To investigate the efficacy and potential mechanisms of MGFKP on rabbit atherosclerotic models.

The left carotid balloon injury surgery were used to establish the rabbit atherosclerotic model, followed by the administration of MGFKP from the second postoperative for 6 weeks. Left carotid ultrasound and histological analysis were determined to evaluate the anti-atherosclerotic efficacy of MGFKP. Additionally, LC-MS and network pharmacology were conducted to identify the active ingredients of MGFKP and their targets, respectively. Lastly, core targets were selected to validate using immunohistochemical staining, western blot or ELISA.

The results revealed that the vascular diameters difference, plaque area, plaque thickness, and ratio of vessel lumen to vessel cross-section radius were significantly improved following treatment with MGFKP (P<0.05). 539 ingredients of MGFKP were identified by LC-MS, and 23 ingredients were screened using SwissADME for network pharmacology. After combining the results of PPI and KEGG analyses with published literature, TLR4, NF-κB, IL-1β, and TNF-α were selected for the ensuing analyses. Molecular docking of most compounds showed satisfactory docking energy between TLR4, NF-κB, IL-1β, and TNF-α with their matched compounds. Finally, immunohistochemical analysis of TLR4 and western blot results of NF-κB, TNF-α, and IL-1β demonstrated that these proteins levels were obviously increased in the model group and significantly decreased in MGFKP group (P<0.05). The levels of TNF-α, IL-6, IL-1β were also significantly reduced following MGFKP treatment.

MGFKP is a potential drug for the treatment of atherosclerosis, and might suppress the TLR4/NF-κB inflammatory pathway to alleviate atherosclerotic plaque progression.

The study is to explore the biosynthesis of cyanidin-3-glucoside-4-vinylcatechol (C3G_VC) through Lactiplantibacillus plantarum-fermented caffeic acid and cyanidin-3-glucoside (C3G) extract (molar ratio = 1:30) in the model medium. C3G_VC was isolated and purified by a venusil ASB-C18 column with a medium-pressure liquid chromatography (MPLC) system. The chemical structure of C3G_VC was identified by high-performance liquid chromatography (HPLC), which showed the maximum absorption wavelength of 505.57 nm. This study showed that Cd exposure of mice induced liver damage, oxidative stress, and inflammation of the gut microbiome. Our findings demonstrated that C3G_VC intervention in Cd-exposed mice significantly mitigated oxidative stress injury by declining the malondialdehyde (MDA) level and increasing the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in the liver, meanwhile alleviating liver injury by decreasing the bile acid (BA) level and accelerating the excretion of fecal BA. Moreover, the Cd_C3G_VC group showed elevated levels of mRNA expression of pro-inflammatory cytokines (IL6, IL1β, and TNF-α) and inhibited BA synthesis (CYP7A1) in Cd-exposed mice. The fermentation results in vitro showed that C3G_VC had a higher residue than that of cyanidin-3-glucoside. The 16S rRNA high-throughput sequencing disclosed that C3G_VC intervention in Cd-exposed mice significantly increased the abundance of Faecalibaculum and unidentified_Lachnospiraceae. It is noteworthy that the C3G_VC supplement increased the abundance of Akkermansia. Overall, this study demonstrated that C3G_VC intervention in Cd-exposed mice had the potential to decrease the occurrence of inflammatory and oxidative stress and maintain bile acid homeostasis by regulating gut microflora.

Cadmium (Cd) is an environmental pollutant with strong immunotoxicity effects. Despite this, the mechanisms by which Cd causes spleen damage in chickens are not well understood. Astilbin (ASB) is a dihydroflavone glycoside with anti-inflammatory and anti-oxidation properties. In the present study, a chicken spleen injury model induced by cadmium exposure (90d) was established to explore the specific mechanisms of Cd-induced spleen injury. If and how ASB ameliorates the damage was also explored. A total of 60 chickens were randomly divided into four groups: Con, Cd, ASB, and Cd+ASB groups. The pathological changes in the spleen were observed by H&E staining. Cd-induced oxidative stress, inflammation, and the involvement of the MAPK/NF-κB/NLRP3 in ameliorating spleen damage were also analyzed by Western blotting, qRT-PCR, and immunohistochemistry. Our results showed that Cd exposure for 90 days damaged the spleen, which mainly manifested as eosinophil infiltration, an increase in MDA content, a decrease in the CAT, GSH, SOD, and T-AOC, and activation of MAPK/NF-κB/NLRP3 signaling pathway. The overall outcome of these events was the induction of oxidative stress and inflammation in the spleen of the chickens. Interestingly, ASB treatment ameliorated Cd-induced damages. In conclusion, the present study revealed the specific mechanism of Cd-induced spleen damage using a chicken model. But ASB ameliorates Cd-induced cadmium poisoning.

Cadmium (Cd) can cause reproductive disorders through epididymal injury. However, the specific molecular mechanism of Cd-induced epididymal toxic injury is rarely reported. In this study, the model of Cd poisoning in pig epididymis was established. Ten 6-week-old male piglets were divided into two groups. The control group was fed a basic diet, while the Cd group received a diet supplemented with 20 mg/kg CdCl2. After 40 days, All piglets were euthanized, and epididymal tissues were collected to detect morphological changes, trace element contents, oxidative stress (OS) parameters, toll like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling pathway and necroptosis marker genes. This study showed that Cd led to an increased concentration of Cd element in pig epididymis. According to morphological observation, pig epididymal tissue in the Cd group was damaged. Cd decreased the contents of glutathione (GSH), total antioxidant capacity (T-AOC), catalase (CAT), dismutase (SOD), and glutathione peroxidase (GSH-px), but the contents of hydrogen peroxide (H2O2) and malondialdehyde (MDA) were increased. Additionally, Caspase 8 expression was decreased, whereas the expression of TLR4, NF-κB, FADD, RIPK1, RIPK3, MLKL and heat shock proteins (HSPs) were increased after Cd stimulation. We concluded that Cd-triggered TLR4/NF-κB signaling pathway and oxidative stress potentially promoted necroptosis in pig epididymis.

Cadmium, a harmful food contaminant, poses severe health risks. There are ongoing efforts to reduce cadmium pollution and alleviate its toxicity, including plant-based dietary intervention. This review hypothesizes that microRNAs (miRNAs), as regulatory eukaryotic transcripts, play crucial roles in modulating cadmium-induced organ damage, and plant food-derived bioactive compounds provide protective effects via miRNA-mediated mechanisms. The review reveals that there are interplays between certain miRNAs and plant food-derived dietary bioactive substances when these bioactives, especially phenolics, counteract cadmium toxicity through regulating physiologic and pathologic events (including oxidative stress, apoptosis, autophagy and inflammation). The review discusses common miRNA-associated physiologic/pathologic events and signal pathways shared by the cadmium toxicity and dietary intervention processes. This paper identifies the existing knowledge gaps and potential future work (e.g. joint actions between miRNAs and other noncoding RNAs in the fights against cadmium). The insights provided by this review can improve food safety strategies and public health outcomes.

Cadmium (Cd) is a heavy metal that pollutes the environment and threatens human and animal health via the food chain. The spleen is one of the target organs affected by Cd toxicity. However, the mechanism of Cd toxicity is not fully understood. In this study, 80 chicks were allocated into 4 groups (n = 20) and exposed to different doses of CdCl2 (0 mg/kg, 35 mg/kg, 70 mg/kg and 140 mg/kg) for 90 d. The pathological changes in the spleen, mitochondrial dynamics-related factors, cytochrome P450 (CYP450) enzyme system contents, activities, transcription levels, nuclear receptors (NRs) response molecule levels, and mitochondrial unfolded protein-related factors were detected. The findings indicate that exposure to Cd significantly leads to spleen injury. In Cd groups, the total contents of CYP450 and cytochrome b5 (Cyt b5) increased, and the activities of the CYP450 enzyme system (APND, ERND, AH, and NCR) changed. The NRs response was induced, and the gene levels of AHR/CAR and corresponding CYP450 isoforms (CYP1B1, CYP1A5, CYP1A1, CYP2C18, CYP2D6 and CYP3A4) were found altered. The study found that Cd exposure altered the mRNA expression levels of mitochondrial dynamics-related factors, such as OPA1, Fis1, MFF, Mfn1, and Mfn2, breaking mitochondrial fusion and cleavage and ultimately leading to mitochondrial dysfunction. Changes were detected in the gene levels of several mitochondrial unfolded protein response (mtUPR)-related factors, namely (SIRT1, PGC-1α, NRF1, TFAM, SOD2, and HtrA2). Cd also altered the gene levels of mitochondrial function-related factors (VDAC1, Cyt-C, COA6, PRDX3, RAF and SIRT3). It is showed that Cd can initiate the NRs response, influence the homeostasis of the CPY450 enzyme system, trigger the mtUPR, impair mitochondrial function, and ultimately lead to Cd toxicity in the spleen of chickens.

Cadmium (Cd) has adverse effects on organisms. Serine is an essential nutritional factor and its nutritional value is extremely high for body. To explore the effects of serine on spleen toxicity induced by Cd in mice, cadmium chloride (CdCl2, 50 mg/L) and serine (50 g/L) were individually administered or co-administrated in drinking water of mice for 18 weeks. Results demonstrated that Cd exposure induced splenic toxicity and serine against the toxicity damage caused by Cd in mice. Under Cd stress, trace element homeostasis was disturbed, the mice's body weight and spleen index were increased, and splenic morphology and ultrastructure were altered. Furthermore, Cd exposure led to the cell populations disorder, which in turn triggers cell death. Notably, Cd treatment induced oxidative stress and inflammation, increased M1/M2 (iNOS, CD68) and Th1/Th2 (T-bet, CD4) levels, decreased M1/M2 (Arg1) and Th1/Th2 (GATA3) levels, while disrupted the macrophages and lymphocytes homeostasis, which trigged apoptosis and pyroptosis in spleen. In contrast, serine supplementation changed the levels of Cd and other elements, weakened Cd-induced tissue damage and inflammation, enhanced antioxidant capacity, significantly restored cell homeostasis, and effectively inhibited Cd-induced apoptosis and pyroptosis in the spleen. Shortly, the results verified that serine had an ameliorating toxicity effect and restored the M1/M2 and Th1/Th2 balance, restrained apoptosis and pyroptosis induced by Cd.

Cancer prevention is currently envisioned as a molecular-based approach to prevent carcinogenesis in pre-cancerous stages, i.e., dysplasia and carcinoma in situ. Cancer is the second-leading cause of mortality worldwide, and a more than 61% increase is expected by 2040. A detailed exploration of cancer progression pathways, including the NF-kβ signaling pathway, Wnt-B catenin signaling pathway, JAK-STAT pathway, TNF-α-mediated pathway, MAPK/mTOR pathway, and apoptotic and angiogenic pathways and effector molecules involved in cancer development, has been discussed in the manuscript. Critical evaluation of these effector molecules through molecular approaches using phytomolecules can intersect cancer formation and its metastasis. Manipulation of effector molecules like NF-kβ, SOCS, β-catenin, BAX, BAK, VEGF, STAT, Bcl2, p53, caspases, and CDKs has played an important role in inhibiting tumor growth and its spread. Plant-derived secondary metabolites obtained from natural sources have been extensively studied for their cancer-preventing potential in the last few decades. Eugenol, anethole, capsaicin, sanguinarine, EGCG, 6-gingerol, and resveratrol are some examples of such interesting lead molecules and are mentioned in the manuscript. This work is an attempt to put forward a comprehensive approach to understanding cancer progression pathways and their management using effector herbal molecules. The role of different plant metabolites and their chronic toxicity profiling in modulating cancer development pathways has also been highlighted.

Florpyrauxifen-benzyl (FPB) is a new arylpicolinate systemic herbicide that has been used to control or suppress the majority of herbicide-resistant biotype weeds in rice. To our knowledge, the impact of FPB on the immune system remains undetected thus far. Hence, this work aimed to address the toxic effects of FPB and the possible related mechanisms on the spleen of exposed mice. Initially, an acute toxicological test was performed to ascertain the median lethal dose (LD50) of FPB for 24 h which was found to be 371.54 mg/kg b.wt. For mechanistic evaluation of FPB toxicity, three sublethal doses (1/20th, 1/10th, and 1/5th LD50) were orally administered to mice for 21 consecutive days. Changes in spleen relative weight, oxidative status, apoptotic and inflammatory markers, histopathological alterations were evaluated. Following the FPB exposure, significant (p < 0.05) decline in spleen index, apoptotic features, histolopathological changes were observed. Additionally, excessive oxidative stress in spleen tissues was monitored by downregulating antioxidant enzymes and upregulating the oxidant parameters. Furthermore, exposure to FPB resulted in notable activation of the NF-қB signaling pathway, accompanied by elevated levels of pro-inflammatory cytokines (namely, IL-1β and TNF-α) as well as CD3 and CD19 levels have decreased significantly in spleen tissues. Collectively, FPB exposure exhibited apoptosis, oxidative stress, immunosuppression, and inflammatory response in a dose-dependent manner, leading to spleen tissue damage and immunotoxicity. Further studies on FPB is recommended to outstand its hazards on ecosystems.

Cadmium (Cd), a heavy metal, is used in a wide range of applications, such as plastics, electroplating process, electronics, and so forth. Due to its bioaccumulation ability, Cd can contaminate soil, water, air and food. To determine the effect of Cd exposure on the necroptosis in pig spleen and its mechanistic investigation, we constructed a model in pigs by feeding them food containing 20 mg/kg Cd. In this study, we analyzed the effects of Cd exposure on pig spleen through HE staining, Quantitative real-time PCR (qRT-PCR), Western blot (WB), and principal component analysis (PCA). Results show that Cd exposure can destroy the structure and function of pig spleen, which is closely related to necroptosis. Further results show that Cd exposure can induce necroptosis through ROS-mediated activation of Signal transducer and activator of transcription 1/Receptor-Interacting Serine/Threonine-Protein Kinase 3 (STAT1/RIPK3) signaling pathway in pig spleen. Additionally, Cd exposure also can affect the stability of mitochondrial-associated endoplasmic reticulum membrane (MAMs) structure, which also contributes to the process of necroptosis. Our study provides insights into the physiological toxicity caused by Cd exposure.

Tumor metastasis is the main cause of death for breast cancer patients. Caffeic acid phenethyl ester (CAPE) has strong anti-tumor effects with very low toxicity and may be a potential candidate drug. However, the anti-metastatic effect and molecular mechanism of CAPE on breast cancer need more research.

MCF-7 and MDA-MB-231 breast cancer cells were used here. Wound healing and Transwell assay were used for migration and invasion detection. Western blot and RT-qPCR were carried out for the epithelial-to-myofibroblast transformation (EMT) process investigation. Western blot and immunofluorescence were performed for fibroblast growth factor receptor1 (FGFR1) phosphorylation and nuclear transfer detection. Co-immunoprecipitation was used for the FGFR1/myeloid differentiation protein2 (MD2) complex investigation.

Our results suggested that CAPE blocks the migration, invasion, and EMT process of breast cancer cells. Mechanistically, CAPE inhibits FGFR1 phosphorylation and nuclear transfer while overexpression of FGFR1 reduces the anti-metastasis effect of CAPE. Further, we found that FGFR1 is bound to MD2, and silencing MD2 inhibits FGFR1 phosphorylation and nuclear transfer as well as cell migration and invasion.

This study illustrated that CAPE restrained FGFR1 activation and nuclear transfer through MD2/FGFR1 complex inhibition and showed good inhibitory effects on the metastasis of breast cancer cells.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a refractory, progressive disease. However, the underlying mechanisms that aggravate femoral head necrosis remain unclear. Extracellular vesicles (EVs) act as molecular carriers in intercellular communication. We hypothesize that EVs derived from human (h) bone marrow stromal cells (BMSC) resident in SONFH lesion areas promote the pathogenesis of SONFH. In the present study, we determined the modulatory effects of SONFH-hBMSCs-derived EVs on the pathogenesis of SONFH in vitro and in vivo. We found that the expression of hsa-miR-182-5p was downregulated in SONFH-hBMSCs and EVs isolated from those hBMSCs. After tail vein injection, EVs isolated from hBMSCs transfected with hsa-miR-182-5p inhibitor aggravated femoral head necrosis in the SONFH mouse model. We conclude that miR-182-5p regulates bone turnover in the SONFH mouse model via targeting MYD88 and subsequent upregulation of RUNX2 expression. We further assume that EVs derived from hBMSCs resident in SONFH lesion areas aggravate femoral head necrosis by downregulating miR-182-5p secreted from hBMSC located outside these lesions. We suggest that miR-182-5p could provide a novel target for future therapeutic approaches to treat or prevent SONFH. © 2023 American Society for Bone and Mineral Research (ASBMR).

Cadmium (Cd), as Group I carcinogen, can induce damage to various organs including the gut. It is of great importance to meet the rising demand for effective therapies against Cd-induced damage and investigate the mechanism. Flammulina velutipes is a popular edible mushroom, despite the well-known health benefits of Flammulina velutipes, little is known about the effect of its polysaccharide (FVP) against CdCl₂-intestinal injury. In this study, a FVP (uronic acid, 5.10 %; degree of methylation, 41.24 %) was produced via hot water extraction (85 °C) and ethanol precipitation. The FVP contained eight major monosaccharides and exhibited good thermal stability at temperatures lower than 139.73 °C. FVP (100 mg/kg b. w., gavage for 4 weeks) alleviated CdCl₂ (1.5 mg/kg b. w., gavage for 4 weeks)-induced intestinal inflammation and apoptosis, intestinal permeability alteration and intestinal barrier disruption. FVP increased the abundance of Bacteroides, whilst decreasing the abundance of Desulfovibrionales and Clostridium. FVP also restored the levels of short-chain fatty acids (SCFAs), including acetic, propionic, isobutyric, butyric, isovaleric and valeric acids. Correlation analysis indicated the interplays among the FVP, gut microbes, SCFAs, intestinal barrier/cells and gut inflammation. FVP enhances the metabolic functions of gut microbiota via functional pathways analyzed by KEGG database. Furthermore, gut microbial transplantation of FVP + CdCl₂ group mice partially alleviated CdCl₂ caused-gut damage. Thus, FVP may be an effective therapeutic agent against CdCl₂-induced gut damage via SCFA-mediated regulation of intestinal inflammation and gut microbiota-related energy metabolism. This study may open a new avenue for developing alternative strategies to prevent CdCl₂-caused injury.

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is an organophosphorus flame retardant that has been utilized in recent years as a primary replacement for polybrominated diphenyl ethers (PBDEs) in a wide variety of fire-sensitive applications. However, the impact of TDCPP on the immune system has not been fully determined. As the largest secondary immune organ in the body, the spleen is considered to be an important study endpoint for determining immune defects in the body. The aim of this study is to investigate the effect of TDCPP toxicity on the spleen and its possible molecular mechanisms. In this study, for 28 consecutive days, TDCPP was administered intragastrically (i.g), and we assessed the general condition of mice by evaluating their 24 h water and food intake. Pathological changes in spleen tissues were also evaluated at the end of the 28-day exposure. To measure the TDCPP-induced inflammatory response in the spleen and its consequences, the expression of the critical players in the NF-κB pathway and mitochondrial apoptosis were detected. Lastly, RNA-seq was performed to identify the crucial signaling pathways of TDCPP-induced splenic injury. The results showed that TDCPP intragastric exposure triggered an inflammatory response in the spleen, likely through activating the NF-κB/IFN-γ/TNF-α/IL-1β pathway. TDCPP also led to mitochondrial-related apoptosis in the spleen. Further RNA-seq analysis suggested that the TDCPP-mediated immunosuppressive effect is associated with the inhibition of chemokines and the expression of their receptor genes in the cytokine-cytokine receptor interaction pathway, including four genes of the CC subfamily, four genes of the CXC subfamily, and one gene of the C subfamily. Taken together, the present study identifies the sub-chronic splenic toxicity of TDCPP and provides insights on the potential mechanisms of TDCPP-induced splenic injury and immune suppression.

Cadmium (Cd) has potential hazards on human beings. Consequently, this study was performed to explore the protective effects of agomelatine (AGO), a melatonin receptor agonist, against Cd-induced toxicity in rats. AGO (40 mg/kg/day) was administered orally concomitant with intra peritoneal injection of Cd (0.4 mg/kg/day) for 14 days. Then, blood, biochemical parameters and histological examination of affected organs including, heart and testis, were evaluated. Interestingly, AGO significantly counteracted Cd-induced elevation of serum cardiac enzymes. Similarly, AGO significantly improved the deterioration of serum testosterone level with Cd administration. The oxidative balance was corrected by AGO, as evidenced by decrease malondialdehyde (MDA), and superoxide dismutase activity in cardiac and testicular tissues. Additionally, AGO increased silent information regulator 1 protein (SIRT-1) and decreased High mobility group box 1 (HMGB1), Toll like receptor-4 (TLR-4), and Myd88 levels that subsequently reduced expression of nuclear factor-κB (NF-κB). Moreover, level of apoptotic marker; caspase-3 was inhibited by AGO. In accordance with the biochemical and molecular results, AGO restored structure of cardiac myofibers and seminiferous tubules. Collectively, AGO mitigated cardiac and testicular toxicity of Cd via modulation of SIRT-1/HMGB1 and its downstream pathway.