TREM2 protects against inflammation by regulating the release of mito-DAMPs from hepatocytes during liver fibrosis.

BACKGROUND: Liver fibrosis typically develops as a result of chronic liver injury, which involves inflammatory and regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM2), predominantly expressing in hepatic non-parenchymal cells, plays a crucial role in regulating the function of macrophages. However, its mechanism in liver fibrosis remains poorly defined. METHODS: Experimental liver fibrosis models in wild type and TREM2-/- mice, and in vitro studies with AML-12 cells and Raw264.7 cells were conducted. The expression of TREM2 and related molecular mechanism were evaluated by using samples from patients with liver fibrosis. RESULTS: We demonstrated that TREM2 was upregulated in murine model with liver fibrosis. Mice lacking TREM2 exhibited reduced phagocytosis activity in macrophages following carbon tetrachloride (CCl4) intoxication. As a result, there was an increased accumulation of necrotic apoptotic hepatocytes. Additionally, TREM2 knockout aggravated the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from dead hepatocytes during CCl4 exposure, and further promoted the occurrence of macrophage-mediated M1 polarization. Then, TREM2-/- mice showed more serious fibrosis pathological changes. In vitro, the necrotic apoptosis inhibitor GSK872 effectively alleviated the release of mito-DAMPs in AML-12 cells after CCl4 intoxication, which confirmed that mito-DAMPs originated from dead liver cells. Moreover, direct stimulation of Raw264.7 cells by mito-DAMPs from liver tissue can induce intracellular inflammatory response. More importantly, TREM2 was elevated and inflammatory factors were markedly accumulated surrounding dead cells in the livers of human patients with liver fibrosis. CONCLUSION: Our study highlights that TREM2 serves as a negative regulator of liver fibrosis, suggesting its potential as a novel therapeutic target.

GSK-126 Enhances All-Trans-Retinoic Acid (ATRA) Response in Hepatocellular Carcinoma (HCC) by Upregulating RARG Expression.

BACKGROUND: Hepatocellular carcinoma (HCC) stands out as one of the most prevalent malignant tumors globally. The combination of all-trans-retinoic acid (ATRA) with FOLFOX chemotherapy has shown promise in enhancing the prognosis of HCC patients. ATRA, serving as a chemosensitizing agent, presents novel possibilities for therapeutic applications. Nevertheless, the responsiveness of HCC cells to ATRA varies. The epigenetic modifier-GSK-126 is currently under investigation as a potential antitumor drug. Our aim is to explore the molecular mechanisms underlying the diverse sensitivity of HCC patients to ATRA, and to propose a new combination regimen. This research aims to lay the groundwork for personalized medication approaches for individuals with HCC. METHODS: A cell model with low expression of retinoic acid receptor Alfa (RARA), retinoic acid receptor belta (RARB), and retinoic acid receptor gamma (RARG) was established through siRNA interference. The impact of reduced expression of RARA, RARB, and RARG on the half maximal inhibitory concentration (IC50) of ATRA in Hep3B cells was assessed using the 3-(4,5-Dimethyl-2-Thiazolyl)-2,5-Diphenyl Tetrazolium Bromide (MTT) cytotoxicity assay. Flow cytometry revealed that RARG emerged as the key receptor influencing the combination's sensitivity. Conducting ChIP-qPCR analysis on genomic DNA from HCC cells through relevant websites demonstrated enrichment of the trimethylation modification of lysine 27 on histone H3 (H3K27me3) upstream of the RARG promoter. ChIP-PCR assay confirmed that GSK-126 could diminish H3K27me3 levels on the RARG promoter, subsequently elevating RARG expression. The synergistic efficacy of GSK-126 and ATRA was validated through MTT assay, flow cytometry apoptosis assay, cell cycle assay, and cell scratch assay. RESULTS: Our study unveiled that the insensitivity of HCC cells to ATRA could be linked to the low expression of RARG. ChIP-qPCR analysis illuminated that GSK-126 activated RARG expression by diminishing H3K27me3 enrichment in the RARG promoter region. Consequently, the concurrent administration of ATRA and GSK-126 to hepatoma cells exhibited a synergistic effect, inhibiting cell proliferation, inducing cell apoptosis, and reducing the proportion of cells in the S-phase. CONCLUSION: Our findings emphasize that the synergistic action of GSK-126 and ATRA enhances the sensitivity of HCC cells by upregulating the expression of RARG. This presents a potential foundation for personalized HCC treatment.

Environmental risk substances in soil on seed germination: Chemical species, inhibition performance, and mechanisms.

Nowadays, numerous environmental risk substances in soil worldwide have exhibited serious germination inhibition of crop seeds, posing a threat to food supply and security. This review provides a comprehensive summary and discussion of the inhibitory effects of environmental risk substances on seed germination, encompassing heavy metals, microplastics, petroleum hydrocarbons, salinity, phenols, essential oil, agricultural waste, antibiotics, etc. The impacts of species, concentrations, and particle sizes of various environmental risk substances are critically investigated. Furthermore, three primary inhibition mechanisms of environmental risk substances are elucidated: hindering water absorption, inducing oxidative damage, and damaging seed cells/organelles/cell membranes. To address these negative impacts, diverse effective coping measures such as biochar/compost addition, biological remediation, seed priming, coating, and genetic modification are proposed. In brief, this study systematically analyzes the negative effects of environmental risk substances on seed germination, and provides a basis for the comprehensive understanding and future implementation of efficient treatments to address this significant challenge and ensure food security and human survival.

Aquatic life criteria of hydrothermal liquefaction wastewater via ecotoxicity test and modeling.

Wastewater resulting from hydrothermal liquefaction (HTL-AP) of biowaste is gaining attention as an emerging hazardous material. However, there is a lack of specific and systematic ecotoxicity studies on HTL-AP. This study addresses this gap by conducting acute toxicity tests on HTL-AP using typical aquatic species and integrating these results with predicted toxicity values from interspecies correlation estimation models to establish aquatic life criteria. HTL-AP exhibited significant toxicity with LC50 of 956.12-3645.4 mg/L, but demonstrated moderate toxicity compared to common freshwater pollutants like commercial microbicides, personal care products, and insect repellents. The resulting hazardous concentration for 5 % of species (HC5), the criterion maximum concentration, and the short-term water quality criteria for aquatic were 506.0, 253.0, and 168.7 mg/L, respectively. Notably, certain organisms like Misgurnus anguillicaudatus and Cipangopaludina chinensis showed high tolerance to HTL-AP, likely due to their metabolic capabilities on HTL-AP components. The significant decrease in HC5 values for some HTL-AP substances compared to pure compounds could indicate the synergistic inhibition effects among HTL-AP compositions. Furthermore, according to the established criteria, HTL-AP required significantly less diluted water (13 t) than carbendazim (1009 t) to achieve biosafety, indicating a safer release. This research establishes a preliminary water quality criterion for HTL-AP, offering a valuable reference for risk assessment and prediction in the utilization of HTL-AP within environmental contexts.

Carbon disulfide induces accumulation of TDP-43 in the cytoplasm and mitochondrial dysfunction in rat spinal cords.

The relationship between environmental neurotoxicant exposure and neurodegenerative diseases is being extensively investigated. Carbon disulfide, a classic neurotoxicant and prototype of dithiocarbamates fungicides and anti-inflammatory agents, has been detected in urban adults, raising questions about whether exposure to carbon disulfide is associated with a high incidence of neurodegenerative diseases. Here, using rat models and SH-SY5Y cells, we investigated the possible mechanistic linkages between carbon disulfide neurotoxicity and the expression of TDP-43 protein, a marker of amyotrophic lateral sclerosis/frontotemporal lobar degeneration. Our results showed that rats exhibited severe dyskinesia and increased TDP-43 expression in the spinal cord following carbon disulfide exposure. Moreover, carbon disulfide exposure induced abnormal cytoplasmic localization and phosphorylation of TDP-43 in motor neurons. Importantly, carbon disulfide treatment led to the accumulation of TDP-43 in the mitochondria of motor neurons and resulted in subsequent mitochondrial damage, including mitochondrial structural disruption, mitochondrial respiratory chain complex I inhibition, and impaired VCP/p97-dependent mitophagy. In summary, our study provides support for carbon disulfide exposure-mediated TDP-43 mislocalization and mitochondrial dysfunction, contributes to understanding the pathogenesis of environmental neurotoxin-induced neurodegeneration, and provides inspiration for potential therapeutic strategies.

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.

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.

Chronic carbon disulfide exposure induces parkinsonian pathology via α-synuclein aggregation and necrosome complex interaction.

Exposure to carbon disulfide (CS2) has been associated with an increased incidence of parkinsonism in workers, but the mechanism underlying this association remains unclear. Using a rat model, we investigated the effects of chronic CS2 exposure on parkinsonian pathology. Our results showed that CS2 exposure leads to significant motor impairment and neuronal damage, including loss of dopaminergic neurons and degeneration of the substantia nigra pars compacta (SNpc). The immunoassays revealed that exposure to CS2 induces aggregation of α-synuclein and phosphorylated α-synuclein, as well as activation of necroptosis in the SNpc. Furthermore, in vitro and in vivo experiments demonstrated that the interaction between α-synuclein and the necrosome complex (RIP1, RIP3, and MLKL) is responsible for the loss of neuronal cells after CS2 exposure. Taken together, our results demonstrate that CS2-mediated α-synuclein aggregation can induce dopaminergic neuron damage and parkinsonian behavior through interaction with the necrosome complex.

Mitochondrial oxidative stress regulates LonP1-TDP-43 pathway and rises mitochondrial damage in carbon tetrachloride-induced liver fibrosis.

Carbon tetrachloride (CCl4)-mediated liver damage has been well recognized, but the sources and mechanisms of mitochondrial damage during this progress still remain poorly understood. Accumulating evidence has revealed that LonP1-TDP-43 pathway affect proper mitochondrial integrity and function in neurodegenerative diseases. The current study aims to investigate whether mitochondrial oxidative stress regulate LonP1-TDP-43 pathway and the possible roles of this pathway in CCl4-driven liver fibrosis. We found that TDP-43 interacted with LonP1 in chronic CCl4 exposure-induced hepatic fibrogenesis. Moreover, CCl4 led to deficiency of LonP1 and excessive accumulation of TDP-43 on mitochondria. Particularly, the gene correlation analysis for liver fibrosis patients RNA sequencing (RNA-seq) results (GSE159676) showed an obvious negative correlation between LonP1 and TDP-43. By contrast, MitoQ enhanced the occurrence of mitochondrial unfolded protein response (mtUPR), especially the activation of LonP1 after CCl4 treatment. Importantly, mitochondrial antioxidant also promoted the degradation of TDP-43 and alleviated mitochondrial damage. In addition, our results showed that CCl4 induced the release of mitochondrial DNA (mtDNA) and effectively elevated cGAS-STING-mediated immune response, which can be inhibited by MitoQ. Finally, MitoQ prevented CCl4-induced liver fibrosis. Together, our study revealed that LonP1-TDP-43 pathway mediated by mitochondrial oxidative stress participated in the progress of CCl4-drived liver fibrosis. Therefore, mitigating or reversing mitochondrial damage through targeting LonP1-TDP-43 pathway may serve as a promising therapeutic strategy for CCl4 exposure-induced liver diseases.

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.

Increased IP3R-3 degradation induced by acrylamide promoted Ca2+-dependent calpain activation and axon damage in rats.

Occupational and environmental exposure to acrylamide (ACR) can cause selective peripheral and central nerve fiber degeneration. IP3R-3 is an important transmembrane Ca2+ channel on the endoplasmic reticulum (ER), previous studies have found that ACR could induce Ca2+-dependent calpain activation and axon injury, but the exact role of IP3R-3 in ACR neuropathy is still unclear. Here we show that ACR exposure (40 mg/kg) markedly increased the ubiquitination of IP3R-3 in rat spinal cords, and promoted the degradation of IP3R-3 through the ubiquitin-proteasome pathway. Furthermore, the normal structure of ER, especially the mitochondrial associated membranes (MAMs) component, was significantly impaired in ACR neuropathy, and the ER stress pathway was activated, which indicated that the aberrant increase of cytoplasmic Ca2+ could be attributed the destruction of IP3R-3. Further investigation demonstrated that the proteasome inhibitor MG-132 effectively rescued the IP3R-3 loss, attenuated the intracellular Ca2+ increase, and reduced the axon loss of Neuron 2a (N2a) cells following ACR exposure. Moreover, the calpain inhibitor ALLN also reduced the loss of IP3R-3 and axon injury in N2a cells, but did not alleviate the Ca2+ increase in cytosol, supporting that the abnormal ubiquitination of IP3R-3 was the upstream of the cellular Ca2+ rise and axon damage in ACR neuropathy. Taken together, our results suggested that the aberrant IP3R-3 degradation played an important role in the disturbance of Ca2+ homeostasis and the downstream axon loss in ACR neuropathy, thus providing a potential therapeutic target for ACR neurotoxicity.

Identification of FKBP10 prognostic value in lung adenocarcinoma patients with surgical resection of brain metastases: A retrospective single-institution cohort study.

OBJECTIVE: To explore the expression levels and clinical value of FKBP10 in lung adenocarcinoma brain metastases. DESIGN: A retrospective single-institution cohort study. PATIENTS: The perioperative records of 71 patients with lung adenocarcinoma brain metastases who underwent surgical resection at the authors' institution between November 2012 and June 2019 were retrospectively analyzed. METHODS: The authors evaluated FKBP10 expression levels using immunohistochemistry in tissue arrays of these patients. Kaplan-Meier survival curves were constructed, and a Cox proportional hazards regression model was used to identify independent prognostic biomarkers. A public database was used to detect FKBP10 expression and its clinical value in primary lung adenocarcinoma. RESULTS: The authors found that the FKBP10 protein was selectively expressed in lung adenocarcinoma brain metastases. Survival analysis showed that FKBP10 expression (p = 0.02, HR = 2.472, 95% CI [1.156, 5.289]), target therapy (p < 0.01, HR = 0.186, 95% CI [0.073, 0.477]), and radiotherapy (p = 0.006, HR = 0.330, 95% CI [0.149, 0.731]) were independent prognostic factors for survival in lung adenocarcinoma patients with brain metastases. The authors also detected FKBP10 expression in primary lung adenocarcinoma using a public database, found that FKBP10 is also selectively expressed in primary lung adenocarcinoma, and affects the overall survival and disease-free survival of patients. LIMITATIONS: The number of enrolled patients was relatively small and patients' treatment options varied. CONCLUSIONS: A combination of surgical resection, adjuvant radiotherapy, and precise target therapy may benefit the survival of selected patients with lung adenocarcinoma brain metastases. FKBP10 is a novel biomarker for lung adenocarcinoma brain metastases, which is closely associated with survival time and may serve as a potential therapeutic target.

Overexpression of Podoplanin Predicts Poor Prognosis in Patients With Glioma.

High podoplanin (PDPN) expression correlates with poor prognosis in various cancers. However, the expression and clinical value of PDPN in glioma are unclear. In this study, PDPN expression was compared in 227 glioma tissues and 22 paired non-neoplastic tissues, and its association with prognostic factors was statistically analyzed. The effect of PDPN knockdown on the proliferation ability of glioma cells (U87MG and U118MG cell lines) was assessed along with the underlying molecular mechanism. Overexpression of PDPN was observed in the majority of glioma tissues compared with the expression in normal tissues. PDPN overexpression was positively correlated with IDH wild-type status, TERT promoter mutation status, and ATRX retention status, and was negatively correlated with 1p/19q codeletion status. The expression level of PDPN was positively correlated with the glioma grade in the diffuse astrocytoma, IDH wild-type. High PDPN expression was also negatively correlated with survival in astrocytoma patients with IDH mutation or wild-type and in glioblastoma patients with IDH wild-type. Grade, radiochemotherapy, and PDPN overexpression emerged as independent indicators for a poor prognosis of glioma patients. PDPN knockdown suppressed proliferation and reduced p-Akt and p-mTOR protein expression in glioma cells. PDPN is a potential biomarker or therapeutic target for glioma that is closely associated with tumor grade and poor prognosis, which may play a role in enhancing cell proliferation via Akt/mTOR signaling.

Coproduction of amino acids and biohythane from microalgae via cascaded hydrothermal and anaerobic process.

In search of the candidate for animal feed and clean energy, a new vision of algal biorefinery was firstly proposed to coproduce amino acids and biohythane via hydrothermal treatment and two-stage anaerobic fermentation. This study focused on the comprehensive analysis of amino acids recovered from Chlorella sp. and the subsequent biohythane production from microalgal residues. The content and recovery rate of amino acids were in the range of 2.07-27.62 g/100 g and 3.65 %-48.66 % with increasing temperature due to more cell wall disruptions. Furthermore, it was rich in essential amino acids for livestock, including leucine, arginine, isoleucine, valine and phenylalanine. A comparable hydrogen production (9 mL/g volatile solids (VS)) was reached at 70 °C and 90 °C, while it reduced to 5.84 mL/gVS at 150 °C. The group at 70 °C got the maximum methane generation of 311.9 mL/gVS, which was 16.67 %, 24.94 %, 38.38 % and 46.49 % higher than that of other groups. Microalgal residues at lower temperature contained more organics, which was the reason for the better biohythane production. The coproduction of amino acids and biohythane at 130 °C was favorable, which led to 43.71 % amino acids recovery and 93.82 mL biohythane production from per gVS of Chlorella sp. The improved microalgal biorefinery could provide an alternative way to mitigate the crisis of food and energy, but animal experimentations and techno-economic assessments should be considered for further study.

Changes in brain structure and related functional connectivity during menstruation in women with primary dysmenorrhea.

Background: Neuroimaging studies have identified altered brain structures and functions in women with primary dysmenorrhea (PDM). However, previous studies focused on either structural or functional changes in specific brain regions rather than combining structural and functional analysis. Therefore, this prospective cross-sectional study aimed to investigate the changes in whole brain structure, and functional variation along with structural abnormalities in women with PDM during menstruation. Methods: In all, 31 patients with PDM (PTs) and 31 healthy controls (HCs) were recruited. Voxel-based morphometry (VBM) and surface-based morphometry (SBM) analyses were applied to investigate structural changes based on high-resolution T1-weighted magnetic resonance images. Functional connectivity (FC) analysis was performed to evaluate functional variations related to the brain regions that showed structural group differences. Pearson correlation analysis was performed to assess the relationship between neuroimaging changes and clinical measures. Results: Compared to HCs, PTs had reduced gray matter volume (GMV) in the right superior temporal gyrus (STG) and reduced thickness in the bilateral orbitofrontal cortex (OFC), left postcentral gyrus (PoCG), and left superior occipital gyrus (SOG). Among these areas, the STG and PoCG are responsible for altered resting-state FC patterns in PTs. Results showed decreased FC between the STG and the left cerebellar posterior lobe (poCb), the right dorsolateral prefrontal cortex (DLPFC), and the left precentral gyrus (PrCG). Results also showed decreased FC between the PoCG and the right precuneus and the right DLPFC. We also found greater FCs between the PoCG and the bilateral poCb, the left middle temporal gyrus (MTG), and the left angular gyrus. In addition, the FCs between the STG and poCb, and DLPFC in PTs were positively correlated with history and Cox menstrual symptom scale (CMSS) scores, respectively, while the FCs between STG and PrCG were negatively correlated with the onset age of PDM. Conclusions: Our research found structural abnormalities and related FC changes in several brain regions that were mainly involved in the emotional and sensory aspects of menstrual pain in PDM. These findings could help us understand the occurrence of PDM from a neuroimaging perspective.

Mitochondrial dysfunction promotes the necroptosis of Purkinje cells in the cerebellum of acrylamide-exposed rats.

Acrylamide (ACR) is a common neurotoxicant that can induce central-peripheral neuropathy in human beings. ACR from occupational setting and foods poses a potential threat to people's health. Purkinje cells are the only efferent source of cerebellum, and their output is responsible for coordinating motor activity. Recent studies have reported that Purkinje cell injury is one of the earliest neurotoxicity at any dose rate of ACR. However, the mechanism underlying ACR-mediated damage to Purkinje cells remains unclear. This research aimed to investigate whether necroptosis is involved in ACR-induced Purkinje cell death and its regulatory mechanism. In this study, rats were treated with ACR (40 mg/kg/every other day) for 6 weeks to establish an animal model of ACR neuropathy. Furthermore, an intervention experiment was achieved by rapamycin (RAPA), which is commonly used to activate mitophagy and maintain mitochondrial homeostasis. The results demonstrated ACR exposure caused necroptosis of Purkinje cells, mitochondrial dysfunction, and inflammatory response. By contrast, RAPA alleviated mitochondrial dysfunction and inhibited activation of necroptosis signaling pathway following ACR. In conclusion, our findings suggest that mitochondrial dysfunction and activation of necroptotic signaling are associated with the loss of Purkinje cells in ACR poisoning, which can be a potential therapeutic target for ACR neurotoxicity.

The therapeutic potential of berberine chloride against SARM1-dependent axon degeneration in acrylamide-induced neuropathy.

Chronic acrylamide (ACR) intoxication causes typical pathology of axon degeneration. Moreover, sterile-α and toll/interleukin 1 receptor motif-containing protein 1 (SARM1), the central executioner of the programmed axonal destruction process under various insults, is up-regulated in ACR neuropathy. However, it remains unclear whether inhibitors targeting SARM1 are effective or not. Among all the pharmacological antagonists, berberine chloride (BBE), a natural phytochemical and the first identified non-competitive inhibitor of SARM1, attracts tremendous attention. Here, we observed the protection of 100 µM BBE against ACR-induced neurites injury (2 mM ACR, 24 hr) in vitro, and further evaluated the neuroprotective effect of BBE (100 mg/kg p.o. three times a week for 4 weeks) in ACR-intoxicated rats (40 mg/kg i.p. three times a week for 4 weeks). The expression of SARM1 was also detected. BBE intervention significantly inhibited the overexpression of SARM1, ameliorated axonal degeneration, alleviated pathological changes in the sciatic nerve and spinal cord, and improved neurobehavioral symptoms in ACR-poisoned rats. Thus, BBE exhibits a strong neuroprotective effect against the SARM1-dependent axon destruction in ACR neuropathy. Meanwhile, our study underscores the need for appropriate inhibitor selection in diverse situations that would benefit from blocking the SARM1-dependent axonal destruction pathway.

Identification of FKBP10 prognostic value in lung adenocarcinoma patients with surgical resection of brain metastases: A retrospective single-institution cohort study

Abstract Objective To explore the expression levels and clinical value of FKBP10 in lung adenocarcinoma brain metastases. Design A retrospective single-institution cohort study. Patients The perioperative records of 71 patients with lung adenocarcinoma brain metastases who underwent surgical resection at the authors' institution between November 2012 and June 2019 were retrospectively analyzed. Methods The authors evaluated FKBP10 expression levels using immunohistochemistry in tissue arrays of these patients. Kaplan-Meier survival curves were constructed, and a Cox proportional hazards regression model was used to identify independent prognostic biomarkers. A public database was used to detect FKBP10 expression and its clinical value in primary lung adenocarcinoma. Results The authors found that the FKBP10 protein was selectively expressed in lung adenocarcinoma brain metastases. Survival analysis showed that FKBP10 expression (p = 0.02, HR = 2.472, 95% CI [1.156, 5.289]), target therapy (p < 0.01, HR = 0.186, 95% CI [0.073, 0.477]), and radiotherapy (p = 0.006, HR = 0.330, 95% CI [0.149, 0.731]) were independent prognostic factors for survival in lung adenocarcinoma patients with brain metastases. The authors also detected FKBP10 expression in primary lung adenocarcinoma using a public database, found that FKBP10 is also selectively expressed in primary lung adenocarcinoma, and affects the overall survival and disease-free survival of patients. Limitations The number of enrolled patients was relatively small and patients' treatment options varied. Conclusions A combination of surgical resection, adjuvant radiotherapy, and precise target therapy may benefit the survival of selected patients with lung adenocarcinoma brain metastases. FKBP10 is a novel biomarker for lung adenocarcinoma brain metastases, which is closely associated with survival time and may serve as a potential therapeutic target.

A review of plant antipathogenic constituents: Source, activity and mechanism.

Green prevention and control of plant pathogens is a development direction of sustainable and low-carbon agriculture given the limitation of traditional chemicals. Plant-derived antipathogenic constituents (PAPCs) exhibit the advantages of being environmental benign and a broad spectrum of target pathogens over traditional chemicals. Here, we review the research advances on plant sources, chemical compositions, activities of antipathogenic constituents in the past 20 years. Reported PAPCs are classified into categories of phenols, flavonoids, terpenoids, alkaloids and antimicrobial peptides. Angiosperms, gymnosperms and some lower plants are the main plant source of detected PAPCs. The PAPCs act on pathogens through multiple pathways including destroying cell structures, blocking key composition synthesis and inhibiting cell metabolism. The development trends of PAPCs are finally prospected. This review serves as a comprehensive review on the study of plant antipathogenic constituents and a key reference for forecasting the source, characteristic and activity of PAPC.

MitoQ alleviates carbon tetrachloride-induced liver fibrosis in mice through regulating JNK/YAP pathway.

Background: Liver fibrosis is a pathological wound-healing response caused by chronic liver damage. Mitochondria regulate hepatic energy metabolism and oxidative stress. Accumulating evidence has revealed that increased mitochondrial oxidative stress contributes to the activation of fibrogenesis. However, the roles and underlying mechanisms of mitochondrial oxidative stress in liver fibrosis remain unknown. Methods and results: In this study, C57BL/6 mice were used to establish a model of liver fibrosis via oral gavage with CCl4 treatment for 8 weeks. Furthermore, intervention experiments were achieved by CCl4 combined with the intraperitoneal injection of mitoquinone mesylate (mitoQ). We demonstrated that the chronic CCl4 exposure resulted in severe hepatic fibrogenesis and significantly promoted the production of reactive oxygen species (ROS) and mitochondrial abnormalities. Besides, JNK/YAP pathway was also activated. By contrast, the administration of mitoQ markedly inhibited the expression of pro-fibrogenic transforming growth factor-ß as well as type I collagen. The antifibrotic effects of mitoQ were also confirmed by hematoxylin and eosin staining and Sirius red staining. Moreover, mitoQ substantially reduced CCl4-induced mitochondrial damage and the release of ROS. Further studies suggested that this protection against liver fibrosis was mechanistically related to the inhibition of phosphorylation of JNK and the nuclear translocation of YAP. Conclusion: In conclusion, these findings revealed that mitoQ attenuated liver fibrosis by inhibiting ROS production and the JNK/YAP signaling pathway. Selective targeting JNK/YAP may serve as a therapeutic strategy for retarding progression of chronic liver disease.