Nrf2/ASPM axis regulated vasculogenic mimicry formation in hepatocellular carcinoma under hypoxia.

BACKGROUND: Hypoxic microenvironment is a common feature of most solid tumors including hepatocellular carcinoma (HCC). Vasculogenic mimicry (VM) formation by tumor cells could provide blood supply to tumor cells under hypoxia. NFE2 like basic leucine zipper (bZIP) transcription factor 2 (Nrf2), a regulator of cellular homeostasis, may promote tumor progression in the hypoxic conditions. However, the role and regulatory mechanisms of Nrf2 in HCC are not fully elucidated. METHODS: Nrf2 and assembly factor for spindle microtubules (ASPM) expression modulations were conducted by lentiviral transfections. Western blot, immunofluorescence, ChIP-qPCR, dual-luciferase reporter gene assay, flow cytometry, RNA sequencing, multiple bioinformatics databases analysis, cell function assays in vitro, mouse model in vivo and human HCC tissues were employed to assess the effect of Nrf2/ASPM axis on HCC progression under hypoxia. RESULTS: Nrf2 and ASPM expression facilitated epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) feature, and VM formation of HCC cells under hypoxia. Furthermore, Nrf2-regulated ASPM expression, via binding directly to the promoter region of ASPM and transcriptionally promoting ASPM expression. ASPM re-expression in Nrf2 knockdown cells or ASPM knockdown in Nrf2 overexpression cells reversed the cellular function caused by Nrf2. Meantime, retinol metabolism pathway was disrupted following abnormal ASPM expression. Nrf2/ASPM axis in murine models accelerated tumor growth and VM, corroborating in vitro findings. All-trans retinoic acid treatment reversed stemness and VM of HCC cells in vitro and in vivo. Clinically, Nrf2 and ASPM expressions were related to poor prognosis of HCC patients. CONCLUSIONS: Nrf2 drives EMT, CSCs characteristics and VM in HCC under hypoxia through the modulation of ASPM. Retinol metabolism pathway was dysregulated in HCC cells with ASPM overexpression. Nrf2/ASPM axis and related pathway provided potential therapeutic target for HCC.

Pyrrole adducts mediated mitochondrial dysfunction activates SARM1-dependent axon degeneration in 2,5-hexanedione-induced neuropathy.

2,5-hexanedione (HD) is the γ-diketone metabolite of industrial organic solvent n-hexane, primarily responsible for n-hexane neurotoxicity. Previous studies have shown that the formation of pyrrole adducts (PAs) is crucial for the toxic axonopathy induced by HD. However, the exact mechanism underlying PAs-induced axonal degeneration remains unclear. Recently, Sterile α and toll/interleukin 1 receptor motif-containing protein 1 (SARM1) has been identified as the central executor of axon degeneration. This study was designed to investigate the role of SARM1-mediated axon degeneration in rats exposed to HD. Furthermore, the causal relationship between PAs and SARM1-mediated axon degeneration was further explored using Sarm1 KO mice. Our findings suggest that HD causes axon degeneration and neuronal loss in animals. Mechanistic studies revealed that HD activates SARM1-dependent axonal degeneration machinery. In contrast, Sarm1 KO attenuates motor dysfunction and rescues neuron loss following HD exposure. Interestingly, the PAs formed by the binding of HD to proteins primarily accumulate on mitochondria, leading to mitochondrial dysfunction. This dysfunction serves as an upstream event in HD-induced nerve injuries. Our findings highlight the crucial role of PAs formation in the major pathological changes during n-hexane poisoning, providing a potential therapeutic target for n-hexane neuropathy.

NLRP3 inflammasome activation triggers severe inflammatory liver injury in N, N-dimethylformamide-exposed mice.

N,N-dimethylformamide (DMF) is a widely utilized chemical solvent with various industrial applications. Previous studies have indicated that the liver is the most susceptible target to DMF exposure, whereas the underlying mechanisms remain to be elucidated. This study aimed to investigate the role of NLRP3 inflammasome in DMF-induced liver injury in mice by using two NLRP3 inflammasome inhibitors, Nlrp3-/- mice, Nfe2l2-/- mice, and a macrophage-depleting agent. RNA sequencing revealed that endoplasmic reticulum (ER) stress and NLRP3 inflammasome-associated pathways were activated in the mouse liver after acute DMF exposure, which was validated by Western blotting. Interestingly, DMF-induced liver injury was effectively suppressed by two inflammasome inhibitors, MCC950 and Dapansutrile. In addition, knockout of Nlrp3 markedly attenuated DMF-induced liver injury without affecting the metabolism of DMF. Furthermore, silencing Nfe2l2 aggravated the liver injury and the NLRP3 inflammasome activation in mouse liver. Finally, the depletion of hepatic macrophages by clodronate liposomes significantly reduced the liver damage caused by DMF. These results suggest that NLRP3 inflammasome activation is the upstream molecular event in the development of acute liver injury induced by DMF.

Desmoglein 2 and desmocollin 2 depletions promote malignancy through distinct mechanisms in triple-negative and luminal breast cancer.

BACKGROUND: Aberrant expressions of desmoglein 2 (Dsg2) and desmocollin 2(Dsc2), the two most widely distributed desmosomal cadherins, have been found to play various roles in cancer in a context-dependent manner. Their specific roles on breast cancer (BC) and the potential mechanisms remain unclear. METHODS: The expressions of Dsg2 and Dsc2 in human BC tissues and cell lines were assessed by using bioinformatics analysis, immunohistochemistry and western blotting assays. Wound-healing and Transwell assays were performed to evaluate the cells' migration and invasion abilities. Plate colony-forming and MTT assays were used to examine the cells' capacity of proliferation. Mechanically, Dsg2 and Dsc2 knockdown-induced malignant behaviors were elucidated using western blotting assay as well as three inhibitors including MK2206 for AKT, PD98059 for ERK, and XAV-939 for ß-catenin. RESULTS: We found reduced expressions of Dsg2 and Dsc2 in human BC tissues and cell lines compared to normal counterparts. Furthermore, shRNA-mediated downregulation of Dsg2 and Dsc2 could significantly enhance cell proliferation, migration and invasion in triple-negative MDA-MB-231 and luminal MCF-7 BC cells. Mechanistically, EGFR activity was decreased but downstream AKT and ERK pathways were both activated maybe through other activated protein tyrosine kinases in shDsg2 and shDsc2 MDA-MB-231 cells since protein tyrosine kinases are key drivers of triple-negative BC survival. Additionally, AKT inhibitor treatment displayed much stronger capacity to abolish shDsg2 and shDsc2 induced progression compared to ERK inhibition, which was due to feedback activation of AKT pathway induced by ERK inhibition. In contrast, all of EGFR, AKT and ERK activities were attenuated, whereas ß-catenin was accumulated in shDsg2 and shDsc2 MCF-7 cells. These results indicate that EGFR-targeted therapy is not a good choice for BC patients with low Dsg2 or Dsc2 expression. Comparatively, AKT inhibitors may be more helpful to triple-negative BC patients with low Dsg2 or Dsc2 expression, while therapies targeting ß-catenin can be considered for luminal BC patients with low Dsg2 or Dsc2 expression. CONCLUSION: Our finding demonstrate that single knockdown of Dsg2 or Dsc2 could promote proliferation, motility and invasion in triple-negative MDA-MB-231 and luminal MCF-7 cells. Nevertheless, the underlying mechanisms were cellular context-specific and distinct.

PTGER3 knockdown inhibits the vulnerability of triple-negative breast cancer to ferroptosis.

Prostaglandin E receptor 3 (PTGER3) is involved in a variety of biological processes in the human body and is closely associated with the development and progression of a variety of cancer types. However, the role of PTGER3 in triple-negative breast cancer (TNBC) remains unclear. In the present study, low PTGER3 expression was found to be associated with poor prognosis in TNBC patients. PTGER3 plays a crucial role in regulating TNBC cell invasion, migration, and proliferation. Upregulation of PTGER3 weakens the epithelial-mesenchymal phenotype in TNBC and promotes ferroptosis both in vitro and in vivo by repressing glutathione peroxidase 4 (GPX4) expression. On the other hand, downregulation of PTGER3 inhibits ferroptosis by increasing GPX4 expression and activating the PI3K-AKT pathway. Upregulation of PTGER3 also enhances the sensitivity of TNBC cells to paclitaxel. Overall, this study has elucidated critical pathways in which low PTGER3 expression protects TNBC cells from undergoing ferroptosis, thereby promoting its progression. PTGER3 may thus serve as a novel and promising biomarker and therapeutic target for TNBC.

Elevated intracellular Ca2+ functions downstream of mitodysfunction to induce Wallerian-like degeneration and necroptosis in organophosphorus-induced delayed neuropathy.

Neurotoxic organophosphorus compounds can induce a type of delayed neuropathy in humans and sensitive animals, known as organophosphorus-induced delayed neuropathy (OPIDN). OPIDN is characterized by axonal degeneration akin to Wallerian-like degeneration, which is thought to be caused by increased intra-axonal Ca2+ concentrations. This study was designed to investigate that deregulated cytosolic Ca2+ may function downstream of mitodysfunction in activating Wallerian-like degeneration and necroptosis in OPIDN. Adult hens were administrated a single dosage of 750 mg/kg tri-ortho-cresyl phosphate (TOCP), and then sacrificed at 1 day, 5 day, 10 day and 21 day post-exposure, respectively. Sciatic nerves and spinal cords were examined for pathological changes and proteins expression related to Wallerian-like degeneration and necroptosis. In vitro experiments using differentiated neuro-2a (N2a) cells were conducted to investigate the relationship among mitochondrial dysfunction, Ca2+ influx, axonal degeneration, and necroptosis. The cells were co-administered with the Ca2+-chelator BAPTA-AM, the TRPA1 channel inhibitor HC030031, the RIPK1 inhibitor Necrostatin-1, and the mitochondrial-targeted antioxidant MitoQ along with TOCP. Results demonstrated an increase in cytosolic calcium concentration and key proteins associated with Wallerian degeneration and necroptosis in both in vivo and in vitro models after TOCP exposure. Moreover, co-administration with BATPA-AM or HC030031 significantly attenuated the loss of NMNAT2 and STMN2 in N2a cells, as well as the upregulation of SARM1, RIPK1 and p-MLKL. In contrast, Necrostatin-1 treatment only inhibited the TOCP-induced elevation of p-MLKL. Notably, pharmacological protection of mitochondrial function with MitoQ effectively alleviated the increase in intracellular Ca2+ following TOCP and mitigated axonal degeneration and necroptosis in N2a cells, supporting mitochondrial dysfunction as an upstream event of the intracellular Ca2+ imbalance and neuronal damage in OPIDN. These findings suggest that mitochondrial dysfunction post-TOCP intoxication leads to an elevated intracellular Ca2+ concentration, which plays a pivotal role in the initiation and development of OPIDN through inducing SARM1-mediated axonal degeneration and activating the necroptotic signaling pathway.

High-fat diet exacerbates 1-Bromopropane-induced loss of dopaminergic neurons in the substantia nigra of mice through mitochondrial damage associated necroptotic pathway.

In recent years, accumulating evidence supports that occupational exposure to solvents is associated with an increased incidence of Parkinson's disease (PD) among workers. The neurotoxic effects of 1-bromopropane (1-BP), a widely used new-type solvent, are well-established, yet data on its relationship with the etiology of PD remain limited. Simultaneously, high-fat consumption in modern society is recognized as a significant risk factor for PD. However, whether there is a synergistic effect between a high-fat diet and 1-BP exposure remains unclear. In this study, adult C57BL/6 mice were fed either a chow or a high-fat diet for 18 weeks prior to 12-week 1-BP treatment. Subsequent neurobehavioral and neuropathological examinations were conducted to assess the effects of 1-BP exposure on parkinsonian pathology. The results demonstrated that 1-BP exposure produced obvious neurobehavioral abnormalities and dopaminergic degeneration in the nigral region of mice. Importantly, a high-fat diet further exacerbated the impact of 1-BP on motor and cognitive abnormalities in mice. Mechanistic investigation revealed that mitochondrial damage and mtDNA release induced by 1-BP and high-fat diet activate NLRP3 and cGAS-STING pathway- mediated neuroinflammatory response, and ultimately lead to necroptosis of dopaminergic neurons. In summary, our study unveils a potential link between chronic 1-BP exposure and PD-like pathology with motor and no-motor defects in experimental animals, and long-term high-fat diet can further promote 1-BP neurotoxicity, which underscores the pivotal role of environmental factors in the etiology of PD.

Macrophage AHR-TLR4 cross-talk drives p-STAT3 (Ser727)-mediated mitochondrial oxidative stress and upregulates IDO/ICAM-1 in the steatohepatitis induced by aflatoxin B1.

Aflatoxin B1 (AFB1) is a major mycotoxin contaminant showing in the environment and foods. In this study, the molecular initiating events (MIEs) of AFB1-induced steatohepatitis were explored in mice and human cell model. We observed dose-dependent steatohepatitis in the AFB1-treated mice, including triglyceride accumulation, fibrotic collagen secretion, enrichment of CD11b + and F4/80+ macrophages/Kupffer cells, cell death, lymphocytes clusters and remarkable atrophy areas. The gut barrier and gut-microbiota were also severely damaged after the AFB1 treatment and pre-conditioned colitis in the experimental mice aggravated the steatohepatitis phenotypes. We found that macrophages cells can be pro-inflammatorily activated to M1-like phenotype by AFB1 through an AHR/TLR4/p-STAT3 (Ser727)-mediated mitochondrial oxidative stress. The phenotypes can be rescued by AHR inhibitors in the mice model and human cell model. We further showed that this signaling axis is based on the cross-talk interaction between AHR and TLR4. Gene knock-up experiment found that the signaling is dependent on AFB1 ligand-binding with AHR, but not protein expressions of TLR4. The signaling elevated NLRP3 and two immune metabolic enzymes ICAM-1 and IDO that are associated with macrophage polarization. Results from intervention experiments with natural anti-oxidant and AHR inhibitor CH223191 suggest that the macrophage polarization may rely on AHR and ROS. Our study provides novel and critical references to the food safety and public health regulation of AFB1.

Cyclin-dependent Kinase 5 and Neurodegenerative Diseases.

Neurodegenerative diseases are a group of diseases characterized by the progressive loss of neurons, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. These diseases have a high incidence and mortality rate globally, placing a heavy burden on patients and their families. The pathogenesis of neurodegenerative diseases is complex, and there are no effective treatments at present. Cyclin-dependent kinase 5 is a proline-directed serine/threonine protein kinase that is closely related to the development and function of the nervous system. Under physiological conditions, it is involved in regulating the process of neuronal proliferation, differentiation, migration, and synaptic plasticity. Moreover, there is increasing evidence that cyclin-dependent kinase 5 also plays an important role in the pathogenesis of neurodegenerative diseases. In this review, we address the biological characteristics of cyclin-dependent kinase 5 and its role in neurodegenerative diseases. In particular, this review highlights the underlying mechanistic linkages between cyclin-dependent kinase 5 and mitochondrial dysfunction, oxidative stress and neuroinflammation in the context of neurodegeneration. Finally, we also summarize the currently available cyclin-dependent kinase 5 inhibitors and their prospects for the treatment of neurodegenerative diseases. Taken together, a better understanding of the molecular mechanisms of cyclin-dependent kinase 5 involved in neurodegenerative diseases can lead to the development of new strategies for the prevention and treatment of these devastating diseases.

Deregulated mitochondrial quality control, the heel of Achilles in elucidating the role of autophagy in SARM1-mediated axon degeneration.

Autophagic dysfunction in neurodegenerative diseases is being extensively studied, yet the exact mechanism of macroautophagy/autophagy in axon degeneration is still elusive. A recent study by Kim et al. links autophagic stress to the sterile α and toll/interleukin 1 receptor motif containing protein 1 (SARM1)-dependent core axonal degeneration program, providing a new insight into the role of autophagy in axon degeneration. In the classical Wallerian axon degeneration model of axotomy, disruption of axonal transport destroys the coordinated activity of pro-survival and pro-degenerative factors in the axoplasm and activates the NADase activity of SARM1, thus triggering the axonal self-destruction program. However, the mechanism for SARM1 activation in the chronic neurodegenerative disorders is more complex. Mitochondrial defects and oxidative stress contribute to the activation of SARM1, while mitophagy can inhibit mitochondrial dysfunction and promote the clearance of SARM1 on mitochondria, thus protecting against neuronal degeneration. Therefore, in-depth elucidation of the underlying mechanisms of mitophagy during axonal degeneration can help develop promising strategies for the prevention and treatment of various neurodegenerative disorders.

Aberrant mitochondrial aggregation of TDP-43 activated mitochondrial unfolded protein response and contributed to recovery of acetaminophen induced acute liver injury.

Mitochondrial dysfunction is a key pathological event in the acute liver injury following the overdose of acetaminophen (APAP). Calpain is the calcium-dependent protease, recent studies demonstrate that it is involved in the impairment of mitochondrial dynamics. The mitochondrial unfolded protein response (UPRmt) is commonly activated in the context of mitochondrial damage following pathological insults and contributes to the maintenance of the mitochondrial quality control through regulating a wide range of gene expression. More importantly, it is reported that abnormal aggregation of TDP-43 in mitochondria induced the activation of UPRmt. However, whether it is involved in APAP induced-hepatotoxicity remains unclear. In the present study, C57/BL6 mice were given 300 mg/kg APAP to establish a time-course model of acute liver injury. Furthermore, Calpeptin, the specific inhibiter of calpains, was used to conduct the intervention experiment. Our results showed, APAP exposure produced severe liver injury. Moreover, TDP-43 was obviously accumulated within mitochondria whereas mitochondrial protease LonP1 was significantly decreased. However, these changes exhibited significant recovery at 48 h. By contrast, the mitochondrial protease ClpP and chaperone mtHSP70 and HSP60 were consistently increased, which supported the UPRmt was activated to promote protein homeostasis. Further investigation revealed that calpain-mediated cleavage of TDP-43 could promote the accumulation of TDP-43 in mitochondria compartment, thereby facilitating the activation of UPRmt. Additionally, Calpeptin pretreatment not only protected against APAP-induced liver injury, but also suppressed the formation of TDP-43 aggregates and the activation of UPRmt. Taken together, our findings indicated that in APAP-induced acute liver injury, calpain-mediated cleavage of TDP43 caused its aberrant aggregation on the mitochondria. As a stress-protective response, the induction of UPRmt contributed to the recovery of mitochondrial function.

Chronic di(2-ethylhexyl) phthalate exposure at environmental-relevant doses induces osteoporosis by disturbing the differentiation of bone marrow mesenchymal stem cells.

Di(2-ethylhexyl) phthalate (DEHP) is a widely used plastic additive with persistent characteristics in the environment. This study was designed to investigate the detrimental effects of chronic DEHP exposure at environmental-relevant doses on bone metabolism and the underlying mechanisms. It was found that exposure to 25 µg/kg bw and 50 µg/kg bw DEHP for 29 weeks led to a reduction of whole-body bone mineral density (BMD), femur microstructure damage, decreased femur new bone formation, and increased femur bone marrow adipogenesis in C57BL/6 female mice, which was not observed in mice exposed to 5000 µg/kg bw DEHP. Further in vitro study showed that DEHP treatment robustly promoted adipogenic differentiation and suppressed osteogenic differentiation of the bone marrow mesenchymal stem cells (BMSCs). Mechanistically, DEHP exposure resulted in elevated expressions of DYRK1B, CDK5, PPARγ, and p-PPARγSer273 in both bone tissue and BMSCs. Interestingly, co-IP analysis showed potential interactions among DYRK1B, PPARγ, and CDK5. Lastly, antagonists of DYRK1B and CDK5 effectively alleviated the BMSCs differentiation disturbance induced by DEHP. These results suggest that DEHP may disturb the BMSCs differentiation by upregulating the PPARγ signaling which may be associated with the activation of DYRK1B and CDK5.

Interactive transgenerational effects of parental co-exposure to prochloraz and chlorpyrifos: Disruption in multiple biological processes and induction of genotoxicity.

The application of different types of pesticides can result in the coexistence of multiple pesticide residues in our food and the environment. This can have detrimental effects on the health of offspring across generations when parents are exposed to these pesticides. Therefore, it is imperative to understand the long-term effects that can be inherited by future generations when assessing the risks associated with pesticides. To study the genotoxic effects of commonly used pesticides, prochloraz (PRO) and chlorpyrifos (CHL), and assess whether their combined exposures have a different toxic effect, we modeled the transgenerational effects of parental (F0-generation) and/or offspring (F1-generation) exposures on zebrafish embryos in the F1-generation. Following the exposures, we proceeded to assess the impacts of these exposures on a range of biological processes in F1-generation zebrafish. Our results revealed that exposure to PRO and CHL altered multiple biological processes, such as inflammation, apoptosis, oxidative stress, and thyroid hormone synthesis, and detoxification system, providing molecular targets for subsequent studies on toxicity mechanisms. Notably, our study also found that the biological processes of F1-generation zebrafish embryos were altered even though they were not exposed to any pesticide when F0-generation zebrafish were exposed to PRO or CHL, suggesting potential genotoxicity. In conclusion, we provided in-vivo evidence that parental exposure to PRO and/or CHL can induce genotoxicity in the offspring. Moreover, we observed that the toxic effects resulting from the combined exposure were interactive, suggesting a potential synergistic impact on the offspring.

Environmental surveillance in Jinan city of East China (2014-2022) reveals improved air quality but remained health risks attributable to PM2.5-bound metal contaminants.

PM2.5-bound metal contaminants are associated with multiple chronic diseases in human. At global level, the contamination status has not been well controlled yet. Here we report findings from a long-term air pollution surveillance in Jinan city of Shandong, China. During 2014-2022, the dynamics and trends of PM2.5-bound heavy metal contaminants were monitored in an industrial area and a downtown area. The surveillance targets included: antimony (Sb), aluminum (Al), arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr), mercury (Hg), lead (Pb), manganese (Mn), nickel (Ni), selenium (Se). The human exposure and health risks were calculated and we found that the health risks of most contaminants showed peak values in autumn and winter. But Al, Mn, Hg and Be were found to result in highest health risk in spring or summer in the downtown area. In the industrial area we identified 100% alarming health index >1 (ranged from 1.12 to 3.35) in autumn and winter. In winter the total non-carcinogenic HI was all above 1 (peak value 2.21). Mn and As together posed >85% non-carcinogenic risk. As and Cd were ranked as major drivers of carcinogenic risks (5.84 × 10-6 and 2.78 × 10-6). Pd and Cd both showed non-negligible environmental levels but risk assessment model for their air-exposure associated non-carcinogenic risks are not yet available. This study updates air pollution data and status for air pollution status in China. This study provides valuable 9 year long-term reference to experimental and field studies in the related fields.

High-fat diet exacerbated motor dysfunction via necroptosis and neuroinflammation in acrylamide-induced neurotoxicity in mice.

Health risks associated with acrylamide (ACR) or high-fat diet (HFD) exposure alone have been widely concerned in recent years. In a realistic situation, ACR and HFD are generally co-existence, and both are risk factors for the development of neurological diseases. The purpose of the present study was to investigate the combined effects of ACR and HFD on the motor nerve function. As a result, neurobehavioral tests and Nissl staining disclosed that long-term HFD exacerbated motor dysfunction and the damage of spinal cord motor neurons in ACR-exposed mice. Co-exposure of ACR and HFD resulted in morphological changes in neuronal mitochondria of the spinal cord, a significantly reduced mitochondrial subunits NDUFS1, UQCRC2, and MTCO1, released the mitochondrial DNA (mtDNA) into the cytoplasm, and promoted the production of reactive oxygen species (ROS). Combined exposure of HFD and ACR activated the calpain/CDK5/Drp1 axis and caused the mitochondrial excessive division, ultimately increasing MLKL-mediated necroptosis in spinal cord motor neurons. Meanwhile, HFD significantly exacerbated ACR-induced activation of NFkB, NLRP3 inflammasome, and cGAS-STING pathway. Taken together, our findings demonstrated that combined exposure of ACR and HFD aggravated the damage of spinal cord motor neurons via neuroinflammation and necroptosis signaling pathway, pointing to additive effects in mice than the individual stress effects.

UTP23 Functions in Breast Cancer Progression and Predicts Poor Prognosis of Luminal a Breast Cancer.

BACKGROUND: Luminal A breast cancer is the most common molecular subtype of breast cancer. Exploring biomarkers to identify luminal A breast cancer patients at high risk of recurrence and metastasis has important clinical significance. UTP23 is a component of ribosomal small-subunit processome, which is involved in ribosome synthesis and RNA maturation. The role of UTP23 in breast cancer has not been reported. METHODS: TCGA-BRCA data, LinkedOmics, STRING, Metascape and ssGSEA were used to analyze UTP23 expression in breast cancer and evaluate prognosis. Quantitative real-time PCR, western blot and in vitro cell experiment were used to demonstrate the role of UTP23 in breast cancer. RESULTS: UTP23 showed abnormally high expression in multiple cancers and was associated with poor prognosis. UTP23 was associated with T stage, lymph node metastasis, race, histological type, molecular subtypes and survival status in breast cancer. Importantly, UTP23 was significantly associated with poor OS in luminal A or early breast cancer, not in non-luminal A or advanced breast cancer. UTP23 expression was significantly correlated with immune cells infiltration. Enrichment analysis suggested that UTP23 might regulate cell cycle and cell division. Bioinformatics analysis showed DCAF13 might be downstream factor of UTP23. UTP23 expression promoted MCF-7 cells proliferation, migration and invasion possibly through regulating DCAF13 expression. CONCLUSIONS: UTP23 may function in breast cancer progression. The elevated UTP23 may be a potential prognostic biomarker for luminal A or early breast cancer.

Mitophagy suppresses motor neuron necroptotic mitochondrial damage and alleviates necroptosis that converges to SARM1 in acrylamide-induced dying-back neuropathy.

Acrylamide (ACR), a common industrial ingredient that is also found in many foodstuffs, induces dying-back neuropathy in humans and animals. However, the mechanisms remain poorly understood. Sterile alpha and toll/interleukin 1 receptor motif-containing protein 1 (SARM1) is the central determinant of axonal degeneration and has crosstalk with different cell death programs to determine neuronal survival. Herein, we illustrated the role of SARM1 in ACR-induced dying-back neuropathy. We further demonstrated the upstream programmed cell death mechanism of this SARM1-dependent process. Spinal cord motor neurons that were induced to overexpress SARM1 underwent necroptosis rather than apoptosis in ACR neuropathy. Mechanically, non-canonical necroptotic pathways mediated mitochondrial permeability transition pore (mPTP) opening, reactive oxygen species (ROS) production, and mitochondrial fission. What's more, the final executioner of necroptosis, phosphorylation-activated mixed lineage kinase domain-like protein (MLKL), aggregated in mitochondrial fractions. Rapamycin intervention removed the impaired mitochondria, inhibited necroptosis for axon maintenance and neuronal survival, and alleviated ACR neuropathy. Our work clarified the functional links among mitophagy, necroptosis, and SARM1-dependent axonal destruction during ACR intoxication, providing novel therapeutic targets for dying-back neuropathies.

Metagenomic surveillance in Jinan, China, reveals serum microbiome and biochemistry features in fever of unknown origin (FUO) patients.

Here we aim to build up a metagenomics-centered surveillance on the infectious microbiome showing in the fever of unknown origin (FUO) patients. We collected venous blood, bronchoalveolar lavage fluid, cerebrospinal fluid, tissue block, sputum, bone marrow biopsy, and purulent liquid samples from 123 patients. Metagenomic sequencing (mNGS) for both DNA and RNA sequences was performed to profile the total pathogenic microbiome in the samples. A large pool of infectious or conditional infectious bacteria was found, belonging to Enterobacteriaceae, Staphylococcaceae (10.55%), Burkholderiaceae (10.05%), and Comamonadaceae (4.25%). The major virus families detected from mNGS analysis include Adenoviridae, Anelloviridae, Peribunyaviridae, Flaviviridae, and Herpesviridae, showing up in 34.96%, 47.37%, 30.89%, 5.69%, 3.25%, and 1.63% of patients, respectively. Using the Ward clustering method, two clusters of patients were organized: high-variety group and low-variety group. The patients in the high-variety group demonstrated higher levels of immune cells and inflammatory indicators such as lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase. The patients in the low-variety group showed higher levels of inflammatory lipids such as 13,14-dihy-15-keto PGE2 (fold > 10, P = 0.021); tetra-PGDM (fold = 5.29, P = 0.037); and 20-HETE (fold > 10, P = 0.02). The mNGS surveillance system demonstrated remarkable potential in preventing infectious diseases using mNGS data.

High expression of RNF31 is associated with tumor immune cell infiltration and leads to poor prognosis in liver hepatocellular carcinoma.

Ring finger protein 31 (RNF31) has been found to play an important role in tumor immunity. However, the role of RNF31 in liver hepatocellular carcinoma (LIHC) has not been reported. Therefore, we investigated the expression and prognostic value of RNF31 in patients with LIHC and explored its relationship with immune cell infiltration. The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset was downloaded to analyse the impact of RNF31 on the prognosis and immune cell infiltration of LIHC. The Tumor Immune Estimation Resource (TIMER) database was used to analyse the correlation between RNF31 and tumor immune cell infiltration in LIHC. Additionally, we analysed the relationship between RNF31 and tumor necrosis factor (TNF) as well as the interferon-gamma (IFN-γ) signaling pathway. The expression of RNF31 in LIHC was significantly higher than that in normal tissues. Increased RNF31 expression was associated with decreased overall survival (OS) and relapse-free survival (RFS). An increase in RNF31 expression was closely related to the infiltration levels of immune cells (e.g., natural killer (NK) cells, CD8 + T cells, and B cells). RNF31 was also positively correlated with the expression of immune checkpoint genes in LIHC. Moreover, RNF31 may participate in TNF and IFN-γ signaling pathways. In conclusion, RNF31 is a potentially valuable prognostic biomarker in LIHC. RNF31 is also associated with immune cell infiltration in LIHC. RNF31 may be a potential target for immunotherapy of LIHC.