Multifunctional carbomer based ferulic acid hydrogel promotes wound healing in radiation-induced skin injury by inactivating NLRP3 inflammasome.

BACKGROUND: Radiation-induced skin injury is a significant adverse reaction to radiotherapy. However, there is a lack of effective prevention and treatment methods for this complication. Ferulic acid (FA) has been identified as an effective anti-radiation agent. Conventional administrations of FA limit the reaching of it on skin. We aimed to develop a novel FA hydrogel to facilitate the use of FA in radiation-induced skin injury. METHODS: We cross-linked carbomer 940, a commonly used adjuvant, with FA at concentrations of 5%, 10%, and 15%. Sweep source optical coherence tomography system, a novel skin structure evaluation method, was applied to investigate the influence of FA on radiation-induced skin injury. Calcein-AM/PI staining, CCK8 assay, hemolysis test and scratch test were performed to investigate the biocompatibility of FA hydrogel. The reducibility of DPPH and ABTS radicals by FA hydrogel was also performed. HE staining, Masson staining, laser Doppler blood flow monitor, and OCT imaging system are used to evaluate the degree of skin tissue damage. Potential differentially expressed genes were screened via transcriptome analysis. RESULTS: Good biocompatibility and in vitro antioxidant ability of the FA hydrogels were observed. 10% FA hydrogel presented a better mechanical stability than 5% and 15% FA hydrogel. All three concentrations of FA remarkably promoted the recovery of radiation-induced skin injury by reducing inflammation, oxidative conidiation, skin blood flow, and accelerating skin tissue reconstruction, collagen deposition. FA hydrogel greatly inhibiting the levels of NLRP3, caspase-1, IL-18, pro-IL-1ß and IL-1ß in vivo and vitro levels through restraining the activation of NLRP3 inflammasome. Transcriptome analysis indicated that FA might regulate wound healing via targeting immune response, inflammatory response, cell migration, angiogenesis, hypoxia response, and cell matrix adhesion. CONCLUSIONS: These findings suggest that the novel FA hydrogel is a promising therapeutic method for the prevention and treatment of radiation-induced skin injury patients.

Low-dose radiation-induced SUMOylation of NICD1 negatively regulates osteogenic differentiation in BMSCs.

Various biological effects of ionizing radiation, especially continuous exposure to low-dose radiation (LDR), have attracted considerable attention. Impaired bone structure caused by LDR has been reported, but little is known about the mechanism involved in the disruption of bone metabolism. In this study, given that LDR was found to (at a cumulative dose of 0.10 Gy) disturb the serum Mg2+ level and Notch1 signal in the mouse femur tissues, the effects of LDR on osteogenesis and the underlying molecular mechanisms were investigated based on an in vitro culture system for bone marrow stromal cells (BMSCs). Our data showed that cumulative LDR suppressed the osteogenic potential in BMSCs as a result of upregulation of Notch1 signaling. Further analyses indicated that the upregulation of NICD1 (Notch1 intracellular domain), the key intracellular domain for Notch1 signaling, under LDR was a consequence of enhanced protein stabilization caused by SUMOylation (small ubiquitin-like modification). Specifically, the downregulation of SENP1 (sentrin/SUMO-specific protease 1) expression induced by LDR enhanced the SUMOylation of NICD1, causing the accumulation of Notch1 signaling, which eventually inhibited the osteogenic potential of BMSCs. In conclusion, this work expounded on the mechanisms underlying the impacts of LDR on bone metabolism and shed light on the research on bone regeneration under radiation.

A circular single-stranded DNA mycovirus infects plants and confers broad-spectrum fungal resistance.

Circular single-stranded DNA (ssDNA) viruses have been rarely found in fungi, and the evolutionary and ecological relationships among ssDNA viruses infecting fungi and other organisms remain unclear. In this study, a novel circular ssDNA virus, tentatively named Diaporthe sojae circular DNA virus 1 (DsCDV1), was identified in the phytopathogenic fungus Diaporthe sojae isolated from pear trees. DsCDV1 has a monopartite genome (3185 nt in size) encapsidated in isometric virions (21-26 nm in diameter). The genome comprises seven putative open reading frames encoding a discrete replicase (Rep) split by an intergenic region, a putative capsid protein (CP), several proteins of unknown function (P1-P4), and a long intergenic region. Notably, the two split parts of DsCDV1 Rep share high identities with the Reps of Geminiviridae and Genomoviridae, respectively, indicating an evolutionary linkage with both families. Phylogenetic analysis based on Rep or CP sequences placed DsCDV1 in a unique cluster, supporting the establishment of a new family, tentatively named Gegemycoviridae, intermediate to both families. DsCDV1 significantly attenuates fungal growth and nearly erases fungal virulence when transfected into the host fungus. Remarkably, DsCDV1 can systematically infect tobacco and pear seedlings, providing broad-spectrum resistance to fungal diseases. Subcellular localization analysis revealed that DsCDV1 P3 is systematically localized in the plasmodesmata, while its expression in trans-complementation experiments could restore systematic infection of a movement-deficient plant virus, suggesting that P3 is a movement protein. DsCDV1 exhibits unique molecular and biological traits not observed in other ssDNA viruses, serving as a link between fungal and plant ssDNA viruses and presenting an evolutionary connection between ssDNA viruses and fungi. These findings contribute to expanding our understanding of ssDNA virus diversity and evolution, offering potential biocontrol applications for managing crucial plant diseases.

Single-cell analysis reveals one cancer-associated fibroblasts subtype linked to metastasis in breast cancer: MXRA5 as a potential novel marker for prognosis.

Cancer-associated fibroblasts (CAFs) are prevalent in the tumor microenvironment of breast cancer, comprising a group of cell subpopulations with spatial, phenotypic, and functional heterogeneity. Due to the lack of specific markers for CAF subpopulations, their specific mechanisms in breast cancer remain unclear. We identified eight distinct CAF phenotypes in breast cancer using multiple single-cell RNA sequencing datasets and determined distinct transcription factors (TFs) of CAFs through SCENIC analysis. Our study highlights one CAF subtype in breast cancer, FN1+CAF2, associated with metastasis and macrophage polarization. We observed elevated FN1 expression in the stromal tissue of breast cancer patients. Furthermore, FN1 knockdown in CAFs reduced the migration ability of breast cancer cells. We identified a regulatory gene, MXRA5, in CAF2, which may play crucial roles in breast cancer. Our results indicated upregulated MXRA5 expression in breast cancer tissues and CAFs from patients with lymph node metastasis in the following experiment. Overall, our study reveals that the FN1+CAF2 subtype is associated with metastasis and suggests that MXRA5 may be a novel marker mediating the effects of CAF2 on breast cancer metastasis. This study enriches our understanding of CAF heterogeneity and offers new insights for treating breast cancer metastasis.

LRPPRC promotes glycolysis by stabilising LDHA mRNA and its knockdown plus glutamine inhibitor induces synthetic lethality via m6 A modification in triple-negative breast cancer.

BACKGROUND: Targeted therapy for triple-negative breast cancer (TNBC) remains a challenge. N6-methyladenosine (m6 A) is the most abundant internal mRNA modification in eukaryotes, and it regulates the homeostasis and function of modified RNA transcripts in cancer. However, the role of leucine-rich pentatricopeptide repeat containing protein (LRPPRC) as an m6 A reader in TNBC remains poorly understood. METHODS: Western blotting, reverse transcription-polymerase chain reaction (RT-qPCR) and immunohistochemistry were used to investigate LRPPRC expression levels. Dot blotting and colorimetric enzyme linked immunosorbent assay (ELISA) were employed to detect m6 A levels. In vitro functional assays and in vivo xenograft mouse model were utilised to examine the role of LRPPRC in TNBC progression. Liquid chromatography-mass spectrometry/mass spectrometry and Seahorse assays were conducted to verify the effect of LRPPRC on glycolysis. MeRIP-sequencing, RNA-sequencing, MeRIP assays, RNA immunoprecipitation assays, RNA pull-down assays and RNA stability assays were used to identify the target genes of LRPPRC. Patient-derived xenografts and organoids were employed to substantiate the synthetic lethality induced by LRPPRC knockdown plus glutaminase inhibition. RESULTS: The expressions of LRPPRC and m6 A RNA were elevated in TNBC, and the m6 A modification site could be recognised by LRPPRC. LRPPRC promoted the proliferation, metastasis and glycolysis of TNBC cells both in vivo and in vitro. We identified lactate dehydrogenase A (LDHA) as a novel direct target of LRPPRC, which recognised the m6 A site of LDHA mRNA and enhanced the stability of LDHA mRNA to promote glycolysis. Furthermore, while LRPPRC knockdown reduced glycolysis, glutaminolysis was enhanced. Moreover, the effect of LRPPRC on WD40 repeat domain-containing protein 76 (WDR76) mRNA stability was impaired in an m6 A-dependent manner. Then, LRPPRC knockdown plus a glutaminase inhibition led to synthetic lethality. CONCLUSIONS: Our study demonstrated that LRPPRC promoted TNBC progression by regulating metabolic reprogramming via m6 A modification. These characteristics shed light on the novel combination targeted therapy strategies to combat TNBC.

Pro-osteogenic role of interleukin-22 in calcific aortic valve disease.

BACKGROUND AND AIMS: Although calcific aortic valve disease (CAVD) is a common valvular disease among elderly populations and its incidence has markedly increased in recent decades, the pathogenesis of CAVD remains unclear. In this study, we explored the potential role of interleukin (IL)-22 and the underlying molecular mechanism in CAVD. METHODS AND RESULTS: Our results showed that IL-22 was upregulated in calcific aortic valves from CAVD patients, and its main sources were CD3+ T cells and CD68+ macrophages. Human aortic valve interstitial cells (VICs) expressed the IL-22-specific receptor IL-22R1, and IL-22R1 expression also was elevated in calcified valves. Treatment of cultured human VICs with recombinant human IL-22 resulted in markedly increased expression of osteogenic proteins Runt-related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP), as well as increased matrix calcium deposition. Moreover, siRNA silencing of IL-22R1 blocked the pro-osteogenic effect of IL-22 in VICs. In IL-22-treated VICs, we also observed increased phosphorylation of JAK3 and STAT3 and nuclear translocation of STAT3. Pretreatment with a specific JAK3 inhibitor, WHIP-154, or siRNA knockout of STAT3 effectively mitigated the IL-22-induced osteoblastic trans-differentiation of human VICs. CONCLUSIONS: Together, these data indicate that IL-22 promotes osteogenic differentiation of VICs by activating JAK3/STAT3 signaling. Based on our results demonstrating a pro-osteogenic role of IL-22 in human aortic valves, pharmacological inhibition of IL-22 signaling may represent a potential strategy for alleviating CAVD.

Undesirable ER stress induced by bavachin contributed to follicular atresia in zebrafish ovary.

Fructus psoraleae (FP) is a commonly used herb with potential reproductive toxicity. Bavachin (BV), one of essential active ingredients of FP, was found to exhibit estrogenic activity, but its effect on female reproductive system remains unknown. In this study, the impact of BV on the female zebrafish reproductive system and underlying molecular mechanism were determined in vivo and ex vivo. The results showed that BV could accumulate in zebrafish ovary, leading to obvious follicular atresia and increase in gonadal index and vitellogenin content. Endoplasmic reticulum (ER) swelling and hypertrophy were observed in the BV-treated zebrafish ovary, accompanied by an increase in the expressions of ER stress and unfolded protein response (UPR) related genes, namely atf6, ire-1α and xbp1s. In the ex vivo study, BV was found to decrease the survival rate and maturation rate of oocytes, while increasing the expression of Ca2+. Additionally, BV led to an elevation in the level of estrogen receptor ESR1 and the expressions of genes involved in ER stress and UPR, including atf6, ire-1α, xbp1s, chop and perk. Moreover, molecular docking revealed that BV could directly bind to immunoglobulin heavy chain binding protein (BiP) and estrogen receptor 1 (ESR1). Besides, the alterations induced by BV could be partially reversed by fulvestrant (FULV) and 4-phenylbutyric acid (4-PBA), respectively. Thus, long-termed BV-containing medicine treatment could generate reproductive toxicity in female zebrafish by causing follicular atresia through BiP- and ESR-mediated ER stress and UPR, providing a potential target for the prevention of reproductive toxicity caused by BV.

Abnormal mechanical stress on bicuspid aortic valve induces valvular calcification and inhibits Notch1/NICD/Runx2 signal.

Background: Bicuspid aortic valve (BAV) is a congenital cardiac deformity, increasing the risk of developing calcific aortic valve disease (CAVD). The disturbance of hemodynamics can induce valvular calcification, but the mechanism has not been fully identified. Methods: We constructed a finite element model (FEM) of the aortic valve based on the computed tomography angiography (CTA) data from BAV patients and tricuspid aortic valve (TAV) individuals. We analyzed the hemodynamic properties based on our model and investigated the characteristics of mechanical stimuli on BAV. Further, we detected the expression of Notch, NICD and Runx2 in valve samples and identified the association between mechanical stress and the Notch1 signaling pathway. Results: Finite element analysis showed that at diastole phase, the equivalent stress on the root of BAV was significantly higher than that on the TAV leaflet. Correspondingly, the expression of Notch1 and NICH decreased and the expression of Runx2 elevated significantly on large BAV leaflet belly, which is associated with equivalent stress on leaflet. Our findings indicated that the root of BAV suffered higher mechanical stress due to the abnormal hemodynamic environment, and the disturbance of the Notch1/NICD/Runx2 signaling pathway caused by mechanical stimuli contributed to valvular calcification.

m6A reader HNRNPA2B1 destabilization of ATG4B regulates autophagic activity, proliferation and olaparib sensitivity in breast cancer.

N6-methyladenosine RNA (m6A) is the most extensive epigenetic modification in mRNA and influences tumor progression. However, the role of m6A regulators and specific mechanisms in breast cancer still need further study. Here, we investigated the significance of the m6A reader HNRNPA2B1 and explored its influence on autophagy and drug sensitivity in breast cancer. HNRNPA2B1 was selected by bioinformatics analysis, and its high expression level was identified in breast cancer tissues and cell lines. HNRNPA2B1 was related to poor prognosis. Downregulation of HNRNPA2B1 reduced proliferation, enhanced autophagic flux, and partially reversed de novo resistance to olaparib in breast cancer. ATG4B was determined by RIP and MeRIP assays as a downstream gene of HNRNPA2B1, by which recognized the m6A site in the 3'UTR. Overexpression of ATG4B rescued the malignancy driven by HNRNPA2B1 in breast cancer cells and increased the olaparib sensitivity. Our study revealed that the m6A reader HNRNPA2B1 mediated proliferation and autophagy in breast cancer cell lines by facilitating ATG4B mRNA decay and targeting HNRNPA2B1/m6A/ATG4B might enhance the olaparib sensitivity of breast cancer cells.

Ginsenoside Rb1 Ameliorated Bavachin-Induced Renal Fibrosis via Suppressing Bip/eIF2α/CHOP Signaling-Mediated EMT.

The nephrotoxicity of Fructus Psoraleae, an effective traditional Chinese medicine for vitiligo treatment, has been reported. As one of the main toxic components in Fructus Psoraleae, bavachin (BV) was considered to be related to Fructus Psoraleae-caused adverse outcomes, but the direct evidence and molecular mechanism underlying BV-induced nephrotoxicity are not well elucidated. Therefore, this study was designed to confirm whether BV would cause toxic effects on the kidney and explore the possible mode of action. Our results demonstrated that days' treatment with 0.5 µM BV indeed caused obvious renal fibrosis in the zebrafish kidney. The obvious E- to N-cadherin switch and the expressions of proteins promoting epithelial-mesenchymal transition (EMT) were observed in BV-treated human renal tubular epithelial and zebrafish kidneys. In addition, elevated reactive oxygen species (ROS) levels and Bip/eIF2α/CHOP-mediated endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) were caused by BV, both of which could be reversed by ROS scavenger N-acetyl-L-cysteine (NAC). Also, blocking ER stress-caused cytoplasmic Ca2+ overload with 4-PBA notably alleviated BV-induced alterations in key molecular events related to EMT and renal fibrosis. Furthermore, of the natural compounds subjected to screening, ginsenoside Rb1 significantly downregulated BV-induced ER stress by inhibiting ROS generation and following the activation of Bip/eIF2α/CHOP signaling in HK2 cells. Subsequently, BV-triggered EMT and renal fibrosis were both ameliorated by ginsenoside Rb1. In summary, our findings suggested that BV-induced ROS promoted the appearance of EMT and renal fibrosis mainly via Bip/eIF2α/CHOP-mediated ER stress. This ER stress-related toxic pathway might be a potential intervention target for BV-caused renal fibrosis, and ginsenoside Rb1 would be a promising drug against BV- or Fructus Psoraleae-induced nephrotoxicity.

Indoleamine 2,3-dioxygenase 1 regulates breast cancer tamoxifen resistance through interleukin-6/signal transducer and activator of transcription.

Breast cancer is the primary cause of cancer-related deaths in women. Tamoxifen (TAM) is the preferred drug for treating premenopausal luminal-type breast cancer, but TAM resistance restricts its ability to benefit patients. To date, the mechanism of this resistance remains unclear, and there is currently no effective treatment for reversing it. The expression of indoleamine 2,3-dioxygenase 1 (IDO1) has been shown to be elevated in various malignancies. Here, we aimed to investigate the role of IDO1 in TAM-resistant breast cancer. We confirmed that IDO1 is strongly expressed in TAM-resistant breast cancer, and it mediates drug-resistant cell proliferation, metastasis, and TAM resistance in vivo and in vitro through interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3). We also found that the mechanism by which TAM upregulates IDO1 is dependent on STAT1 activation. In summary, IDO1 regulates TAM resistance and can serve as a novel target for treatment of TAM-resistant breast cancer.

Low-dose radiation-induced demethylation of 3ß-HSD participated in the regulation of testosterone content.

The effects of low-dose radiation (LDR, ≤0.1 Gy) on living organisms have been the hot areas of radiation biology but do not reach a definitive conclusion yet. So far, few studies have adequately accounted for the male reproductive system responses to LDR, particularly the regulation of testosterone content. Hence, this study was designed to evaluate the effects of LDR on Leydig cells and testicular tissue, especially the ability to synthesize testosterone. We found that less than 0.2-Gy 60 Co gamma rays did not cause significant changes in the hemogram index and the body weight; also, pathological examination did not find obvious structural alterations in testis, epididymis, and other radiation-sensitive organs. Consistently, the results from in vitro showed that only more than 0.5-Gy gamma rays could induce remarkable DNA damage, cycle arrest, and apoptosis. Notably, LDR disturbed the contents of testosterone in mice serums and culture supernatants of TM3 cells and dose dependently increased the expression of 3ß-HSD. After cotreatment with trilostane (Tril), the inhibitor of 3ß-HSD, increased testosterone could be partially reversed. Besides, DNA damage repair-related enzymes, including DNMT1, DNMT3B, and Sirt1, were increased in irradiated TM3 cells, accompanying by evident demethylation in the gene body of 3ß-HSD. In conclusion, our results strongly suggest that LDR could induce obvious perturbation in the synthesis of testosterone without causing organic damage, during which DNA demethylation modification of 3ß-HSD might play a crucial role and would be a potential target to prevent LDR-induced male reproductive damage.

Targeting OPA1-Mediated Mitochondrial Fusion Contributed to Celastrol's Anti-Tumor Angiogenesis Effect.

Celastrol, an active triterpenoid extracted from one of the most famous traditional Chinese medicines (TCMs), Tripterygium wilfordii Hook.f., is a novel anti-cancer drug with significant anti-angiogenesis activity. However, the exact molecular mechanisms underlying its anti-tumor angiogenesis effect remain unclear. The process of angiogenesis needs lots of energy supply, which mostly derives from mitochondria, the "energy factory" in our body. This study shows that celastrol exerts visible suppression on tumor growth and angiogenesis in a cell-derived xenograft (CDX). Likewise, it reduced the tube formation and migration of human umbilical vein endothelial cells (HUVECs), suppressed the energy metabolism of mitochondria in the Seahorse XF Mito Stress Test, and triggered mitochondrial fragmentation and NF-κB activation. Mechanically, celastrol downregulated the expression of mitochondrial-sharping protein optic atrophy protein 1 (OPA1), which was further estimated by the OPA1 knockdown model of HUVECs. Specifically, celastrol directly suppressed OPA1 at the mRNA level by inhibiting the phosphorylation of STAT3, and stattic (STAT3 inhibitor) showed the same effects on OPA1 suppression and anti-angiogenesis activity. Overall, this study indicates that celastrol inhibits tumor angiogenesis by suppressing mitochondrial function and morphology via the STAT3/OPA1/P65 pathway and provides new insight for mitochondrion-targeted cancer therapy.

Emodin-Induced Oxidative Inhibition of Mitochondrial Function Assists BiP/IRE1α/CHOP Signaling-Mediated ER-Related Apoptosis.

Cassiae Semen is a widely used herbal medicine and a popular edible variety in many dietary or health beverage. Emerging evidence disclosed that improper administration of Cassiae Semen could induce obvious liver injury, which is possibly attributed to emodin, one of the bioactive anthraquinone compounds in Cassiae Semen, which caused hepatotoxicity, but the underlying mechanisms are not completely understood. Hence, the present study firstly explored the possible role of oxidative stress-mediated mitochondrial dysfunction and ER stress in emodin-cause apoptosis of L02 cells, aiming to elaborate possible toxic mechanisms involved in emodin-induced hepatotoxicity. Our results showed that emodin-induced ROS activated ER stress and the UPR via the BiP/IRE1α/CHOP signaling pathway, followed by ER Ca2+ release and cytoplasmic Ca2+ overloading. At the same time, emodin-caused redox imbalance increased mtROS while decreased MMP and mitochondrial function, resulting in the leaks of mitochondrial-related proapoptotic factors. Interestingly, blocking Ca2+ release from ER by 2-APB could inhibit emodin-induced apoptosis of L02, but the restored mitochondrial function did not reduce the apoptosis rates of emodin-treated cells. Besides, tunicamycin (TM) and doxorubicin (DOX) were used to activate ER stress and mitochondrial injury at a dosage where obvious apoptosis was not observed, respectively. We found that cotreatment with TM and DOX significantly induced apoptosis of L02 cells. Thus, all the results indicated that emodin-induced excessive ROS generation and redox imbalance promoted apoptosis, which was mainly associated with BiP/IRE1α/CHOP signaling-mediated ER stress and would be enhanced by oxidative stress-mediated mitochondrial dysfunction. Altogether, this finding has implicated that redox imbalance-mediated ER stress could be an alternative target for the treatment of Cassiae Semen or other medicine-food homologous varieties containing emodin-induced liver injury.

The effect of salting on Toxoplasma gondii viability evaluated and implemented in a quantitative risk assessment of meat-borne human infection.

The protozoan parasite Toxoplasma gondii can infect all warm-blooded animals and it causes the disease toxoplasmosis. Meat containing viable T. gondii tissue cysts is considered one of the main sources of human infection. The relative importance of the different types of meat depends, not only on the prevalence of T. gondii infection in the different livestock species, but also on consumed volumes and preparation habits. To take these factors into account and to estimate the relative contribution of different meat products to human infection, a quantitative risk assessment model for meat-borne T. gondii infection was previously developed. However, at the time, the effect of salting on parasite viability was estimated based on a single experiment. In recent years, data using salting methods that are more in line with processing of meat products have come available. Literature data on the effect of salting on T. gondii viability were collected and used to fit a predictive model. In addition to the new salting model, a lower concentration of bradyzoites in cattle, more specific heating profiles, and more recent consumption data were implemented in the QMRA model for meat-borne T. gondii infection in the Netherlands. Results show that beef remains the most important source, as it contributed 84% of the total number of predicted infections in the Dutch population, followed by pork (12%), mutton (3.7%), lamb (0.2%) pork/beef mixed products (0.1%), and veal (0.01%). The predicted number of T. gondii infections is reasonably in line with epidemiological data. At the product level, filet americain (a raw beef spread) alone contributed 80% of the total predicted infections in the base model, but scenario analyses demonstrate that its contribution is highly dependent on the salting parameters. A clear identification of the most risky meat products is important, as interventions focussing on these products could have a great impact on reducing T. gondii disease burden in the Netherlands. For that reason, it is important that the effects of salting and other processing methods are evaluated in line with industrial processing and incorporated in quantitative risk assessment models for meat-borne toxoplasmosis.

Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity.

Aristolactam I (ALI) is an active component derived from some Traditional Chinese medicines (TCMs), and also the important metabolite of aristolochic acid. Long-term administration of medicine-containing ALI was reported to be related to aristolochic acid nephropathy (AAN), which was attributed to ALI-induced nephrotoxicity. However, the toxic mechanism of action involved is still unclear. Recently, pathogenic ferroptosis mediated lipid peroxidation was demonstrated to cause kidney injury. Therefore, this study explored the role of ferroptosis induced by mitochondrial iron overload in ALI-induced nephrotoxicity, aiming to identify the possible toxic mechanism of ALI-induced chronic nephropathy. Our results showed that ALI inhibited HK-2 cell activity in a dose-dependent manner and significantly suppressed glutathione (GSH) levels, accompanying by significant increases in intracellular 4-hydroxynonenal (4-HNE) and intracellular iron ions. Moreover, the ALI-mediated cytotoxicity could be reversed by deferoxamine mesylate (DFO). Compared with other inhibitors, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, obviously alleviated ALI-induced cytotoxicity. Furthermore, we have shown that ALI could remarkably increase the levels of superoxide anion and ferrous ions in mitochondria, and induce mitochondrial damage and condensed mitochondrial membrane density, the morphological characteristics of ferroptosis, all of which could be reversed by DFO. Interestingly, ALI dose-dependently inhibited these protein contents of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4), which could be partly rescued by Tin-protoporphyrin IX (SnPP) and mitoTEMPO co-treatment. In conclusion, our results demonstrated that mitochondrial iron overload-mediated antioxidant system inhibition would assist ALI-induced ferroptosis in renal tubular epithelial cells, and Nrf2-HO-1/GPX4 antioxidative system could be an important intervention target to prevent medicine containing ALI-induced nephropathy.

A quantitative risk assessment for human Taenia solium exposure from home slaughtered pigs in European countries.

BACKGROUND: Taenia solium, a zoonotic tapeworm, is responsible for about a third of all preventable epilepsy human cases in endemic regions. In Europe, adequate biosecurity of pig housing and meat inspection practices have decreased the incidence of T. solium taeniosis and cysticercosis. Pigs slaughtered at home may have been raised in suboptimal biosecurity conditions and slaughtered without meat inspection. As a result, consumption of undercooked pork from home slaughtered pigs could pose a risk for exposure to T. solium. The aim of this study was to quantify the risk of human T. solium exposure from meat of home slaughtered pigs, in comparison to controlled slaughtered pigs, in European countries. A quantitative microbial risk assessment model (QMRA) was developed and porcine cysticercosis prevalence data, the percentage of home slaughtered pigs, meat inspection sensitivity, the cyst distribution in pork and pork consumption in five European countries, Bulgaria, Germany, Poland, Romania and Spain, were included as variables in the model. This was combined with literature about cooking habits to estimate the number of infected pork portions eaten per year in a country. RESULTS: The results of the model showed a 13.83 times higher prevalence of contaminated pork portions from home slaughtered pigs than controlled slaughtered pigs. This difference is brought about by the higher prevalence of cysticercosis in pigs that are home raised and slaughtered. Meat inspection did not affect the higher exposure from pork that is home slaughtered. Cooking meat effectively lowered the risk of exposure to T. solium-infected pork. CONCLUSIONS: This QMRA showed that there is still a risk of obtaining an infection with T. solium due to consumption of pork, especially when pigs are reared and slaughtered at home, using data of five European countries that reported porcine cysticercosis cases. We propose systematic reporting of cysticercosis cases in slaughterhouses, and in addition molecularly confirming suspected cases to gain more insight into the presence of T. solium in pigs and the risk for humans in Europe. When more data become available, this QMRA model could be used to evaluate human exposure to T. solium in Europe and beyond.

Melatonin ameliorates ANIT­induced cholestasis by activating Nrf2 through a PI3K/Akt­dependent pathway in rats.

Cholestasis is a devastating liver condition which is increasing in prevalence worldwide; however, its underlying pathogenic mechanisms remain to be fully elucidated. It was hypothesised that melatonin may alleviate the hepatic injury associated with cholestasis due to its established antioxidant effects. Therefore, the effect and potential anticholestatic properties of melatonin were investigated in rats with α­naphthylisothiocyanate (ANIT)­induced liver injury, a common animal model that mimics the cholestasis­associated liver injury in humans. The rats received intraperitoneal injection of ANIT with or without subsequent treatment with melatonin, and were sacrificed 24 h later. The serum biochemistry parameters of the liver were measured using conventional laboratory assays, and the liver tissue was subjected to conventional histological examination, reverse transcription­quantitative polymerase chain reaction analysis and western blotting. The levels of alanine transaminase, aspartate transaminase, total bilirubin, direct bilirubin, total bile acids, alkaline phosphatase, γ­glutamyl transferase and glutathione were restored in rats treated with melatonin. Histological examination provided further evidence supporting the protective effect of melatonin against ANIT­induced cholestasis. In addition, the mRNA and protein expression levels of glutamate cysteine ligase, phosphorylated Akt and nuclear factor­erythroid 2­related factor­2 were restored in rats treated with melatonin. These findings indicate that melatonin is a natural agent that appears to be promising for the treatment of cholestasis, and that the anticholestatic effects of melatonin involve the alleviation of oxidative stress.

Medical Image Classification Based on Deep Features Extracted by Deep Model and Statistic Feature Fusion with Multilayer Perceptron‬.

Medical image classification is a key technique of Computer-Aided Diagnosis (CAD) systems. Traditional methods rely mainly on the shape, color, and/or texture features as well as their combinations, most of which are problem-specific and have shown to be complementary in medical images, which leads to a system that lacks the ability to make representations of high-level problem domain concepts and that has poor model generalization ability. Recent deep learning methods provide an effective way to construct an end-to-end model that can compute final classification labels with the raw pixels of medical images. However, due to the high resolution of the medical images and the small dataset size, deep learning models suffer from high computational costs and limitations in the model layers and channels. To solve these problems, in this paper, we propose a deep learning model that integrates Coding Network with Multilayer Perceptron (CNMP), which combines high-level features that are extracted from a deep convolutional neural network and some selected traditional features. The construction of the proposed model includes the following steps. First, we train a deep convolutional neural network as a coding network in a supervised manner, and the result is that it can code the raw pixels of medical images into feature vectors that represent high-level concepts for classification. Second, we extract a set of selected traditional features based on background knowledge of medical images. Finally, we design an efficient model that is based on neural networks to fuse the different feature groups obtained in the first and second step. We evaluate the proposed approach on two benchmark medical image datasets: HIS2828 and ISIC2017. We achieve an overall classification accuracy of 90.1% and 90.2%, respectively, which are higher than the current successful methods.

Seroprevalence of Toxoplasma gondii in pregnant women and livestock in the mainland of China: a systematic review and hierarchical meta-analysis.

Primary Toxoplasma gondii infection in pregnant women may result in abortion, stillbirth, or lifelong disabilities of the unborn child. One of the main transmission routes to humans is consumption of raw or undercooked meat containing T. gondii tissue cysts. We aim to determine and compare the regional distribution of T. gondii seroprevalence in pregnant women and meat-producing livestock in China through a systematic literature review. A total of 272 eligible publications were identified from Medline, Scopus, Embase and China National Knowledge Infrastructure. Apparent and true seroprevalence were analysed by region using a novel Bayesian hierarchical model that allowed incorporating sensitivity and specificity of the applied serological assays. The true seroprevalence of T. gondii in pregnant women was 5.0% or less in seven regions of China. The median of the regional true seroprevalences in pigs (24%) was significantly higher than in cattle (9.5%), but it was not significantly higher than in chickens (20%) and small ruminants (20%). This study represents the first use of a Bayesian hierarchical model to obtain regional true seroprevalence. These results, in combination with meat consumption data, can be used to better understand the contribution of meat-producing animals to human T. gondii infection in China.