chickens. Following the gavage of 109 CFU S. Typhi to 240 broilers from 21-d to 23-d aged, various growth performance parameters such as body weight (BW), average daily gain (ADG), average daily feed intake (ADFI), and feed ratio (FCR) were measured before and after infection. Intestinal morphology was assessed to determine the villus height, crypt depth, and chorionic cryptologic ratio. To evaluate intestinal barrier integrity, levels of serum diamine oxidase (DAO), D-lactic acid, tight junction proteins, and the related genes were measured in each group of broilers. An analysis was conducted on inflammatory-related cytokines, oxidase activity, and Nuclear Factor Kappa B (NF-kappa B) and Nuclear factor erythroid2-related factor 2 (Nrf2) pathway-related proteins and mRNA expression. The results revealed a significant decrease in BW, ADG, and FCR in S. typhi-infected broilers. HNa tended to increase FCR (P = 0.056) while the supplementation of Zn/Se-HNa significantly restored BW and ADG (P < 0.05). HNa and Zn/Se-HNa exhibit favorable and comparable effects in enhancing the levels of serum DAO, Dlactate, and mRNA and protein expression of jejunum and ileal tight junction. In comparison to HNa, Zn/SeHNa demonstrates a greater reduction in S. Typhi shedding in feces, as well as superior efficacy in enhancing the intestinal morphology, increasing serum catalase (CAT) activity, inhibiting pro-inflammatory cytokines, and suppressing the activation of the NF-kappa B pathway. Collectively, Zn/Se-HNa was a more effective treatment than HNa to alleviate adverse impact of S. Typhi infection in broiler chickens.

Obesity is an important risk factor for breast cancer in women before and after menopause. Adipocytes, key mediators in the tumor microenvironment, play a pivotal role in the relationship between obesity with cancer. However, the potential of dietary components in modulating this relationship remains underexplored. Genistein, a soy-derived isoflavone, has shown promise in reducing breast cancer risk, attenuating obesity-associated inflammation, and improving insulin resistance. However, there are no reports examining whether genistein has the ability to reduce the effects of obesity on breast tumor development. In this study, we constructed a mammary tumor model in ovariectomized obese mice and examined the effects of genistein on body condition and tumor growth. Moreover, the effects of genistein on the tumor microenvironment were examined via experimental observation of peritumoral adipocytes and macrophages. In addition, we further investigated the effect of genistein on adipocyte and breast cancer cell crosstalk via coculture experiments. Our findings indicate that dietary genistein significantly alleviates obesity, systemic inflammation, and metabolic disorders induced by a high-fat diet in ovariectomized mice. Notably, it also inhibits tumor growth in vivo. The impact of genistein extends to the tumor microenvironment, where it reduces the production of cancer-associated adipocytes (CAAs) and the recruitment of M2d-subtype macrophages. In vitro, genistein mitigates the transition of adipocytes into CAAs and inhibits the expression of inflammatory factors by activating PPAR-γ pathway and degrading nuclear NF-κB. Furthermore, it impedes the acquisition of invasive properties and epithelial‒mesenchymal transition in breast cancer cells under CAA-induced inflammation, disrupting the Wnt3a/β-catenin pathway. Intriguingly, the PPAR-γ inhibitor T0070907 counteracted the effects of genistein in the coculture system, underscoring the specificity of its action. Our study revealed that genistein can mitigate the adverse effects of obesity on breast cancer by modulating the tumor microenvironment. These findings provide new insights into how genistein intake and a soy-based diet can reduce breast cancer risk.

The development of cisplatin resistance is one of the major causes of mammary cancer treatment failure, and is associated with changes in Sox4 gene expression. To investigate the characteristic changes that occur in canine mammary gland tumor (CMGT) cells following the development of acquired cisplatin resistance, along with the relationship between these changes and the Sox4 gene. We constructed cisplatin-resistant cell line, CHMpCIS, from the cell line CHMp, which was isolated from the primary lesion of a malignant CMGT. The biological characteristics of these cells were examined by Western blot analysis, Transwell assays, and mammosphere formation assays. Compared to CHMp cells, CHMpCIS cells exhibited elevated cisplatin resistance, apoptotic escape ability, enhanced epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) features, in addition to over-activation of the Wnt/β-catenin signaling pathway and increased Sox4 protein. In CMGT cases, CMGT tissues (CMGTT) expressed higher levels of Sox4 protein and mRNA compared to adjacent tissues (CAMGTT). We found that these changes were inhibited by silencing of Sox4 expression in CHMpCIS cells. Furthermore, activation of the Wnt/β-catenin signaling pathway increased Sox4 expression levels through a positive feedback loop. These results suggested that CHMpCIS cells circumvented the damage caused by cisplatin through altering the expression of the Sox4 gene and activating the Wnt/β-catenin pathway, thereby changing the cellular biological characteristics.

Osteoarthritis (OA) is a common arthritis types in animals that causes persistent pain and reduces quality of life. Although a high-fat diet (HFD) is widely believed to induce obesity and have adverse effects on the body, the connection between HFD and joint health is not well understood. Therefore, in this study, 32 healthy male New Zealand rabbits were randomly divided into four groups: healthy rabbits fed a standard diet (NDG, n=8) or an HFD (HDG, n=8), rabbits fed a standard diet (OAG, n=8) and an HFD (HOG, n=8), and arthritis was induced by intra-articular enzyme injection. After 12 weeks of HFD feeding, articular cartilage, synovium, and subchondral bone were isolated and collected. Joint tissue damage was evaluated using histopathological and imaging tests. The results showed that there was no significant difference in body weight between rabbits fed a normal diet and those fed an HFD. However, the HFD led to an increase in joint injuries in both induced and non-induced arthritis rabbits. Specifically, the HFD induced lipid metabolism disorders and liver damage in vivo, significantly elevating the levels of serum inflammatory cytokines and bone metabolism markers. Moreover, HFD exacerbated articular cartilage damage in the joints and increased the accumulation of inflammatory cells in synovial tissue, resulting in a notable increase in synovial macrophages and inflammatory cytokines. Additionally, HFD accelerated the bone resorption process in subchondral bone, leading to the destruction of bone mass and subchondral bone microstructure. In summary, the results of this study indicate that an HFD can cause histological damage to the articular cartilage, synovium, and subchondral bone in rabbits, exacerbating arthritis in pre-existing joint damage. Notably, weight is not the primary factor in this effect.

Osteoarthritis (OA) is the most common joint disease, causing symptoms such as joint pain, swelling, and deformity, which severely affect patients’ quality of life. Despite advances in medical treatment, OA management remains challenging, necessitating the development of safe and effective drugs. Quercetin (QUE), a natural flavonoid widely found in fruits and vegetables, shows promise due to its broad range of pharmacological effects, particularly in various degenerative diseases. However, its role in preventing OA progression and its underlying mechanisms remain unclear. In this study, we demonstrated that QUE has a protective effect against OA development both in vivo and in vitro, and we elucidated the underlying molecular mechanisms. In vitro, QUE inhibited the expression of IL−1β-induced chondrocyte matrix metalloproteinases (MMP3 and MMP13) and inflammatory mediators such as INOS and COX−2. It also promoted the expression of collagen II, thereby preventing the extracellular matrix (ECM). Mechanistically, QUE exerts its protective effect on chondrocytes by activating the SIRT1/Nrf−2/HO−1 and inhibiting chondrocyte ferroptosis. Similarly, in an OA rat model induced by anterior cruciate ligament transection (ACLT), QUE treatment improved articular cartilage damage, reduced joint pain, and normalized abnormal subchondral bone remodeling. QUE also reduced serum IL−1β, TNF−α, MMP3, CTX−II, and COMP, thereby slowing the progression of OA. QUE exerts chondroprotective effects by inhibiting chondrocyte oxidative damage and ferroptosis through the SIRT1/Nrf−2/HO−1 pathway, effectively alleviating OA progression in rats.

Acute kidney injury (AKI) is a syndrome characterized by the rapid loss of the renal function and has high morbidity and mortality worldwide, yet there is no satisfactory means of prevention and treatment at present. Dioscin, a natural steroidal saponin, has been found to have antioxidant, anti-inflammatory and anti-apoptotic effects. In this experiment, we pretreated cisplatin-induced AKI rats with dioscin and found that dioscin significantly enhanced renal function and reduced renal pathological injury in AKI rats. We also found that dioscin improved renal antioxidant capacity by suppressing the accumulation of oxides such as ROS, MDA and H2O2, and increasing the levels of antioxidant enzymes SOD and CAT. In addition, dioscin down-regulated the expression of inflammation-related proteins (IL-1β, TNF-α, NF-κB) and necroptosis-critical proteins RIP1/RIP3, whereas up-regulated Caspase-8 protein levels in the kidney of AKI rats. Mechanistically, dioscin promoted the nuclear transcription of Nrf2 and activated Nrf2/HO-1 signaling axis to play a positive role in the kidney of AKI rats, while the reno-protective effect of dioscin was significantly attenuated after inhibiting Nrf2. In conclusion, our data indicate that dioscin decreases cisplatin-induced renal oxidative stress and thwarts necroptosis induced inflammation via regulating the Nrf2/HO-1pathway. Our study provides more data and theoretical support for the study of natural drugs to improve AKI.

[This corrects the article DOI: 10.1016/j.csbj.2024.04.024.].

In order to explore the therapeutic effect of Resveratrol (Res)-activated Natural Killer (NK) cells on canine mammary tumors, this study employed a range of assays, including wound healing, colony formation, Transwell, flow cytometry, and Western blot experiments, to investigate the impact of Res-pretreated NK cells on canine mammary tumor cells in vitro. Additionally, a tumor-bearing mouse model was utilized to further analyze the therapeutic effects of Res-pretreated NK cells in vivo. The results showed that Res enhances the capacity of NK cells to induce apoptosis, pyroptosis, and ferroptosis in canine breast tumor cells, while also augmenting their influence on the migration, invasion, and epithelial-mesenchymal transition of these cells. Furthermore, pretreatment of NK cells with Res significantly amplified their inhibitory effect on breast tumor growth in vivo and promoted tumor tissue apoptosis. Additionally, Res enhanced the recruitment of NK cells to other immune cells in the body. In summary, Res has been shown to enhance the anti-breast-tumor effect of NK cells both in vitro and in vivo, offering a new avenue for optimizing immunotherapy for canine breast tumors.