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.

Mitochondrial transfer of α-synuclein mediates carbon disulfide-induced mitochondrial dysfunction and neurotoxicity.

Exposure to carbon disulfide (CS2) is a recognized risk factor in the pathogenesis of Parkinson's disease, yet the underlying mechanisms of deleterious effects on mitochondrial integrity have remained elusive. Here, through establishing CS2 exposure models in rat and SH-SY5Y cells, we demonstrated that highly expressed α-synuclein (α-Syn) is transferred to mitochondria via membrane proteins such as Tom20 and leads to mitochondrial dysfunction and mitochondrial oxidative stress, which ultimately causes neuronal injury. We first found significant mitochondrial damage and oxidative stress in CS2-exposed rat midbrain and SH-SY5Y cells and showed that mitochondrial oxidative stress was the main factor of mitochondrial damage by Mitoquinone intervention. Further experiments revealed that CS2 exposure led to the accumulation of α-Syn in mitochondria and that α-Syn co-immunoprecipitated with mitochondrial membrane proteins. Finally, the use of an α-Syn inhibitor (ELN484228) and small interfering RNA (siRNA) effectively mitigated the accumulation of α-Syn in neurons, as well as the inhibition of mitochondrial membrane potential, caused by CS2 exposure. In conclusion, our study identifies the translocation of α-Syn to mitochondria and the impairment of mitochondrial function, which has important implications for the broader understanding and treatment of neurodegenerative diseases associated with environmental toxins.

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.

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.

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.

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.

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.

Research trends of prostatitis over past 20 years: A bibliometric analysis.

In the past two decades, thousands of documents in the field of prostatitis have been published. This bibliometric analysis aimed to assess the characteristics, hotspots and frontiers trend of global scientific output on prostatitis. With the trend of moderate growth, altogether 2,423 papers were reviewed. The leading role of the United States in global prostatitis research was obvious, while China had developed rapidly in recent years. Queen's University and JOURNAL OF UROLOGY were the most prolific affiliation and journal respectively. Nickel, J. C made the greatest contribution to the field of prostatitis. Five hotspots have been confirmed: (a) male infertility associated with prostatitis and the molecular mechanisms; (b) diagnosis and treatment of prostatitis; (c) inflammation, pain and bladder irritation symptoms; (d) relationship between chronic prostatitis/chronic pelvic pain syndrome, benign prostatic hyperplasia and prostate cancer; (e) epidemiology, complications of prostatitis and improvement of acupuncture. This bibliometric analysis reveals that the international cooperation was becoming more and more close. Hotspot analysis shows that the molecular mechanism of prostatitis will be a hotspot in the future, mainly focussing on inflammatory immunity and oxidative stress.

Effect of organic loading rate on anaerobic digestion of pig manure: Methane production, mass flow, reactor scale and heating scenarios.

The effect of organic loading rate (OLR) with total solid (TS) control (3%-8%) on the performance of anaerobic digestion of pig manure (PM) using completely stirred anaerobic reactor was investigated. Based on the lab data, how OLR affects mass flow, construction scale and heating requirement in a farm-scale biogas plant was calculated. And three scenarios of typical reactor-heating technology were comparatively analyzed. The optimal OLR was 1.89 g volatile solid (VS)/(L.d) with methane yield of 438.38 mL/gVS in the lab condition. The lower OLR, the larger amount of water and energy consumption, lower methane production and larger amount of liquid digestate was observed. Thus, the reactor with low OLR was suitable in tropical regions with the main target of disposing PM and fertilizer production. High OLR has advantage in the investment, but owns risk of instable process for a long-term run. In our study, among the three heating supply scenarios, biogas boiler was the best option for the designed biogas plant with the given breeding scale under moderate OLR. Combined heat and power (CHP) has potential advantage for the biogas plant under high OLR.

[Shenjing Guben Pills for repairing testicular spermatogenic injury induced by oxidative stress in rats].

OBJECTIVE: To investigate the antioxidative and spermatogenesis-repairing effects of Shenjing Guben Pills (SGP), a Chinese medicine for invigorating the kidney and blood circulation, on the testis, epididymis and sperm in rats with oxidative stress injury (OSI) induced by cadmium chloride. METHODS: Seventy-two male Wistar rats were equally randomized into six groups: normal control, OSI model control, Wuzi Yanzong Pills (WYP) and low-, medium- and high-dose SGP. The OSI model was made in the latter five groups by intraperitoneal injection of cadmium chloride at 1 mg/kg, and 24 hours later, the rats of the normal and model control groups treated intragastrically with 0.9% normal saline, those of the WYP group with WYP at 4.5 g/kg/d, and those of the low-, medium- and high-dose SGP groups with SGP at 2.8, 5.6 and 11.2 g/kg/d, respectively, all for 56 days. Then, all the animals were sacrificed for obtainment of the visceral indexes and histopathological changes of the testis, epididymis and seminal vesicle, measurement of sperm concentration and motility and the percentage of morphologically normal sperm (MNS) in the epididymis, and determination of the levels of glutathione perox-idase (GSH-PX), superoxide dismutase (SOD), malondial-dehyde aldehyde (MDA) and serum testosterone (T). RESULTS: Compared with the OSI model controls, the rats in the high-, medium- and low-dose SGP groups showed significantly higher visceral indexes of the testis (ï¼»0.237 ± 0.098ï¼½ vs ï¼»0.403 ± 0.090ï¼½, ï¼»0.357 ± 0.150ï¼½ and ï¼»0.348 ± 0.140ï¼½ g/100 g, P < 0.05) and seminal vesicle (ï¼»0.241 ± 0.118ï¼½ vs ï¼»0.347 ± 0.115ï¼½, ï¼»0.336 ± 0.090ï¼½ and ï¼»0.320 ± 0.065ï¼½ g/100 g, P < 0.05) and those of the high-dose SGP group in the epididymal index (ï¼»0.099 ± 0.088ï¼½ vs ï¼»0.156 ± 0.030ï¼½ g/100 g, P < 0.05). In comparison with the OSI model controls, the animals of the high-, medium- and low-dose SGP groups exhibited significant increases in sperm concentration (ï¼»10.5 ± 17.7ï¼½ vs ï¼»58.1 ± 32.2ï¼½, ï¼»36.0 ± 36.2ï¼½ and ï¼»31.9 ± 32.7ï¼½ ×106/ml, P < 0.05) and serum T (ï¼»2.56 ± 0.75ï¼½ vs ï¼»3.62 ± 0.96ï¼½, ï¼»3.48 ± 1.33ï¼½ and ï¼»3.24 ± 0.83ï¼½ nmol/L, P < 0.05 or P < 0.01), and those of the high- and medium-dose SCG groups in total sperm motility (ï¼»9.5 ± 13.0ï¼½% vs ï¼»26.5 ± 15.5ï¼½% and ï¼»18.9 ± 8.2ï¼½%, P < 0.05) and MNS (ï¼»36.2 ± 40.2ï¼½% vs ï¼»85.3 ± 23.3ï¼½% and ï¼»65.8 ± 28.1ï¼½%, P < 0.05) and the levels GSH-PX (ï¼»3.62 ± 2.22ï¼½ vs ï¼»5.70 ± 1.73ï¼½ and ï¼»5.42 ± 2.35ï¼½ U/mg prot, P < 0.05 ) and SOD (ï¼»41.3 ± 8.8ï¼½ vs ï¼»52.7 ± 14.6ï¼½ and ï¼»51.3 ± 14.7ï¼½ U/mg prot, P < 0.05). The MDA level, however, was markedly decreased in the high-, medium- and low-dose SGP groups (ï¼»0.41 ± 0.29ï¼½, ï¼»0.44 ± 0.19ï¼½ and ï¼»0.47 ± 0.20ï¼½ nmol/mg prot) as compared with that in the OSI model controls (ï¼»0.69 ± 0.28ï¼½ nmol/mg prot) (P < 0.05). Histopathological examinations manifested coagulative necrosis, calcification and disappearance of spermatogenic and Sertoli cells in the seminiferous tubules of the OSI model controls, with decreased intraluminal secretions and atrophic epithelial papillae in the seminal vesicles and non-sperm cells in the narrowed lumens of the atrophic epididymis. With the increased dose of SGP, the proportion of normal seminiferous tubules was enlarged, the epithelia of the seminal vesicle became column-shaped again, and the epididymal lumens grew lager with more sperm cells, which indicated a dose-dependent therapeutic efficacy. Medium- and high-dose SGP achieved a significantly better effect than WYP. CONCLUSIONS: Shenjing Guben Pills can antagonize oxidative stress, elevate the levels of testicular antioxidant enzymes and serum T, repair pathological injury of the testis, epididymis and seminal vesicle, and improve semen quality and spermatogenic function.

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.

Renewable biomass reinvigorates sustainable water-energy nexus.

The water-energy nexus has garnered worldwide interest. Current dual-functional research aimed at co-producing freshwater and electricity faces significant challenges, including sub-optimal capacities ("1 + 1 < 2"), poor inter-functional coordination, high carbon footprints, and large costs. Mainstream water-to-electricity conversions are often compromised owing to functionality separation and erratic gradients. Herein, we present a sustainable strategy based on renewable biomass that addresses these issues by jointly achieving competitive solar-evaporative desalination and robust clean electricity generation. Using hydrothermally activated basswood, our solar desalination exceeded the 100% efficiency bottleneck even under reduced solar illumination. Through simple size-tuning, we achieved a high evaporation rate of 3.56 kg h-1 m-2 and an efficiency of 149.1%, representing 128%-251% of recent values without sophisticated surface engineering. By incorporating an electron-ion nexus with interfacial Faradaic electron circulation and co-ion-predominated micro-tunnel hydrodynamic flow, we leveraged free energy from evaporation to generate long-term electricity (0.38 W m-3 for over 14d), approximately 322% of peer performance levels. This inter-functional nexus strengthened dual functionalities and validated general engineering practices. Our presented strategy holds significant promise for global human-society-environment sustainability.

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.

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.

Discovery of oral and inhaled PDE4 inhibitors.

The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.

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.

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.

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.