Role of the GLP2-Wnt1 axis in silicon-rich alkaline mineral water maintaining intestinal epithelium regeneration in piglets under early-life stress.

Stress-induced intestinal epithelial injury (IEI) and a delay in repair in infancy are predisposing factors for refractory gut diseases in adulthood, such as irritable bowel syndrome (IBS). Hence, it is necessary to develop appropriate mitigation methods for mammals when experiencing early-life stress (ELS). Weaning, as we all know, is a vital procedure that all mammalian newborns, including humans, must go through. Maternal separation (MS) stress in infancy (regarded as weaning stress in animal science) is a commonly used ELS paradigm. Drinking silicon-rich alkaline mineral water (AMW) has a therapeutic effect on enteric disease, but the specific mechanisms involved have not been reported. Herein, we discover the molecular mechanism by which silicon-rich AMW repairs ELS-induced IEI by maintaining intestinal stem cell (ISC) proliferation and differentiation through the glucagon-like peptide (GLP)2-Wnt1 axis. Mechanistic study showed that silicon-rich AMW activates GLP2-dependent Wnt1/ß-catenin pathway, and drives ISC proliferation and differentiation by stimulating Lgr5+ ISC cell cycle passage through the G1-S-phase checkpoint, thereby maintaining intestinal epithelial regeneration and IEI repair. Using GLP2 antagonists (GLP23-33) and small interfering RNA (SiWnt1) in vitro, we found that the GLP2-Wnt1 axis is the target of silicon-rich AMW to promote intestinal epithelium regeneration. Therefore, silicon-rich AMW maintains intestinal epithelium regeneration through the GLP2-Wnt1 axis in piglets under ELS. Our research contributes to understanding the mechanism of silicon-rich AMW promoting gut epithelial regeneration and provides a new strategy for the alleviation of ELS-induced IEI.

Bisphenol A and its alternatives bisphenol S and F exposure with serum uric acid levels, hyperuricemia, and gout prevalence among US adults: a nationally representative cross-sectional study.

BACKGROUND: Recent studies suggested inconclusive associations between bisphenols exposure and hyperuricemia risk. Our objective was to assess the potential association of bisphenol A (BPA) and its substitutes bisphenol S and F (BPS and BPF) exposure with serum uric acid (SUA) levels, hyperuricemia, and gout prevalence among US adults within the NHANES 2013-2016 datasets. METHODS: Multivariable linear and logistic regression models were used to explore the associations of urinary bisphenols concentrations with SUA levels, hyperuricemia, and gout prevalence, in total population and different sex groups. The restricted cubic spline (RCS) model was used to explore the dose-response relationship. RESULTS: In total population, doubling of urinary BPS and ∑BPs concentrations showed associations with an increase of 2.64 µmol/L (95% CI: 0.54, 4.74) and 3.29 µmol/L (95% CI: 0.59, 5.99) in SUA levels, respectively. The RCS model indicated a significantly "J"-shaped dose-response relationship between BPS exposure and SUA levels. Compared to the reference group of urinary BPS, males in the highest quartile displayed a 13.06 µmol/L (95% CI: 0.75, 25.37) rise in SUA levels. For females, doubling of urinary BPS concentrations was associated with a 3.30 µmol/L (95% CI: 0.53, 6.07) increase in SUA levels, with a significant linear dose-response relationship. In total population, doubling of urinary BPA concentrations showed a 1.05-fold (95% CI: 0.97, 1.14) adjusted risk of having hyperuricemia, with an inverted "U" curve. Doubling of urinary ∑BPs concentrations was associated with a 1.05-fold (95% CI: 0.96, 1.14) adjusted risk of hyperuricemia in total population, with a significant monotonic dose-response relationship. In females, doubling of urinary BPS concentrations was associated with a 1.45-fold (95% CI: 1.01, 2.08) adjusted increased risk of having gout, with a "J" shaped relationship. CONCLUSIONS: BPA and BPS exposure to some extent were associated with elevated SUA levels and increased risk of hyperuricemia, with different dose-response relationships and sex differences.

Antihyperuricemic activity and inhibition mechanism of xanthine oxidase inhibitory peptides derived from whey protein by virtual screening.

Xanthine oxidase (XO), a rate-limiting enzyme in uric acid production, is the pivotal therapeutic target for gout and hyperuricemia. In this study, 57 peptides from α-lactalbumin and ß-lactoglobulin were obtained via virtual enzymatic hydrolysis, and 10 XO inhibitory peptides were virtually screened using molecular docking. Then toxicity, allergenicity, solubility, and isoelectric point of the obtained 10 novel peptides were evaluated by in silico tools. The XO activity of these synthetic peptides was tested using an in vitro assay by high-performance liquid chromatography. Their inhibitory mechanism was further explored by molecular docking. The results showed that 4 peptides GL, PM, AL, and AM exhibited higher inhibitory activity, and their half maximal inhibitory concentration in vitro was 10.20 ± 0.89, 23.82 ± 0.94, 34.49 ± 0.89, and 40.45 ± 0.92 mM, respectively. The peptides fitted well with XO through hydrogen bond, hydrophobic interaction, and van der Waals forces, and amino acid residues Glu802, Leu873, Arg880, and Pro1076 played an important role in this process. Overall, this study indicated 4 novel peptides GL, PM, AL, and AM from whey protein exhibited XO inhibitory activity, and they might be useful and safe XO inhibitors for hyperuricemia prevention and treatment.

Nano-selenium alleviates cadmium-induced neurotoxicity in cerebrum via inhibiting gap junction protein connexin 43 phosphorylation.

Cadmium (Cd) as a ubiquitous toxic heavy metal is reported to affect the nervous system. Selenium (Se) has been shown to have antagonistic effects against heavy metal toxicity. In addition, it shows potential antioxidant and anti-inflammatory properties. Thus, the purpose of this study was to determine the possible mechanism of brain injury after high Cd exposure and the mitigation of Nano-selenium (Nano-Se) against Cd-induced brain injury. In this study, the Cd-treated group showed a decrease in the number of neurons in brain tissue, swelling of the endoplasmic reticulum and mitochondria, and the formation of autophagosomes. Nano-Se intervention restored Cd-caused alterations in neuronal morphology, endoplasmic reticulum, and mitochondrial structure, thereby reducing neuronal damage. Furthermore, we found that some differentially expressed genes were involved in cell junction and molecular functions. Subsequently, we selected eleven (11) related differentially expressed genes for verification. The qRT-PCR results revealed the same trend of results as determined by RNA-Seq. Our findings also showed that Nano-Se supplementation alleviated Cx43 phosphorylation induced by Cd exposure. Based on immunofluorescence colocalization it was demonstrated that higher expression of GFAP and lower expressions of Cx43 were restored by Nano-Se supplementation. In conclusion, the data presented in this study establish a direct association between the phosphorylation of Cx43 and the occurrence of autophagy and neuroinflammation. However, it is noteworthy that the introduction of Nano-Se supplementation has been observed to mitigate these alterations. These results elucidate the relieving effect of Nano-Se on Cd exposure-induced brain injury.

Metasilicate-based alkaline mineral water confers diarrhea resistance in maternally separated piglets via the microbiota-gut interaction.

Stress or stress-induced intestinal disturbances, especially diarrhea, are the main triggers for inflammatory bowel disease and irritable bowel syndrome. Diarrhea and intestinal inflammatory disease afflict patients around the world, and it has become a huge burden on the global health care system. Drinking sodium metasilicate-based alkaline mineral water (SM-based AMW) exerts a potential therapeutic effect in gastrointestinal disorders, including gut inflammation, and diarrhea, but the supportive evidence on animal studies and mechanism involved remain unreported. The maternally separated (MS) piglet (Newly weaned piglet) is an excellent model to investigate the treatment of diarrhea in infant. This study aims to determine whether drinking SM-based AMW confers diarrhea resistance in maternally separated (MS) piglets under weaning stress and what the underlying mechanisms are involved. 240 newly weaned piglets were randomly divided into the Control group and the sodium metasilicate pentahydrate (SMP) group. A decreased diarrhea incidence was observed in SMP treatment piglets. The intestine injury and activated stress hormones (COR and ACTH) induced by weaning was alleviated by SM-based AMW. This may be related to the improvement of intestinal microflora structure and function by SMP, especially the increase of s_copri abundance. Meanwhile, SMP maintained the integrity of the duodenal mucus barrier in MS piglets. Importantly, by targeting NF-κB inhibition via the microbiota-gut interaction, SM-based AMW alleviated intestinal inflammation, maintained fluid homeostasis by modulating aquaporins and fluid transporter expression, and enhanced barrier integrity by suppressing MLCK/p-MLC signaling. Therefore, drinking metasilicate-based alkaline mineral water confers diarrhea resistance in MS piglets via the microbiota-gut interaction.

Hydrophobic ion-pairing assembled liposomal Rhein with efficient loading for acute pancreatitis treatment.

AIM: The present study aimed to develop liposomal Rhein by employing a hydrophobic ion-pairing technique (HIP) for improved pancreatitis therapy. METHODS: F127 modified liposomal Rhein (F127-RPC-Lip) was prepared using a two-step process consisting of complexation first, followed by a film-ultrasonic dispersion step. The drug-phospholipid interaction was characterised by FT-IR and P-XRD. Particle size and morphology were investigated using DLS and TEM, respectively. Biodistribution and therapeutic efficacy of F127-RPC-Lip were evaluated in a rat model of acute pancreatitis. RESULTS: F127-RPC-Lip achieved efficient drug encapsulation after complexation with lipids through non-covalent interactions and had an average hydrodynamic diameter of about 141 nm. F127-RPC-Lip demonstrated slower drug release (55.90 ± 3.60%, w/w) than Rhein solution (90.27 ± 5.11%) within 24 h. Compared with Rhein, F127-RPC-Lip exhibited prolonged systemic circulation time, superior drug distribution, and attenuated injury in the pancreas of rats post-injection. CONCLUSIONS: HIP-assembled liposomes are a promising strategy for Rhein in treating pancreatitis.

The Association of Circulating T Follicular Helper Cells and Regulatory Cells with Acute Myeloid Leukemia Patients.

OBJECTIVE: This study aims to investigate the association of circulating T follicular helper (cTfh) cells and T follicular regulatory (cTfr) cells with acute myeloid leukemia (AML) patients. METHODS: A total of 22 newly diagnosed, untreated AML patients as well as 26 healthy controls were enrolled. Percentages of cTfh and cTfr cells were detected using flow cytometry. RESULTS: Compared to healthy controls, a significantly higher percentage of cTfr cells was observed in AML patients (4.10 ± 11.18 vs. 0.63 ± 0.38%) (p < 0.05). In addition, a significantly lower cTfh/cTfr ratio was found in the AML patients' group when compared to the control group (9.04 ± 9.19 vs. 11.66 ± 5.68) (p < 0.05). A lower level of plasma IL-2 and TGF-ß1 was found in AML patients. Based on the complete remission (CR) response after one cycle of inductive chemotherapy, patients were divided into two groups at sample collection: AML with and without CR. Significantly lower percentages of cTfr cells and a higher cTfh/cTfr ratio were found in the group of AML patients with CR than in the AML patients without CR. CONCLUSION: There was a significantly higher percentage of cTfr cells in AML patients. cTfr cells may have a potential association with the pathogenesis of AML patients.

Detection of bovine viral diarrhea virus genotype 1 in aerosol by a real time RT-PCR assay.

BACKGROUND: As a pestivirus of the Flaviviridae family, bovine viral diarrhea virus (BVDV), has imposed a large burden on animal husbandry worldwide, and such virus can be transmitted mainly through direct contact with other infected animals and probably via aerosols. In the present study, we aimed to develop a real-time RT-PCR method for detection of BVDV-1 in aerosol samples. METHODS: A pair of primers specific for highly conserved regions of the BVDV-1 5'-UTR was designed. The standard curve and sensitivity of the developed assay were assessed based on 10-fold serial dilutions of RNA molecular standard. The specificity of the assay was evaluated with other pestiviruses and infectious bovine viruses. The clinical performance was examined by testing 169 aerosol samples. RESULTS: The results showed that a good linear relationship existed between the standard curve and the concentration of template. The lowest detection limit was 5.2 RNA molecules per reaction. This assay was specific for detection of BVDV-1, and no amplification was found for other pestiviruses such as classical swine fever virus (CSFV), border disease virus (BDV), and common infectious bovine viruses, including BVDV-2, infectious bovine rhinotracheitis virus (IBRV), bovine parainfluenza virus type 3 (BPIV-3), bovine respiratory syncytial virus (BRSV), bovine ephemeral fever virus (BEFV) and bovine coronavirus (BcoV). The assay was highly reproducible with low variation coefficient values (CVs) for intra-assay and inter-assay. A total of 169 aerosol samples collected from six dairy herds were tested using this method. The results showed that the positive detection rate of BVDV-1 was 17.2% (29/169), which was significantly higher compared with the conventional RT-PCR. Additionally, the positive samples (n = 29) detected by real-time RT-PCR were verified by BVDV RPA-LFD, and a concordance rate of 100% was obtained between them. CONCLUSIONS: Taken together, we developed a real-time RT-PCR assay for quantitative analysis of BVDV-1 in aerosol samples, and our finding provided valuable insights into the risk on aerosol transmission of BVDV-1.

SOX-mediated molecular crosstalk during the progression of tumorigenesis.

SOX family transcription factor has emerged as a double-edged sword relating to tumorigenesis and metastasis. Multiple studies have revealed different expression patterns and contradictory roles of SOX factors in the tumor initiation and progression. The aberrant expression of SOX factors is regulated by copy number alteration, methylation modulation, microRNAs, transcription factors and post-translational modification. This review summarizes the role of SOX factors in molecular interactions and signaling pathways during different steps of carcinogenesis, such as CSCs stemness maintenance, EMT occurrence, cell invasion, cell proliferation and apoptosis. The Wnt signaling pathway is also shown to provide vital intermediate signaling transduction. We believe that SOX family proteins may be used as prognostic markers for human clinical therapy, and novel therapy strategies targeting SOX factors should be explored in future clinical applications.

[Research in technical regulations for production of pollution-free Chinese herbal medicines].

Aimed to solve the issues of pesticide residue, heavy metal contents and harmful elements in the productive process of Chinese herbal medicines, the research team built the technical regulations for production of pollution-free Chinese herbal medicines. This regulation included the environment of production area, the process of production, quality of products etc., which were the key steps controlled the quality of Chinese herbal medicines. The environment of production area was selected according to the ecological factors which were stipulated by Ecological Suitability Regionalization of Chinese herbal medicines (second edition). The quality of air should be attain the one or two levels of GB/T3095-2012 standard values. The cultivation soils should reach to the one or two levels of GB15618 and NY/T391 standard values. The quality of irrigation water should accord with the stipulation of GB5084-2005. Aimed to the production of Chinese herbal medicines, disease-resistant and superior varieties which were suitable to the local stations should be selected, and the breeding of superior seeds and seedlings should be strengthened. Additionally, rational fertilizer application of pollution-free Chinese herbal medicines should be conformed to the principles, requirements, and the kinds of fertilizers allowed or limited for use, which were stipulated by the standard of DB13/T454. Furthermore, the plant protection policy of priority to prevention and synthetical prevention should be followed; improving ecological environment and strengthening cultivation management should be served as the basics. Agricultural measures, and biological and physical control strategies should be preferred to use; and high toxicity, residue pesticide and its mixture should be inhibited; the use of chemical pesticides should be minimized and then to decrease contamination and residue. Additionally, the quality of products should be reached to the standard of pollution-free Chinese herbal medicines; high toxicity and detection rate of pesticide residues and the contents of heavy metal and harmful elements (e.g. plumbum, cadmium, mercury, arsenic and cuprum) should accord with the common criteria of pollution-free Chinese herbal medicines. Application of technical regulations for production of pollution-free Chinese herbal medicines guarantees significantly social, economic and ecological benefits.

Multicolor tuning towards single red-emission band of upconversion nanoparticles for tunable optical component and optical/x-ray imaging agents via Ce(3+) doping.

A simple strategy of Ce(3+) doping is proposed to realize multicolor tuning and predominant red emission in BaLnF5:Yb(3+)/Ho(3+) (Ln(3+) = Gd(3+), Y(3+), Yb(3+)) systems. A tunable upconversion (UC) multicolor output from green/yellow to red can be readily achieved in a fixed Yb(3+)/Ho(3+) composition by doping Ce(3+), providing an effective route for multicolor tuning widely used for various optical components. Moreover, compared with Ce(3+)-free UC nanoparticles (UCNPs), a remarkable enhancement of the red-to-green (R/G) ratio is observed by doping 30% Ce(3+), arising from the two largely promoted cross-relaxation (CR) processes between Ce(3+) and Ho(3+). UCNPs with pure red emission are selected as in vivo UC bioimaging agents, demonstrating the merits of deep penetration depth, the absence of autofluorescence and high contrast in small animal bioimaging. Moreover, such fluorescence imaging nanoprobes can also be used as contrast agents for three-dimensional (3D) x-ray bioimaging by taking advantage of the high K-edge values and x-ray absorption coefficients of Ba(2+), Gd(3+), and Ce(3+) in our designed nanoprobes. Thus, the simultaneous realization of multicolor output, highly enhanced R/G ratio, and predominant red emission makes the Ce(3+)-doped UCNPs very useful for widespread applications in optical components and bioimaging.

Cadmium causes cerebral mitochondrial dysfunction through regulating mitochondrial HSF1.

Mitochondria, as the powerhouse of the cell, play a vital role in maintaining cellular energy homeostasis and are known to be a primary target of cadmium (Cd) toxicity. The improper targeting of proteins to mitochondria can compromise the normal functions of the mitochondria. However, the precise mechanism by which protein localization contributes to the development of mitochondrial dysfunction induced by Cd is still not fully understood. For this research, Hy-Line white variety chicks (1-day-old) were used and equally distributed into 4 groups: the Control group (fed with a basic diet), the Cd35 group (basic diet with 35 mg/kg CdCl2), the Cd70 group (basic diet with 70 mg/kg CdCl2) and the Cd140 group (basic diet with 140 mg/kg CdCl2), respectively for 90 days. It was found that Cd caused the accumulation of heat shock factor 1 (HSF1) in the mitochondria, and the overexpression of HSF1 in the mitochondria led to mitochondrial dysfunction and neuronal damage. This process is due to the mitochondrial HSF1 (mtHSF1), causing mitochondrial fission through the upregulation of dynamin-related protein 1 (Drp1) content, while inhibiting oligomer formation of single-stranded DNA-binding protein 1 (SSBP1), resulting in the mitochondrial DNA (mtDNA) deletion. The findings unveil an unforeseen role of HSF1 in triggering mitochondrial dysfunction.

Essential oils improve nursery pigs' performance and appetite via modulation of intestinal health and microbiota.

Optimal intestinal health and functionality are essential for animal health and performance, and simultaneously intestinal nutrient transporters and intestinal peptides are also involved in appetite and feed intake control mechanisms. Given the potential of essential oil (EO) in improving animal performance and improving feed palatability, we hypothesized that dietary supplementation of cinnamaldehyde and carvacrol could improve performance and appetite of nursery pigs by modulating intestinal health and microbiota. Cinnamaldehyde (100 mg/kg), carvacrol (100 mg/kg), and their mixtures (including 50 mg/kg cinnamaldehyde and 50 mg/kg carvacrol) were supplemented into the diets of 240 nursery pigs for 42 d, and data related to performance were measured. Thereafter, the influence of EO on intestinal health, appetite and gut microbiota and their correlations were explored. EO supplementation increased (P < 0.05) the body weight, average daily gain (ADG) and average daily feed intake (ADFI) of piglets, and reduced (P < 0.05) diarrhea rates in nursery pigs. Furthermore, EO increased (P < 0.05) the intestinal absorption area and the abundance of tight junction proteins, and decreased (P < 0.05) intestinal permeability and local inflammation. In terms of intestinal development and the mucus barrier, EO promoted intestinal development and increased (P < 0.05) the number of goblet cells. Additionally, we found that piglets in the EO-supplemented group had upregulated (P < 0.05) levels of transporters and digestive enzymes in the intestine, which were significantly associated with daily gain and feed utilization. In addition, EO supplementation somewhat improved appetite in nursery pigs, increased the diversity of the gut microbiome and the abundance of beneficial bacteria, and there was a correlation between altered bacterial structure and appetite-related hormones. These findings indicate that EO is effective in promoting growth performance and nutrient absorption as well as in regulating appetite by improving intestinal health and bacterial structure.

Gas6/AXL Alleviates Hepatic Ischemia/Reperfusion Injury by Inhibiting Ferroptosis via the PI3K/AKT Pathway.

BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury is a major cause of complications in clinical liver surgery. AXL receptor tyrosine kinase (AXL) is a member of the TAM receptor tyrosine kinase family (TYRO3, AXL, and MERTK). Our previous study has shown that AXL expression was markedly upregulated in liver transplantation patients. However, the underlying mechanism of AXL in hepatic I/R injury remains unclear. METHODS: A mouse liver warm I/R model and a primary hepatocyte hypoxia/reoxygenation model were established to investigate the role of AXL activation and ferroptosis in hepatic I/R injury by pretreating with recombinant mouse growth arrest-specific protein 6 (AXL activator) or R428 (AXL inhibitor). Moreover, we used LY294002 (phosphatidylinositol 3-kinase [PI3K] inhibitor) to evaluate the relationship between the PI3K/AKT (the Ser and Thr kinase AKT) pathway and ferroptosis in hepatic I/R injury. RESULTS: Hepatic I/R injury decreased phosphorylation AXL expression and enhanced ferroptosis in liver transplantation patients and hepatic I/R-subjected mice. AXL activation attenuated lipid peroxidation and ferroptosis in hepatic I/R injury in vivo and in vitro. Inhibition of AXL activation exacerbated liver pathological damage and liver dysfunction, as well as iron accumulation and lipid peroxidation in hepatic I/R injury. Mechanistically, activated growth arrest-specific protein 6/AXL and its downstream PI3K/AKT signaling pathway inhibited ferroptosis during hepatic I/R injury. CONCLUSIONS: AXL activation protects against hepatic I/R injury by preventing ferroptosis through the PI3K/AKT pathway. This study is the first investigation on the AXL receptor and ferroptosis, and activating AXL to mitigate ferroptosis may be an innovative therapeutic strategy to combat hepatic I/R injury.

Nano­selenium alleviates cadmium-induced blood-brain barrier destruction by restoring the Wnt7A/ß-catenin pathway.

Selenium (Se), a highly beneficial animal feed additive, exhibits remarkable antioxidant and anti-inflammatory properties. Nano­selenium (Nano-Se) is an advanced formulation of Se featuring a specialized drug delivery vehicle, with good bioavailability, higher efficacy, and lower toxicity compared to the traditional form of Se. With the advancement of industry, cadmium (Cd) contamination occurs in different countries and regions and thereby contaminating different food crops, and the degree of pollution is degree increasing year by year. The present investigation entailed the oral administration of CdCl2 and/or Nano-Se to male chickens of the Hy-Line Variety White breed, which are one day old, subsequent to a 7-day adaptive feeding period, for a duration of 90 days. The study aimed to elucidate the potential protective impact of Nano-Se on Cd exposure. The study found that Nano-Se demonstrates potential in mitigating the blood-brain barrier (BBB) dysfunction characterized by impairment of adherens junctions (AJS) and tight junctions (TJS) by inhibiting reactive oxygen species (ROS) overproduction. In addition, the data uncovered that Nano-Se demonstrates a proficient ability in alleviating BBB impairment and inflammatory reactions caused by Cd through the modulation of the Wnt7A/ß-catenin pathway, highlights its potential to maintain brain homeostasis. Hence, this research anticipates that the utilization of Nano-Se effectively mitigate the detrimental impacts associated with Cd exposure on the BBB.

Di (2-ethylhexyl) phthalate induced lipophagy-related renal ferroptosis in quail (Coturnix japonica).

Di(2-ethylhexyl) phthalate (DEHP) is a synthetic chemical applied as a plasticizer. As an environmental toxicant, DEHP poses a serious health threat. Many studies have revealed that DEHP can cause lead to various degrees of damage to the kidney. However, the evidence of DEHP-induced renal ferroptosis has not been reported. The purpose of this work was to probe the specific role of lipophagy in DEHP-induced renal injury and to investigate the relationship between lipophagy and ferroptosis. Quail were treated with DEHP (250 mg/kg BW/day, 500 mg/kg BW/day and 750 mg/kg BW/day) for 45 days. Microstructural and ultrastructural observations showed that DEHP caused damage to glomerular and tubular cells, and autophagy with multilayer structures were observed, suggesting that DEHP can induce lipophagy. The results indicated that the iron homeostasis was abnormal and the lipid peroxidation was increased. SLC7A11 and SLC3A2 were down-regulated. PTGS2, ACSL4 and LPCAT3 were elevated. In conclusion, DEHP could induce lipid peroxidation, lead to ferroptosis, and damage renal cells. Therefore, the relationship between lipophagy and ferroptosis was elucidated, which provided a new basis for intervention and prevention of DEHP increased diseases.

Lycopene Protects against Atrazine-Induced Kidney STING-Dependent PANoptosis through Stabilizing mtDNA via Interaction with Sam50/PHB1.

Atrazine (ATR) is a widely used herbicide worldwide that can cause kidney damage in humans and animals by accumulation in water and soil. Lycopene (LYC), a carotenoid with numerous biological activities, plays an important role in kidney protection due to its potent antioxidant and anti-inflammatory effects. The current study sought to investigate the role of interactions between mtDNA and the cGAS-STING signaling pathway in LYC mitigating PANoptosis and inflammation in kidneys induced by ATR exposure. In our research, 350 mice were orally administered LYC (5 mg/kg BW/day) and ATR (50 or 200 mg/kg BW/day) for 21 days. Our results reveal that ATR exposure induces a decrease in mtDNA stability, resulting in the release of mtDNA into the cytoplasm through the mPTP pore and the BAX pore and the mobilization of the cGAS-STING pathway, thereby inducing renal PANoptosis and inflammation. LYC can inhibit the above changes caused by ATR. In conclusion, LYC inhibited ATR exposure-induced histopathological changes, renal PANoptosis, and inflammation by inhibiting the cGAS-STING pathway. Our results demonstrate the positive role of LYC in ATR-induced renal injury and provide a new therapeutic target for treating renal diseases in the clinic.

UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance.

Prostate cancer (PCa) is primarily driven by aberrant Androgen Receptor (AR) signaling. Although there has been substantial advancement in antiandrogen therapies, resistance to these treatments remains a significant obstacle, often marked by continuous or enhanced AR signaling in resistant tumors. While the dysregulation of the ubiquitination-based protein degradation process is instrumental in the accumulation of oncogenic proteins, including AR, the molecular mechanism of ubiquitination-driven AR degradation remains largely undefined. We identified UBE2J1 as the critical E2 ubiquitin-conjugating enzyme responsible for guiding AR ubiquitination and eventual degradation. The absence of UBE2J1, found in 5-15% of PCa patients, results in disrupted AR ubiquitination and degradation. This disruption leads to an accumulation of AR proteins, promoting resistance to antiandrogen treatments. By employing a ubiquitination-based AR degrader to adeptly restore AR ubiquitination, we reestablished AR degradation and inhibited the proliferation of antiandrogen-resistant PCa tumors. These findings underscore the fundamental role of UBE2J1 in AR degradation and illuminate an uncharted mechanism through which PCa maintains heightened AR protein levels, fostering resistance to antiandrogen therapies.

ZNF397 Deficiency Triggers TET2-Driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer.

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming that allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified zinc finger protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a ten-eleven translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that a TET2 inhibitor can eliminate the resistance to AR-targeted therapies in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate cancer acquires lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity. Significance: This study reveals a bifurcated role of ZNF397, and a TET2-driven epigenetic mechanism regulating tumor lineage plasticity and therapy response in prostate cancer, enhances the understanding of drug resistance, and unveils a new therapeutic strategy for overcoming androgen receptor-targeted therapy resistance.