Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches.

Ferroptosis, a unique form of programmed cell death, is initiated by an excess of iron accumulation and lipid peroxidation-induced damage. There is a growing body of evidence indicating that ferroptosis plays a critical role in the advancement of tumors. The increased metabolic activity and higher iron levels in tumor cells make them particularly vulnerable to ferroptosis. As a result, the targeted induction of ferroptosis is becoming an increasingly promising approach for cancer treatment. This review offers an overview of the regulatory mechanisms of ferroptosis, delves into the mechanism of action of traditional small molecule ferroptosis inducers and their effects on various tumors. In addition, the latest progress in inducing ferroptosis using new means such as proteolysis-targeting chimeras (PROTACs), photodynamic therapy (PDT), sonodynamic therapy (SDT) and nanomaterials is summarized. Finally, this review discusses the challenges and opportunities in the development of ferroptosis-inducing agents, focusing on discovering new targets, improving selectivity, and reducing toxic and side effects.

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OBJECTIVES: To investigate the structural characteristics of intestinal flora in children with sepsis and its association with inflammatory response. METHODS: A prospective cohort study was conducted. The children with sepsis who were admitted from December 2021 to January 2023 were enrolled as the sepsis group, and the children with non-sepsis who were admitted during the same period were enrolled as the non-sepsis group. The two groups were compared in terms of the distribution characteristics of intestinal flora, peripheral white blood cell count (WBC), C reactive protein (CRP), and cytokines, and the correlation of the relative abundance of fecal flora with WBC, CRP, and cytokines was analyzed. RESULTS: At the genus level, compared with the non-sepsis group, the sepsis group had significantly lower relative abundance of Akkermansia, Ruminococcus, and Alistipes and significantly higher relative abundance of Enterococcus, Streptococcus, and Staphylococcus (P<0.05). At the phylum level, Proteobacteria was the dominant phylum (37.46%) in the group of children with a score of ≤70 from the Pediatric Critical Illness Score (PICS), and Firmicutes was the dominant phylum in the group of children with a score of 71-80 or 81-90 from the PICS (72.20% and 43.88%, respectively). At the genus level, among the 18 specimens, 5 had a relative abundance of >50% for a single flora. Compared with the non-sepsis group, the sepsis group had significant higher levels of WBC, CRP, interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (P<0.05). The Spearman's rank correlation analysis showed that at the genus level, the relative abundance of Ruminococcus, Alistipes, and Parasutterella in the sepsis group was negatively correlated with the levels of WBC, CRP, and IL-6 (P<0.05); the relative abundance of Enterococcus was positively correlated with the CRP level (P<0.01); the relative abundance of Streptococcus and Staphylococcus was positively correlated with the levels of CRP and IL-6 (P<0.05); the relative abundance of Streptococcus was positively correlated with WBC (P<0.05). CONCLUSIONS: Intestinal flora disturbance is observed in children with sepsis, and its characteristics vary with the severity of the disease. The structural changes of intestinal flora are correlated with inflammatory response in children with sepsis.

TL1A Promotes Fibrogenesis in Colonic Fibroblasts via the TGF-ß1/Smad3 Signaling Pathway.

OBJECTIVE: Intestinal fibrosis is a refractory complication of inflammatory bowel disease (IBD). Tumor necrosis factor ligand-related molecule-1A (TL1A) is important for IBD-related intestinal fibrosis in a dextran sodium sulfate (DSS)-induced experimental colitis model. This study aimed to explore the effects of TL1A on human colonic fibroblasts. METHODS: A trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis model of LCK-CD2-TL1A-GFP transgenic (Tg) or wild-type (WT) mice was established to determine the effect and mechanism of TL1A on intestinal fibrosis. The human colonic fibroblast CCD-18Co cell line was treated concurrently with TL1A and human peripheral blood mononuclear cell (PBMC) supernatant. The proliferation and activation of CCD-18Co cells were detected by BrdU assays, flow cytometry, immunocytochemistry and Western blotting. Collagen metabolism was tested by Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: The level of collagen metabolism in the TNBS+ethyl alcohol (EtOH)/Tg group was greater than that in the TNBS+EtOH/WT group. Transforming growth factor-ß1 (TGF-ß1) and p-Smad3 in the TNBS+EtOH/Tg group were upregulated as compared with those in the TNBS+EtOH/WT group. The proliferation of CCD-18Co cells was promoted by the addition of human PBMC supernatant supplemented with 20 ng/mL TL1A, and the addition of human PBMC supernatant and TL1A increased CCD-18Co proliferation by 24.4% at 24 h. TL1A promoted cell activation and increased the levels of COL1A2, COL3A1, and TIMP-1 in CCD-18Co cells. Treatment of CCD-18Co cells with TL1A increased the expression of TGF-ß1 and p-Smad3. CONCLUSION: TL1A promotes TGF-ß1-mediated intestinal fibroblast activation, proliferation, and collagen deposition and is likely related to an increase in the TGF-ß1/Smad3 signaling pathway.

Diagnostic performance of MRI in detecting prostate cancer in patients with prostate-specific antigen levels of 4-10 ng/mL: a systematic review and meta-analysis.

OBJECTIVE: To investigate the diagnostic performance of MRI in detecting clinically significant prostate cancer (csPCa) and prostate cancer (PCa) in patients with prostate-specific antigen (PSA) levels of 4-10 ng/mL. METHODS: A computerized search of PubMed, Embase, Cochrane Library, Medline, and Web of Science was conducted from inception until October 31, 2023. We included articles on the use of MRI to detect csPCa or PCa at 4-10 ng/mL PSA. The primary and secondary outcomes were MRI performance in csPCa and PCa detection, respectively; the estimates of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were pooled in a bivariate random-effects model. RESULTS: Among the 19 studies (3879 patients), there were 10 (2205 patients) and 13 studies (2965 patients) that reported MRI for detecting csPCa or PCa, respectively. The pooled sensitivity and specificity for csPCa detection were 0.84 (95% confidence interval [CI], 0.79-0.88) and 0.76 (95%CI, 0.65-0.84), respectively, for PCa detection were 0.82 (95%CI, 0.75-0.87) and 0.74 (95%CI, 0.65-0.82), respectively. The pooled NPV for csPCa detection was 0.91 (0.87-0.93). Biparametric magnetic resonance imaging also showed a significantly higher sensitivity and specificity relative to multiparametric magnetic resonance imaging (both p < 0.01). CONCLUSION: Prostate MRI enables the detection of csPCa and PCa with satisfactory performance in the PSA gray zone. The excellent NPV for csPCa detection indicates the possibility of biopsy decision-making in patients in the PSA gray zone, but substantial heterogeneity among the included studies should be taken into account. CLINICAL RELEVANCE STATEMENT: Prostate MRI can be considered a reliable and satisfactory tool for detecting csPCa and PCa in patients with PSA in the "gray zone", allowing for reducing unnecessary biopsy and optimizing the overall examination process. KEY POINTS: Prostate-specific antigen (PSA) is a common screening tool for prostate cancer but risks overdiagnosis. MRI demonstrated excellent negative predictive value for prostate cancer in the PSA gray zone. MRI can influence decision-making for these patients, and biparametric MRI should be further evaluated.

Development of lignin-based 3D-printable light responsive shape memory materials: Design of optically controlled devices.

This study employs simple approaches involving melt blending and Fused Deposition Modeling (FDM) 3D printing to fabricate a light-responsive shape memory composite. And, this composite material is used for the design of optically controlled devices that mimics the blooming of flowers in the natural environment. The composite material utilizes poly(ε-caprolactone) (PCL) and thermoplastic polyurethane (TPU) as the matrix, with lignin (L) serving as a functional filler. The analysis indicates that, due to the excellent photothermal conversion efficiency of lignin, under constant illumination the shape memory materials heat up to 50 °C within 40 s, the shape recovery rate exceeds 95.06 %. Lignin ameliorated the rheological deficiencies of TPU, with the composite material viscosity decreasing from 103 to 101 at an angular frequency of 100 rad/s, enhancing its compatibility with FDM processes. This research offers greater economic efficiency compared to conventional light-responsive materials and a simpler production method.

The Role of Ferroptosis in Amyotrophic Lateral Sclerosis Treatment.

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a challenging treatment landscape, due to its complex pathogenesis and limited availability of clinical drugs. Ferroptosis, an iron-dependent form of programmed cell death (PCD), stands distinct from apoptosis, necrosis, autophagy, and other cell death mechanisms. Recent studies have increasingly highlighted the role of iron deposition, reactive oxygen species (ROS) accumulation, oxidative stress, as well as systemic Xc- and glutamate accumulation in the antioxidant system in the pathogenesis of amyotrophic lateral sclerosis. Therefore, targeting ferroptosis emerges as a promising strategy for amyotrophic lateral sclerosis treatment. This review introduces the regulatory mechanism of ferroptosis, the relationship between amyotrophic lateral sclerosis and ferroptosis, and the drugs used in the clinic, then discusses the current status of amyotrophic lateral sclerosis treatment, hoping to provide new directions and targets for its treatment.

Ferroptosis inhibitors: past, present and future.

Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed the mechanisms of its formation and continue to explore effective inhibitors of ferroptosis in disease. Recent studies have shown a correlation between ferroptosis and the pathological mechanisms of neurodegenerative diseases, as well as diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for the treatment of ferroptosis-mediated diseases. This article specifically describes the metabolic pathways of ferroptosis and summarizes the reported mechanisms of action of natural and synthetic small molecule inhibitors of ferroptosis and their efficacy in disease. The paper also describes ferroptosis treatments such as gene therapy, cell therapy, and nanotechnology, and summarises the challenges encountered in the clinical translation of ferroptosis inhibitors. Finally, the relationship between ferroptosis and other modes of cell death is discussed, hopefully paving the way for future drug design and discovery.

Research progress of microRNA in spinal cord injury.

Spinal cord injury (SCI) is a serious central nervous system disease with high disability and mortality rates and complex pathophysiologic mechanisms. MicroRNA (miRNA), as a kind of non-coding RNA, plays an important role in SCI. miRNA is involved in the regulation of inflammatory response, oxidative stress, axonal regeneration, and apoptosis after SCI, and interacts with long non-coding RNA (lncRNA) and circular RNA (circRNA) to regulate the pathophysiological process of SCI. This paper summarizes the changes in miRNA expression after SCI, and reviews the targeting mechanism of miRNA in SCI and the current research status of miRNA-targeted drugs to provide new targets and new horizons for basic and clinical research on SCI.

Ferroptosis: A new strategy for targeting Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a complex pathogenesis, which involves the formation of amyloid plaques and neurofibrillary tangles. Many recent studies have revealed a close association between ferroptosis and the pathogenesis of AD. Factors such as ferroptosis-associated iron overload, lipid peroxidation, disturbances in redox homeostasis, and accumulation of reactive oxygen species have been found to contribute to the pathological progression of AD. In this review, we explore the mechanisms underlying ferroptosis, describe the link between ferroptosis and AD, and examine the reported efficacy of ferroptosis inhibitors in treating AD. Finally, we discuss the potential challenges to ferroptosis inhibitors use in the clinic, enabling their faster use in clinical treatment.

Re-discovery and taxonomic clarification of Oreocharisleveilleana (Gesneriaceae) in Guizhou, China, over 100 years.

Oreocharisleveilleana Fedde was collected in Ta-pin in 1910 and published in 1911. The collected location was verified within western Luodian County, Guizhou Province, China. However, there have been no records of the species' collection for more than 100 years since then. After extensive investigations by our research team on the type locality and its surrounding areas, we found that it is widely distributed in western Luodian County and eastern Wangmo County, Guizhou Province, China. During further research on the original literature, type specimens and type locality of O.leveilleana, the taxonomic position of O.leveilleana, which was once treated as a synonym of O.auricula (S.Moore) C.B.Clarke, was found to have a taxonomic problem. Through morphological research combined with geographical distribution analysis, it has been determined that it should belong to the genus Petrocodon Hance and it is the same species as P.coccineus (C.Y.Wu ex H.W.Li) Yin Z.Wang. According to the regulations and suggestions of the 2018 "International Code of Nomenclature for Algae, Fungi, and Plants (Shenzhen Code)", we propose and confirm a new combination - Petrocodonleveilleanus (Fedde) X.X.Bai & F.Wen and treat P.coccineus as a synonym of the new combination. Due to its unique bright red flowers within Petrocodon, its original Chinese name has been retained.

ACE Gene Mutations (rs577350502) in Early-Onset and Recurrent Myocardial Infarction: A Case Report and Review.

Background: Acute myocardial infarction (AMI) is a severe acute coronary syndrome, demonstrating a trend toward affecting younger individuals in recent years. The association between early-onset myocardial infarction and single nucleotide polymorphism necessitates further exploration and evaluation. Case description: We present a case of a patient experiencing early-onset and recurrent myocardial infarction. The patient underwent stent implantation for myocardial infarction at the age of 53 and subsequently encountered two more myocardial infarctions within a span of 16 years. Following interventional therapy, genetic testing was conducted to assess the efficacy of subsequent anti-heart failure medications, with the aim to preemptively address heart failure risks. Genetic testing revealed a mutation in the angiotensin-converting enzyme (ACE) gene (rs577350502, g.63488533C>A), characterized by an intron-deletion single nucleotide variant. Conclusion: While this variant has not been previously reported to be associated with any specific disease, we hypothesize that it may contribute to the susceptibility and risk of myocardial infarction and coronary heart disease in the patient under consideration. This observation underscores the significance of investigating the insertion/deletion polymorphisms of the ACE gene in the context of AMI and emphasizes the necessity for further validation of this variant and other genetic markers associated with AMI in related diseases.

Probing the Chemistry of Sulfurous Pollutants: Accurate Thermochemistry Determination of Extensive Sulfur-Containing Species.

Sulfur-containing fuels, such as petroleum fuels, natural gas, and biofuels, produce SO2, SO3, and other highly toxic gases upon combustion, which are harmful to human health and the environment, making it essential to understand their thermochemical properties. This study used high-level quantum chemistry calculations to determine thermodynamic parameters, including entropy, enthalpy, and specific heat capacity for an extensive set of sulfur-containing species. The B3LYP/cc-pVTZ level of theory was used for geometry optimization, vibration frequency, and dihedral scan calculations. To determine an appropriate ab initio method for energy calculation, the Bland-Altman diagram, a statistical analysis method, was employed to visualize the 298 K enthalpy value between experimental data and three sets of ab initio methods: G3, CBS-QB3, and the average of G3 plus CBS-QB3. The CBS-QB3 method exhibited the highest accuracy and was eventually selected for the energy calculation in this study. Thermochemical property parameters were then calculated with the MultiWell program suite for all these sulfur-containing species, and the results were in good agreement with the thermochemical data of organic compounds and the National Institute of Standards and Technology Chemistry WebBook databases. The thermochemical property database established in this study is essential to studying sulfur-containing species in desulfurization.

Unexplained fetal tachycardia: A case report.

BACKGROUND: This study aimed to explore the possible etiology and treatment of severe fetal tachycardia in the absence of organic disease and provide a reference for clinical management of severe fetal tachycardia. CASE SUMMARY: A 29-year-old pregnant woman, with a gravidity 1 parity 0, presented with a fetal heart rate (FHR) of 243 beats per minute during a routine antenatal examination at 31 + 2 wk of gestation. Before termination of pregnancy at 38 wk of gestation, the FHR repeatedly showed serious abnormalities, lasting more than 30 min. However, the pregnant woman and the fetus had no clinical symptoms, and repeated examination revealed no organic lesions. The mother and the baby were regularly followed up. CONCLUSION: This was a case of severe fetal tachycardia with no organic lesions and management based on clinical experience.

Proteomic Profiling of Muscular Adaptations to Short-Term Concentric Versus Eccentric Exercise Training in Humans.

The molecular mechanisms underlying muscular adaptations to concentric (CON) and eccentric (ECC) exercise training have been extensively explored. However, most previous studies have focused on specifically selected proteins, thus, unable to provide a comprehensive protein profile and potentially missing the crucial mechanisms underlying muscular adaptation to exercise training. We herein aimed to investigate proteomic profiles of human skeletal muscle in response to short-term resistance training. Twenty young males were randomly and evenly assigned to two groups to complete a 4-week either ECC or CON training program. Measurements of body composition and physiological function of the quadriceps femoris were conducted both before and after the training. Muscle biopsies from the vastus lateralis of randomly selected participants (five in ECC and four in CON) of both before and after the training were analyzed using the liquid-chromatography tandem mass spectrometry in combination with bioinformatics analysis. Neither group presented a significant difference in body composition or leg muscle mass; however, muscle peak torque, total work, and maximal voluntary contraction were significantly increased after the training in both groups. Proteomics analysis revealed 122 differentially abundant proteins (DAPs; p value < 0.05 & fold change >1.5 or <0.67) in ECC, of which the increased DAPs were mainly related to skeletal muscle contraction and cytoskeleton and enriched specifically in the pentose phosphate pathway, extracellular matrix-receptor interaction, and PI3K-Akt signaling pathway, whereas the decreased DAPs were associated with the mitochondrial respiratory chain. One hundred one DAPs were identified in CON, of which the increased DAPs were primarily involved in translation/protein synthesis and the mitochondria respiratory, whereas the decreased DAPs were related to metabolic processes, cytoskeleton, and de-ubiquitination. In conclusion, the 4-week CON and ECC training resulted in distinctly different proteomic profiles, especially in proteins related to muscular structure and metabolism.

A New Perspective in the Treatment of Ischemic Stroke: Ferroptosis.

Ischemic stroke is a common neurological disease. Currently, there are no Food and Drug Administration-approved drugs that can maximize the improvement in ischemic stroke-induced nerve damage. Hence, treating ischemic stroke remains a clinical challenge. Ferroptosis has been increasingly studied in recent years, and it is closely related to the pathophysiological process of ischemic stroke. Iron overload, reactive oxygen species accumulation, lipid peroxidation, and glutamate accumulation associated with ferroptosis are all present in ischemic stroke. This article focuses on describing the relationship between ferroptosis and ischemic stroke and summarizes the relevant substances that ameliorate ischemic stroke-induced neurological damage by inhibiting ferroptosis. Finally, the problems in the treatment of ischemic stroke targeting ferroptosis are discussed, hoping to provide a new direction for its treatment.

Deciphering the Plastomic Code of Chinese Hog-Peanut (Amphicarpaea edgeworthii Benth., Leguminosae): Comparative Genomics and Evolutionary Insights within the Phaseoleae Tribe.

The classification and phylogenetic relationships within the Phaseoleae tribe (Leguminosae) have consistently posed challenges to botanists. This study addresses these taxonomic intricacies, with a specific focus on the Glycininae subtribe, by conducting a comprehensive analysis of the highly conserved plastome in Amphicarpaea edgeworthii Benth., a critical species within this subtribe. Through meticulous genomic sequencing, we identified a plastome size of 148,650 bp, composed of 128 genes, including 84 protein-coding genes, 36 tRNA genes, and 8 rRNA genes. Comparative genomic analysis across seven Glycininae species illuminated a universally conserved circular and quadripartite structure, with nine genes exhibiting notable nucleotide diversity, signifying a remarkable genomic variability. Phylogenetic reconstruction of 35 Phaseoleae species underscores the affinity of Amphicarpaea with Glycine, placing Apios as a sister lineage to all other Phaseoleae species, excluding Clitorinae and Diocleinae subtribes. Intriguingly, Apios, Butea, Erythrina, and Spatholobus, traditionally clumped together in the Erythrininae subtribe, display paraphyletic divergence, thereby contesting their taxonomic coherence. The pronounced structural differences in the quadripartite boundary genes among taxa with unresolved subtribal affiliations demand a reevaluation of Erythrininae's taxonomic classification, potentially refining the phylogenetic contours of the tribe.

Molecular Mechanisms and Biological Characteristics of Botrytis cinerea Field Isolate Resistance to Pyrisoxazole in Liaoning Province.

Botrytis cinerea is a broad-host-range necrotrophic phytopathogen responsible for serious diseases in leading crops worldwide. The novel sterol 14α-demethylase inhibitor (DMI) pyrisoxazole was recently registered for the control of tomato gray mold caused by B. cinerea in China. One hundred fifty-seven isolates of B. cinerea were collected from tomato greenhouses in 14 cities of Liaoning Province from 2016 to 2021 and examined for sensitivity to pyrisoxazole, with a mean EC50 value of 0.151 µg/ml. Three highly resistant isolates, XD-5, DG-4, and GQ-3, were screened, and the EC50 values were 0.734, 0.606, and 0.639 µg/ml with corresponding resistance factors of 12.88, 10.63, and 11.21, respectively. Compared with field-sensitive strains, the highly resistant isolate XD-5 exhibited fitness defects in traits, including mycelial growth, conidial production, and pathogenicity, but DG-4 and GQ-3 did not experience fitness costs. Positive cross-resistance was observed only between pyrisoxazole and the DMIs tebuconazole and prochloraz but not between pyrisoxazole and the non-DMIs iprodione, procymidone, pyrimethanil, fludioxonil, fluazinam, and fluopyram. Sequence alignment of the CYP51 gene indicated that three point mutations were observed in the highly resistant mutant, namely, V24I in XD-5, G461S in GQ-3, and R464K in DG-4. When exposed to pyrisoxazole, the induced expression levels of the ABC transporter AtrD and MFS transporter Mfs1 increased in the resistant isolates compared with those in the sensitive isolates, whereas the expression level of the CYP51 gene did not change significantly. Molecular docking suggested that the G461S and R464K mutations both led to a decrease in the binding energy between CYP51 and pyrisoxazole, whereas no change was found with the V24I mutation. Thus, two point mutations in the CYP51 protein combined with induced expression of the Mfs1 and AtrD genes appeared to mediate the pyrisoxazole resistance of the highly resistant mutants DG-4 and GQ-3, while the overexpression of the Mfs1 and AtrD genes was responsible for the highly resistant mutant XD-5.

Fatalism and Suicidal Behaviors Among Chinese College Students: The Mediating Role of Depressive Symptoms and the Moderating Role of Coping Strategies.

The aim of this study was to investigate the relationship between fatalism and suicidal behaviors, the mediating role of depressive symptoms, and the moderating effect of coping strategies on the mediating process. A total of 519 participants completed the Multidimensional Fatalism Scale for General Life Events, the Center for Epidemiologic Studies-Depression scale, the Simplified Coping Style Questionnaire, and the Suicidal Behaviors Questionnaire-Revised. Results suggest that depressive symptoms partially mediated the relationship between fatalism and suicidal behaviors. Active coping moderated the mediating effect of depressive symptoms. The higher the active coping level, the weaker the mediating effect. The findings revealed that the mechanism of fatalism affecting suicidal behaviors, and had theoretical and empirical value for the prevention and intervention of suicide among college students.