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Abstract Ferroptosis, an iron-dependent form of cell death characterized by uncontrolled lipid peroxidation, is governed by molecular networks involving diverse molecules and organelles. Since its recognition as a non-apoptotic cell death pathway in 2012, ferroptosis has emerged as a crucial mechanism in numerous physiological and pathological contexts, leading to significant therapeutic advancements across a wide range of diseases. This review summarizes the fundamental molecular mechanisms and regulatory pathways underlying ferroptosis, including both GPX4-dependent and -independent antioxidant mechanisms. Additionally, we examine the involvement of ferroptosis in various pathological conditions, including cancer, neurodegenerative diseases, sepsis, ischemia–reperfusion injury, autoimmune disorders, and metabolic disorders. Specifically, we explore the role of ferroptosis in response to chemotherapy, radiotherapy, immunotherapy, nanotherapy, and targeted therapy. Furthermore, we discuss pharmacological strategies for modulating ferroptosis and potential biomarkers for monitoring this process. Lastly, we elucidate the interplay between ferroptosis and other forms of regulated cell death. Such insights hold promise for advancing our understanding of ferroptosis in the context of human health and disease.

Abstract Ferroptosis is a type of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture and intracellular content release. Originally investigated as a targeted therapy for cancer cells carrying oncogenic RAS mutations, ferroptosis induction now exhibits potential to complement chemotherapy, immunotherapy, and radiotherapy in various cancer types. However, it can lead to side effects, including immune cell death, bone marrow impairment, liver and kidney damage, cachexia (severe weight loss and muscle wasting), and secondary tumorigenesis. In this review, we discuss the advantages and offer an overview of the diverse range of documented side effects. Furthermore, we examine the underlying mechanisms and explore potential strategies for side effect mitigation.

Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive solid malignancy with low 5-year survival and limited treatment options. We conducted an unbiased screening using FDA-approved drug and demonstrated that cetylpyridinium chloride (CPC), a component commonly found in mouthwash and known for its robust bactericidal and antifungal attributes, exhibits anticancer activity against human PDAC cells. CPC inhibited PDAC cell growth and proliferation by inducing paraptosis, rather than apoptosis. Mechanistically, CPC induced paraptosis through the initiation of endoplasmic reticulum stress, leading to the accumulation of misfolded proteins. Subsequently, the endoplasmic reticulum stress to nucleus signaling 1 (ERN1)-mitogen-activated protein kinase kinase kinase 5 (MAP3K5)-p38 mitogen-activated protein kinase (MAPK) signaling pathway was activated, ultimately culminating in the induction of paraptosis. In vivo experiments, including those involving patient-derived xenografts, orthotopic models, and genetically engineered mouse models of PDAC, provided further evidence of CPC’s effectiveness in suppressing the growth of pancreatic tumors.

Cancer patients undergoing chemotherapy are susceptible to various bacterial infections, necessitating prompt and precise antimicrobial treatment with antibiotics. Ciprofloxacin is a clinically utilized broad-spectrum antimicrobial agent known for its robust antiseptic activity. While ferroptosis, an oxidative form of cell death, has garnered attention as a promising avenue in cancer therapy, the potential impact of ciprofloxacin on the anticancer effects of ferroptosis remains unclear. This study seeks to investigate the potential influence of antibiotics on ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Here, we report a previously unrecognized role of ciprofloxacin in inhibiting ferroptosis in human PDAC cells. Mechanistically, ciprofloxacin suppresses erastin-induced endoplasmic reticulum (ER) stress through the activating transcription factor 6 (ATF6) and ER to nucleus signaling 1 (ERN1) pathway. Excessive ER stress activation can trigger glutathione peroxidase 4 (GPX4) degradation through autophagic mechanisms. In contrast, ciprofloxacin enhances the protein stability of GPX4, a crucial regulator that suppresses ferroptosis by inhibiting lipid peroxidation. Thus, our study demonstrates the anti-ferroptotic role of ciprofloxacin, highlighting the importance of careful consideration when contemplating the combination of ciprofloxacin with specific ferroptosis inducers in PDAC patients.

This study aimed to elucidate the impact of ultrasound-assisted cellulase (UC) pretreatment on nutrients, phytic acid, and the bioavailability of phenolics during brown rice sprouting. It sought to unveil the underlying mechanisms by quantifying the activity of key enzymes implicated in these processes. The sprouted brown rice (SBR) surface structure was harmed by the UC pretreatment, which also increased the amount of γ-oryzanol and antioxidant activity in the SBR. Concurrently, the UC pretreatment boosted the activity of phytase, glutamate decarboxylase, succinate semialdehyde dehydrogenase, Gamma-aminobutyric acid (GABA) transaminase, chalcone isomerase, and phenylalanine ammonia lyase, thereby decreasing the phytic acid content and increasing the GABA, flavonoid, and phenolic content in SBR. In addition, UC-pretreated SBR showed increased phenolic release and bioaccessibility during in vitro digestion when compared to the treated group. These findings might offer theoretical direction for using SBR to maximize value.

In this study, we propose an improved betweenness centrality (FDBC) algorithm to identify vulnerabilities in airport field operations, assist controllers in formulating emergency response strategies, and enhance the safety resilience of the maneuvering area network during external disturbances. The algorithm is developed by constructing a transportation network model for the airport movement area and extracting key nodes based on considerations of traffic flow and road class. Utilizing aircraft field operation rules, we define an assessment index for the average shortest path length of inbound and outbound activities. Comparative analyses of comprehensive resilience indexes under various recovery strategies are conducted to assess the network’s recovery ability (RA) and adaptability in the face of external disturbances. The goal is to identify the optimal recovery strategy that achieves a dynamic balance between development and safety. To validate our approach, we conducted an empirical study at an airport in southwest China, simulating the resilience of the airport movement area transportation network under varying road class coefficients, traffic flow weights, and road class weights. The results indicate that the airport movement area transportation network in the southwest region lacks small-world and scale-free network characteristics. The identification of important road intersections through the FDBC strategy proves to be more effective in discerning potential safety hazard orientations. Under the FDBC-based recovery strategy, as traffic flow weights increase, the comprehensive resilience index of the network initially shows a smooth trend, followed by a decrease, then another period of smoothness before decreasing again. Increasing the road class coefficient can enhance the network’s recovery efficiency and resilience level, enabling the network to maintain a high level of recovery for an extended period. This is beneficial for enhancing the safety and stability of flight operations. However, in cases where traffic flow weights are high, the FDBC-based recovery strategy, which solely considers traffic, exhibits a relatively slower network RA in response to degree-valued perturbations. Overall, the traffic network in the airport movement area demonstrates the highest resilience under the FDBC-based recovery strategy. It can rapidly transition the network from a failure state to a normal stable state, thereby improving emergency response efficiency and ensuring the safe operation of the traffic network in the airport movement area.

The deployment of intelligent surveillance systems to monitor tomato plant growth poses substantial challenges due to the dynamic nature of disease patterns and the complexity of environmental conditions such as background and lighting. In this study, an integrated cascade framework that synergizes detectors and trackers was introduced for the simultaneous identification of tomato leaf diseases and fruit counting. We applied an autonomous robot with smartphone camera to collect images for leaf disease and fruits in greenhouses. Further, we improved the deep learning network YOLO-TGI by incorporating Ghost and CBAM modules, which was trained and tested in conjunction with premier lightweight detection models like YOLOX and NanoDet in evaluating leaf health conditions. For the cascading with various base detectors, we integrated state-of-the-art trackers such as Byte-Track, Motpy, and FairMot to enable fruit counting in video streams. Experimental results indicated that the combination of YOLO-TGI and Byte-Track achieved the most robust performance. Particularly, YOLO-TGI-N emerged as the model with the least computational demands, registering the lowest FLOPs at 2.05 G and checkpoint weights at 3.7 M, while still maintaining a mAP of 0.72 for leaf disease detection. Regarding the fruit counting, the combination of YOLO-TGI-S and Byte-Track achieved the best R2 of 0.93 and the lowest RMSE of 9.17, boasting an inference speed that doubles that of the YOLOX series, and is 2.5 times faster than the NanoDet series. The developed network framework is a potential solution for researchers facilitating the deployment of similar surveillance models for a broad spectrum of fruit and vegetable crops.

Abstract Ferroptosis is a form of regulated cell death characterized by oxidative injury-induced lipid peroxidation. However, the detailed protein post-translational modification regulatory mechanism of ferroptosis remains largely unknown. Here, we report that E1A binding protein P300 (EP300) acetyltransferase promotes ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells via the acetylation of heat shock protein family A (Hsp70) member 5 (HSPA5), also known as GRP78 or BIP) on the site of K353. Acetylated HSPA5 loses its ability to inhibit lipid peroxidation and subsequent ferroptotic cell death. Genetic or pharmacological inhibition of EP300-mediated HSPA5 acetylation on K353 increases PDAC cell resistance to ferroptosis. Moreover, histone deacetylase 6 (HDAC6) limits HSPA5 acetylation and subsequent ferroptosis. Collectively, these findings not only identify regulatory pathways for HSPA5 acetylation during ferroptosis, but also highlight promising strategies to increase ferroptosis sensitivity in PDAC cells.

To investigate the effect of phenyllactic acid (PLA) on Listeria monocytogenes biofilms, crystal violet method was used to measure the biomass of L. monocytogenes biofilms, and inverted microscope and scanning electron microscope were used to observe the structure of L. monocytogenes biofilms, the content of extracellular polysaccharide, extracellular protein and extracellular DNA in biofilm was measured by phenol-sulfuric acid method, Folin-phenol method and diphenylamine method, respectively. The effect of PLA on the transcription of genes associated with biofilm formation of L. monocytogenes was detected by real-time quantitative PCR. The results showed that the minimum inhibitory concentration values of PLA against eight L. monocytogenes strains were 6 mg/mL. PLA inhibited L. monocytogenes biofilm formation by reducing the synthesis of extracellular polysaccharides and extracellular proteins. For mature biofilms of L. monocytogenes, PLA destroyed the biofilm structure and reduced the biofilm biomass by reducing the amount of extracellular polysaccharides and extracellular proteins. PLA also inhibited the swarming motility of L. monocytogenes. The transcription levels of quorum sensing system agr in L. monocytogenes were significantly (P

Calcium (Ca2+), a second messenger, plays a crucial role in plant growth and development as well as in responding to biotic and abiotic stresses. In this work, we explored the role of exogenous calcium in alleviating cold stress and examined the relationship between calcium chloride (CaCl2) and calcium channel blockers, lanthanum chloride (LaCl3), in tea plants under cold stress at the physiological and transcriptional levels. Exogenous Ca2+ partially offsets the negative impacts of cold stress which increased the tolerance of tea plants by significantly raising the photochemical efficiency of PSII, protective enzyme activities, and the ABA content, which reduced the relative electrical conductivity (REC) level and the malondialdehyde (MDA) concentration. At the transcriptome level, exogenous Ca2+ significantly enhanced the expression of key genes involved in cold response pathways. Nevertheless, LaCl3 treatment not only significantly inhibited the activities of antioxidant enzymes including superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), but also increased cold damage. This study aims to provide essential insight into the role of exogenous Ca2+ in tea plants responding to cold stress, and to better understand the molecular mechanisms that facilitate Ca-mediated cold tolerance.

Compared to conventional energy sources, wind power is a clean energy source with high intermittence and uncertainty. As a system that converts wind energy into electricity, wind farms inevitably face severe reliability issues. In this paper, based on reliability theory, a new reliability modeling method for wind farms is proposed. Firstly, a belief reliability model for wind farms is constructed. Then, a power generation model based on two-directional rotor equivalent wind speed is established to represent the wind farm performance in the belief reliability model. Finally, several numerical studies are conducted to verify the power generation model under different wind speeds and directions, to demonstrate the belief reliability model with different levels of uncertainty, and to compare the belief reliability considering two-directional rotor equivalent wind speed with other methods.

In this paper, a new reliability assessing method for structures influenced by both aleatory and epistemic uncertainty simultaneously is developed. To handle hybrid types of uncertainties, chance theory is introduced to define a new hybrid reliability index. By mathematical derivation and theorems proofs, the new index is showed to be effective and compatible with hybrid types of uncertainties. Correspondingly, a generalized first-order second-moment (GFOSM) algorithm is established for practical reliability assessment of structures with hybrid uncertainties. Based on the first two moments of basic variables, the GFOSM method can perform fast and effective reliability assessment without large-scale integration operations and can be considered as an extension and expansion of the traditional FOSM method. Two numerical cases further illustrate the effectiveness and practicability of the proposed method from different perspectives.

ABSTRACTTraditional ferroptosis activators typically suppress antitumor immunity. Our discovery shows that N6F11, a small molecule compound, can selectively induce ferroptosis by targeting TRIM25-mediated GPX4 degradation in cancer cells while sparing immune cells. This breakthrough establishes a safe and effective strategy to enhance ferroptosis-driven antitumor immunity.

Summary: Ferroptosis is a type of regulated cell death characterized by lipid peroxidation and subsequent damage to the plasma membrane. Here, we report a ferroptosis resistance mechanism involving the upregulation of TXNDC12, a thioredoxin domain-containing protein located in the endoplasmic reticulum. The inducible expression of TXNDC12 during ferroptosis in leukemia cells is inhibited by the knockdown of the transcription factor ATF4, rather than NFE2L2. Mechanistically, TXNDC12 acts to inhibit lipid peroxidation without affecting iron accumulation during ferroptosis. When TXNDC12 is overexpressed, it restores the sensitivity of ATF4-knockdown cells to ferroptosis. Moreover, TXNDC12 plays a GPX4-independent role in inhibiting lipid peroxidation. The absence of TXNDC12 enhances the tumor-suppressive effects of ferroptosis induction in both cell culture and animal models. Collectively, these findings demonstrate an endoplasmic reticulum-based anti-ferroptosis pathway in cancer cells with potential translational applications.

Abstract Alkaliptosis is a recently discovered type of pH-dependent cell death used for tumor therapy. However, its underlying molecular mechanisms and regulatory networks are largely unknown. Here, we report that the acetate-activating enzyme acetyl-CoA short-chain synthase family member 2 (ACSS2) is a positive regulator of alkaliptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Using qPCR and western blot analysis, we found that the mRNA and protein expression of ACSS2 was upregulated in human PDAC cell lines (PANC1 and MiaPaCa2) in response to the classic alkaliptosis activator JTC801. Consequently, the knockdown of ACSS2 by shRNAs inhibited JTC801-induced cell death in PDAC cells, and was accompanied by an increase in cell clone formation and a decrease in intracellular pH. Mechanically, ACSS2-mediated acetyl-coenzyme A production and subsequent histone acetylation contributed to NF-κB–dependent CA9 downregulation, and this effect was enhanced by the histone deacetylase inhibitor trichostatin A. These findings may provide new insights for understanding the metabolic basis of alkaliptosis and establish a potential strategy for PDAC treatment.

To detect the moisture of dried Goji (Lycium barbarum L.) berries nondestructively, a near-infrared (NIR) hyperspectral imager was used for experiments. NIR hyperspectral data were obtained and processed by standard normal variate (SNV) calculation using the MATLAB software v.R2016a. On the basis of the actual moisture of dried Goji berries, the predicted moisture was obtained based on the partial least squares (PLS) algorithm and a prediction model for the moisture of dried goji berries was established. It was found that the moisture of dried Goji berries was responsive to the NIR hyperspectral imager. The established prediction model could accurately predict the moisture of dried goji berries, and its R2-value was 0.9981. The results provide a theoretical basis for the design of non-destructive moisture-detecting equipment for dried Goji berries.

Malignant tumors represent a major threat to global health and the search for effective treatments is imperative. While various treatments exist, including surgery, radiotherapy, chemotherapy, immunotherapy and combination therapies, there remains a need to develop therapies that target regulated cell death pathways to eliminate cancer cells while preserving normal cells. Alkaliptosis, a pH-dependent cell death process triggered by the small molecular compound JTC801, has been identified as a novel approach for malignant tumor treatment, particularly in pancreatic cancer. Two major signaling pathways, the NF-κB-CA9 pathway and the ATP6V0D1-STAT3 pathway, contribute to the induction of alkaliptosis. This review summarizes recent developments in our understanding of alkaliptosis signals, mechanisms, and modulation, and explores its context-dependent effects on drug resistance, inflammation, and immunity. By providing a deeper understanding of the heterogeneity and plasticity of cell death mechanisms, this information holds promise for informing the design of more effective anti-tumor therapies.

Ferroptosis is cell death caused by lipid peroxidation and plasma membrane rupture. Here, the authors report an additional role for the lipid flippase SLC47A1 as a regulator of lipid remodeling and survival during ferroptosis, thereby providing a metabolic target for overcoming drug resistance.

Ferroptosis is lipid peroxidation-dependent cell death that has potential to be harnessed as a cancer therapeutic. Here, the authors show that the translation initiation factor eIF4E can repress ALDH1B1 independent of translation, increasing lipid peroxidation levels to promote ferroptosis.

ABSTRACT The Agr quorum sensing (QS) system is known to contribute to biofilm formation in Listeria monocytogenes. Cinnamaldehyde, a natural food preservative, is considered an inhibitor of Agr-mediated QS in L. monocytogenes. However, the exact mechanism by which cinnamaldehyde acts on Agr remains unclear. In this study, we assessed the effects of cinnamaldehyde on the histidine kinase AgrC and the response regulator AgrA in the Agr system. AgrC kinase activity was not influenced by cinnamaldehyde, and binding between AgrC and cinnamaldehyde was not observed when microscale thermophoresis (MST) was performed, indicating that AgrC was not the target of cinnamaldehyde. AgrA is specifically bound to the agr promoter (P2) to activate the transcription of the Agr system. However, AgrA-P2 binding was prevented by cinnamaldehyde. The interaction between cinnamaldehyde and AgrA was further confirmed with MST. Two conserved amino acids, Asn-178 and Arg-179, located in the LytTR DNA-binding domain of AgrA, were identified as the key sites for cinnamaldehyde-AgrA binding by alanine mutagenesis and MST. Coincidentally, Asn-178 was also involved in the AgrA-P2 interaction. Taken together, these results suggest that cinnamaldehyde acts as a competitive inhibitor of AgrA in AgrA-P2 binding, which leads to suppressed transcription of the Agr system and reduced biofilm formation in L. monocytogenes. IMPORTANCE Listeria monocytogenes can form biofilms on various food contact surfaces, posing a serious threat to food safety. Biofilm formation of L. monocytogenes is positively regulated by the Agr quorum sensing system. Thus, an alternative strategy for controlling L. monocytogenes biofilms is interfering with the Agr system. Cinnamaldehyde is considered an inhibitor of the L. monocytogenes Agr system; however, its exact mechanism of action is still unclear. Here, we found that AgrA (response regulator), rather than AgrC (histidine kinase), was the target of cinnamaldehyde. The conserved Asn-178 in the LytTR DNA-binding domain of AgrA was involved in cinnamaldehyde-AgrA and AgrA-P2 binding. Therefore, the occupation of Asn-178 by cinnamaldehyde suppressed transcription of the Agr system and reduced biofilm formation in L. monocytogenes. Our findings could provide a better understanding of the mechanism by which cinnamaldehyde inhibits L. monocytogenes biofilm formation.

Abstract Carboplatin is the most used first-line drug for the treatment of human retinoblastoma (RB), a rare form of cancer in infancy and childhood. However, the clinical application of carboplatin is restricted due to the emergence of acquired multi-drug resistance (MDR) after long-term treatment. Here, we report a new strategy to eliminate MDR RB cells by inducing autophagy-dependent ferroptosis. Compared with parent cells, carboplatin-resistant human RB cells have higher autophagy activity, which drives the formation of MDR to other chemotherapeutic drugs (e.g., etoposide and vincristine). In addition to confirming the traditional strategy of inhibiting autophagy to overcome MDR, we also establish an approach of inducing selective ferritinophagy to eliminate drug-resistant cells. We evaluate the effectiveness and safety of 4-octyl itaconate, a cell-permeable derivative of the metabolite itaconate, in inducing ferritinophagy-dependent ferroptosis in the treatment of MDR RB cells in vitro and in xenograft mouse models. These findings may provide essential clues for initiating clinical trials that target autophagy-dependent ferroptosis to kill drug-tolerant persistent cells during RB therapy.

The main objective of this study is to compare the differences between different gradation types of mixtures (stone matrix asphalt (SMA), large stone asphalt (LSA), stone asphalt concrete (SAC), and superior performing asphalt pavements (Superpave)) and conventional dense-graded mixtures (asphalt concrete (AC)) in terms of resistance to rutting, moisture damage, low-temperature cracking, and water permeability. The paper reports a study of the effect of different asphalt binders on the performance of asphalt mixtures. The experimental results demonstrated that the gradation types had a significant effect on the engineering performance of asphalt mixtures. SMA20, SAC20, and LSA30 exhibited lower rutting potential than AC20. In addition, SAC20 had a larger stripping ratio, while AC13 had a smaller stripping ratio. The stone matrix asphalt displayed the largest failure strain, while the SAC had the smallest, and Superpave ranged between SMA and SAC. SAC20 had the maximum permeability coefficient, followed by SMA20 and AC20, and Superpave20 had the smallest. The nominal maximum aggregate sizes significantly affected the resistance to permanent deformation, resistance to low-temperature cracking, and moisture sensitivity of the asphalt mixtures. Styrene–butadiene–styrene (SBS)-modified asphalt was found to significantly improve the performance of asphalt mixtures compared with ordinary asphalt.

Glioblastoma (GBM) is the most common malignant primary brain tumor with a poor 5-year survival rate. Autophagy is a conserved intracellular degradation system that plays a dual role in GBM pathogenesis and therapy. On one hand, stress can lead to unlimited autophagy to promote GBM cell death. On the other hand, elevated autophagy promotes the survival of glioblastoma stem cells against chemotherapy and radiation therapy. Ferroptosis is a type of lipid peroxidation-mediated regulated necrosis that initially differs from autophagy and other types of cell death in terms of cell morphology, biochemical characteristics, and the gene regulators involved. However, recent studies have challenged this view and demonstrated that the occurrence of ferroptosis is dependent on autophagy, and that many regulators of ferroptosis are involved in the control of autophagy machinery. Functionally, autophagy-dependent ferroptosis plays a unique role in tumorigenesis and therapeutic sensitivity. This mini-review will focus on the mechanisms and principles of autophagy-dependent ferroptosis and its emerging implications in GBM.

Summary: Alkaliptosis, a type of regulated cell death driven by intracellular alkalization, was first described in pancreatic ductal adenocarcinoma (PDAC) cells after treatment with the opioid analgesic drug JTC801. Here, we used mass-spectrometry-based drug target identification, cellular thermal shift assay, and point mutation technologies to reveal ATP6V0D1 as a direct JTC801 target that drives alkaliptosis in human PDAC cells. Functionally, the protein stability of ATP6V0D1, when mediated by JTC801, increases the interaction between ATP6V0D1 and STAT3, resulting in increased expression and activity of STAT3 for sustaining lysosome homeostasis. Consequently, the pharmacological or genetic inhibition of STAT3 restores the sensitivity of ATP6V0D1-deficient cells to alkaliptosis in vitro or in suitable mouse models. Clinically, a high expression of ATP6V0D1 correlates with prolonged survival of patients with PDAC. Together, these results illustrate a link between ATP6V0D1 and PDAC and advance our understanding of alkaliptosis in targeted therapy.

Background & Aims: Pancreatitis is characterized by acinar cell death and persistent inflammation. Ferroptosis is a type of lipid peroxidation-dependent necrosis, which is negatively regulated by glutathione peroxidase 4. We studied how trypsin, a serine protease secreted by pancreatic acinar cells, affects the contribution of ferroptosis to triggering pancreatitis. Methods: In vitro, the mouse pancreatic acinar cell line 266-6 and mouse primary pancreatic acinar cells were used to investigate the effect of exogenous trypsin on ferroptosis sensitivity. Short hairpin RNAs were designed to silence gene expression, whereas a library of 1080 approved drugs was used to identify new ferroptosis inhibitors in 266-6 cells. In vivo, a Cre/LoxP system was used to generate mice with a pancreas-specific knockout of Gpx4 (Pdx1-Cre;Gpx4flox/flox mice). Acute or chronic pancreatitis was induced in these mice (Gpx4flox/flox mice served as controls) by cerulein injections or a Lieber–DeCarli alcoholic liquid diet. Pancreatic tissues, acinar cells, and serum were collected and analyzed by histology, immunoblot, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, or immunohistochemical analyses. Results: Supraphysiological doses of trypsin (500 or 1000 ng/mL) alone did not trigger significant cell death in 266-6 cells and mouse primary pancreatic acinar cells, but did increase the sensitivity of these cells to ferroptosis upon treatment with cerulein, L-arginine, alcohol, erastin, or RSL3. Proteasome 26S subunit, non–adenosine triphosphatase 4–dependent lipid peroxidation caused ferroptosis in pancreatic acinar cells by promoting the proteasomal degradation of glutathione peroxidase 4. The drug screening campaign identified the antipsychotic drug olanzapine as an antioxidant inhibiting ferroptosis in pancreatic acinar cells. Mice lacking pancreatic Gpx4 developed more severe pancreatitis after cerulein infection or ethanol feeding than control mice. Conversely, olanzapine administration protected against pancreatic ferroptotic damage and experimental pancreatitis in Gpx4-deficient mice. Conclusions: Trypsin-mediated sensitization to ferroptotic damage increases the severity of pancreatitis in mice, and this process can be reversed by olanzapine.

Sepsis is a life-threatening clinical syndrome and one of the most challenging health problems in the world. Pathologically, sepsis and septic shock are caused by a dysregulated host immune response to infection, which can eventually lead to multiple organ failure and even death. As an adaptor transporter between the endoplasmic reticulum and Golgi apparatus, stimulator of interferon response cGAMP interactor 1 (STING1, also known as STING or TMEM173) has been found to play a vital role at the intersection of innate immunity, inflammation, autophagy, and cell death in response to invading microbial pathogens or endogenous host damage. There is ample evidence that impaired STING1, through its immune and non-immune functions, is involved in the pathological process of sepsis. In this review, we discuss the regulation and function of the STING1 pathway in sepsis and highlight it as a suitable drug target for the treatment of lethal infection.

An accurate identification of poisonous mushrooms and the confirmation of the toxins involved are both of great importance in the treatment of mushroom poisoning incidents. In recent years, cases of mushroom poisoning by Inosperma spp. have been repeatedly reported from tropical Asia. It is urgent to know the real species diversity of Inosperma in this region. In the present study, we proposed two new Inosperma species from tropical Asia, namely I. muscarium and I. hainanense. They were described based on morphology and multilocus phylogeny. Detailed descriptions, color photographs and the discussion with other closely related species of the two new taxa were provided. In addition, a comprehensive muscarine determination of these two new species using ultrahigh performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) approach has been performed. Results showed that these two species were muscarine positive, with a content of 16.03 ± 1.23 g/kg in I. muscarium and a content of 11.87 ± 3.02 g/kg in I. hainanense, much higher than the known species I. virosum. Recovery of muscarine ranged from 93.45% to 97.25%, and the average recovery is 95.56%.

Abstract Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade.

The covalent KRAS-G12C inhibitors (G12Ci) are rapidly changing the treatment landscape for advanced non-small cell lung cancer, but drug resistance remains a clinical challenge. Two recent studies have developed bispecific T cell engagers that form a link between T cells and tumor cells to selectively eliminate G12Ci-resistant cells.

Interferon gamma (IFNG/IFNγ)-induced adaptive immune resistance remains a challenge for tumor therapy. We observed that the chaperone heat shock protein 90 (HSP90) stabilizes the transcription factor signal transducer and activator of transcription 1 (STAT1), resulting in IFNγ-induced expression of immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1) and programmed death-ligand 1 (PD-L1/CD274). Pharmacological inhibition of HSP90 enhances the efficacy of programmed cell death 1 (PDCD1/PD-1) targeting immunotherapy in suitable mouse models without any toxicity.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and noncancerous cells. Recent works have revealed that the dynamic interaction between cancer cells and neuronal cells leads to perineural invasion (PNI), a clinical pathological feature of PDAC. The formation and function of PNI are dually regulated by molecular (e.g., involving neurotrophins, cytokines, chemokines, and neurotransmitters), metabolic (e.g., serine metabolism), and cellular mechanisms (e.g., involving Schwann cells, stromal cells, T cells, and macrophages). Such integrated mechanisms of PNI not only support tumor development, growth, invasion, and metastasis but also mediate the formation of pain, all of which are closely related to poor disease prognosis in PDAC. This review details the modulation, signaling pathways, detection, and clinical relevance of PNI and highlights the opportunities for further exploration that may benefit PDAC patients.

Cuproptosis is a recently recognized modality of cell death driven by intracellular copper-dependent mitochondrial stress. However, the mediators of the sterile inflammatory response to cuproptotic death are undetermined. Here, we report that high-mobility group box 1 (HMGB1), a damage-associated molecular pattern, is released by cuproptotic cells to initiate inflammation. Mechanically, copper accumulation-induced adenosine triphosphate (ATP) depletion activates AMP-activated protein kinase (AMPK) to promote HMGB1 phosphorylation, resulting in increased extracellular release. In contrast, genetic (using RNAi) or pharmacologic (using dorsomorphin) inhibition of AMPK activation limits cuproptosis and HMGB1 release. Functionally, the ability of HMGB1-deficient cuproptotic cells to promote advanced glycosylation end product-specific receptor (AGER, also known as RAGE)-dependent inflammatory cytokine production is greatly reduced. Thus, HMGB1 is a key immune mediator of cuproptosis-initiated sterile inflammation.

Summary: ACOD1 (also known as IRG1) has emerged as a regulator of immunometabolism that operates by producing metabolite itaconate. Here, we report a key role of STING1 (also known as STING and TMEM173) in mediating ACOD1 expression in myeloid cells in response to toll-like receptor (TLR) signaling. The activation of STING1 through exogenous cyclic dinucleotides (e.g., 3′3′-cGAMP) or endogenous gain-of-function mutation (e.g., V155M) enhances lipopolysaccharide-induced ACOD1 expression and itaconate production in macrophages and monocytes, whereas the deletion of STING1 blocks this process. The adaptor protein MYD88, instead of DNA sensor cyclic GMP-AMP synthase (CGAS), favors STING1-dependent ACOD1 expression. Mechanistically, MYD88 directly blocks autophagic degradation of STING1 and causes subsequent IRF3/JUN-mediated ACOD1 gene transcription. Consequently, the conditional deletion of STING1 in myeloid cells fails to produce ACOD1 and itaconate, thereby protecting mice against endotoxemia and polymicrobial sepsis. Our results, therefore, establish a direct link between TLR4 signaling and ACOD1 expression through the STING1-MYD88 complex during septic shock.

Lipid metabolism, cell death, and autophagy are interconnected processes in cells. Dysregulation of lipid metabolism can lead to cell death, such as via ferroptosis and apoptosis, while lipids also play a crucial role in the regulation of autophagosome formation. An increased autophagic response not only promotes cell survival but also causes cell death depending on the context, especially when selectively degrading antioxidant proteins or organelles that promote ferroptosis. ACSL4 is an enzyme that catalyzes the formation of long-chain acyl-CoA molecules, which are important intermediates in the biosynthesis of various types of lipids. ACSL4 is found in many tissues and is particularly abundant in the brain, liver, and adipose tissue. Dysregulation of ACSL4 is linked to a variety of diseases, including cancer, neurodegenerative disorders, cardiovascular disease, acute kidney injury, and metabolic disorders (such as obesity and non-alcoholic fatty liver disease). In this review, we introduce the structure, function, and regulation of ACSL4; discuss its role in apoptosis, ferroptosis, and autophagy; summarize its pathological function; and explore the potential implications of targeting ACSL4 in the treatment of various diseases.

To explore the mixed traffic characteristics of vehicles and aircraft on the airport surface and solve the problem of real-time conflict detection at key intersections. According to the actual taxiing procedures and airport control rules in China, this paper focus on abstracting the mixed motion process of aircraft and vehicles in the maneuvering area, defining the convergent cross-safety operation scenario. To quantify the driver’s attention to safety separation and the degree of conservatism in adjusting speed, the vehicle deceleration rate and acceleration rate are defined with α as the exponent. Under the same spacing, the vehicle deceleration rate is directly proportional to α, and α is named the vehicle safety sensitivity. At the same time, the rules of speed change of vehicles and aircraft will be designed, and a convergent operation model of aircraft and vehicles will be proposed. Based on real-time speed and separation dynamic assessment of safety and efficiency under different traffic strategies, the computer simulation results show that vehicle safety sensitivity and deceleration rules determine the sequence of vehicles and aircraft when they are passing through in the short term and can affect the proportion of mixed traffic flow in the long run. The safety probability of vehicles passing the intersection first is negatively correlated with vehicle safety sensitivity, while the safety probability of aircraft passing the intersection first is correlated positively with vehicle safety sensitivity. The efficiency of passing without conflict with mixed traffic has an inverse relationship with vehicle safety sensitivity. When the vehicle safety sensitivity takes the value in the interval [0.4, 0.6], a mixed traffic flow with higher safety and efficiency, better stability, and a balanced ratio of locomotives can be obtained.

Abstract Cell death and immune response are at the core of life. In past decades, the endoplasmic reticulum (ER) protein STING1 (also known as STING or TMEM173) was found to play a fundamental role in the production of type I interferons (IFNs) and pro-inflammatory cytokines in response to DNA derived from invading microbial pathogens or damaged hosts by activating multiple transcription factors. In addition to this well-known function in infection, inflammation, and immunity, emerging evidence suggests that the STING1-dependent signaling network is implicated in health and disease by regulating autophagic degradation or various cell death modalities (e.g., apoptosis, necroptosis, pyroptosis, ferroptosis, mitotic cell death, and immunogenic cell death [ICD]). Here, we outline the latest advances in our understanding of the regulating mechanisms and signaling pathways of STING1 in autophagy and cell death, which may shed light on new targets for therapeutic interventions.

Abstract. Pancreatic ductal adenocarcinoma is the main cause of cancer-related mortality, with a lack of effective treatments and overall survival rates far lower than other solid cancers. This clinical challenge is related to late diagnosis as well as primary or acquired resistance to therapy-induced apoptosis. Targeting nonapoptotic cell death pathways may provide alternative therapeutic strategies to overcome drug resistance. In particular, recent studies have suggested that ferroptosis, a type of iron-dependent nonapoptotic cell death, is a promising target for pancreatic ductal adenocarcinoma. Ferroptosis can be triggered by inhibiting or activating the redox or iron metabolism-related pathways, mediated by extrinsic/membrane transports (e.g., solute carrier family 7 member 11) or intrinsic/enzymes (e.g., glutathione peroxidase 4). Although the exact effector molecule remains obscure, reactive oxygen species-induced lipid peroxidation and subsequent plasma membrane damage appears to play a central role in mediating ferroptotic death. While treatment-induced ferroptosis is beneficial to suppress tumor growth, inflammation-related immunosuppression caused by ferroptotic damage may promote the occurrence of pancreatic ductal adenocarcinoma. In this review, we outline the latest knowledge about the regulation and function of ferroptosis in pancreatic tumorigenesis and therapy.

Abstract Innate immunity serves as the rapid and first-line defense against invading pathogens, and this process can be regulated at various levels, including epigenetic mechanisms. The bromodomain and extraterminal domain (BET) family of proteins consists of four conserved mammalian members (BRD2, BRD3, BRD4, and BRDT) that regulate the expression of many immunity-associated genes and pathways. In particular, in response to infection and sterile inflammation, abnormally expressed or dysfunctional BETs are involved in the activation of pattern recognition receptor (e.g., TLR, NLR, and CGAS) pathways, thereby linking chromatin machinery to innate immunity under disease or pathological conditions. Mechanistically, the BET family controls the transcription of a wide range of proinflammatory and immunoregulatory genes by recognizing acetylated histones (mainly H3 and H4) and recruiting transcription factors (e.g., RELA) and transcription elongation complex (e.g., P-TEFb) to the chromatin, thereby promoting the phosphorylation of RNA polymerase II and subsequent transcription initiation and elongation. This review covers the accumulating data about the roles of the BET family in innate immunity, and discusses the attractive prospect of manipulating the BET family as a new treatment for disease.

Ferroptosis is an iron-dependent form of oxidative cell death. In this study, the authors show that NUPR1, a stress-inducible transcription factor, may be a driver of ferroptosis resistance.

As a maintenance strategy to reduce unexpected failures and enable safe operation, condition-based maintenance (CBM) has been widely used in recent years. The maintenance decision criteria of CBM in the literature mostly originate from statistical failure data or degradation states, few of which can directly and effectively reflect the current state and analyze condition monitoring data, maintenance measures, and reliability together at the same time. In this paper, we introduce the performance margin as a decision criterion of CBM. We propose a condition-based maintenance optimization method using performance margin. Considering a CBM optimization problem for a degrading and periodically inspected component, a newly developed performance margin degradation model is established when three different maintenance measures become involved. Maintenance measure effect factors, maintenance decision vectors, and maintenance measure threshold vectors are developed to update the degradation model. And to build a maintenance optimization model, both cost and loss related to maintenance decision problems and reliability obtained by performance margin have been taken into consideration. Finally, a numerical example is provided to illustrate the proposed optimization method.

This paper copes with a joint Location-Allocation-Inventory problem in a three-echelon base-level spare part support system with epistemic uncertainty in uncertain demands of bases. The aim of the paper is to propose an optimization model under the uncertainty theory to minimize the total cost, which integrates crucial characterizations of the inventory control decisions and the location-allocation scheme arrangement under a periodic review order-up-to-S (T, S) policy. Uncertainty theory is introduced in this paper to characterize epistemic uncertainty, where demands are treated as uncertain variables and stockout loss is represented by value-at-risk in uncertain measurement. To solve the original uncertain optimization model, an equivalent deterministic model is derived and addressed by an improved bilevel genetic algorithm. Moreover, the proposed models and algorithm are encoded into numerical examples for supply chain programming. The results highlight the applicability of the model and the algorithm’s effectiveness in approaching the optimal solution compared with traditional genetic algorithm. Sensitivity analyses are further made for the impacts of review time and inventory capacity on different cost components.

Ferroptosis is an iron-dependent mechanism of cell death. In this mouse study, the authors show that diets high in iron or depletion of the antioxidant Gpx4 potentiates pancreatic damage and tumour formation by activating the DNA damage pathway and recruiting macrophages to the pancreas.

Stimulator of interferon response cGAMP interactor 1 (STING1), also known as TMEM173, is an immune adaptor protein that governs signal crosstalk that is implicated in many physiological and pathological processes. Although it has been established that STING1 traffics from the endoplasmic reticulum (ER) to Golgi apparatus (Golgi) upon DNA-triggered activation, emerging evidence reveals that STING1 can be transported to different organelles, which dictate its immune-dependent (e.g., the production of type I interferons and pro-inflammatory cytokines) and -independent (e.g., the activation of autophagy and cell death) functions. In this brief review, we outline the roles of STING1 in different organelles (including the ER, ER-Golgi intermediate compartment, Golgi, mitochondria, endosomes, lysosomes, and nucleus) and discuss the potential relevance of these roles to diseases and pharmacological interventions.

Benzalkonium chloride (BC) is widely used for disinfection in food industry. However, prolonged exposure to BC may lead to the emergence of BC adapted strains of Listeria monocytogenes, an important foodborne pathogen. Until now, two communication systems, the LuxS/AI-2 system and the Agr system, have been identified in L. monocytogenes. This study aimed to investigate the role of communication systems in BC adaptation and the effect of BC adaptation on two communication systems and the communication-controlled behaviors in L. monocytogenes. Results demonstrated that the Agr system rather than the LuxS system plays an important role in BC adaptation of L. monocytogenes. Neither luxS expression nor AI-2 production was affected by BC adaptation. On the other hand, the expression of the agr operon and the activity of the agr promoter were significantly increased after BC adaptation. BC adaptation enhanced biofilm formation of L. monocytogenes. However, swarming motility was reduced by BC adaptation. Data from qRT-PCR showed that flagella-mediated motility-related genes (flaA, motA, and motB) were downregulated in BC adapted strains. BC adaptation increased the ability of L. monocytogenes to adhere to and invade Caco-2 cells but did not affect the hemolytic activity. Compared with the wild-type strains, the expression levels of virulence genes prfA, plcA, mpl, actA, and plcB increased more than 2-fold in BC adapted strains; however, lower than 2-fold changes in the expression of hemolysis-associated gene hly were observed. Our study suggests that BC adaptation could increase the expression of the Agr system and enhance biofilm formation, invasion, and virulence of L. monocytogenes, which brings about threats to food safety and public health. Therefore, effective measures should be taken to avoid the emergence of BC adapted strains of L. monocytogenes.

3D printed medical titanium alloy has shown great advantages in manufacturing complex and personalized scaffolds for tissue engineering. To promote the repair of bone defects, fabrication of a scaffold with high accuracy and excellent cell behaviors is required. However, the partially melted or un-melted powders must be removed in the post-process. In this study, the effects of unfused metal powders on the biocompatibility of 3D printed Ti alloy scaffolds were analyzed by co-culture with MC3T3-E1 cells and RAW 264.7 cells, and the surface treatment strategy was proposed. Results showed that surface treatment can enhance the biocompatibility of the 3D printed Ti alloy scaffolds. The vitro tests with MC3T3-E1 cells demonstrated that the ETi5Cu (etched Ti5Cu) showed the better cell proliferation and osteogenic potential, and the lower cell apoptosis rates. Moreover, higher concentration of powders showed inhibitory effects on cytocompatibility and osteogenesis of MC3T3-E1 cells, and promoted the polarization of macrophages to M1 type. In summary, the removal of metal powders on the 3D printed scaffolds plays an important role in the biological performance, which provided a promising strategy for the application of Ti implants.

Summary: Background: Spatialized HIV genetic transmission networks can help understand dynamic changes of HIV-1 at the regional level. This study aimed to combine genomic, epidemiological, and spatial data to investigate the patterns of the HIV-1 epidemic at both individual and regional levels among people living with HIV (PLWH) with virological failure of antiretroviral therapy (ART). Methods: We evaluated the transmission patterns of 5,790 PLWH with identified pol sequences of the five main HIV-1 subtypes (B, CRF08_BC, CRF85_BC, CRF07_BC, and CRF01_AE) in Sichuan Province, China. A phylogenetic cluster was defined as a group of sequences with genetically similar HIV strains, with all phylogenetic clusters forming an HIV-1 genetic transmission network for each subtype. Logistic regression was used to identify the potential risk factors for phylogenetic clustering. Spatial analysis was applied to demonstrate the geographic patterns of phylogenetic clustering rates; intensity matrices and flow maps were made to demonstrate the intensity of transmission within and between cities. Findings: There were 2,159 (37.3%) of 5,790 PLWH, distributed in 452 phylogenetic clusters. Some individual clinical and behavioral factors were associated with phylogenetic clustering, including a viral load of >50,000 copies/ml (OR=1.16, 95%CI=1.02-1.33), infection of other sexually transmitted diseases (OR=1.38, 95%CI=1.12-1.69), and ≥5 non-marital sexual partners (OR=1.25, 95%CI=1.03-1.51), while >3 years of treatment since the initial ART was associated with less likelihood of phylogenetic clustering (OR=0.82, 95%CI=0.70-0.97). The phylogenetic clustering rates varied regionally and were highest in the central region of Sichuan, especially for subtype CRF08_BC. The significant spatial clusters of high and low phylogenetic clustering rates were detected in the east (Dazhou for B; Zigong and Luzhou for CFR08_BC) and west (Yaan and Ganzi for CRF07_BC), respectively. The proportion of intercity transmission varied across cities from 0.14 (Yibin) and 1.00 (Ganzi). Stronger intercity transmission than average existed between some cities, e.g., between Deyang and Neijiang. CRF07_BC was the most widespread subtype between cities, and CRF85_BC (a novel HIV-1 subtype) showed strong intercity transmission (e.g., between Yibin and Guangan). Interpretation: The phylogenetic clustering rates and intercity connections of HIV-1 have varied geographically, possibly due to varying human mobility, traffic convenience, and economic activities. Our findings enhanced the understanding of the dynamics of HIV-1 transmission from individual to city level, and demonstrated a novel cross-disciplinary (epidemiological, genetic, and spatial) approach by which we identified high-risk populations and areas. Our approach could be adapted to other regions for precision public health interventions. Funding: The National Natural Science Foundation of China, Sichuan Science and Technology Program, Project of Sichuan Provincial Health Committee, Science and Technology Project of Sichuan Provincial Health Committee, Wuhan University 351 Talent Program, 2020, and the International Institute of Spatial Lifecourse Epidemiology (ISLE).

Abstract. Ferroptosis is a oxidative damage-dependent form of regulated cell death that has become an emerging target for disease prevention and treatment. Here, we show that dual-specificity phosphatase 1 (DUSP1), a phosphatase playing multiple roles in stress-signaling pathways, is a new repressor of ferroptosis in human pancreatic cancer cells. Several classical ferroptosis activators (eg, erastin and RSL3) induce the expression of DUSP1, but not other members of DUSP, which depends on extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Moreover, shRNA-mediated DUSP1 knockdown increases the anticancer activity of ferroptosis activators in pancreatic cancer cells through activating lipid peroxidation in vitro and in vivo. Importantly, DUSP1-mediated autophagy is responsible for lipid peroxidation-mediated ferroptotic cell death. Thus, the DUSP1-related ferroptotic pathway may represent a potential target for therapeutic intervention in pancreatic cancer.

The rolling bearing is an important part of rotary machineries and the health state monitoring is currently a hot research topic. There are four typical failure modes of a rolling bearing: the inner race failure, the outer race failure, the rolling element failure and the support frame failure. Based on the principle of the coherent demodulation, a new method for rolling bearing fault diagnosis is proposed in this work. This method establishes a coherent demodulator simulation model which is usually adopted in the field of radio communications. The proposed method first demodulates the vibration signal with coherent demodulation principle. Then, the characteristic frequencies related the different failures modes are extracted to obtain the fault characteristic amplitudes, to diagnose the ongoing failure mode. The bearing fault data from the Case Western Reserve University Bearing Test Center is taken as an example to verify and analyze the effectiveness of the proposed method. The results show that this method can accurately diagnose the corresponding failure mode with different locations and sizes.

Pancreatic cancer is a devastating gastrointestinal cancer, characterized by late diagnosis, low treatment success rate, and poor survival prognosis. The most common pathological type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which is mainly driven by the K-Ras oncogene. Ferroptosis was originally described as Ras-dependent cell death, but is now defined as lipid peroxidation-mediated regulated necrosis, accompanied by excessive activation of the autophagy degradation pathway and limited membrane repair capacity. The impaired ferroptotic pathway is involved in many types of cancer, including PDAC. On the one hand, the chronic inflammation caused by ferroptotic damage contributes to the formation of K-Ras-driven PDAC. On the other hand, drug-induced ferroptosis is an emerging strategy to suppress tumor growth in established PDAC. In this mini-review, we outline the core process of ferroptosis, discuss the regulatory mechanism of ferroptosis in PDAC, and highlight some of the challenges of targeting ferroptosis in PDAC therapy.

Pelvic organ prolapse (POP) is a frequent chronic illness, which severely affects women's quality of life. In this work, four composite electrospun scaffold were developed for POP using decellularized amniotic matrix (dHAM) and biocompatible polymers like poly(ε-caprolactone) (PCL) and poly(lactide-co-glycolide) polymers (PLGA). Tests to assess the physicochemical characterizations of the novel scaffold were performed. The results showed that scaffolds had good hydrophilicity, suitable degradation time and mechanical properties for pelvic floor regeneration. Cell tests with human umbilical cord mesenchymal stem cells (hUC-MSCs) showed that scaffolds were non-cytotoxic. In conclusion, composite electrospun scaffold containing dHAM showed promising potential for POP.