Research progress of ubiquitin and ubiquitin-like signaling in Toxoplasma gondii.

Toxoplasmosis, a zoonotic parasitic disease caused by Toxoplasma gondii (T. gondii), is prevalent worldwide. The fact should be emphasized that a considerable proportion of individuals infected with T. gondii may remain asymptomatic; nevertheless, the condition can have severe implications for pregnant women or immunocompromised individuals. The current treatment of toxoplasmosis primarily relies on medication; however, traditional anti-toxoplasmosis drugs exhibit significant limitations in terms of efficacy, side effects, and drug resistance. The life cycles of T. gondii are characterized by distinct stages and its body morphology goes through dynamic alterations during the growth cycle that are intricately governed by a wide array of post-translational modifications (PTMs). Ubiquitin (Ub) signaling and ubiquitin-like (Ubl) signaling are two crucial post-translational modification pathways within cells, regulating protein function, localization, stability, or interactions by attaching Ub or ubiquitin-like proteins (Ubls) to target proteins. While these signaling mechanisms share some functional similarities, they have distinct regulatory mechanisms and effects. T. gondii possesses both Ub and Ubls and plays a significant role in regulating the parasite's life cycle and maintaining its morphology through PTMs of substrate proteins. Investigating the role and mechanism of protein ubiquitination in T. gondii will provide valuable insights for preventing and treating toxoplasmosis. This review explores the distinctive characteristics of Ub and Ubl signaling in T. gondii, with the aim of inspiring research ideas for the identification of safer and more effective drug targets against toxoplasmosis.

Edwardsiella tarda Attenuates Virulence upon Oxytetracycline Resistance.

The relationship between antibiotic resistance and bacterial virulence has not yet been fully explored. Here, we use Edwardsiella tarda as the research model to investigate the proteomic change upon oxytetracycline resistance (LTB4-ROTC). Compared to oxytetracycline-sensitive E. tarda (LTB4-S), LTB4-ROTC has 234 differentially expressed proteins, of which the abundance of 84 proteins is downregulated and 15 proteins are enriched to the Type III secretion system, Type VI secretion system, and flagellum pathways. Functional analysis confirms virulent phenotypes, including autoaggregation, biofilm formation, hemolysis, swimming, and swarming, are impaired in LTB4-ROTC. Furthermore, the in vivo bacterial challenge in both tilapia and zebrafish infection models suggests that the virulence of LTB4-ROTC is attenuated. Analysis of immune gene expression shows that LTB4-ROTC induces a stronger immune response in the spleen but a weaker response in the head kidney than that induced by LTB4-S, suggesting it's a potential vaccine candidate. Zebrafish and tilapia were challenged with a sublethal dose of LTB4-ROTC as a live vaccine followed by LTB4-S challenge. The relative percentage of survival of zebrafish is 60% and that of tilapia is 75% after vaccination. Thus, our study suggests that bacteria that acquire antibiotic resistance may attenuate virulence, which can be explored as a potential live vaccine to tackle bacterial infection in aquaculture.

Uncommon Presentation of Systemic Lupus Erythematosus: Intracranial Mass Lesions as the First Manifestation.

BACKGROUND Multi-system damage is a hallmark of systemic lupus erythematosus (SLE), a chronic systemic autoimmune disease. The typical initial symptoms of SLE are arthritis and dermatosis, whereas the presence of intracranial mass lesions as the first manifestation of systemic lupus erythematosus is very rare. This report describes an 18-year-old woman with intracranial mass lesions associated with SLE. CASE REPORT An 18-year-old woman was initially admitted to the hospital because of headache for 3 days, weakness in left arm, and blurred vision for 1 day. Magnetic resonance imaging (MRI) of her brain showed multiple abnormal occupying lesions in the right frontoparietal lobe. However, no evidence of tumor or infection was found. One month later, she was readmitted with right limb weakness and aphasia for 1 day. Brain MRI showed obvious and new abnormal signal shadows in both the right parietal lobe and the left frontotemporal parieto-occipital lobes compared with the previous MRI. She responded positively to immunotherapy, which, in a woman of child-bearing age, supports the diagnosis of SLE. Ultimately, the presence of focal neurological symptoms, abnormal autoantibodies (such as antinuclear antibodies, anti-dsDNA antibodies, anti-SSA autoantibodies, and anti-ribosomal P protein antibodies), as well as her positive response to immunotherapy, contributed to the diagnosis of SLE with intracranial mass lesions. No recurrence was seen during 1 year of follow-up. CONCLUSIONS It is unusual for SLE to present with intracranial mass lesions as the initial symptoms. The pathogenesis of the neurological symptoms of the patient may be small vessel thrombosis or vasculitis leading to cerebral mass-like necrosis.

Nanoelectrochemistry reveals how presynaptic neurons regulate vesicle release to sustain synaptic plasticity under repetitive stimuli.

Synaptic plasticity is the ability of synapses to modulate synaptic strength in response to dynamic changes within, as well as environmental changes. Although there is a considerable body of knowledge on protein expression and receptor migration in different categories of synaptic plasticity, the contribution and impact of presynaptic vesicle release and neurotransmitter levels towards plasticity remain largely unclear. Herein, nanoelectrochemistry using carbon fiber nanoelectrodes with excellent spatio-temporal resolution was applied for real-time monitoring of presynaptic vesicle release of dopamine inside single synapses of dopaminergic neurons, and exocytotic variations in quantity and kinetics under repetitive electrical stimuli. We found that the presynaptic terminal tends to maintain synaptic strength by rapidly recruiting vesicles, changing the dynamics of exocytosis, and maintaining sufficient neurotransmitter release in following stimuli. Except for small clear synaptic vesicles, dense core vesicles are involved in exocytosis to sustain the neurotransmitter level in later periods of repetitive stimuli. These data indicate that vesicles use a potential regulatory mechanism to establish short-term plasticity, and provide new directions for exploring the synaptic mechanisms in connection and plasticity.

Functional teeth and cognitive function among the Chinese elderly: The chain mediating effect of depressive symptoms and social participation.

The objective of this study was to investigate the chain mediating effects of depressive symptoms and social participation between functional teeth and cognitive function based on the biopsychosocial model. Data from the 2018 China Health and Retirement Longitudinal Study were analyzed. The findings revealed a favorable connection between the lack of edentulism and cognitive function, persisting even when accounting for the mediating factors of denture usage, depressive symptoms, and social participation. Furthermore, the study identified six indirect pathways in this relationship. The present study has substantiated the correlation between edentulism and cognitive function, thereby proposing that interventions aimed at denture usage, depressive symptoms, and social participation could potentially serve as preventive measures against cognitive decline in elderly individuals afflicted with edentulism. This underscores the significance of addressing these factors to alleviate cognitive decline.

α-Ketoglutarate downregulates thiosulphate metabolism to enhance antibiotic killing.

Potentiation of the effects of currently available antibiotics is urgently required to tackle the rising antibiotics resistance. The pyruvate (P) cycle has been shown to play a critical role in mediating aminoglycoside antibiotic killing, but the mechanism remains unexplored. In this study, we investigated the effects of intermediate metabolites of the P cycle regarding the potentiation of gentamicin. We found that α-ketoglutarate (α-KG) has the best synergy with gentamicin compared to the other metabolites. This synergistic killing effect was more effective with aminoglycosides than other types of antibiotics, and it was effective against various types of bacterial pathogens. Using fish and mouse infection models, we confirmed that the synergistic killing effect occurred in vivo. Furthermore, functional proteomics showed that α-KG downregulated thiosulphate metabolism. Upregulation of thiosulphate metabolism by exogenous thiosulphate counteracted the killing effect of gentamicin. The role of thiosulphate metabolism in antibiotic resistance was further confirmed using thiosulphate reductase knockout mutants. These mutants were more sensitive to gentamicin killing, and less tolerant to antibiotics compared to their parental strain. Thus, our study highlights a strategy for potentiating antibiotic killing by using a metabolite that reduces antibiotic resistance.

Nanosensor detection of reactive oxygen and nitrogen species leakage in frustrated phagocytosis of nanofibres.

Exposure to widely used inert fibrous nanomaterials (for example, glass fibres or carbon nanotubes) may result in asbestos-like lung pathologies, becoming an important environmental and health concern. However, the origin of the pathogenesis of such fibres has not yet been clearly established. Here we report an electrochemical nanosensor that is used to monitor and quantitatively characterize the flux and dynamics of reactive species release during the frustrated phagocytosis of glass nanofibres by single macrophages. We show the existence of an intense prolonged release of reactive oxygen and nitrogen species by single macrophages near their phagocytic cups. This continued massive leakage of reactive oxygen and nitrogen species damages peripheral cells and eventually translates into chronic inflammation and lung injury, as seen during in vitro co-culture and in vivo experiments.

A Combination of EGFR Inhibitors and AE-PDT Could Synergistically Suppress Breast Cancer Progression.

BACKGROUND: Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancerrelated deaths in women. Activation of EGFR by EC-secreted EGFR ligands promotes breast cancer progression. Current treatments provide limited benefits in triple-negative breast cancer (TNBC). Photodynamic therapy (PDT) has been proven effective for the treatment of TNBC through the EGFR pathway, but the underlying mechanism is still unclear. PURPOSE: The purpose of this study was to determine the role of the EGFR pathway in the treatment of PDT on TNBC in a co-culture system. METHODS: MB-231 and HUVEC were co-cultured for experiments (HU-231). Cell viability and ROS production were detected after AE-PDT, a combination of EGFR inhibitors (AEE788)with PDT to test angiogenesis, apoptosis, and pyroptosis. WB detects expression of EGFR. EGFR, P-EGFR, VEGF, caspase-1, capase-3, and GSDMD . RESULTS: AE-PDT inhibited HU-231 cell proliferation and tumor angiogenesis, and induced cell apoptosis and pyroptosis by promoting ROS production. AEE788, an inhibitor of the EGFR, enhanced HU-231 cell killing after AE-PDT. CONCLUSION: Our study suggested that the combination of EGFR inhibitors and AE-PDT could synergistically suppress breast cancer progression, providing a new treatment strategy.

Erratum: [Corrigendum] Lidocaine inhibits the invasion and migration of TRPV6­expressing cancer cells by TRPV6 downregulation.

[This corrects the article DOI: 10.3892/ol.2016.4709.].

MOFs-based Fe@YAU-101/GCE electrochemical sensor platform for highly selective detecting trace multiplex heavy metal ions.

The construction of sensors with specific recognition functions can easily, sensitively and efficiently detect heavy metal ions, which is a demand in the field of electrochemical sensing and an important topic in the detection of environmental pollutants. An electrochemical sensor based on MOFs composites was developed for sensing of multiplex metal ions. The large surface area, adjustable porosities and channels in MOFs facilitate successful loading of sufficient quantities highly active units. The active units and pore structures of MOFs are regulated and synergetic with each other to enhance the electrochemical activity of MOFs composites. Thus, the selectivity, sensitivity and reproducibility of MOFs composites have been improved. Fortunately, after characterization, Fe@YAU-101/GCE sensor with strong signal was successfully constructed. In the presence of target metal ions in solution, the Fe@YAU-101/GCE can efficiently and synchronously identify Hg2+, Pb2+, and Cd2+. The detection limits (LOD) are 6.67 × 10-10 M(Cd2+), 3.33 × 10-10 M(Pb2+) and 1.33 × 10-8 M (Hg2+), and are superior to the permissible limits set by the National Environmental Protection Agency. The electrochemical sensor is simple without sophisticated instrumentation and testing processes, hence promising for practical applications.

The ALK1­Smad1/5­ID1 pathway participates in tumour angiogenesis induced by low­dose photodynamic therapy.

Photodynamic therapy (PDT) is an effective and low­invasive tumour therapy. However, it can induce tumour angiogenesis, which is a main factor leading to tumour recurrence and metastasis. Activin receptor­like kinase­1 (ALK1) is a key factor regulating angiogenesis. However, it remains unclear whether ALK1 plays an unusual role in low­dose PDT­induced tumour angiogenesis. In the present study, human umbilical vein endothelial cells (HUVECs) co­cultured with breast cancer MDA­MB­231 cells (termed HU­231 cells) were used to construct an experimental model of tumour angiogenesis induced by low­dose PDT. The viability, and the proliferative, invasive, migratory, as well as the tube­forming ability of the HU­231 cells were evaluated following low­dose PDT. In particular, ALK1 inhibitor and and an adenovirus against ALK1 were used to further verify the role of ALK1 in low­dose PDT­induced tumour angiogenesis. Moreover, the expression of ALK1, inhibitor of DNA binding 1 (ID1), Smad 1, p­Smad1/5, AKT and PI3K were detected in order to verify the underlying mechanisms. The findings indicated that low­dose PDT enhanced the proliferative ability of the HU­231 cells and reinforced their migratory, invasive and tube formation capacity. However, these effects were reversed with the addition of an ALK1 inhibitor or by the knockdown of ALK1 using adenovirus. These results indicated that ALK1 was involved and played a critical role in tumour angiogenesis induced by low­dose PDT. Furthermore, ALK1 was found to participate in PDT­induced tumour angiogenesis by activating the Smad1/5­ID1 pathway, as opposed to the PI3K/AKT pathway. On the whole, the present study, for the first time, to the best of our knowledge, demonstrates that ALK1 is involved in PDT­induced tumour angiogenesis. The inhibition of ALK1 can suppress PDT­induced tumour angiogenesis, which can enhance the effects of PDT and may thus provide a novel treatment strategy for PDT.

Deficient chaperone-mediated autophagy in macrophage aggravates inflammation of nonalcoholic steatohepatitis by targeting Nup85.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH), a more severe subtype of nonalcoholic fatty liver disease, can cause cirrhosis and hepatocellular carcinoma. Macrophages play critical roles in initiating and maintaining NASH-induced liver inflammation and fibrosis. However, the underlying molecular mechanism of macrophage chaperone-mediated autophagy (CMA) in NASH remains unclear. We aimed to investigate the effects of macrophage-specific CMA on liver inflammation and identify a potential therapeutic target for NASH treatment. METHODS: The CMA function of liver macrophages was detected using Western blot, quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and flow cytometry. By constructing myeloid-specific CMA deficiency mice, we evaluated the effects of deficient CMA of macrophages on monocyte recruitment, liver injury, steatosis and fibrosis in NASH mice. A label-free mass spectrometry was utilized to screen the substrates of CMA in macrophages and their mutual interactions. The association between CMA and its substrate was further examined by immunoprecipitation, Western blot and RT-qPCR. RESULTS: A typical hallmark in murine NASH models was impaired CMA function in hepatic macrophages. Monocyte-derived macrophages (MDM) were the dominant macrophage population in NASH, and CMA function was impaired in MDM. CMA dysfunction aggravated liver-targeted recruitment of monocyte and promoted steatosis and fibrosis. Mechanistically, Nup85 functions as a substrate for CMA and its degradation was inhibited in CMA-deficient macrophages. Inhibition of Nup85 attenuated the steatosis and monocyte recruitment caused by CMA deficiency in NASH mice. CONCLUSIONS: We proposed that the impaired CMA-induced Nup85 degradation aggravated monocyte recruitment, promoting liver inflammation and disease progression of NASH.

Ginseng-derived panaxadiol ameliorates STZ-induced type 1 diabetes through inhibiting RORγ/IL-17A axis.

Retinoic-acid-receptor-related orphan receptor γ (RORγ) is a major transcription factor for proinflammatory IL-17A production. Here, we revealed that the RORγ deficiency protects mice from STZ-induced Type 1 diabetes (T1D) through inhibiting IL-17A production, leading to improved pancreatic islet ß cell function, thereby uncovering a potential novel therapeutic target for treating T1D. We further identified a novel RORγ inverse agonist, ginseng-derived panaxadiol, which selectively inhibits RORγ transcriptional activity with a distinct cofactor recruitment profile from known RORγ ligands. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for panaxadiol in the RORγ ligand-binding pocket. Despite its inverse agonist activity, panaxadiol induced the C-terminal AF-2 helix of RORγ to adopt a canonical active conformation. Interestingly, panaxadiol ameliorates mice from STZ-induced T1D through inhibiting IL-17A production in a RORγ-dependent manner. This study demonstrates a novel regulatory function of RORγ with linkage of the IL-17A pathway in pancreatic ß cells, and provides a valuable molecule for further investigating RORγ functions in treating T1D.

Tranexamic versus aminocaproic acids in patients with total hip arthroplasty: a retrospective study.

BACKGROUND: Recently, tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) have been applied in total hip arthroplasty (THA). However, doubts in clinicians' minds about which medicine is more efficient and economical in THA need to be clarified. Therefore, this study compared the efficacy and cost of the intraoperative administration of TXA and EACA per surgery in decreasing perioperative blood transfusion rates in THA. METHODS:  This study enrolled patients who underwent THA between January 2019 to December 2020. A total of 295 patients were retrospectively divided to receive topical combined with intravenous TXA (n = 94), EACA (n = 97) or control (n = 104). The primary endpoints included transfusions, estimated perioperative blood loss, cost per patient and the drop in the haemoglobin and haematocrit levels. RESULTS: Patients who received EACA had greater total blood loss, blood transfusion rates, changes in HGB levels and mean cost of blood transfusion per patient (P < 0.05) compared with patients who received TXA. In addition, both TXA and EACA groups had significantly fewer perioperative blood loss, blood transfusion, operation time and changes in haemoglobin and haematocrit levels than the control group (P < 0.05). Cost savings in the TXA and EACA groups were 736.00 RMB and 408.00 RMB per patient, respectively. CONCLUSIONS: The application of perioperative antifibrinolytics notably reduces the need for perioperative blood transfusions. What's more, this study demonstrated that TXA is superior to EACA for decreasing blood loss and transfusion rates while at a lower cost per surgery. These results indicate that TXA may be the optimum antifibrinolytics for THA in Chinese area rather than EACA.

Transcripts related with ammonium use and effects of gibberellin on expressions of the transcripts responding to ammonium in two invasive and native Xanthium species.

Soil nitrogen forms are important for exotic plant invasions. However, little effort has been made to study the molecular mechanisms underlying the utilization of different N forms in co-occurring invasive and native plants. The invasive plant Xanthium strumarium prefers nitrate relative to ammonium, and mainly invades nitrate-dominated environments, while it co-occurring native congener X. sibiricum prefers ammonium. Here, we addressed the genetic bases for the interspecific difference in ammonium use and the effects of gibberellin (GA). Twenty-six transcripts related with GA biosynthesis and ammonium utilization were induced by ammonium in X. sibiricum, while only ten in X. strumarium and none for ammonium uptake. XsiAMT1.1a, XsiGLN1.1 and XsiGLT1b may be crucial for the strong ability to absorb and assimilate ammonium in X. sibiricum. All tested transcripts were significantly up-regulated by GA1 and GA4 in X. sibiricum. XsiGA3OX1a, which was also induced by ammonium, may be involved in this regulation. Consistently, glutamine synthetase activity increased significantly with increasing ammonium-N/nitrate-N ratio for X. sibiricum, while decreased for X. strumarium. Our study is the first to determine the molecular mechanisms with which invasive and native plants use ammonium differently, contributing to understanding the invasion mechanisms of X. strumarium and its invasion habitat selection.

Effectiveness of peripheral defocus spectacle lenses in myopia control: a Meta-analysis and systematic review.

AIM: To evaluate the effectiveness of peripheral defocus spectacle lenses (PDLs) in myopia control. METHODS: Literature retrieval on PubMed, Cochrane Library, Embase, and Web of Science databases, and the search time limit was from the establishment of each database to December 29, 2021 were conducted. Change of spherical equivalent refraction (SER) and axial change (AL) were extracted from the literatures that met the inclusion criteria, and RevMan5.3 software was used for Meta-analysis. RESULTS: A total of 4 randomized controlled trials (RCTs) were included in this Meta-analysis, involving 770 myopic children. The results showed that PDLs could delay the progression of myopia in children with myopia compared with single vision spectacle lenses (SVLs; WMD=0.21 D, 95%CI: 0.01, 0.41, P=0.04). However, there was no significant difference in controlling the growth of axial length (AL) in myopic children (WMD=-0.10 mm, 95%CI: -0.21, 0.01, P=0.07). The results of the effectiveness of myopia control between the two spectacle lenses showed that PDLs were more effective in controlling the progression of myopia (OR=5.73, 95%CI: 2.58, 12.70, P<0.001) and delaying the growth of AL (OR=44.25, 95%CI: 8.84, 221.58, P<0.001) than SVLs, and the differences were statistically significant. CONCLUSION: PDLs can control the progression of myopia compared with SVLs, but cannot delay the growth of AL, and the effectiveness of PDLs in myopia control better than SVLs.

Homeostasis inside Single Activated Phagolysosomes: Quantitative and Selective Measurements of Submillisecond Dynamics of Reactive Oxygen and Nitrogen Species Production with a Nanoelectrochemical Sensor.

Reactive oxygen and nitrogen species (ROS/RNS) are generated by macrophages inside their phagolysosomes. This production is essential for phagocytosis of damaged cells and pathogens, i.e., protecting the organism and maintaining immune homeostasis. The ability to quantitatively and individually monitor the four primary ROS/RNS (ONOO-, H2O2, NO, and NO2-) with submillisecond resolution is clearly warranted to elucidate the still unclear mechanisms of their rapid generation and to track their concentration variations over time inside phagolysosomes, in particular, to document the origin of ROS/RNS homeostasis during phagocytosis. A novel nanowire electrode has been specifically developed for this purpose. It consisted of wrapping a SiC nanowire with a mat of 3 nm platinum nanoparticles whose high electrocatalytic performances allow the characterization and individual measurements of each of the four primary ROS/RNS. This allowed, for the first time, a quantitative, selective, and statistically robust determination of the individual amounts of ROS/RNS present in single dormant phagolysosomes. Additionally, the submillisecond resolution of the nanosensor allowed confirmation and measurement of the rapid ability of phagolysosomes to differentially mobilize their enzyme pools of NADPH oxidases and inducible nitric oxide synthases to finely regulate their homeostasis. This reveals an essential key to immune responses and immunotherapies and rationalizes its biomolecular origin.

FXR: structures, biology, and drug development for NASH and fibrosis diseases.

The nuclear receptor farnesoid-X-receptor (FXR) plays an essential role in bile acid, glucose, and lipid homeostasis. In the last two decades, several diseases, such as obesity, type 2 diabetes, nonalcoholic fatty liver disease, cholestasis, and chronic inflammatory diseases of the liver and intestine, have been revealed to be associated with alterations in FXR functions. FXR has become a promising therapeutic drug target, particularly for enterohepatic diseases. Despite the large number of FXR modulators reported, only obeticholic acid (OCA) has been approved for primary biliary cholangitis (PBC) therapy as FXR modulator. In this review, we summarize the structure and function of FXR, the development of FXR modulators, and the structure-activity relationships of FXR modulators. Based on the structural analysis, we discuss potential strategies for developing future therapeutic FXR modulators to overcome current limitations, providing new perspectives for enterohepatic and metabolic diseases treatment.

Spatiotemporal characteristics of PM2.5 and ozone concentrations in Chinese urban clusters.

Despite China's public commitment to emphasise air pollution investigation and control, trends in PM2.5 and ozone concentrations in Chinese urban clusters remain unclear. This study quantifies the spatiotemporal variations in PM2.5 and surface ozone at the scale of Chinese urban clusters by using a long-term integrated dataset from 2015 to 2020. Nonlinear Granger causality testing was used to explore the spatial association patterns of PM2.5 and ozone pollution in five megacity cluster regions. The results show a significant downward trend in annual mean PM2.5 concentrations from 2015 to 2020, with a decline rate of 2.8 µg m-3 yr-1. By contrast, surface ozone concentrations increased at a rate of 2.1 µg m-3 yr-1 over the 6 years. The annual mean PM2.5 concentrations in urban clusters show significant spatial clustering characteristics, mainly in Beijing-Tianjin-Hebei (BTH), Fenwei Plain (FWP), Northern slope of Tianshan Mountains urban cluster (NSTM), Sichuan Basin urban cluster (SCB), and Yangtze River Delta (YRD). Surface ozone shows severe summertime pollution and distributional variability, with increased ozone pollution in major urban clusters. The highest increases were observed in BTH, Yangtze River midstream urban cluster (YRMR), YRD, and Pearl River Delta (PRD). Nonlinear Granger causality tests showed that PM2.5 was a nonlinear Granger cause of ozone, further supporting the literature's findings that PM2.5 reduction promoted photochemical reaction rates and stimulated ozone production. The nonlinear test statistic passed the significance test in magnitude and statistical significance. FWP was an exception, with no significant long-term nonlinear causal link between PM2.5 and ozone. This study highlights the challenges of compounded air pollution caused primarily by ozone and secondary PM2.5. These results have implications for the design of synergistic pollution abatement policies for coupled urban clusters.

[α-lipoic acid ameliorates liver injury in rats with type 2 diabetes mellitus via activating AMPK/mTOR pathway].

OBJECTIVE: To investigate the effect of α-lipoic acid in ameliorating liver injury in rats with type 2 diabetes mellitus via activating adenosine 5'-monophosphate-activate protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. METHODS: The T2DM rat models were established by feeding with high-fat, high-sucrose diet and intraperitoneal injection of 27.5 mg/(kg·d) streptozotocin. The 32 rats with T2DM were randomly divided into 4 groups: T2DM group, α-lipoic acid group (LA), Compound C group (Comp C, an inhibitor of AMPK) and LA+Comp C group, with 8 rats in each group. Additionally, 8 Sprague-Dawlay (SD) rats without diabetes were set as normal control. The rats received α-lipoic acid at a dosage of 100 mg/(kg·d) or Compound C at a dosage of 20 mg/(kg·d) by intraperitoneal injection for 8 weeks as needed. The levels of relevant biochemical indexes were detected. The weight of liver was recorded to calculate liver weight index (LWI), and the pathological changes of liver tissues were detected by light and electron microscopy. The levels of AMPK, p-AMPK, mTOR, p-mTOR in rat liver were detected by Western blot. RESULTS: Compared with control group, the levels of LWI, homeostasis model assessment of insulin resistance, fasting blood glucose, alanine transaminase, aspartate transaminase, gamma glutamyl transferase and triglyceride in T2DM group were increased significantly (all P＜0.05). The liver tissue lesions were more serious and hepatic steatosis grade was higher. The expression of p-AMPK was decreased (P＜0.05) and the expression of p-mTOR was increased significantly(P＜0.05). α-lipoic acid could reverse the above-mentioned changes, ameliorate insulin resistance (all P＜0.05), protect the structure and function of liver, and activate the AMPK/mTOR pathway (P＜0.05). The protection of α-lipoic acid was weakened by the inhibition of AMPK with Compound C (P＜0.05). CONCLUSION: α-lipoic acid could protect the liver of rats with T2DM by activating AMPK/mTOR pathway.