Activation of lipophagy ameliorates cadmium-induced neural tube defects via reducing low density lipoprotein cholesterol levels in mouse placentas.

Neural tube defects (NTDs) represent a prevalent and severe category of congenital anomalies in humans. Cadmium (Cd) is an environmental teratogen known to cause fetal NTDs. However, its underlying mechanisms remain elusive. This study aims to investigate the therapeutic potential of lipophagy in the treatment of NTDs, providing valuable insights for future strategies targeting lipophagy activation as a means to mitigate NTDs.We successfully modeled NTDs by Cd exposure during pregnancy. RNA sequencing was employed to investigate the transcriptomic alterations and functional enrichment of differentially expressed genes in NTD placental tissues. Subsequently, pharmacological/genetic (Atg5-/- placentas) experiments confirmed that inducing placental lipophagy can alleviate Cd induced-NTDs. We found that Cd exposure caused NTDs. Further analyzed transcriptomic data from the placentas with NTDs which revealed significant downregulation of low-density lipoprotein receptor associated protein 1(Lrp1) gene expression responsible for positive regulation of low-density lipoprotein cholesterol (LDL-C) transport. Correspondingly, there was an increase in maternal serum/placenta/amniotic fluid LDL-C content. Subsequently, we have discovered that Cd exposure activated placental lipophagy. Pharmacological/genetic (Atg5-/- placentas) experiments confirmed that inducing placental lipophagy can alleviate Cd induced-NTDs. Furthermore, our findings demonstrate that activation of placental lipophagy effectively counteracts the Cd-induced elevation in LDL-C levels. Lipophagy serves to mitigate Cd-induced NTDs by reducing LDL-C levels within mouse placentas.

A Strong, Tough, and Stable Composite with Nacre-Inspired Sandwich Structure.

Improving the fracture resistance of nacre-inspired composites is crucial in addressing the strength-toughness trade-off. However, most previously proposed strategies for enhancing fracture resistance in these composites have been limited to interfacial modification by polymer, which restricts mechanical enhancement. Here, a composite material consisting of graphene oxide (GO) lamellae and nanocrystalline reinforced amorphous alumina nanowires (NAANs) has been developed. The structure of the composite is inspired by nacre and is composed of stacked GO nanosheets with NAANs in between, forming a sandwich-like structure. This design enhances the fracture resistance of the composite through the pull-out of GO nanosheets at the nanoscale and GO/NAANs sandwich-like coupling at the micro-scale, while also providing stiff ceramic support. This composite simultaneously possesses high strength (887.8 MPa), toughness (31.6 MJ m-3), superior cyclic stability (1600 cycles), and long-term (2 years) immersion stability, which outperform previously reported GO-based lamellar composites. The hierarchical fracture design provides a new path to design next-generation strong, tough, and stable materials for advanced engineering applications.

A Pilot Study on a Possible Mechanism behind Olfactory Dysfunction in Parkinson's Disease: The Association of TAAR1 Downregulation with Neuronal Loss and Inflammation along Olfactory Pathway.

Parkinson's disease (PD) is characterized not only by motor symptoms but also by non-motor dysfunctions, such as olfactory impairment; the cause is not fully understood. Our study suggests that neuronal loss and inflammation in brain regions along the olfactory pathway, such as the olfactory bulb (OB) and the piriform cortex (PC), may contribute to olfactory dysfunction in PD mice, which might be related to the downregulation of the trace amine-associated receptor 1 (TAAR1) in these areas. In the striatum, although only a decrease in mRNA level, but not in protein level, of TAAR1 was detected, bioinformatic analyses substantiated its correlation with PD. Moreover, we discovered that neuronal death and inflammation in the OB and the PC in PD mice might be regulated by TAAR through the Bcl-2/caspase3 pathway. This manifested as a decrease of anti-apoptotic protein Bcl-2 and an increase of the pro-apoptotic protein cleaved caspase3, or through regulating astrocytes activity, manifested as the increase of TAAR1 in astrocytes, which might lead to the decreased clearance of glutamate and consequent neurotoxicity. In summary, we have identified a possible mechanism to elucidate the olfactory dysfunction in PD, positing neuronal damage and inflammation due to apoptosis and astrocyte activity along the olfactory pathway in conjunction with the downregulation of TAAR1.

Identified S100A9 as a target for diagnosis and treatment of ulcerative colitis by bioinformatics analysis.

Ulcerative colitis (UC) is a chronic, recurrent inflammatory bowel disease. UC confronts with severe challenges including the unclear pathogenesis and lack of specific diagnostic markers, demanding for identifying predictive biomarkers for UC diagnosis and treatment. We perform immune infiltration and weighted gene co-expression network analysis on gene expression profiles of active UC, inactive UC, and normal controls to identify UC related immune cell and hub genes. Neutrophils, M1 macrophages, activated dendritic cells, and activated mast cells are significantly enriched in active UC. MMP-9, CHI3L1, CXCL9, CXCL10, CXCR2 and S100A9 are identified as hub genes in active UC. Specifically, S100A9 is significantly overexpressed in mice with colitis. The receiver operating characteristic curve demonstrates the excellent performance of S100A9 expression in diagnosing active UC. Inhibition of S100A9 expression reduces DSS-induced colonic inflammation. These identified biomarkers associated with activity in UC patients enlighten the new insights of UC diagnosis and treatment.

Dual-ROS Sensitive Moieties Conjugate Inhibits Curcumin Oxidative Degradation for Colitis Precise Therapy.

Curcumin, a natural bioactive polyphenol with diverse molecular targets, is well known for its anti-oxidation and anti-inflammatory potential. However, curcumin exhibits low solubility (<1 µg mL-1), poor tissue-targeting ability, and rapid oxidative degradation, resulting in poor bioavailability and stability for inflammatory therapy. Here, poly(diselenide-oxalate-curcumin) nanoparticle (SeOC-NP) with dual-reactive oxygen species (ROS) sensitive chemical moieties (diselenide and peroxalate ester bonds) is fabricated by a one-step synthetic strategy. The results confirmed that dual-ROS sensitive chemical moieties endowed SeOC-NP with the ability of targeted delivery of curcumin and significantly suppress oxidative degradation of curcumin for high-efficiency inflammatory therapy. In detail, the degradation amount of curcumin for SeOC is about 4-fold lower than that of free curcumin in an oxidative microenvironment. As a result, SeOC-NP significantly enhanced the antioxidant activity and anti-inflammatory efficacy of curcumin in vitro analysis by scavenging intracellular ROS and suppressing the secretion of nitric oxide and pro-inflammatory cytokines. In mouse colitis models, orally administered SeOC-NP can remarkably alleviate the symptoms of IBD and maintain the homeostasis of gut microbiota. This work provided a simple and effective strategy to fabricate ROS-responsive micellar and enhance the oxidation stability of medicine for precise therapeutic inflammation.

The History and Prediction of Prebiotics and Postbiotics: A Patent Analysis.

Prebiotics and postbiotics have gained attention as functional food additives due to their substantial influence on the gut microbiome and potential implications for human health on a broader scale. In addition, the number of patents for these additives has also increased, yet their functional classification has been problematic. In this study, we classified 2215 patents granted from 2001 to 2020 by functionality to enable predictions of future development directions. These patents encompassed subjects as diverse as feed supplementation, regulation of intestinal homeostasis, prevention of gastrointestinal ailments, targeted drug administration and augmentation of drug potency. The progression of patents issued during this time frame could be divided into three phases: occasional accounts prior to 2001, a period from 2001 to 2013 during which an average of 42 patents were issued annually, followed by a surge exceeding 140 patents annually after 2013. The latter increase has indicated that pre- and post-biotics have been recognized as biologically relevant. Patent mining therefore can enable forecasts of the future trajectory of these biologics and provide insights to evaluate their advancement. Moreover, this research is the first attempt to generalize and predict the directions of prebiotics and postbiotics using patent information and offers a comprehensive perspective for the potential utilization of prebiotics and postbiotics across a wide variety of fields.

Multigenerational paternal obesity enhances the susceptibility to male subfertility in offspring via Wt1 N6-methyladenosine modification.

There is strong evidence that obesity is a risk factor for poor semen quality. However, the effects of multigenerational paternal obesity on the susceptibility to cadmium (a reproductive toxicant)-induced spermatogenesis disorders in offspring remain unknown. Here, we show that, in mice, spermatogenesis and retinoic acid levels become progressively lower as the number of generations exposed to a high-fat diet increase. Furthermore, exposing several generations of mice to a high fat diet results in a decrease in the expression of Wt1, a transcription factor upstream of the enzymes that synthesize retinoic acid. These effects can be rescued by injecting adeno-associated virus 9-Wt1 into the mouse testes of the offspring. Additionally, multigenerational paternal high-fat diet progressively increases METTL3 and Wt1 N6-methyladenosine levels in the testes of offspring mice. Mechanistically, treating the fathers with STM2457, a METTL3 inhibitor, restores obesity-reduced sperm count, and decreases Wt1 N6-methyladenosine level in the mouse testes of the offspring. A case-controlled study shows that human donors who are overweight or obese exhibit elevated N6-methyladenosine levels in sperm and decreased sperm concentration. Collectively, these results indicate that multigenerational paternal obesity enhances the susceptibility of the offspring to spermatogenesis disorders by increasing METTL3-mediated Wt1 N6-methyladenosine modification.

A High-Entropy Prussian Blue Analog for Aqueous Potassium-Ion Batteries.

Aqueous potassium-ion batteries (AKIBs) are considered promising electrochemical energy storage systems owing to their high safety and cost-effectiveness. However, the structural degradation resulting from the repeated accommodation of large K-ions and the dissolution of active electrode materials in highly dielectric aqueous electrolytes often lead to unsatisfactory electrochemical performance. This study introduces a high-entropy Prussian blue analog (HEPBA) cathode material for AKIBs, demonstrating significantly enhanced structural stability and reduced dissolution. The HEPBA exhibits a highly reversible specific capacity of 102.4 mAh g-1, with 84.4% capacity retention after undergoing 3448 cycles over a duration of 270 days. Mechanistic insights derived from comprehensive experimental investigations, supported by theoretical calculations, reveal that the HEPBA features a robust structure resistant to dissolution, a solid-solution reaction pathway with negligible volume variation during charge-discharge, and efficient ion transport kinetics characterized by a reduced band gap and a low energy barrier. This study represents a measurable step forward in the development of long-lasting electrode materials for aqueous AKIBs.

Self-assembly of H2S-responsive nanoprodrugs based on natural rhein and geraniol for targeted therapy against Salmonella Typhimurium.

Salmonellosis is a globally extensive food-borne disease, which threatens public health and results in huge economic losses in the world annually. The rising prevalence of antibiotic resistance in Salmonella poses a significant global concern, emphasizing an imperative to identify novel therapeutic agents or methodologies to effectively combat this predicament. In this study, self-assembly hydrogen sulfide (H2S)-responsive nanoprodrugs were fabricated with poly(α-lipoic acid)-polyethylene glycol grafted rhein and geraniol (PPRG), self-assembled into core-shell nanoparticles via electrostatic, hydrophilic and hydrophobic interactions, with hydrophilic exterior and hydrophobic interior. The rhein and geraniol are released from self-assembly nanoprodrugs PPRG in response to Salmonella infection, which is known to produce hydrogen sulfide (H2S). PPRG demonstrated stronger antibacterial activity against Salmonella compared with rhein or geraniol alone in vitro and in vivo. Additionally, PPRG was also able to suppress the inflammation and modulate gut microbiota homeostasis. In conclusion, the as-prepared self-assembly nanoprodrug sheds new light on the design of natural product active ingredients and provides new ideas for exploring targeted therapies for specific Enteropathogens. Graphical  illustration for construction of self-assembly nanoprodrugs PPRG and its antibacterial and anti-inflammatory activities on experimental Salmonella infection in mice.

LncRNA-edited biomimetic nanovaccines combined with anti-TIM-3 for augmented immune checkpoint blockade immunotherapy.

T-cell immunoglobulin mucin (TIM)-3 blockade ameliorates T cell exhaustion and triggers dendritic cell (DC) inflammasome activation, showing great potential in immune checkpoint blockade (ICB) immunotherapy. However, pharmacokinetic profile and T cell/DC infiltration in tumor microenvironment is still undesired. Here, we develop a long noncoding RNA (lncRNA)-edited biomimetic nanovaccine combined with anti-TIM-3 to mediate dual-effect antigen cross-presentation and dampen T cell immunosuppression for reinforced ICB immunotherapy. LncRNA inducing major histocompatibility complex I and immunogenicity of tumor (LIMIT)-edited tumor cell membrane is used to encapsulate anti-TIM-3, formulating LCCT. Afterward, LCCT nanoparticles are embedded into an alginate-based hydrogel for suppressing post-surgical tumor relapse. LCCT retains TIM-3 blockade efficacy of anti-TIM-3 in both DCs and CD8+ T cells (beyond 75%). Moreover, the integrated anti-TIM-3 augments endocytosis of LCCT in DCs (1.5-fold), amplifying inflammasome activation and antigen cross-presentation. Furthermore, such DC activation synergistic with LCCT-induced CD8+ T-cell dampened immunosuppression and direct cross-presentation stimulates effector and memory-precursor CD8+ T cells against tumors. This lncRNA-edited biomimetic nanovaccine strategy brings a new sight to improve current ICB immunotherapy.

Like father, like daughter:Paternal cadmium exposure causes hepatic glucose metabolic disorder and phospholipids accumulation in adult female offspring.

Cadmium (Cd), is a well-known reproductive toxicant. The impacts of paternal Cd exposure on offspring glucose and lipid metabolism remain unclear, despite the abundance of adverse reports following early exposure from the mother. Here, we assessed paternally acquired metabolic derailment using a mouse model. LC-MS/MS, transcriptomics and molecular experimental techniques were subsequently applied in this study to explore the potential mechanism. We found that paternal Cd exposure caused glucose intolerance, lower insulin sensitivity and abnormal hepatic glycogen storage in adult female offspring, but not in males. LC-MS/MS data showed that hepatic phospholipids accumulation was also only observed in adult female offspring after paternal Cd exposure. Gene expression data showed that the level of insulin signaling and lipid transport-related genes was decreased in Cd-treated adult female offspring livers. Meanwhile, AHR, a transcription factor that combines with phospholipids to promote insulin resistance, was increased in Cd-treated adult female offspring livers. In addition, the escalation of the afore-mentioned lipid metabolites in the liver occurred as early as fetal stages in the female pups following paternal Cd exposure, suggesting the potential for these lipid species to be selected as early markers of disease for metabolic derailment later in life. Altogether, paternal Cd exposure causes offspring glucose metabolism disorder and phospholipids accumulation in a sex-dependent manner. This study provides a theoretical framework for future understanding of paternal-originated metabolic diseases.

Loss of Atg5 in Sertoli cells enhances the susceptibility of cadmium-impaired testicular spermatogenesis in mice.

Cadmium (Cd), one of the most common contaminants in diet and drinking water, impairs testicular germ cell development and spermatogenesis. Autophagy is essential for maintaining Sertoli cell function and Sertoli-germ cell communication. However, the role of Sertoli cell autophagy in Cd-caused spermatogenesis disorder remains unclear. Here, the mice of autophagy-related gene 5 (Atg5) knockouts in Sertoli cells were used to investigate the effect of autophagy deficiency on Cd-impaired spermatogenesis and its underlying mechanisms. Results showed that Sertoli cell-specific knockout of Atg5 exacerbated Cd-reduced sperm count and MVH (a specific marker for testicular germ cells) level in mice. Additionally, Sertoli cell Atg5 deficiency reduced the number of spermatocytes and decreased the level of meiosis-related proteins (SYCP3 and STRA8) in Cd-treated mouse testes. Loss of Atg5 in Sertoli cell exacerbated Cd-reduced the level of retinoic acid (RA) and retinal dehydrogenase (ALDH1A1 and ALDH1A) in mouse testes. Meanwhile, we found that the level of transcription factor WT1 was significantly downregulated in Atg5-/- plus Cd-treated testes. Further experiments showed that Wt1 overexpression restored Cd-decreased the levels of ALDH1A1 in Sertoli cells. Collectively, the above data suggest that knockout of Atg5 in Sertoli cell enhances the susceptibility of Cd-impaired testicular spermatogenesis. These findings provide new insights into autophagy of Sertoli cell preventing environmental toxicants-impaired testicular spermatogenesis.

Sperm Rhoa m6A modification mediates intergenerational transmission of paternally acquired hippocampal neuronal senescence and cognitive deficits after combined exposure to environmental cadmium and high-fat diet in mice.

Little is currently known about the effect and mechanism of combined paternal environmental cadmium (Cd) and high-fat diet (HFD) on offspring cognitive ability. Here, using in vivo model, we found that combined paternal environmental Cd and HFD caused hippocampal neuronal senescence and cognitive deficits in offspring. MeRIP-seq revealed m6A level of Rhoa, a regulatory gene of cellular senescence, was significantly increased in combined environmental Cd and HFD-treated paternal sperm. Interestingly, combined paternal environmental Cd and HFD markedly enhanced Rhoa mRNA, its m6A and reader protein IGF2BP1 in offspring hippocampus. STM2457, the inhibitor of m6A modification, markedly mitigated paternal exposure-caused the elevation of hippocampal Rhoa m6A, neuronal senescence and cognitive deficits in offspring. In vitro experiments, Rhoa siR significantly reversed mouse hippocampal neuronal senescence. Igf2bp1 siR obviously reduced the level and stability of Rhoa in aging mouse hippocampal neuronal cells. In conclusion, combined paternal environmental Cd and HFD induce offspring hippocampal neuronal senescence and cognitive deficits by promoting IGF2BP1-mediated Rhoa stabilization in offspring hippocampus via elevating Rhoa m6A in paternal sperm.

Gestational cadmium exposure disrupts fetal liver development via repressing estrogen biosynthesis in placental trophoblasts.

Cadmium (Cd), commonly found in diet and drinking water, is known to be harmful to the human liver. Nevertheless, the effects and mechanisms of gestational Cd exposure on fetal liver development remain unclear. Here, we reported that gestational Cd (150 mg/L) exposure obviously downregulated the expression of critical proteins including PCNA, Ki67 and VEGF-A in proliferation and angiogenesis in fetal livers, and lowered the estradiol concentration in fetal livers and placentae. Maternal estradiol supplement alleviated aforesaid impairments in fetal livers. Our data showed that the levels of pivotal estrogen synthases, such as CYP17A1 and 17ß-HSD, was markedly decreased in Cd-stimulated placentae but not fetal livers. Ground on ovariectomy (OVX), we found that maternal ovarian-derived estradiol had no major effects on Cd-impaired development in fetal liver. In addition, Cd exposure activated placental PERK signaling, and inhibited PERK activity could up-regulated the expressions of CYP17A1 and 17ß-HSD in placental trophoblasts. Collectively, gestational Cd exposure inhibited placenta-derived estrogen synthesis via activating PERK signaling, and therefore impaired fetal liver development. This study suggests a protective role for placenta-derived estradiol in fetal liver dysplasia shaped by toxicants, and provides a theoretical basis for toxicants to impede fetal liver development by disrupting the placenta-fetal-liver axis.

Identification of Aging and Young Subtypes for Predicting Colorectal Cancer Prognosis and Immunotherapy Responses.

Colorectal cancer (CRC) is critically related to aging and severely threatens human lives. To better explore the effects of aging on CRC progression and therapy outcome, a reliable aging subtypes identification of CRC is urgently desired. Here, 28 aging-related genes associated with the CRC prognosis were selected by univariate Cox analyses. Based on these 28 genes, CRC patients were divided into the aging subtype and young subtype by non-negative matrix factorization clustering. Aging subtype and young subtype of CRC were identified with distinct molecular features and clinical prognosis. The aging subtype was characterized by upregulation of senescence-associated secretory phenotype, higher frequencies of TP53 and immune checkpoint molecules, and high sensitivity to protein kinase and angiogenesis inhibitors. Furthermore, 14 genes were selected by LASSO penalized Cox regression analyses for aging-related risk signature construction. The constructed aging risk signature exhibited good prediction and the nomogram showed robust discrimination power over the traditional CRC staging system. In conclusion, this study successfully established aging subtype and young subtype of CRC, which is helpful to identify patients with aging characteristics to evaluate prognosis and treatment outcomes. Introducing aging-based subtypes into clinical concern and patient prognostication provides new opportunities for personalized CRC treatment.

The expression pattern of pyroptosis-related genes predicts the prognosis and drug response of melanoma.

Cutaneous melanoma (CM, hereafter referred to as melanoma) is a highly malignant tumor that typically undergoes early metastasis. Pyroptosis, as a special programmed cell death process that releases inflammatory factors and has been widely studied in tumors, but its role in melanoma has not been fully elucidated. In this study, we examined the relationship between pyroptosis and the prognosis of melanoma through bioinformatic analysis of RNA-sequencing data. Our results demonstrated that pyroptosis is a protective factor associated with melanoma prognosis. A higher pyroptosis score was associated with a more favorable overall survival. We used weighted gene co-expression networks analysis (WGCNA) to establish an effective prognosis model based on 12 pyroptosis-related genes. We then validated it in two independent cohorts. Furthermore, a nomogram combining clinicopathological characteristics and a pyroptosis-related gene signature (PGS) score was designed to effectively evaluate the prognosis of melanoma. Additionally, we analyzed the potential roles of pyroptosis in the tumor immune microenvironment and drug response. Interestingly, we found that the elevated infiltration of multiple immune cells, such as CD4+ T cells, CD8+ T cells, dendritic cells, and M1 macrophages, may be associated with the occurrence of pyroptosis. Pyroptosis was also related to a better response of melanoma to interferon-α, paclitaxel, cisplatin and imatinib. Through Spearman correlation analysis of the 12 pyroptosis-related genes and 135 chemotherapeutic agents in the Genomics of Drug Sensitivity in Cancer database, we identified solute carrier family 31 member 2 (SLC31A2) and collagen type 4 alpha 5 chain (COL4A5) as being associated with resistance to most of these drugs. In conclusion, this PGS is an effective and novelty prognostic indicator in melanoma, and also has an association with the melanoma immune microenvironment and melanoma treatment decision-making.

The addition of radiotherapy to breast-conserving surgery improves survival for elderly patients with early breast cancer.

Purpose: To evaluate whether adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) was associated with better survival among elderly (≥70 years) breast cancer patients with T1-2N0 and estrogen receptor (ER) positive disease. Methods: We included patients who met the inclusion criteria between 2010 and 2014 from the Surveillance, Epidemiology, and End Results program. Patients were subdivided into three groups based on surgery and RT: BCS alone, BCS plus RT, and refusal of RT. The primary outcomes were breast cancer-specific survival (BCSS) and overall survival (OS). Chi-squared tests, Kaplan-Meier method, and Multivariate Cox regression analysis were used for statistical analysis. Propensity score matching (PSM) was performed to minimize the potential selection bias. Results: A total of 26586 patients were included in this analysis. The median follow-up was 66 months. Of these patients, 15591 (58.6%) patients received RT, RT was recommended but not performed due to patient refusal for 1270 (4.8%) patients, and RT was not recommended for 9725 (36.6%) patients. The 5-year BCSS was 98.3% for patients receiving RT, 97.1% for patients refusal of RT, and 96.4% for patients not recommended RT (P<0.001). The 5-year OS was 88.6% for patients receiving RT, 77.6% for patients who refused RT, and 72.1% for patients not recommended RT (P<0.001). Multivariate Cox regression analyses showed that patients who received adjuvant RT after BCS had significantly better BCSS (hazard ratio [HR] 0.523, 95%confidence interval [CI] 0.447-0.612, P<0.001) and OS (HR 0.589, 95%CI 0.558-0.622, P<0.001) compared to those without RT. A total of 7721 pairs of patients were matched successfully between those with and without RT using PSM. The results also showed that patients who received RT after BCS had significantly better BCSS (HR 562, 95%CI 0.467-0.676, P<0.001) and OS (HR 0.612, 95%CI 0.0.575-0.652, P<0.001) compared to those without RT. Conclusions: These data suggest that individual counseling is important for treatment decision-making in elderly breast cancer patients with T1-2N0 and ER-positive disease. Given the relatively lower toxicity of modern RT techniques, adjuvant RT should be recommended in patients with high life expectancy.

miR-193a-5p Enhances the Radioresistance of Pancreatic Cancer Cells by Targeting ZFP57 and Activating the Wnt Pathway.

This study was to investigate whether miR-193a-5p and ZFP57 are involved in the radioresistance of pancreatic cancer and to explore its working mechanism. Pancreatic cancer tissues were harvested from patients who achieved CR (complete remission) and PR (partial remission) and those who achieved PD (progressive disease) and SD (stable disease). The mRNA and protein expressions of ZFP57 and miR-193a-5p were determined by RT-qPCR and WB (Western blot), respectively. For in vitro experiments, the parental BxPC-3 cell line was irradiated by X-ray at a total dose of 40 Gy to induce the irradiation-resistant subtype BxPC-3-RR. ZFP57 was downregulated in radioresistant pancreatic cancer cells. The results of dual-luciferase reporter gene assay, RNA pull-down assay, RT-qPCR, and WB confirmed that miR-193a-5p targeted ZFP57 and inhibited ZFP57 expression. The MTT assay and the colony formation assay showed that the radioresistant pancreatic cancer cells had higher viability and survival fraction. The results of WB indicated that in the radioresistant pancreatic cancer cells, the cyclin D1, Bax, CDk4, cleaved caspase-3, Bcl-2, and γ-H2AX proteins were upregulated to varying degrees. The results of the in vitro nude mouse experiment were consistent with those of in vivo experiments. According to the cell transfection and salvage experiments, miR-193a-5p down regulated ZFP57 after radiotherapy. As a result, the Wnt pathway was activated, which further induced radioresistance of pancreatic cancer cells. Our experiments showed that the miR-193a-5p/ZFP57/Wnt pathway mediated the radioresistance of pancreatic cancer cells, providing novel clues for the treatment of pancreatic cancer.

Combination of high-fat diet and cadmium impairs testicular spermatogenesis in an m6A-YTHDF2-dependent manner.

Environmental cadmium (Cd) or high-fat diet (HFD) exposure alone are risk factors of male infertility. However, the effect and mechanism of co-exposure to HFD and Cd on sperm quality remain unclear. This study was aimed to explore the combined effects of HFD and Cd on spermatogenesis as well as its m6A-dependent mechanism in vivo and in vitro. As a result, co-exposure of HFD and Cd resulted in a significant decrease in the number of mature testicular seminiferous tubules and epididymis sperm quantity in mice, compared with Cd or HFD exposure alone. Correspondingly, the mRNAs expression of Smc3(spermatocytes marker), Acrv1(round spermatids marker) and Lzumo3(elongated spermatids marker) were downregulated in HFD and Cd group. Furthermore, combined exposure downregulated the expression of meiosis-related proteins (STRA8 and SYCP3), increased the m6A level of Stra8, and upregulated the expression of m6A-related proteins (METTL3 and YTHDF2) in mouse spermatocytes. Mechanistically, the above-mentioned impacts caused by co-exposure were markedly restored by Mettl3 siR and Ythdf2 siR. In addition, RNA stability assay showed that Ythdf2 siR obviously reversed co-exposure-increased Stra8 mRNA degradation rate in actinomycin-D-treated mouse spermatocytes. Meanwhile, excess ROS was observed in combined-exposure group, and a free radical scavenger N-tert-Butyl-α-phenylnitrone (PBN) attenuated co-exposure-upregulated expression of METTL3 and YTHDF2 in mouse spermatocytes. These results suggested that combination of HFD and Cd impaired spermatogenesis by degrading Stra8 in an m6A-YTHDF2-dependent manner via ROS activation.

Rechargeable LiNi0.65 Co0.15 Mn0.2 O2 ||Graphite Batteries Operating at -60 °C.

The rechargeability of contemporary lithium-ion batteries (LIBs) is challenging at low temperatures, mainly due to the hurdles faced by graphite anodes. Herein, by exploiting the Li-solvent co-intercalation into graphite, its low-temperature rechargeability is boosted. Experimental characterizations aided by theoretical calculations demonstrate that the co-intercalation process is featured by low interfacial resistance with a small charge transfer activation energy (0.23 eV atom-1 ) and an extremely low diffusion energy barrier (0.09 eV atom-1 ) which leads to nearly temperature-independent diffusion coefficients of the solvated Li-ion in graphite, enabling graphite to be stably charged-discharged at -60 °C with 73.7 % of its room-temperature capacity. Consequently, the full-cell consisting of a LiNi0.65 Co0.15 Mn0.2 O2 cathode and a graphite anode shows impressive rechargeability under -60 °C. This work provides an alternative approach to develop low-temperature rechargeable LIBs.