Geranylgeranylated-SCF FBXO10 Regulates Selective Outer Mitochondrial Membrane Proteostasis and Function.

E3-ubiquitin ligases (E3s) are main components of the ubiquitin-proteasome system (UPS), as they determine substrate specificity in response to internal and external cues to regulate protein homeostasis. However, the regulation of membrane protein ubiquitination by E3s within distinct cell membrane compartments or organelles is not well understood. We show that FBXO10, the interchangeable component of the SKP1/CUL1/F-box ubiquitin ligase complex (SCF-E3), undergoes lipid-modification with geranylgeranyl isoprenoid at Cysteine953 (C953), facilitating its dynamic trafficking to the outer mitochondrial membrane (OMM). FBXO10 polypeptide does not contain a canonical mitochondrial targeting sequence (MTS); instead, its geranylgeranylation at C953 and the interaction with two cytosolic factors, PDE6δ (a prenyl group-binding protein), and HSP90 (a mitochondrial chaperone) orchestrate specific OMM targeting of prenyl-FBXO10 across diverse membrane compartments. The geranylgeranylation-deficient FBXO10(C953S) mutant redistributes away from the OMM, leading to impaired mitochondrial ATP production, decreased mitochondrial membrane potential, and increased mitochondrial fragmentation. Phosphoglycerate mutase 5 (PGAM5) was identified as a potential substrate of FBXO10 at the OMM using comparative quantitative mass spectrometry analyses of enriched mitochondria (LFQ-MS/MS), leveraging the redistribution of FBXO10(C953S). FBXO10, but not FBXO10(C953S), promoted polyubiquitylation and degradation of PGAM5. Examination of the role of this pathway in a physiological context revealed that the loss of FBXO10 or expression of prenylation-deficient-FBXO10(C953S) inhibited PGAM5 degradation, disrupted mitochondrial homeostasis, and impaired myogenic differentiation of human iPSCs and murine myoblasts. Our studies identify a mechanism for selective E3-ligase mediated regulation of mitochondrial membrane proteostasis and metabolic health, potentially amenable to therapeutic intervention.

Autophagy-dependent lysosomal calcium overload and the ATP5B-regulated lysosomes-mitochondria calcium transmission induce liver insulin resistance under perfluorooctane sulfonate exposure.

Perfluorooctane sulfonate (PFOS), an officially listed persistent organic pollutant, is a widely distributed perfluoroalkyl substance. Epidemiological studies have shown that PFOS is intimately linked to the occurrence of insulin resistance (IR). However, the detailed mechanism remains obscure. In previous studies, we found that mitochondrial calcium overload was concerned with hepatic IR induced by PFOS. In this study, we found that PFOS exposure noticeably raised lysosomal calcium in L-02 hepatocytes from 0.5 h. In the PFOS-cultured L-02 cells, inhibiting autophagy alleviated lysosomal calcium overload. Inhibition of mitochondrial calcium uptake aggravated the accumulation of lysosomal calcium, while inhibition of lysosomal calcium outflowing reversed PFOS-induced mitochondrial calcium overload and IR. Transient receptor potential mucolipin 1 (TRPML1), the calcium output channel of lysosomes, interacted with voltage-dependent anion channel 1 (VDAC1), the calcium intake channel of mitochondria, in the PFOS-cultured cells. Moreover, we found that ATP synthase F1 subunit beta (ATP5B) interacted with TRPML1 and VDAC1 in the L-02 cells and the liver of mice under PFOS exposure. Inhibiting ATP5B expression or restraining the ATP5B on the plasma membrane reduced the interplay between TRPML1 and VDAC1, reversed the mitochondrial calcium overload and deteriorated the lysosomal calcium accumulation in the PFOS-cultured cells. Our research unveils the molecular regulation of the calcium crosstalk between lysosomes and mitochondria, and explains PFOS-induced IR in the context of activated autophagy.

Exploring the role of histone deacetylase and histone deacetylase inhibitors in the context of multiple myeloma: mechanisms, therapeutic implications, and future perspectives.

Histone deacetylase inhibitors (HDACis) are a significant category of pharmaceuticals that have developed in the past two decades to treat multiple myeloma. Four drugs in this category have received approval from the U.S. Food and Drug Administration (FDA) for use: Panobinonstat (though canceled by the FDA in 2022), Vorinostat, Belinostat and Romidepsin. The efficacy of this group of drugs is attributed to the disruption of many processes involved in tumor growth through the inhibition of histone deacetylase, and this mode of action leads to significant anti-multiple myeloma (MM) activity. In MM, inhibition of histone deacetylase has many downstream consequences, including suppression of NF-κB signaling and HSP90, upregulation of cell cycle regulators (p21, p53), and downregulation of antiapoptotic proteins including Bcl-2. Furthermore, HDACis have a variety of direct and indirect oxidative effects on cellular DNA. HDAC inhibitors enhance normal immune function, thereby decreasing the proliferation of malignant plasma cells and promoting autophagy. The various biological effects of inhibiting histone deacetylase have a combined or additional impact when used alongside other chemotherapeutic and targeted drugs for multiple myeloma. This helps to decrease resistance to treatment. Combination treatment regimens that include HDACis have become an essential part of the therapy for multiple myeloma. These regimens incorporate drugs from other important classes of anti-myeloma agents, such as immunomodulatory drugs (IMiDs), conventional chemotherapy, monoclonal antibodies, and proteasome inhibitors. This review provides a comprehensive evaluation of the clinical efficacy and safety data pertaining to the currently approved histone deacetylase inhibitors, as well as an explanation of the crucial function of histone deacetylase in multiple myeloma and the characteristics of the different histone deacetylase inhibitors. Moreover, it provides a concise overview of the most recent developments in the use of histone deacetylase inhibitors for treating multiple myeloma, as well as potential future uses in treatment.

Balloon Pressure and Clinical Effectiveness of Percutaneous Microballoon Compression in the Treatment of Primary Trigeminal Neuralgia.

BACKGROUND: Primary trigeminal neuralgia (PTN) is a type of chronic neuropathic pain disorder caused by neurovascular compression. Percutaneous balloon compression (PBC) is a widely used method for the treatment of PTN. OBJECTIVES: To examine the correlation of balloon pressure (BP) during percutaneous microballoon compression (PBC) with postoperative pain relief and complications in the treatment of primary trigeminal neuralgia (PTN). STUDY DESIGN: Forty-five patients diagnosed with PTN and treated with PBC were recruited. The BP was recorded at 2 time points: when the balloon achieved the ideal pear shape (initial BP [IBP]) and when the pressure was maintained for 2 min (final BP [FBP]). SETTING: This study was conducted at the Department of Pain and Rehabilitation of the Second Affiliated Hospital at the University of South China in Hunan, China. METHODS: The patients' Barrow Neurological Institute (BNI) pain intensity score, BNI facial numbness score, masticatory muscle weakness score, and recurrence were recorded before and after surgery. The receiver operating characteristic (ROC) curves were generated for the IBP to predict treatment effectiveness, severe facial numbness, and severe masticatory muscle weakness. RESULTS: The BNI pain intensity score, BNI facial numbness score, and masticatory muscle weakness score were significantly decreased after surgery (all P < 0.001). IBP was positively correlated with the difference between IBP and FBP (P < 0.01). Both IBP and the difference between IBP and FBP were negatively correlated with the BNI pain intensity score and positively correlated with the BNI facial numbness score and masticatory muscle weakness score (P < 0.01). The IBP and the difference between the IBP and FBP were significantly lower in patients experiencing recurrence than in the nonrecurrent group (P < 0.05). The areas under the ROC curves of the IBP for predicting effective pain relief, severe facial numbness, and severe masticatory muscle weakness were 0.875, 0.980, and 0.988, respectively. LIMITATIONS: The sample size was relatively small, and the follow-up time was short. The correlations between the BP and other factors, such as filling amount, Meckel's cavity, and the size of the foramen ovale, were not investigated. The impact of the BP on long-term postoperative outcomes was not explored. CONCLUSIONS: An intraoperative BP of 138.65-153.90 KPa can be maintained for effective PBC treatment without causing serious complications.

Deep learning on tertiary lymphoid structures in hematoxylin-eosin predicts cancer prognosis and immunotherapy response.

Tertiary lymphoid structures (TLSs) have been associated with favorable immunotherapy responses and prognosis in various cancers. Despite their significance, their quantification using multiplex immunohistochemistry (mIHC) staining of T and B lymphocytes remains labor-intensive, limiting its clinical utility. To address this challenge, we curated a dataset from matched mIHC and H&E whole-slide images (WSIs) and developed a deep learning model for automated segmentation of TLSs. The model achieved Dice coefficients of 0.91 on the internal test set and 0.866 on the external validation set, along with intersection over union (IoU) scores of 0.819 and 0.787, respectively. The TLS ratio, defined as the segmented TLS area over the total tissue area, correlated with B lymphocyte levels and the expression of CXCL13, a chemokine associated with TLS formation, in 6140 patients spanning 16 tumor types from The Cancer Genome Atlas (TCGA). The prognostic models for overall survival indicated that the inclusion of the TLS ratio with TNM staging significantly enhanced the models' discriminative ability, outperforming the traditional models that solely incorporated TNM staging, in 10 out of 15 TCGA tumor types. Furthermore, when applied to biopsied treatment-naïve tumor samples, higher TLS ratios predicted a positive immunotherapy response across multiple cohorts, including specific therapies for esophageal squamous cell carcinoma, non-small cell lung cancer, and stomach adenocarcinoma. In conclusion, our deep learning-based approach offers an automated and reproducible method for TLS segmentation and quantification, highlighting its potential in predicting immunotherapy response and informing cancer prognosis.

Eliminating bias: enhancing children's book recommendation using a hybrid model of graph convolutional networks and neural matrix factorization.

Managing user bias in large-scale user review data is a significant challenge in optimizing children's book recommendation systems. To tackle this issue, this study introduces a novel hybrid model that combines graph convolutional networks (GCN) based on bipartite graphs and neural matrix factorization (NMF). This model aims to enhance the precision and efficiency of children's book recommendations by accurately capturing user biases. In this model, the complex interactions between users and books are modeled as a bipartite graph, with the users' book ratings serving as the weights of the edges. Through GCN and NMF, we can delve into the structure of the graph and the behavioral patterns of users, more accurately identify and address user biases, and predict their future behaviors. Compared to traditional recommendation systems, our hybrid model excels in handling large-scale user review data. Experimental results confirm that our model has significantly improved in terms of recommendation accuracy and scalability, positively contributing to the advancement of children's book recommendation systems.

Intrathecal morphine delivery at prepontine cistern to control refractory cancer-related pain: a case report of extensive metastatic and refractory cancer pain.

BACKGROUND: Extensive metastatic and refractory cancer pain is common, and exhibits a dissatisfactory response to the conventional intrathecal infusion of opioid analgesics. CASE PRESENTATION: The present study reports a case of an extensive metastatic esophageal cancer patient with severe intractable pain, who underwent translumbar subarachnoid puncture with intrathecal catheterization to the prepontine cistern. After continuous infusion of low-dose morphine, the pain was well-controlled with a decrease in the numeric rating scale (NRS) of pain score from 9 to 0, and the few adverse reactions to the treatment disappeared at a low dose of morphine. CONCLUSIONS: The patient achieved a good quality of life during the one-month follow-up period.

Operative Positioning and Intraoperative-Acquired Pressure Injury: A Retrospective Cohort Study.

OBJECTIVE: To comprehensively assess the association between operative positioning with intraoperative-acquired pressure injury (IAPI) development. METHODS: This retrospective cohort study included 455 patients who underwent surgery between October 2020 and January 2021. The authors grouped patients by operative positioning into the prone position and nonprone position groups. They used propensity-score matching at a 1:2 ratio to control for preoperative confounders, applied multiple logistic regression models to analyze the effects between positioning and IAPI, and assessed interactions of positioning and intraoperative factors on IAPI. RESULTS: The final enrollment was 92 cases in the prone position group and 181 in the nonprone position group. Multivariable logistic analysis suggested that the prone position had a 2.92 times higher risk of IAPI than the nonprone position (odds ratio, 2.92; 95% CI, 1.13-7.57; P = .026). Subgroup analysis showed a significant multiplicative interaction between positioning and foam dressing on IAPI (P < .05), which was not observed in other intraoperative factors (P > .05). CONCLUSIONS: This study provides evidence that prone operative positioning can increase IAPI risk. Patients in the prone position may particularly benefit from using dressings in Chinese populations. Further large-sample longitudinal studies are required to confirm these findings.

Clinical application of medical adhesive in endovascular embolization treatment of peripheral pseudoaneurysm.

Objectives: This study explores the clinical application value of medical adhesive in endovascular embolization treatment of peripheral pseudoaneurysm. Material and Methods: This was a retrospective review on 31 patients with peripheral pseudoaneurysm treated with medical adhesive endovascular embolization at the First Affiliated Hospital of Shihezi University from July 2021 to July 2023. Follow-up for 3-6 months was to observe the clinical efficacy and postoperative complications of medical adhesive embolization treatment. Results: A total of 32 pseudoaneurysms were embolized in 31 patients with peripheral pseudoaneurysms. All pseudoaneurysms originated from visceral arteries. Among them, 29 pseudoaneurysms were embolized with medical adhesive alone, and three pseudoaneurysms were embolized with coil-assisted medical adhesive. After endovascular embolization with medical adhesive, all pseudoaneurysms were successfully embolized. Technical success was 100%. All patients experienced cessation of bleeding after endovascular embolization with medical adhesive, and there were no serious post-operative complications. Clinical success was 100%. During the follow-up period, two patients experienced recurrent bleeding but no pseudoaneurysm recurrence was observed. Conclusion: Endovascular medical adhesive embolization is a safe and effective method for treating pseudoaneurysm, with high hemostatic efficiency and permanent occlusion of the pseudoaneurysm after embolization, which is worthy of clinical promotion and application.

p53-dependent HIF-1α /autophagy mediated glycolysis to support Cr(VI)-induced cell growth and cell migration.

Cr(VI) is known to be seriously toxic and carcinogenic. Hypoxia-inducible factor-1α (HIF-1α) is a crucial regulator to promote tumor development. In this study, we found that Cr(VI) significantly increased the expression of HIF-1α in A549 cells and in lung of BALB/c mice but not in HELF cells. Treatment with Lificiguat (YC-1), HIF-1α inhibitor, or CoCl2, HIF-1α inducer, could alter Cr(VI)-induced autophagy, glycolysis, and cell growth in A549 cells but not in HELF cells, validating the involvement of HIF-1α in these effects of Cr(VI) in A549 cells. Co-treatments of pcATG4B with YC-1, or siATG4B with CoCl2 demonstrated the role of HIF-1α / autophagy axis in inducing glycolysis and cell growth in A549 cells. In HELF cells, however, only autophagy but not HIF-1α played a role in inducing glycolysis. The protein level of p53 was significantly lower in A549 cells than in HELF cells. RITA, a p53 inducer, attenuated Cr(VI)-induced HIF-1α and LC3-II in A549 cells, suggesting that p53 might be the mechanism underlying the different effects of Cr(VI) on HIF-1α in A549 and HELF cells. Thus, p53-dependent HIF-1α / autophagy-mediated glycolysis plays a role in facilitating Cr(VI)-induced carcinogenesis.

The Complement System and C4b-Binding Protein: A Focus on the Promise of C4BPα as a Biomarker to Predict Clopidogrel Resistance.

The complement system plays a dual role in the body, either as a first-line defense barrier when balanced between activation and inhibition or as a potential driver of complement-associated injury or diseases when unbalanced or over-activated. C4b-binding protein (C4BP) was the first circulating complement regulatory protein identified and it functions as an important complement inhibitor. C4BP can suppress the over-activation of complement components and prevent the complement system from attacking the host cells through the binding of complement cleavage products C4b and C3b, working in concert as a cofactor for factor I in the degradation of C4b and C3b, and consequently preventing or reducing the assembly of C3 convertase and C5 convertase, respectively. C4BP, particularly C4BP α-chain (C4BPα), exerts its unique inhibitory effects on complement activation and opsonization, systemic inflammation, and platelet activation and aggregation. It has long been acknowledged that crosstalk or interplay exists between the complement system and platelets. Our unpublished preliminary data suggest that circulating C4BPα exerts its antiplatelet effects through inhibition of both complement activity levels and complement-induced platelet reactivity. Plasma C4BPα levels appear to be significantly higher in patients sensitive to, rather than resistant to, clopidogrel, and we suggest that a plasma C4BPα measurement could be used to predict clopidogrel resistance in the clinical settings.

Involvement of Embryo-Derived and Monocyte-Derived Intestinal Macrophages in the Pathogenesis of Inflammatory Bowel Disease and Their Prospects as Therapeutic Targets.

Inflammatory bowel disease (IBD) is a group of intestinal inflammatory diseases characterized by chronic, recurrent, remitting, or progressive inflammation, which causes the disturbance of the homeostasis between immune cells, such as macrophages, epithelial cells, and microorganisms. Intestinal macrophages (IMs) are the largest population of macrophages in the body, and the abnormal function of IMs is an important cause of IBD. Most IMs come from the replenishment of blood monocytes, while a small part come from embryos and can self-renew. Stimulated by the intestinal inflammatory microenvironment, monocyte-derived IMs can interact with intestinal epithelial cells, intestinal fibroblasts, and intestinal flora, resulting in the increased differentiation of proinflammatory phenotypes and the decreased differentiation of anti-inflammatory phenotypes, releasing a large number of proinflammatory factors and aggravating intestinal inflammation. Based on this mechanism, inhibiting the secretion of IMs' proinflammatory factors and enhancing the differentiation of anti-inflammatory phenotypes can help alleviate intestinal inflammation and promote tissue repair. At present, the clinical medication of IBD mainly includes 5-aminosalicylic acids (5-ASAs), glucocorticoid, immunosuppressants, and TNF-α inhibitors. The general principle of treatment is to control acute attacks, alleviate the condition, reduce recurrence, and prevent complications. Most classical IBD therapies affecting IMs function in a variety of ways, such as inhibiting the inflammatory signaling pathways and inducing IM2-type macrophage differentiation. This review explores the current understanding of the involvement of IMs in the pathogenesis of IBD and their prospects as therapeutic targets.

Emerging applications of single-cell profiling in precision medicine of atherosclerosis.

Atherosclerosis is a chronic, progressive, inflammatory disease that occurs in the arterial wall. Despite recent advancements in treatment aimed at improving efficacy and prolonging survival, atherosclerosis remains largely incurable. In this review, we discuss emerging single-cell sequencing techniques and their novel insights into atherosclerosis. We provide examples of single-cell profiling studies that reveal phenotypic characteristics of atherosclerosis plaques, blood, liver, and the intestinal tract. Additionally, we highlight the potential clinical applications of single-cell analysis and propose that combining this approach with other techniques can facilitate early diagnosis and treatment, leading to more accurate medical interventions.

Advances in research on arboviral acquisition from hosts to mosquitoes.

Arboviral acquisition is a critical step in virus transmission. In this review, we present an overview of the interactions between viruses and host blood-derived factors, highlighting the diverse ways in which they interact. Moreover, the review outlines the impact of host blood on gut barriers during viral acquisition, emphasizing the crucial role of this physiological process in virus dissemination. Additionally, the review investigates the responses of symbioses to invading arboviruses, providing insights into the dynamic reactions of these vital relationships to the presence of arboviruses.

Association of air pollution and risk of chronic kidney disease: A systematic review and meta-analysis.

Although epidemiological studies have evaluated the association between ambient air pollution and chronic kidney disease (CKD), the results remain mixed. To clarify the nature of the association, we conducted a comprehensive systematic review and meta-analysis to assess the global relationship between air pollution and CKD. The Web of Science, PubMed, Embase and Cochrane Library databases systematically were searched for studies published up to July 2023 and included 32 studies that met specific criteria. The random effects model was used to derive overall risk estimates for each pollutant. The meta-analysis estimated odds ratio (ORs) of risk for CKD were 1.42 (95% confidence interval [CI]: 1.31-1.54) for each 10 µg/m3 increase in PM2.5 ; 1.20 (95% CI: 1.14-1.26) for each 10 µg/m3 increase in PM10 ; 1.07 (95% CI: 1.05-1.09) for each 10 µg/m3 increase in NO2 ; 1.03 (95% CI: 1.02-1.03) for each 10 µg/m3 increase in NOX ; 1.07 (95% CI: 1.01-1.12) for each 1 ppb increase in SO2 ; 1.03 (95% CI: 1.00-1.05) for each 0.1 ppm increase in CO. Subgroup analysis showed that this effect varied by gender ratio, age, study design, exposure assessment method, and income level. Furthermore, PM2.5 , PM10 , and NO2 had negative effects on CKD even within the World Health Organization-recommended acceptable concentrations. Our results further confirmed the adverse effect of air pollution on the risk of CKD. These findings can contribute to enhance the awareness of the importance of reducing air pollution among public health officials and policymakers.

p32/OPA1 axis-mediated mitochondrial dynamics contributes to cisplatin resistance in non-small cell lung cancer.

Cisplatin resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). p32 and OPA1 are the key regulators of mitochondrial morphology and function. This study aims to investigate the role of the p32/OPA1 axis in cisplatin resistance in NSCLC and its underlying mechanism. The levels of p32 protein and mitochondrial fusion protein OPA1 are higher in cisplatin-resistant A549/DDP cells than in cisplatin-sensitive A549 cells, which facilitates mitochondrial fusion in A549/DDP cells. In addition, the expression of p32 and OPA1 protein is also upregulated in A549 cells during the development of cisplatin resistance. Moreover, p32 knockdown effectively downregulates the expression of OPA1, stimulates mitochondrial fission, decreases ATP generation and sensitizes A549/DDP cells to cisplatin-induced apoptosis. Furthermore, metformin significantly downregulates the expressions of p32 and OPA1 and induces mitochondrial fission and a decrease in ATP level in A549/DDP cells. The co-administration of metformin and cisplatin shows a significantly greater decrease in A549/DDP cell viability than cisplatin treatment alone. Moreover, D-erythro-Sphingosine, a potent p32 kinase activator, counteracts the metformin-induced downregulation of OPA1 and mitochondrial fission in A549/DDP cells. Taken together, these findings indicate that p32/OPA1 axis-mediated mitochondrial dynamics contributes to the acquired cisplatin resistance in NSCLC and that metformin resensitizes NSCLC to cisplatin, suggesting that targeting p32 and mitochondrial dynamics is an effective strategy for the prevention of cisplatin resistance.

3D walkable DNA gears for ultrasensitive detection of multiple microRNAs in lung cancer cell lysates.

As a tumor biomarker with therapeutic application potential, microRNA (miRNA) was crucial for the accurate and sensitive detection of early-stage tumors. Herein, a unique three dimensional (3D) DNA nanomachine (DNM) was created, which was capable detecting lung cancer-related biomarkers miRNA-21, miRNA-205 and miRNA-125b in lung cancer cell lysates with extreme sensitivity. The 3D DNM was composed of DNA scissors and three flexible walkable DNA gears modified with various species of silver nanoclusters (AgNCs). Based on the flexibility of DNA scissors and the walkability of DNA gears, neighboring DNA gears closed the distance between different species of AgNCs by walking in the presence of targets, generating fluorescence resonance energy transfer (FRET) effect and emitting different kinds of fluorescence to complete the highly sensitive detection of single targets and multiple targets. The findings demonstrated that a linear model provided an excellent match for the association between fluorescence signal and target miRNAs. For miRNA-21, miRNA-205, and miRNA-125b, the limits of detection (LODs) (signal/noise = 3) were 4.2 pmol/L (pM), 6.3 pM, and 10.2 pM, respectively. Their recoveries in A549 cell lysate samples ranged from 95.3 to 108.8 % with relative standard deviations of 1.26 %-4.88 %. Satisfactorily, the 3D DNM displayed exceptional analytical performance with high sensitivity and stability, strong specificity and reproducibility, which was triumphantly employed to identify miRNAs in tumor cell lysates, providing a workable technique in creating adaptable nanostructure for dependable bioanalysis and clinical diagnosis of cancer biomarkers.

Mitochondrial dysfunction and endoplasmic reticulum stress induced by activation of PPARα leaded testicular to apoptosis in SD rats explored to di-(2-ethylhexyl) phthalate (DEHP).

Di-2-ethylhexyl phthalate (DEHP), as a common endocrine disrupting chemicals, can induce toxicity to reproductive system. However, the mechanism remains to be explored. In our study, DEHP exposure induced testicular injury in rats. The high throughput transcriptional sequencing was performed to identify differentially expressed genes (DEGs) between the treatment and control groups. KEGG analysis revealed that DEGs were enriched in apoptosis, PPARα, and ER stress pathway. DEHP up-regulated the expression of PPARα, Bax, Bim, caspase-4. GRP78, PERK, p-PERK, eIF2α, p-eIF2α, ATF4 and CHOP. This view has also been confirmed in TM3 and TM4 cells. In vitro, after pre-treatment with GW6471 (an inhibitor of PPARα) or GSK (an inhibitor of PERK), the apoptosis was inhibited and mitochondrial dysfunction was improved. Moreover, the improvement of mitochondrial dysfunction decreased the expression of PERK pathway by using SS-31(a protective agent for mitochondrial function). Interestingly, ER stress promoted the accumulation of ROS by ERO1L (the downstream of CHOP during ER stress), and the ROS further aggravated the ER stress, thus forming a feedback loop during the apoptosis. In this process, a vicious cycle consisting of PERK, eIF2α, ATF4, CHOP, ERO1L, ROS was involved. Taken together, our results suggested that mitochondrial dysfunction and ER stress-ROS feedback loop caused by PPARα activation played a crucial role in DEHP-induced apoptosis. This work provides insight into the mechanism of DEHP-induced reproductive toxicity.

Electrochemiluminescence Properties and Sensing Application of Zn(II)-Metal-Organic Frameworks Constructed by Mixed Ligands of Para Dicarboxylic Acids and 1,10-Phenanthroline.

Four metal-organic frameworks (MOFs) were designed and prepared through a mixed-ligand strategy by controlling the combination of various dicarboxylic acid ligands with invariant center metal and o-phenanthroline heterocyclic ligand. The regulatory effects of ligand electronic band and crystal structure on the electrochemiluminescence (ECL) characteristics of MOFs were verified by experimental results and density functional theory (DFT) calculations. The flexible chain structure of MOF-2 promotes electron transfer between MOF electroactive free radicals and the co-reactant, making it show outstanding ECL characteristics among all of the four MOFs with the luminescence quantum efficiency 8.37 times that of tris(bipyridine)-ruthenium(II) ([Ru(bpy)3]2+). Meanwhile, a new ECL mechanism for MOF luminescent crystal materials with reactive oxygen species in solvents as a co-reactant in the aqueous aerobic environment has been proposed. MOF-2 was selected to construct an ECL sensor for the determination of glucose in human urine samples. This study provides a useful idea for the development and design of new luminescent molecular crystal materials.

IGF­1 inhibits palmitic acid­induced mitochondrial apoptosis in macrophages.

Insulin growth factor­1 (IGF­1) is an endocrine regulator that plays an important role in normal growth and development. IGF­1 mediated effects may result in protecting macrophages from immunometabolic response. However, it is unclear whether IGF­1 has a protective effect on fatty acid­induced macrophages damage. In the present study, THP­1 cells were differentiated into macrophages and stimulated with palmitic acid (PA) in the absence or presence of IGF­1. Macrophages apoptosis was measured by Cell Counting Kit­8 assay, flow cytometry, Hoechst 33342 staining and western blotting. The mitochondrial damage was evaluated using JC­1 staining and mitochondrial reactive oxygen species detection. The activation of mitophagy was assessed using immunofluorescence and western blotting. As a result, IGF­1 significantly restored the survival rate in macrophages, while the apoptosis was inhibited through mitochondrial pathway. In addition, IGF­1 protected the mitochondrial damage induced by PA. Furthermore, PA induced mitophagy via phosphatase and tensin homolog­induced putative kinase protein 1/Parkin, which was reversed by IGF­1. Taken together, the present study demonstrated the protective effect of IGF­1 on PA­induced mitochondrial apoptosis in macrophages, which might provide a potential therapeutic strategy for treatment of lipotoxicity.