Synergistic suppression of ovarian cancer by combining NRF2 and GPX4 inhibitors: in vitro and in vivo evidence.

Ovarian cancer is a significant challenge in women's health due to the lack of effective screening and diagnostic methods, often leading to late detection and the highest mortality rate among all gynecologic tumors worldwide. Recent research has shown that ovarian cancer has an "iron addiction" phenotype which makes it vulnerable to ferroptosis inducers. We tested the combination of NRF2-targeted inhibitors with GPX4-targeted inhibitors in ovarian cancer through in vitro and in vivo experiment. The data showed that combination treatment effectively suppressed adherent cell growth, inhibited suspended cell spheroid formation, and restrained the ability of spheroid formation in 3D-culture. Mechanistically, the combination induced accumulation of ROS, 4-HNE, as well as activation of caspase-3 which indicates that this combination simultaneously increases cell ferroptosis and apoptosis. Notably, inhibition of GPX4 or NRF2 can suppress ovarian cancer spreading and growth in the peritoneal cavity of mice, while the combination of NRF2 inhibitor ML385 with GPX4 inhibitors showed a significant synergistic effect compared to individual drug treatment in a syngeneic mouse ovarian cancer model. Overall, these findings suggest that combining NRF2 inhibitors with GPX4 inhibitors results in a synergy suppression of ovarian cancer in vitro and in vivo, and maybe a promising therapeutic strategy for the treatment of ovarian cancer.

Immobilization of purified enzyme EreB in metalorganic framework (MOF) mesopores for erythromycin degradation.

Erythromycin, a commonly used macrolide antibiotic, plays a crucial role in both human medicine and animal husbandry. However, its abuse has led to residual presence in the environment, with problems such as the emergence of resistant bacteria and enrichment of resistance genes. These issues pose significant risks to human health. Thus far, there are no effective, environmentally friendly methods to manage this problem. Enzymes can specifically degrade erythromycin without causing other problems, but their unrecyclability and environmental vulnerability hinder large-scale application. Enzyme immobilization may help to solve these problems. This study used Cu-BTC, a synthetic metal-organic framework, to immobilize the erythromycin-degrading enzyme EreB. The loading temperature and enzyme quantity were optimized. The Cu-BTC and EreB@Cu-BTC were characterized by various methods to confirm the preparation of Cu-BTC and immobilization of EreB. The maximum enzyme loading capacity was 66.5 mg g-1. In terms of enzymatic properties, immobilized EreB had improved heat (25-45 °C) and alkaline (6.5-10) tolerance, along with greater affinity between the enzyme and its substrate; Km decreased from 438.49 to 372.30 mM. Recycling was also achieved; after 10 cycles, 57.12% of the enzyme activity was maintained. After composite degradation, the antibacterial activity of erythromycin-containing wastewater was examined; the results showed that the novel composite could completely inactivate erythromycin. In summary, Cu-BTC was an ideal carrier for immobilization of the enzyme EreB, and the EreB@Cu-BTC composite has good prospects for the treatment of erythromycin-containing wastewater.

Hematochezia caused by tandospirone in a patient with major depressive disorder and anxious distress: a case report.

Background: Major depressive disorder (MDD) with anxious distress is a relatively common condition that is often associated with a poor treatment response. In order to enhance the effectiveness of MDD treatment, 5-HT1A agonists like tandospirone are often prescribed in conjunction with antidepressants. While it is known that antidepressants can increase the risk of bleeding, whether tandospirone poses a similar risk remains uncertain. Case presentation: We presented the case of a 55-year-old Chinese woman diagnosed with MDD and anxious distress. After receiving various types of antidepressants, she experienced hematochezia following the administration of tandospirone, sertraline, and agomelatine. The occurrence of hematochezia ceased after tandospirone was discontinued. The patient was subsequently discharged with a treatment regime consisting of sertraline and agomelatine. During the 1-month follow-up, she reported no hematochezia. Conclusion: Tandospirone may potentially increase the risk of hematochezia in patients with MDD and anxious distress.

Environmental factors induced macrolide resistance genes in composts consisting of erythromycin fermentation residue, cattle manure, and maize straw.

With the growing concerns about antibiotic resistance, it is more and more important to prevent the environmental pollution caused by antibiotic fermentation residues. In this study, composted erythromycin fermentation residue (EFR) with the mixture of cattle manure and maize straw at ratios of 0:10 (CK), 1:10 (T1), and 3:10 (T2) explores the effects on physicochemical characteristics, mobile genetic elements (MGEs), and antibiotic resistance genes (ARGs). Results reflected that the addition of EFR reduced the carbon/nitrogen ratio of each compost and improved the piles' temperature, which promoted the composting process. However, the contents of Na+, SO42-, and erythromycin were also significantly increased. After 30 days of composting, the degradation rates of erythromycin in CK, T1, and T2 were 72.7%, 20.3%, and 37.1%, respectively. Meanwhile, the total positive rates for 26 detected ARGs in T1 and T2 were 65.4%, whereas that of CK was only 23.1%. Further analysis revealed that ARGs responsible for ribosomal protection, such as ermF, ermT, and erm(35), dominated the composts of T1 and T2, and most were correlated with IS613, electrical conductivity (EC), nitrogen, and Zn2+. Above all, adding EFR helps to improve the nutritional value of composts, but the risks in soil salinization and ARG enrichment caused by high EC and erythromycin content should be further investigated and eliminated.

ACSL1-induced ferroptosis and platinum resistance in ovarian cancer by increasing FSP1 N-myristylation and stability.

Reprogramming of lipid metabolism, which modulates energy utilization and cell signaling, maintains cell survival and promotes cancer metastasis in cancer cells. Ferroptosis is a type of cell necrosis caused by an overload of lipid oxidation, which has been demonstrated to be involved in cancer cell metastasis. However, the mechanism by which fatty acid metabolism regulates the anti-ferroptosis signaling pathways is not fully understood. The formation of ovarian cancer spheroids helps to counteract the hostile microenvironment of the peritoneal cavity with low oxygen, shortage of nutrients, and subjected to platinum therapy. Previously, we demonstrated that Acyl-CoA synthetase long-chain family member 1 (ACSL1) promotes cell survival and peritoneal metastases in ovarian cancer, but the mechanism is still not well elucidated. In this study, we demonstrate that the formation of spheroids and under exposure to platinum chemotherapy increased the levels of anti-ferroptosis proteins as well as ACSL1. Inhibition of ferroptosis can enhance spheroid formation and vice versa. Genetic manipulation of ACSL1 expression showed that ACSL1 reduced the level of lipid oxidation and increased the resistance to cell ferroptosis. Mechanistically, ACSL1 increased the N-myristoylation of ferroptosis suppressor 1 (FSP1), resulting in the inhibition of its degradation and translocation to the cell membrane. The increase in myristoylated FSP1 functionally counteracted oxidative stress-induced cell ferroptosis. Clinical data also suggested that ACSL1 protein was positively correlated with FSP1 and negatively correlated with the ferroptosis markers 4-HNE and PTGS2. In conclusion, this study demonstrated that ACSL1 enhances antioxidant capacity and increases ferroptosis resistance by modulating the myristoylation of FSP1.

Antimicrobial peptides CS-piscidin-induced cell death involves activation of RIPK1/PARP, and modification with myristic acid enhances its stability and tumor-targeting capability.

Ovarian cancer (OC) is a highly lethal gynecological malignancy, often diagnosed at advanced stages with limited treatment options. Here, we demonstrate that the antimicrobial peptide CS-piscidin significantly inhibits OC cell proliferation, colony formation, and induces cell death. Mechanistically, CS-piscidin causes cell necrosis by compromising the cell membrane. Furthermore, CS-piscidin can activate Receptor-interacting protein kinase 1 (RIPK1) and induce cell apoptosis by cleavage of PARP. To improve tumor targeting ability, we modified CS-piscidin by adding a short cyclic peptide, cyclo-RGDfk, to the C-terminus (CS-RGD) and a myristate to the N-terminus (Myr-CS-RGD). Our results show that while CS-RGD exhibits stronger anti-cancer activity than CS-piscidin, it also causes increased cytotoxicity. In contrast, Myr-CS-RGD significantly improves drug specificity by reducing CS-RGD toxicity in normal cells while retaining comparable antitumor activity by increasing peptide stability. In a syngeneic mouse tumor model, Myr-CS-RGD demonstrated superior anti-tumor activity compared to CS-piscidin and CS-RGD. Our findings suggest that CS-piscidin can suppress ovarian cancer via multiple cell death forms and that myristoylation modification is a promising strategy to enhance anti-cancer peptide performance.

Biodegradation efficiency and mechanism of erythromycin degradation by Paracoccus versutus W7.

Continuous and excessive usage of erythromycin results in serious environmental pollution and presents a health risk to humans. Biological treatment is considered as an efficient and economical method to remove it from the environment. In this study, a novel erythromycin-degrading bacterial strain, W7, isolated from sewage sludge was identified as Paracoccus versutus. Strain W7 degraded 58.5% of 50 mg/L erythromycin in 72 h under the optimal conditions of 35 °C, pH 7.0, and 0.1% sodium citrate with yeast powder in mineral salt medium. It completely eliminated erythromycin from erythromycin fermentation residue at concentrations of 100 and 300 mg/L within 36 and 60 h, respectively. Erythromycin esterase (EreA) was found to be involved in erythromycin metabolism in this strain and was expressed successfully. EreA could hydrolyze erythromycin, and its maximum activity occurred at pH 8.5 and 35 °C. Finally, six intermediates of erythromycin degraded by strain W7 were detected by high performance liquid chromatography mass spectrometry. Based on the novel intermediates and enzymes, we determined two possible pathways of erythromycin degradation by strain W7. This study broadened our understanding of the erythromycin catabolic processes of P. versutus and developed a feasible microbial strategy for removing erythromycin from erythromycin fermentation residue, wastewater, and other erythromycin-contaminated environments.

The RNAome landscape of tomato during arbuscular mycorrhizal symbiosis reveals an evolving RNA layer symbiotic regulatory network.

Arbuscular mycorrhizal symbiosis (AMS) is an ancient plant-fungus relationship that is widely distributed in terrestrial plants. The formation of symbiotic structures and bidirectional nutrient exchange requires the regulation of numerous genes. However, the landscape of RNAome during plant AMS involving different types of regulatory RNA is poorly understood. In this study, a combinatorial strategy utilizing multiple sequencing approaches was used to decipher the landscape of RNAome in tomato, an emerging AMS model. The annotation of the tomato genome was improved by a multiple-platform sequencing strategy. A total of 3,174 protein-coding genes were upregulated during AMS, 42% of which were alternatively spliced. Comparative-transcriptome analysis revealed that genes from 24 orthogroups were consistently induced by AMS in eight phylogenetically distant angiosperms. Seven additional orthogroups were specifically induced by AMS in all surveyed dicot AMS host plants. However, these orthogroups were absent or not induced in monocots and/or non-AMS hosts, suggesting a continuously evolving AMS-responsive network in addition to a conserved core regulatory module. Additionally, we detected 587 lncRNAs, ten miRNAs, and 146 circRNAs that responded to AMS, which were incorporated to establish a tomato AMS-responsive, competing RNA-responsive endogenous RNA (ceRNA) network. Finally, a tomato symbiotic transcriptome database (TSTD, https://efg.nju.edu.cn/TSTD) was constructed to serve as a resource for deep deciphering of the AMS regulatory network. These results help elucidate the reconfiguration of the tomato RNAome during AMS and suggest a sophisticated and evolving RNA layer responsive network during AMS processes.

Acne caused by ziprasidone in a young patient with bipolar disorder: A case report.

Background: Ziprasidone is a second-generation antipsychotic drug commonly used to treat schizophrenia and bipolar disorder. Acne is a common inflammatory disease of sebaceous glands in adolescents that is often co-morbid with anxiety and depression, which may reduce treatment compliance. Through unknown mechanisms, ziprasidone may cause a range of inflammatory responses. Whether ziprasidone can cause acne in young patients with bipolar disorder has not been reported. Case summary: We report a 23-year-old woman with a 5-year history of bipolar disorder who experienced acne during use of ziprasidone. She was admitted to our hospital during 1-month aggravation of her symptoms and was diagnosed with bipolar I disorder (current or most recent episode of depression) with psychotic features. She was given ziprasidone and soon developed acne, which she never had before; the rash worsened substantially when the ziprasidone dose was increased. At the same time, levels of inflammatory factors increased. The rash resolved after ziprasidone therapy was stopped. Conclusion: When prescribing ziprasidone to young people with bipolar disorder, clinicians should consider the potential for adverse skin reactions. It may be useful to assay levels of inflammatory markers during ziprasidone therapy and adjust the dose if necessary in order to ensure treatment compliance.

First-episode olfactory hallucination in a patient with anxiety disorder: A case report.

Background: Olfactory hallucination refers to olfactory perception in the absence of chemical stimuli. Although it has been associated with many neurological and psychotic disorders, it has rarely been reported as the first and only symptom in patients with anxiety disorder, and its treatment remains inadequate. Case summary: A 66-year-old woman who had been experiencing gradually worsening olfactory hallucinations for almost 4 years was diagnosed with generalized anxiety disorder. Olfactory hallucination disappeared after treatment with anti-anxiety drugs. Conclusion: Olfactory hallucination can be the first and only symptom in patients with anxiety disorder and may be effectively treated with anti-anxiety medication. In fact, it can precede the diagnosis of anxiety disorder by several years.

Effects of pH and Metal Ions on the Hydrothermal Treatment of Penicillin: Kinetic, Pathway, and Antibacterial Activity.

Antibiotic residues lead to the risk of resistance gene enrichment, which is the main reason why penicillin mycelial dreg (PMD) is defined as hazardous waste. Hydrothermal treatment (HT) is an effective method to treat penicillin mycelial dreg, but the degradation mechanism of penicillin is unclear. In the study, we researched the effects of pH (4-10) at 80-100 °C and metal ions (Mn2+, Fe2+, Cu2+, and Zn2+) at several concentrations on the HT of penicillin, identified the degradation products (DPs) under different conditions, and evaluated the antibacterial activity of hydrothermally treated samples. The results show that penicillin degradation kinetics highly consistent with pseudo-first-order model (R2 = 0.9447-0.9999). The degradation rates (k) at pH = 4, 7, and 10 were 0.1603, 0.0039, and 0.0485 min-1, indicating acidic conditions were more conducive to penicillin degradation. Among the four tested metal ions, Zn2+ had the most significant catalytic effect. Adding 5 mg·L-1 Zn2+ caused 100% degradation rate at pH = 7 after HT for 60 min. Six degradation products (DPs) with low mass-to-charge (m/z ≤ 335) were detected under acidic condition. However, only two and three DPs were observed in the samples catalyzed by Zn2+ and alkali, respectively, and penilloic acid (m/z = 309) was the main DPs under these conditions. Furthermore, no antibacterial activity to Bacillus pumilus was detected in the medium with up to 50% addition of the treated samples under acidic condition. Even though acid, alkali, and some metal ions can improve the degradation ability of penicillin, it was found that the most effective way for removing its anti-bacterial activity was under the acidic condition. Therefore, resistance residue indicates the amount of additive in the process of resource utilization, and avoids the enrichment of resistance genes.

Immobilization of EreB on Acid-Modified Palygorskite for Highly Efficient Degradation of Erythromycin.

Erythromycin is one of the most commonly used macrolide antibiotics. However, its pollution of the ecosystem is a significant risk to human health worldwide. Currently, there are no effective and environmentally friendly methods to resolve this issue. Although erythromycin esterase B (EreB) specifically degrades erythromycin, its non-recyclability and fragility limit the large-scale application of this enzyme. In this work, palygorskite was selected as a carrier for enzyme immobilization. The enzyme was attached to palygorskite via a crosslinking reaction to construct an effective erythromycin-degradation material (i.e., EreB@modified palygorskite), which was characterized using FT-IR, SEM, XRD, and Brunauer-Emmett-Teller techniques. The results suggested the successful modification of the material and the loading of the enzyme. The immobilized enzyme had a higher stability over varying temperatures (25-65 °C) and pH values (6.5-10.0) than the free enzyme, and the maximum rate of reaction (Vmax) and the turnover number (kcat) of the enzyme increased to 0.01 mM min-1 and 169 min-1, respectively, according to the enzyme-kinetics measurements. The EreB@modified palygorskite maintained about 45% of its activity after 10 cycles, and degraded erythromycin in polluted water to 20 mg L-1 within 300 min. These results indicate that EreB could serve as an effective immobilizing carrier for erythromycin degradation at the industrial scale.

Hiccups induced by aripiprazole combined with sertraline in an adolescent with olfactory reference disorder: A case report.

Background: Hiccup can cause significant distress to patients and affect medication compliance. Individuals with olfactory reference disorder (ORD) who might develop persistent hiccups when treated with a combination of antidepressant and antipsychotic, leading to significant distress and impairment. Case summary: We report a rare case of an adolescent with ORD who was treated with aripiprazole combined with sertraline and who began to hiccup persistently after 6 days on this treatment. He stopped hiccupping after the aripiprazole had been suspended for 12 h. After discharge, the patient continued on sertraline alone and reported no hiccupping at 1-month follow-up. Conclusion: Clinicians should consider that the combination of aripiprazole and sertraline can induce hiccups during the acute administration period in adolescents with ORD.

Mental state, biological rhythm and social support among healthcare workers during the early stages of the COVID-19 epidemic in Wuhan.

Background: The COVID-19 pandemic has put the mental health of healthcare workers at risk. However, the potential psychosocial factors underlying mental health problems, such as depression and anxiety, require further investigation. The present study aimed to explore the factors that influence the mental state of healthcare workers. Methods: A total of 276 healthcare workers completed a set of online self-report questionnaires from February 4 to 7, 2020, in the following order: general information related to the COVID-19 outbreak, Biological Rhythms Interview of Assessment in Neuropsychiatry, Beck Depression Inventory-II, Beck Anxiety Inventory, and Social Support Rating Scale. Results: Our study revealed that both social support and age moderated the ability of biological rhythm disturbance to exacerbate depression (R2 = 0.47; effect size f2 = 0.85). Higher levels of social support buffered the amplification of depression associated with increased biological rhythm disturbance in all age groups, and especially in younger individuals (mean age = 26.57, se = 0.04). Depressive symptoms were predicted by both social and sleeping rhythms, whereas anxiety symptoms were predicted only by social rhythm. Married individuals had lower biological rhythm disturbance ratings and higher social support ratings. Females also reported higher ratings in social support. Conclusions: Our study suggests that biological rhythm intervention along with social support can reduce the negative effect of biological rhythm disturbance on mood disorders, especially in younger people. We also provide evidence for the ability of social support to buffer stress in a major health crisis and demonstrate the effects of marital status and sex, which provide a different perspective for studying mental crisis management.

miR-93-5p suppresses ovarian cancer malignancy and negatively regulate CCND2 by binding to its 3'UTR region.

Ovarian cancer is the most fatal gynecological cancer worldwide, yet the fundamental mechanism of malignancy acquisition in ovarian cancer remains unknown. miRNA has been implicated to a variety of diseases, including cancer initiation and progression. Cyclin-D2 (CCND2) is ubiquitously implicated in cancer uncontrol cell proliferation. Bioinformatic research revealed that CCND2 is a candidate gene for miR-93-5p with a binding site in its 3'UTR region in the current study. Using our ovarian cancer sample, we verified that miR-93-5p is negatively correlated with CCND2 mRNA and protein levels. Luciferase report assay revealed miR-93-5p inhibits CCND2 production through binding to the 3'UTR region. The expression of miR-93-5p in ovarian cancer patient samples was then determined, and a survival analysis was performed. Our findings showed that miR-93-5p is downregulated in ovarian cancer and is a favorable predictive factor in ovarian cancer patient. CCK8 assay, wound healing assay and flow cytometry-based cell cycle and apoptotic cell analyses were employed here. We found that miR-93-5p suppresses ovarian cancer cell proliferation and migration while enhances cell death. Our research certified that miR-93-5p reduces ovarian cancer malignancy by targeting CCND2.

An angiosperm NLR Atlas reveals that NLR gene reduction is associated with ecological specialization and signal transduction component deletion.

Nucleotide-binding leucine-rich-repeat (NLR) genes comprise the largest family of plant disease-resistance genes. Angiosperm NLR genes are phylogenetically divided into the TNL, CNL, and RNL subclasses. NLR copy numbers and subclass composition vary tremendously across angiosperm genomes. However, the evolutionary associations between genomic NLR content and ecological adaptation, or between NLR content and signal transduction components, are poorly characterized because of limited genome availability. In this study, we established an angiosperm NLR atlas (ANNA, https://biobigdata.nju.edu.cn/ANNA/) that includes NLR genes from over 300 angiosperm genomes. Using ANNA, we revealed that NLR copy numbers differ up to 66-fold among closely related species owing to rapid gene loss and gain. Interestingly, NLR contraction was associated with adaptations to aquatic, parasitic, and carnivorous lifestyles. The convergent NLR reduction in aquatic plants resembles the lack of NLR expansion during the long-term evolution of green algae before the colonization of land. A co-evolutionary pattern between NLR subclasses and plant immune pathway components was also identified, suggesting that immune pathway deficiencies may drive TNL loss. Finally, we identified a conserved TNL lineage that may function independently of the EDS1-SAG101-NRG1 module. Collectively, these findings provide new insights into the evolution of NLR genes in the context of ecological adaptation and genome content variation.

Genome-Wide Analysis of NLR Disease Resistance Genes in an Updated Reference Genome of Barley.

Barley is one of the top 10 crop plants in the world. During its whole lifespan, barley is frequently infected by various pathogens. In this study, we performed genome-wide analysis of the largest group of plant disease resistance (R) genes, the nucleotide binding site-leucine-rich repeat receptor (NLR) gene, in an updated barley genome. A total of 468 NLR genes were identified from the improved barley genome, including one RNL subclass and 467 CNL subclass genes. Proteins of 43 barley CNL genes were shown to contain 25 different integrated domains, including WRKY and BED. The NLR gene number identified in this study is much larger than previously reported results in earlier versions of barley genomes, and only slightly fewer than that in the diploid wheat Triticum urartu. Barley Chromosome 7 contains the largest number of 112 NLR genes, which equals to seven times of the number of NLR genes on Chromosome 4. The majority of NLR genes (68%) are located in multigene clusters. Phylogenetic analysis revealed that at least 18 ancestral CNL lineages were presented in the common ancestor of barley, T. urartu and Arabidopsis thaliana. Among them fifteen lineages expanded to 533 sub-lineages prior to the divergence of barley and T. urartu. The barley genome inherited 356 of these sub-lineages and duplicated to the 467 CNL genes detected in this study. Overall, our study provides an updated profile of barley NLR genes, which should serve as a fundamental resource for functional gene mining and molecular breeding of barley.

Focal adhesion kinase inhibitors, a heavy punch to cancer.

Kinases are the ideal druggable targets for diseases and especially were highlighted on cancer therapy. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and its aberrant signaling extensively implicates in the progression of most cancer types, involving in cancer cell growth, adhesion, migration, and tumor microenvironment (TME) remodeling. FAK is commonly overexpressed and activated in a variety of cancers and plays as a targetable kinase in cancer therapy. FAK inhibitors already exhibited promising performance in preclinical and early-stage clinical trials. Moreover, substantial evidence has implied that targeting FAK is more effective in combination strategy, thereby reversing the failure of chemotherapies or targeted therapies in solid tumors. In the current review, we summarized the drug development progress, chemotherapy strategy, and perspective view for FAK inhibitors.

[Expression and clinical significance of serum high-mobility group protein box 1 in children with Henoch-Schönlein purpura].

OBJECTIVE: To determine the expression of high-mobility group protein box 1 (HMGB1), high-sensitivity C-reactive protein (hs-CRP), and D-dimer (D-D) in the peripheral blood of children with Henoch-Schönlein purpura (HSP) and to investigate the clinical significance of HMGB1 in children with HSP. METHODS: A total of 40 children with HSP (HSP group) and 30 healthy children (control group) were involved in the study. The level of serum HMGB1 was determined using enzyme-linked immunosorbent assay, and the levels of serum hs-CRP and plasma D-D were determined using automatic biochemical analyzer and automatic blood coagulation analyzer, respectively. RESULTS: The levels of HMGB1, hs-CRP, and D-D in the peripheral blood of the HSP group in the acute phase were significantly higher than in the control group (P<0.05). The levels of the three indicators were significantly higher in HSP children with renal damage than in those without renal damage (P<0.05). In children with HSP, the expression of HMGB1 was positively correlated with the expression of hs-CRP and D-D (r=0.878, P<0.001; r=0.625, P<0.001). CONCLUSIONS: The expression of HMGB1 is related to the inflammatory response and hypercoagulability in children with HSP. HMGB1 may be involved in the development of HSP and associated renal damage in children.