BACKGROUND:Diffuse Gastric Cancer (DGC) is a highly aggressive form of gastric cancer with a poor prognosis. Oxaliplatin (OX) is one of the first-line chemotherapeutic agents for the treatment of gastric cancer. However, some patients with DGC do not benefit from OX therapy. Resibufogenin (RBF), one of the main active components of the Chinese medicine Huachansu, has demonstrated significant anti-cancer effects. Nevertheless, the potential of RBF to enhance the sensitivity of OX treatment in DGC and its underlying mechanisms have not been reported. OBJECTIVE:The aim of this study is to investigate the sensitizing effect of RBF on OX therapy for DGC, as well as to elucidate the potential targets and mechanisms of action. This exploration is of significant importance for the development of sensitizers that can improve the therapeutic efficacy of OX and for the advancement of patentable innovations in this field. METHODS:MTT assay, flow cytometry, Western blotting, and immunofluorescence assays were employed to assess the inhibitory effects of Resibufogenin (RBF) in combination with OX on DGC in vitro. Human DGC cell xenografts were established in a mouse model to evaluate the efficacy and safety of RBF and OX for treating DGC in vivo. RESULTS AND DISCUSSION:It was found that RBF inhibited the proliferation of DGC cells in a timeand dose-dependent manner. When RBF was used in combination with OX, the sensitivity of DGC cells to OX was improved. Significantly, the combination of OX and RBF acts synergistically to induce apoptosis and autophagy while inhibiting migration and invasion of DGC cells in vitro. In vivo, the combination of OX and RBF dramatically inhibited the progression of DGC in the subcutaneous xenograft model without observable toxicity. Mechanistically, RBF significantly inhibited the expression and activation of FAK. OX and RBF synergistically inhibited the phosphorylation of FAK, AKT, and GSK3β to abrogate the entry of β-catenin into the cell nucleus. RBF sensitizes DGC to oxaliplatin via FAK suppression. CONCLUSION:RBF exhibits a pronounced suppressive effect on FAK, and its combination with OX synergistically blocks the FAK/AKT/GSK3β/β-catenin signaling cascade, thereby inhibiting the growth and metastasis of DGC. This study provides a novel avenue for future research and patent development of FAK inhibitors, with the potential to enhance the therapeutic efficacy of DGC treatment and overcome drug resistance.

Calcium dysregulation is closely associated with cancer cell proliferation, migration, and invasion. Transient receptor potential canonical 1 (TRPC1) plays an essential role in regulating calcium homeostasis. However, the role of TRPC1 in calcium dysregulation in gliomas remains incompletely understood. In this study, we demonstrate that TRPC1 promotes glioma cell migration by increasing Signal transduction and transcription activator 3 (STAT3) protein levels. Furthermore, we show that TRPC1 modulates STAT3 stability by inhibiting chaperone-mediated autophagy (CMA), and we identify STAT3 as a novel substrate of CMA. Additionally, TRPC1 modulates the interaction between HDAC6 and Heat Shock Cognate 70 through intracellular Ca2+ homeostasis, which is associated with changes in CMA activity. These changes prevent STAT3 degradation, highlighting the TRPC1-HDAC6 axis as a regulator of glioma progression. Thus, the TRPC1-HDAC6 axis inhibits STAT3 degradation by suppressing CMA activity, contributing to glioma progression. This pathway may represent a potential therapeutic target.

Parkinson’s Disease (PD) is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). PANoptosis, a programmed inflammatory cell death integrating pyroptosis, apoptosis, and necroptosis, contributes to DA neuron degeneration in PD. The E3 ubiquitin ligase Parkin and the inflammasome sensor NOD-like receptor protein 3 (NLRP3) are known to play critical regulatory roles in DA neuron degeneration. However, whether Parkin modulated NLRP3 via chaperone-mediated autophagy (CMA) to inhibit PANoptosis remained unclear. To verify the above hypothesis, SN4741 cells and C57BL/6 mice were treated with rotenone to establish PD models. PANoptosis activation and DA neurons degeneration were observed in PD models, and these pathological manifestations were mitigated by the NLRP3 inhibitor MCC950. Besides, Parkin interacted with NLRP3, ubiquitinated its K353 residue, and then promoted NLRP3 degradation via CMA. Parkin overexpression or CMA activation alleviated DA neuron damage and PANoptosis, while K353R mutation abolished these effects. It was revealed that Parkin mediated CMA-dependent degradation of NLRP3 (targeting K353) to suppress PANoptosis and protect DA neurons in PD. CMA activators or NLRP3 inhibitors may serve as disease-modifying therapies for PD.

Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.

[This corrects the article DOI: 10.3389/fonc.2022.807597.].

INTRODUCTION:Systemic therapies for advanced gastric cancer (GC), including chemotherapy, targeted therapy and immunotherapy, have evolved significantly in the past few years. The combination of immune checkpoint inhibitors (ICIs) and chemotherapy has become the standard first-line (1L) treatment for advanced gastric or gastro-oesophageal junction (G/GEJ) cancer, although there remains a need for improvement in efficacy. Fruquintinib, an oral and highly selective vascular endothelial growth factor receptor inhibitor, has shown a synergistic antitumour effect when paired with ICI or chemotherapy. Moreover, it has demonstrated a tolerable safety profile and high potential for synergy with chemotherapy or immunotherapy, suggesting that a combination of fruquintinib, sintilimab and oxaliplatin+capecitabine (CAPEOX) can be a promising treatment for locally advanced G/GEJ cancer. This phase 1b/2 study aims to investigate the safety and efficacy of the combination of fruquintinib, sintilimab and CAPEOX regimen as a 1L combination therapy for unresectable advanced or metastatic G/GEJ cancer. METHODS AND ANALYSIS:The FUNCTION trial (NCT06329973) is a single-arm, prospective, multicentre, phase Ib/II clinical trial that will consist of a dose escalation phase and an expansion phase. The study is planned to be conducted at 16 public hospitals. A total of 70 participants will be enrolled, comprising nine in the dose escalation phase and 61 in the expansion phase. The dosing regimen during the dose escalation phase will include three different doses of fruquintinib (3 mg, 4 mg and 5 mg, per oral, once per day days 1-14) + sintilimab, 200 mg, intravenous, day 1 +oxaliplatin 130 mg/m2, day 1, intravenous, + capecitabine 800 mg/m2, per oral, twice daily, days 1-14, every 21 days. The recommended phase 2 dose (RP2D) and maximum tolerated dose will be determined in the escalation phase, and the RP2D will be used in the expansion phase. The primary endpoints will be the maximum tolerated dose and objective response rate; the secondary endpoints will include OS, progression-free survival, disease control rate, duration of response, surgical conversion rate and adverse events and identification of molecular biomarkers for efficacy. The results from this study will provide evidence for expanding the clinical applications of fruquintinib plus sintilimab and CAPEOX as a 1L combination therapy in metastatic or non-resectable, locally advanced G/GEJ cancer and lay the foundation for future large-scale clinical investigations. ETHICS AND DISSEMINATION:This study will be conducted in full compliance with the ICH (The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH) GCP (Good Clinical Practice, GCP) guidelines, the rules of the Declaration of Helsinki and ICH E2A (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting) Guidelines . The study protocol has received approval from the Henan Cancer Hospital ethical committee (Approval No. 2023-237-002). Written informed consent will be obtained from all patients prior to enrolment. For patients who have the mental capacity for informed consent, their consent for participation will be sought and will not be overridden by their family members. For patients who have impaired cognition, informed consent will be sought from their legally acceptable representative. On completion of the analyses, the study findings will be disseminated locally and internationally through manuscript publications in peer-reviewed journals and conference presentations. TRIAL REGISTRATION:NCT06329973.

Background:Peer support is increasingly recognized as a valuable method for managing blood glucose levels and reducing the risk of chronic complications in patients with diabetes. This systematic review and meta-analysis specifically evaluated the effect of peer support on HbA1c levels in middle-aged and elderly patients with type 2 diabetes and explored the potential benefits of peer interactions on glycemic control. Methodology:A comprehensive search was conducted across six databases from January 2018 to July 2023, with a focus on randomized controlled trials (RCTs) that compared peer support interventions to standard diabetic care in adults. Among the 3,395 articles identified, eleven studies involving 2,187 participants were included. The quality of each study was assessed using the Cochrane risk of bias tool. A random-effects model was employed to calculate the mean difference (MD) in HbA1c changes, with additional subgroup analyses for specific contexts. Results:The findings revealed a modest but statistically significant improvement in HbA1c levels in groups receiving peer support (MD: -0.20; 95% CI [-0.37 to -0.02]; p = 0.03). More pronounced benefits were observed in interventions conducted within formal medical settings, those involving high-frequency contact, and those in group sessions, particularly among elderly patients. Conclusions:The results suggest that while peer support provides a slight improvement in HbA1c levels, other intervention strategies-such as frequent contact, group sessions, and formal medical settings-may offer greater glycemic control benefits in elderly patients with type 2 diabetes. These findings support incorporating peer support into diabetes care and underscore the need for further research with larger samples and standardized protocols.

Curcumin is a hydrophobic polyphenolic compound with potent anti-inflammatory properties. However, whether it can achieve therapeutic effects by alleviating neuroinflammation in patients with Parkinson's disease (PD) and its potential mechanism are still unknown. This study explored the effects of curcumin on neuroinflammation in dopaminergic neurons and deciphered its direct target in the histone deacetylase 6 (HDAC6)-Nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) pathway, revealing the potential role of curcumin in the treatment of Parkinson's disease. Here, we show that curcumin alleviated the degeneration of neurons in a PD model by mitigating the activation of the NLRP3-mediated inflammatory response both in vivo and in vitro. Furthermore, we discovered that curcumin prevented neuroinflammation by blocking the HDAC6-NLRP3 pathway in a PD model. Moreover, overexpression of HDAC6 could eliminate the effect of curcumin on the neuroinflammatory response mediated by NLRP3. Curcumin and the HDAC6 inhibitor WT161 could alleviate neurodegeneration. In addition, activated HDAC6 directly deacetylated NLRP3 at lysine 84 to maintain its stability, which increased the inflammatory response and promoted neurodegeneration. These findings show that curcumin, a neuroinflammation inhibitor, blocks neurodegeneration via the HDAC6-NLRP3 pathway and represents a potentially practical pharmacological approach for treating neuroinflammation-driven neurodegenerative diseases. For the first time, HDAC6 was shown to directly regulate the acetylation of NLRP3.

Changes in calcium signalling are crucial for the development of glioma cells. Whether mitochondrial calcium balance is involved in glial cell development is still unknown. Mitochondrial Calcium Uniporter (MCU) plays an important role in regulating glioma progression. In this work, we found that MCU and p38 expression were positively correlated with glioma grade and the degree tumour progression. MCU increases glioma cell migration by upregulating p38. Furthermore, p38 promotes glioma progression by activating Transcription Factor EB (TFEB)-mediated autophagy. Thus, MCU promotes glioma cell migration by activating autophagy in a p38/TFEB pathway-dependent manner, which provides a theoretical basis for new therapeutic targets for gliomas.

Rotenone remains an efficient pesticide used extensively in agriculture, leading to neurotoxicity and the increase of the prevalence of Parkinson's disease (PD). Previous studies indicated that Parkin, a neurohomeostasis regulatory factor, and NOD-like receptor protein 3 (NLRP3), a core factor driving the inflammatory response, interacted with each other, which affected neuroinflammation occurrence. However, whether rotenone accelerated PD progression via Parkin-NLRP3 loop and the specific mechanisms were still unclear. Here, a novel negative feedback mechanism of Parkin-NLRP3 that regulated PD caused by rotenone was certified. Rotenone treatment induced neurodegeneration in vitro- and vivo-models. The activation of NLRP3 inflammasome and Parkin was increased and decreased, respectively, and the expression of pyroptosis related proteins was up-regulated, because of the addition of rotenone. Notably, the overexpression of Parkin promoted NLRP3 ubiquitination, which down regulated pyroptosis mediated by NLRP3, protected mitochondrial function as well as preventing neurodegeneration. Additionally, the NLRP3 inhibitor MCC950 restored the activation of Parkin and down regulated pyroptosis mediated by NLRP3 in rotenone-induced PD. It was revealed that the Parkin-NLRP3 negative feedback loop participated in rotenone-induced PD by regulating pyroptosis, representing a new idea for the prevention and treatment of neurodegenerative diseases.

Rotenone, a widely used pesticide, causes dopaminergic neurons loss and increase the risk of Parkinson's disease (PD). However, few studies link the role of PARP1 to neuroinflammatory response and autophagy dysfunction in rotenone-induced neurodegeneration. Here, we identified that PARP1 overactivation caused by rotenone led to autophagy dysfunction and NLRP3-mediated inflammation. Further results showed that PARP1 inhibition could reduce NLRP3-mediated inflammation, which was effectively eliminated by TFEB knockdown. Moreover, PARP1 poly(ADP-ribosyl)ated TFEB that reduced autophagy. Of note, PARP1 inhibition could rescue rotenone-induced dopaminergic neurons loss. Overall, our study revealed that PARP1 blocks autophagy through poly (ADP-ribosyl)ating TFEB and inhibited NLRP3 degradation, which suggests that intervention of PARP1-TFEB-NLRP3 signaling can be a new treatment strategy for rotenone-induced neurodegeneration.

The airway epithelial barrier dysfunction plays a crucial role in pathogenesis of asthma and causes the amplification of downstream inflammatory signal pathway. S100 calcium binding protein A4 (S100A4), which promotes metastasis, have recently been discovered as an effective inflammatory factor and elevated in bronchoalveolar lavage fluid in asthmatic mice. Vascular endothelial growth factor-A (VEGFA), is considered as vital regulator in vascular physiological activities. Here, we explored the probably function of S100A4 and VEGFA in asthma model dealt with house dust mite (HDM) extracts. Our results showed that secreted S100A4 caused epithelial barrier dysfunction, airway inflammation and the release of T-helper 2 cytokines through the activation of VEGFA/VEGFR2 signaling pathway, which could be partial reversed by S100A4 polyclonal antibody, niclosamide and S100A4 knockdown, representing a potential therapeutic target for airway epithelial barrier dysfunction in asthma.

The accumulation of exogenous silver nanoparticles (AgNPs) will terminally bring about liver injury, including cell death, where DNA methylation tends to be a crucial epigenetic modulator. The change in the cell autophagy level verified to be closely associated with hepatocyte death has been followed with wide interest. But the molecular toxicological mechanisms of AgNPs in relation to DNA methylation, autophagy, and cell death remain inconclusive. To address the issue above, in LO2 cells treated with increasing concentrations of AgNPs (0, 5, 10, and 20 μg/mL), a cell cytotoxicity assay was performed to analyze the level of cell death, which also helped to choose an optimal concentration for next experiments. An immunofluorescence assay was used to determine the autophagic flux as well as TFEB translocation, with qRT-PCR and western blot being used to analyze the expression level of autophagy-related genes and proteins. According to our findings, in the determination of cell viability, 20 μg/mL (AgNPs) was adopted as the best working concentration. LO2 cell death, autophagy, and TFEB nuclear translocation were induced by AgNPs, which could be inhibited by lysosome inhibitor chloroquine (CQ) or siRNA specific for TFEB. Moreover, AgNP exposure led to DNA hypermethylation, with DNMT1 taking part mainly, which could be obviously prevented by 5-Aza-2′-deoxycytidine (5-AzaC) or trichostatin A (TSA) treatment or DNMT1 knockout in LO2 cells. Our studies suggest that through TFEB-dependent cell autophagy, increased DNMT1 may facilitate cell death induced by AgNPs.

Long-term exposure to benzene or its metabolite, hydroquinone (HQ), can causally contribute to acute myeloid leukemia. Long-noncoding RNAs are essential epigenetic regulators with critical roles in tumor initiation and malignant progression; however, the mechanism by which aberrantly expressed LINC00173 (long intergenic nonprotein coding RNA 173) regulates the pathogenesis of acute myeloid leukemia is not fully understood. Here, we found that the expression of LINC00173 decreased while the expression of DNA methyltransferase 1 (DNMT1) increased, and the methylation of LINC00173 promoter was negatively correlated with LINC00173 expression in GEPIA, CCLE databases, benzene-exposed workers, B-cell non-Hodgkin’s lymphoma, K562, U937, or HQ-induced malignantly transformed TK6 (HQ-MT cells). Furthermore, in 5-aza-2’-deoxycytidine (DNA methyltransferase inhibitor) or trichostatin A (histone deacetylation inhibitor)-treated HQ-MT cells, the expression of LINC00173 was restored by reduced DNA promoter methylation levels. HQ-MT cells with DNMT1 knockout by CRISPR/Cas9 restored the expression of LINC00173 and inhibited the DNA methylation of its promoter as well as enrichment of DNMT1 to promoter. Overexpression of LINC00173 inhibited the expression of DNMT1, cell proliferation, tumor growth, enhanced chemosensitivity to cisplatin, and apoptosis in HQ-MT cells. LINC00173 interacts with DNMT1 to regulate the methylation of LINC00173 promoter. Overall, this study provides evidence that interaction between DNMT1 and LINC00173 regulates the expression of LINC00173 by regulating its promoter methylation level, thus regulating the function of HQ-MT cells in vitro and in vivo, providing a new therapeutic target for benzene-induced tumor.

Hydroquinone (HQ) is one of the major metabolites of benzene and can cause abnormal gene expression. It is a known carcinogen that alters cell cycle disruption and cell proliferation. However, its chemical mechanism remain a mystery. Circular RNAs (circRNAs) are a subtype of noncoding RNAs (ncRNAs) that play a variety of roles in biological processes. Hsa_circ_001944 expression was upregulated in 30 leukemia patients and HQ-induced malignant transformed TK6 cells. Hsa_circ_001944 silencing inhibited the growth of HQ-TK6 cells and halted the cell cycle. The silencing of hsa_circ_0001944 led to increased cell accumulation in G1 versus S phase, increased apoptosis in the sh1944 versus the shNC group, and increased levels of DNA damage (γ-H2AX), leading to cell cycle arrest. In summary, inhibition of hsa_circ_001944 restricted cell growth by inhibiting cell cycle arrest and induced growth of HQ-TK6 cells by modulating PARP1 expression. Hsa_circ_0001944 targeted HuR, which is a kind of RNA-binding protein, to control PARP1 expression via RNAinter, RBPmap, and RBPdb. Fluorescence in situ hybridization combined with immunofluorescent labeling and western blotting experiments showed that hsa_circ_001944 was able to dissociate HuR and PARP1 binding in HQ-TK6 cells, control PARP1 production, and ultimately alter the PARP1/H-Ras pathway.

The harmful effects of air pollution can cause various diseases. Most research on the hazards of air pollution focuses on lung and cardiovascular diseases. In contrast, the impact of air pollution on neurological disorders is not widely recognized. Air pollution can cause various neurological conditions and diseases, such as neural inflammation, neurodegeneration, and cerebrovascular barrier disorder; however, the mechanisms underlying the neurological diseases induced by various components of air pollutants remain unclear. The present paper summarizes the effects of different components of air pollutants, including particulate matter, ozone, sulfur oxides, carbon oxides, nitrogen oxides, and heavy metals, on the nervous system and describes the impact of various air pollutants on neurological disorders, providing ideas for follow-up research.

Exposure to benzene or its metabolite hydroquinone (HQ) is a risk factor for a series of myeloid malignancies, and long noncoding RNAs play an important role in the process of pathogenesis. Urothelial cancer-associated 1 (UCA1) functions as an oncogene in the development of acute myeloid leukemia. However, the association between DNMT1 and UCA1 with benzene or HQ exposure has not been explored. We characterized UCA1 expression in cells briefly exposed to HQ (HQ-ST cells) and HQ-induced malignantly transformed (TK6-HT cells) treated with 5-aza-2'-deoxycytidine (5-AzaC) or trichostatin A (TSA). Compared to that in control cells, UCA1 expression was increased, whereas DNMT1 was decreased in HQ-ST cells and TK6-HT cells treated with 5-AzaC or TSA. Moreover, UCA1 expression was also upregulated and positively correlated with benzene exposure time in benzene-exposed workers. Furthermore, the expression of UCA1 was negatively associated with the DNA methylation level of its promoter in benzene-exposed workers. DNMT1 rather than DNMT3b knockout in TK6-HT cells activated the expression of UCA1 by inducing its promoter hypomethylation. These results suggest that benzene or HQ exposure leads to UCA1 upregulation via DNA hypomethylation in the UCA1 promoter, which is mediated by DNMT1.

Abstract Background Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), accompanied by accumulation of α-synuclein, chronic neuroinflammation and autophagy dysfunction. Previous studies suggested that misfolded α-synuclein induces the inflammatory response and autophagy dysfunction in microglial cells. The NLRP3 inflammasome signaling pathway plays a crucial role in the neuroinflammatory process in the central nervous system. However, the relationship between autophagy deficiency and NLRP3 activation induced by α-synuclein accumulation is not well understood. Methods Through immunoblotting, immunocytochemistry, immunofluorescence, flow cytometry, ELISA and behavioral tests, we investigated the role of p38-TFEB-NLRP3 signaling pathways on neuroinflammation in the α-synuclein A53T PD models. Results Our results showed that increased protein levels of NLRP3, ASC, and caspase-1 in the α-synuclein A53T PD models. P38 is activated by overexpression of α-synuclein A53T mutant, which inhibited the master transcriptional activator of autophagy TFEB. And we found that NLRP3 was degraded by chaperone-mediated autophagy (CMA) in microglial cells. Furthermore, p38-TFEB pathways inhibited CMA-mediated NLRP3 degradation in Parkinson's disease. Inhibition of p38 had a protective effect on Parkinson's disease model via suppressing the activation of NLRP3 inflammasome pathway. Moreover, both p38 inhibitor SB203580 and NLRP3 inhibitor MCC950 not only prevented neurodegeneration in vivo, but also alleviated movement impairment in α-synuclein A53T-tg mice model of Parkinson’s disease. Conclusion Our research reveals p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease, which could be a potential therapeutic strategy for PD. Graphical abstract p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease. In this model, p38 activates NLRP3 inflammasome via inhibiting TFEB in microglia. TFEB signaling negatively regulates NLRP3 inflammasome through increasing LAMP2A expression, which binds to NLRP3 and promotes its degradation via chaperone-mediated autophagy (CMA). NLRP3-mediated microglial activation promotes the death of dopaminergic neurons.

Extrachromosomal circular DNA (eccDNA) refers to a type of circular DNA that originate from but are likely independent of chromosomes. Due to technological advancements, eccDNAs have recently emerged as multifunctional molecules with numerous characteristics. The unique topological structure and genetic characteristics of eccDNAs shed new light on the monitoring, early diagnosis, treatment, and prediction of cancer. EccDNAs are commonly observed in both normal and cancer cells and function via different mechanisms in the stress response to exogenous and endogenous stimuli, aging, and carcinogenesis and in drug resistance during cancer treatment. The structural diversity of eccDNAs contributes to the function and numerical diversity of eccDNAs and thereby endows eccDNAs with powerful roles in evolution and in cancer initiation and progression by driving genetic plasticity and heterogeneity from extrachromosomal sites, which has been an ignored function in evolution in recent decades. EccDNAs show great potential in cancer, and we summarize the features, biogenesis, evaluated functions, functional mechanisms, related methods, and clinical utility of eccDNAs with a focus on their role in evolution and cancer.

Rotenone, a component of pesticides, is widely used in agriculture and potentially causes Parkinson's disease (PD). However, the regulatory mechanisms of rotenone-induced PD are unclear. Here, we revealed a novel feedback mechanism of p38-Parkin-ROS regulating rotenone-induced PD. Rotenone treatment led to not only the activation of p38 but also Parkin inactivation and reactive oxygen species (ROS) overproduction in SN4741 cells. Meanwhile, p38 activation regulated Parkin phosphorylation at serine 131 to disrupt Parkin-mediated mitophagy. Notably, both p38 inhibition and Parkin overexpression decreased ROS levels. Additionally, the ROS inhibitor N-acetyl-l-cysteine (NAC) inhibited p38 and activated Parkin-mediated mitophagy. Both p38 inhibition and the ROS inhibitor NAC exerted a protective effect by restoring cell death and mitochondrial function in rotenone-induced PD models. Based on these results, the p38-Parkin-ROS signaling pathway is involved in neurodegeneration. This pathway represents a valuable treatment strategy for rotenone-induced PD, and our study provides basic research evidence for the safe use of rotenone in agriculture.