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Killer cell lectin-like receptor G1 (KLRG1) is an immune checkpoint receptor expressed predominantly in NK and T-cell subsets that downregulates the activation and proliferation of immune cells and participates in cell-mediated immune responses. Accumulating evidence has demonstrated the importance of KLRG1 as a noteworthy disease marker and therapeutic target that can influence disease onset, progression, and prognosis. Blocking KLRG1 has been shown to effectively mitigate the effects of downregulation in various mouse tumor models, including solid tumors and hematologic malignancies. However, KLRG1 inhibitors have not yet been approved for human use, and the understanding of KLRG1 expression and its mechanism of action in various diseases remains incomplete. In this review, we explore alterations in the distribution, structure, and signaling pathways of KLRG1 in immune cells and summarize its expression patterns and roles in the development and progression of autoimmune diseases, infectious diseases, and cancers. Additionally, we discuss the potential applications of KLRG1 as a tool for tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Carpal tunnel syndrome (CTS), an entrapment neuropathy caused by pressure of the median nerve, is a progressive condition that can lead to a decreased quality of life. Studies suggest an association between CTS and arthritis; however, previous studies examining osteoarthritis (OA) and CTS are limited in number, scope and study design. This study estimated the incidence and risk of CTS among patients with OA, both overall and by specific joints, in a large population-based cohort in the United States. Methods: Patients from the Optum claims database aged ≥ 45 years and diagnosed with OA between January 1, 2018, and December 31, 2022, were eligible for the OA cohort. The non-OA cohort included those without a diagnosis of OA at the index date and no history of OA for 12 months pre-index. Baseline characteristics were balanced using propensity score matching. The risk of CTS in the OA and non-OA cohort were evaluated using incidence rates and adjusted hazard ratios that were estimated using Cox regression. Results: After applying the inclusion/exclusion criteria, 3,610,240 of the 6,023,384 adults with a diagnosis of OA remained in the OA cohort. After propensity-score matching, each cohort included 1,033,439 individuals. The incidence rates for CTS per 1000 person-years were 7.35 (95% confidence interval [CI] 7.21–7.49) in the OA cohort and 1.44 (95% CI 1.38–1.50) in the non-OA cohort. The risk of developing CTS in patients with OA was ~ 4 times that of patients without (hazard ratio = 3.80; 95% CI 3.54–4.07). This increased risk was found across all OA joint types, with OA of the hand/wrist having the highest risk for CTS. Additionally, multiple OA joints presented a higher risk compared with a single affected joint. Conclusions: OA increases the risk of CTS, but this is not limited to patients with hand/wrist OA, suggesting a systemic impact of OA on CTS. While the risk appears highest for patients with hand/wrist OA, patients with more distant affected joints like knee or hip also have an increased risk of CTS. [ABSTRACT FROM AUTHOR]

Background: Acute type A aortic dissection (ATAAD) complicated by mesenteric malperfusion is a critical and complicated condition. The optimal treatment strategy remains controversial, debate exists as to whether aortic dissection or mesenteric malperfusion should be addressed first, and the exact time window for mesenteric ischemia intervention is still unclear. To solve this problem, we developed a new concept based on the pathophysiological mechanism of mesenteric ischemia, using a 6-hour time window to divide newly admitted patients by the time from onset to admission, applying different treatment protocols to improve the clinical outcomes of patients with ATAAD complicated by mesenteric malperfusion. Methods: This was a retrospective study that covered a five-year period. From July 2018 to December 2020(phase I), all patients underwent emergency open surgery. From January 2021 to June 2023(phase II), patients with an onset within 6 h all underwent open surgical repair, followed by immediately postoperative examination if the malperfusion is suspected, while the restoration of mesenteric perfusion and visceral organ function was performed first, followed by open repair, in patients with an onset beyond 6 h. Results: There were no significant differences in baseline and surgical data. In phase I, eleven patients with mesenteric malperfusion underwent open surgery, while in phase II, our novel strategy was applied, with sixteen patients with an onset greater than 6 h and eleven patients with an onset less than 6 h. During the waiting period, none died of aortic rupture, but four patients died of organ failure, twelve patients had organ function improvement and underwent surgery successfully survived. The overall mortality rate decreased with the use of this novel strategy (54.55% vs. 18.52%, p = 0.047). Furthermore, the surgical mortality rate between the two periods showed even stronger statistical significance (54.55% vs. 4.35%, p = 0.022). Moreover, the proportions of patients with sepsis and multiorgan failure also showed differences. Conclusions: Our novel strategy for patients with ATAAD complicated by mesenteric malperfusion not only improves the surgical success rate but also reduces the overall mortality rate. [ABSTRACT FROM AUTHOR]

Myeloperoxidase (MPO) plays critical role in the pathology of cerebral ischemia–reperfusion (I/R) injury via producing hypochlorous acid (HOCl) and inducing oxidative modification of proteins. High-mobility group box 1 (HMGB1) oxidation, particularly disulfide HMGB1 formation, facilitates the secretion and release of HMGB1 and activates neuroinflammation, aggravating cerebral I/R injury. However, the cellular sources of MPO/HOCl in ischemic brain injury are unclear yet. Whether HOCl could promote HMGB1 secretion and release remains unknown. In the present study, we investigated the roles of microglia-derived MPO/HOCl in mediating HMGB1 translocation and secretion, and aggravating the brain damage and blood-brain barrier (BBB) disruption in cerebral I/R injury. In vitro, under the co-culture conditions with microglia BV cells but not the single culture conditions, oxygen–glucose deprivation/reoxygenation (OGD/R) significantly increased MPO/HOCl expression in PC12 cells. After the cells were exposed to OGD/R, MPO-containing exosomes derived from BV2 cells were released and transferred to PC12 cells, increasing MPO/HOCl in the PC12 cells. The HOCl promoted disulfide HMGB1 translocation and secretion and aggravated OGD/R-induced apoptosis. In vivo, SD rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) plus different periods of reperfusion. Increased MPO/HOCl production was observed at the reperfusion stage, accomplished with enlarged infarct volume, aggravated BBB disruption and neurological dysfunctions. Treatment of MPO inhibitor 4-aminobenzoic acid hydrazide (4-ABAH) and HOCl scavenger taurine reversed those changes. HOCl was colocalized with cytoplasm transferred HMGB1, which was blocked by taurine in rat I/R-injured brain. We finally performed a clinical investigation and found that plasma HOCl concentration was positively correlated with infarct volume and neurological deficit scores in ischemic stroke patients. Taken together, we conclude that ischemia/hypoxia could activate microglia to release MPO-containing exosomes that transfer MPO to adjacent cells for HOCl production; Subsequently, the production of HOCl could mediate the translocation and secretion of disulfide HMGB1 that aggravates cerebral I/R injury. Furthermore, plasma HOCl level could be a novel biomarker for indexing brain damage in ischemic stroke patients. [ABSTRACT FROM AUTHOR]

The application of nano fertilizers is one of the hotspots in current agricultural production. In this study, nano silicon materials were mixed with compound fertilizers to make nano silicon fertilizer. The effects of different amounts of nano silicon application on the breaking-resistance strength, lodging-resistance index, lignin accumulation, lignin synthesis related enzymes, and the relative expression of lignin synthesis related genes in the second stem node of wheat were mainly studied. Four treatments were set up: CK (750 kg·ha−1 compound fertilizer), T1 (750 kg·ha−1 compound fertilizer + 0.9 kg·ha−1 nano silicon), T2 (750 kg·ha−1 compound fertilizer + 1.8 kg·ha−1 nano silicon), T3 (750 kg·ha−1 compound fertilizer + 2.7 kg·ha−1 nano silicon). The results of the two-year experiment showed that the breaking-resistance strength, lodging-resistance index, lignin accumulation in the second stem node of wheat treated with nano silicon fertilizer were higher than CK. In the first year of the experiment, the lignin accumulation of T2 was 130.73%, 5.14% and 7.25% higher than that of CK, T1 and T3 respectively at the maturity stage. In the second year of the experiment, the lignin accumulation of T2 was 20.33%, 11.19% and 9.89% higher than that of CK, T1 and T3 respectively at the maturity stage. And the activities of PAL, 4CL, CAD, and related gene expression levels were also higher than CK. And among them, T2 performed the best, indicating that the application of nano silicon fertilizer is beneficial for improving the lodging resistance of wheat stems and is of great significance for improving the quality of wheat. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRNAs) are involved in various pathological processes, such as proliferation, growth, and apoptosis, of intervertebral disc (IVD) cells and play an important role in the development of intervertebral disc degeneration (IDD). Although some studies have reported the role of miRNAs in IDD, scientific econometric analysis in this field is not available. Objectives: We designed this study to describe the current research trends and potential mechanisms associated with the role of miRNAs in IDD and to provide new ideas for future research in this field. Methods: We conducted a bibliometric analysis of the publications on the role of miRNAs in IDD included in the Web of Science core collection database to elucidate the current research trends in this field. The potential mechanisms were constructed using the Arrowsmith project. Results: We found that the number of miRNAs and IDD-related publications increased over the years. China was the most important contributor to research in this field. The top three institutions in terms of number of articles published were Huazhong University of Science and Technology, Shanghai Jiao Tong University, and Xi'an Jiao Tong University. Shanghai Jiao Tong University had the highest number of citations. Experimental and thermal medicine had the maximum number of documents, and Cell promotion had the most citations. The journal with the most mean times cited per study was Annals of the Rheumatic Diseases. The author Wang K had the highest number of publications, and Wang HQ had the highest number of citations. These two authors made important contributions to the research in this field. The keyword analysis showed that recent studies have focused on miRNAs regulating nucleus pulposus cell apoptosis and proliferation. Moreover, we revealed the potential mechanisms of miRNAs associated with IDD, including miRNAs regulating the extracellular matrix (ECM) degradation, mediating cartilage endplate (CEP) degeneration, and participating in inflammatory responses. Conclusion: We demonstrated the knowledge map of miRNAs and IDD-related research through bibliometric analysis and elucidated the current research status and hotspots in this field. The mechanisms by which miRNAs regulate the apoptosis and proliferation of degenerated IVDs, promote ECM degradation, mediate CEP degeneration, and participate in inflammatory responses should be explored in further studies. [ABSTRACT FROM AUTHOR]

Background: Radiation-induced lung injury (RILI) is considered one of the most common complications of thoracic radiation. Recent studies have focused on stem cell properties to obtain ideal therapeutic effects, and Sox9 has been reported to be involved in stem cell induction and differentiation. However, whether Sox9-expressing cells play a role in radiation repair and regeneration remains unknown. Methods: We successfully obtained Sox9CreER, RosatdTomato and RosaDTA mice and identified Sox9-expressing cells through lineage tracing. Then, we evaluated the effects of the ablation of Sox9-expressing cells in vivo. Furthermore, we investigated the underlying mechanism of Sox9-expressing cells during lung regeneration via an online single-cell RNA-seq dataset. Results: In our study, we demonstrated that Sox9-expressing cells promote the regeneration of lung tissues and that ablation of Sox9-expressing cells leads to severe phenotypes after radiation damage. In addition, analysis of an online scRNA-Seq dataset revealed that the PI3K/AKT pathway is enriched in Sox9-expressing cells during lung epithelium regeneration. Finally, the AKT inhibitor perifosine suppressed the regenerative effects of Sox9-expressing cells and the AKT pathway agonist promotes proliferation and differentiation. Conclusions: Taken together, the findings of our study suggest that Sox9-expressing cells may serve as a therapeutic target in lung tissue after RILI. [ABSTRACT FROM AUTHOR]

Background: Neural Tube Defects (NTDs) are congenital malformations of the central nervous system resulting from the incomplete closure of the neural tube during early embryonic development. Neuroinflammation refers to the inflammatory response in the nervous system, typically resulting from damage to neural tissue. Immune-related processes have been identified in NTDs, however, the detailed relationship and underlying mechanisms between neuroinflammation and NTDs remain largely unclear. In this study, we utilized integrated multi-omics analysis to explore the role of neuroinflammation in NTDs and identify potential prenatal diagnostic markers using a murine model. Methods: Nine public datasets from Gene Expression Omnibus (GEO) and ArrayExpress were mined using integrated multi-omics analysis to characterize the molecular landscape associated with neuroinflammation in NTDs. Special attention was given to the involvement of macrophages in neuroinflammation within amniotic fluid, as well as the dynamics of macrophage polarization and their interactions with neural cells at single-cell resolution. We also used qPCR assay to validate the key TFs and candidate prenatal diagnostic genes identified through the integrated analysis in a retinoic acid-induced NTDs mouse model. Results: Our analysis indicated that neuroinflammation is a critical pathological feature of NTDs, regulated both transcriptionally and epigenetically within central nervous system tissues. Key alterations in gene expression and pathways highlighted the crucial role of STATs molecules in the JAK-STAT signaling pathway in regulating NTDs-associated neuroinflammation. Furthermore, single-cell resolution analysis revealed significant polarization of macrophages and their interaction with neural cells in amniotic fluid, underscoring their central role in mediating neuroinflammation associated with NTDs. Finally, we identified a set of six potential prenatal diagnostic genes, including FABP7, CRMP1, SCG3, SLC16A10, RNASE6 and RNASE1, which were subsequently validated in a murine NTDs model, indicating their promise as prospective markers for prenatal diagnosis of NTDs. Conclusions: Our study emphasizes the pivotal role of neuroinflammation in the progression of NTDs and underlines the potential of specific inflammatory and neural markers as novel prenatal diagnostic tools. These findings provide important clues for further understanding the underlying mechanisms between neuroinflammation and NTDs, and offer valuable insights for the future development of prenatal diagnostics. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy brings new hope to patients with advanced gastric cancer. However, liver metastases can reduce the efficacy of immunotherapy in patients. Tumor-associated macrophages (TAMs) may be the cause of this reduction in efficacy. SPP1 + TAMs are considered to have immunosuppressive properties. We aimed to investigate the involvement of SPP1 + TAMs in the metastasis of gastric cancer. Methods: The single-cell transcriptome was combined with batched BULK datasets for analysis. Animal models were used to verify the analysis results. Results: We reveal the interaction of SPP1 + TAMs with CD8 + exhausted T cells in metastatic cancer. Among these interactions, GDF15-TGFBR2 may play a key immunosuppressive role. We constructed an LR score to quantify interactions based on ligands and receptors. The LR score is highly correlated with various immune features and clinical molecular subtypes. The LR score may also guide the prediction of the efficacy of immunotherapy and prognosis. Conclusions: The crosstalk between SPP1 + TAMs and CD8 + exhausted T cells plays a key immunosuppressive role in the gastric metastatic cancer microenvironment. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is a systemic bone disease which can increase the risk of osteoporotic fractures. Dual-energy X-ray absorptiometry (DXA) is considered as the clinical standard for diagnosing osteoporosis by detecting the bone mineral density (BMD) in patients, but it has flaws in distinguishing between calcification and other degenerative diseases, thus leading to inaccurate BMD levels in subjects. Mindways quantitative computed tomography (Mindways QCT) is a classical QCT system. Similar to DXA, Mindways QCT can directly present the density of trabecular bone, vascular or tissue calcification; therefore, it is more accurate and sensitive than DXA and has been widely applied in clinic to evaluate osteoporosis. iCare QCT osteodensitometry was a new phantom-based QCT system, recently developed by iCare Inc. (China). It has been gradually applied in clinic by its superiority of taking 3-dimensional BMD of bone and converting BMD values to T value automatically. This study aimed at evaluating the osteoporosis detection rate of iCare QCT, compared with synchronous Mindways QCT (USA). Methods: In this study, 131 patients who underwent hip phantom-based CT scan were included. Bone mineral density (BMD) of the unified region of interests (ROI) defined at the European spine phantom (ESP, German QRM) including L1 (low), L2 (medium), and L3 (high) vertebral bodies was detected for QCT quality control and horizontal calibration. Every ESP scan were taken for 10 times, and the mean BMD values measured by iCare QCT and Mindways QCT were compared. Hip CT scan was conducted with ESP as calibration individually. T-scores gained from iCare QCT and Mindways QCT were analyzed with Pearson correlation test. The detection rates of osteoporosis were compared between iCare QCT and Mindways QCT. The unified region of interests (ROI) was delineated in the QCT software. Results: The results showed that there was no significant difference between iCare QCT and Mindways QCT in the evaluation of L1, L2, and L3 vertebrae bodies in ESP. A strong correlation between iCare QCT and Mindways QCT in the assessment of hip T-score was found. It was illustrated that iCare QCT had a higher detection rate of osteoporosis with the assessment of hip T-score than Mindways QCT did. In patients < 50 years subgroup, the detection rate of osteoporosis with iCare QCT and Mindways QCT was equal. In patients ≥ 50 years subgroup, the detection rate of osteoporosis with iCare QCT (35/92, 38.0%) was higher than that with Mindways QCT. In female subgroup, the detection rate of osteoporosis with iCare QCT was significantly higher than Mindways QCT. In male subgroup, the detection rate of osteoporosis with iCare QCT was also markedly higher than Mindways QCT. The detection rate of osteoporosis by iCare QCT was higher than Mindways QCT with hip bone assessment. Of course, the results of the present study remain to be further verified by multicenter studies in the future. [ABSTRACT FROM AUTHOR]

The reversible oxidation-reduction homeostasis mechanism functions as a specific signal transduction system, eliciting related physiological responses. Disruptions to redox homeostasis can have negative consequences, including the potential for cancer development and progression, which are closely linked to a series of redox processes, such as adjustment of reactive oxygen species (ROS) levels and species, changes in antioxidant capacity, and differential effects of ROS on downstream cell fate and immune capacity. The tumor microenvironment (TME) exhibits a complex interplay between immunity and regulatory cell death, especially autophagy and apoptosis, which is crucially regulated by ROS. The present study aims to investigate the mechanism by which multi-source ROS affects apoptosis, autophagy, and the anti-tumor immune response in the TME and the mutual crosstalk between these three processes. Given the intricate role of ROS in controlling cell fate and immunity, we will further examine the relationship between traditional cancer therapy and ROS. It is worth noting that we will discuss some potential ROS-related treatment options for further future studies. [ABSTRACT FROM AUTHOR]

Background: Uveitis and posterior scleritis are sight-threatening diseases with undefined pathogenesis and accurate diagnosis remains challenging. Methods: Two plasma-derived extracellular vesicle (EV) subpopulations, small and large EVs, obtained from patients with ankylosing spondylitis-related uveitis, Behcet's disease uveitis, Vogt-Koyanagi-Harada syndrome, and posterior scleritis were subjected to proteomics analysis alongside plasma using SWATH-MS. A comprehensive bioinformatics analysis was performed on the proteomic profiles of sEVs, lEVs, and plasma. Candidate biomarkers were validated in a new cohort using ELISA. Pearson correlation analysis was performed to analyze the relationship between clinical parameters and proteomic data. Connectivity map database was used to predict therapeutic agents. Results: In total, 3,668 proteins were identified and over 3000 proteins were quantified from 278 samples. When comparing diseased group to healthy control, the proteomic profiles of the two EV subgroups were more correlated with disease than plasma. Comprehensive bioinformatics analysis highlighted potential pathogenic mechanisms for these diseases. Potential biomarker panels for four diseases were identified and validated. We found a negative correlation between plasma endothelin-converting enzyme 1 level and mean retinal thickness. Potential therapeutic drugs were proposed, and their targets were identified. Conclusions: This study provides a proteomic landscape of plasma and EVs involved in ankylosing spondylitis-related uveitis, Behcet's disease uveitis, Vogt-Koyanagi-Harada syndrome, and posterior scleritis, offers insights into disease pathogenesis, identifies valuable biomarker candidates, and proposes promising therapeutic agents. [ABSTRACT FROM AUTHOR]

Background: Langerhans cell histiocytosis (LCH) is a rare disorder. The treatment options vary depending on how many organs are involved and how extensive the disease is. In this report, a case of LCH with isolated 6th cervical vertebra (C6) collapse was presented. This case was treated with anterior corpectomy and instrumented fusion, followed by local radiotherapy (RT), with a good clinical outcome up to postoperative six months. Case presentation: This was a 47-year-old female patient with a complaint of neck pain and bilateral shoulder pain for two months before consultation. She was initially treated with analgesics, but the pain was persistent. Further radiological evaluations revealed an osteolytic lesion within the C6 vertebral body with a pathological fracture. Magnetic resonance imaging (MRI) with contrast of the cervical spine revealed diffused hypointense signal changes on the T1-weighted images and hyperintense signal changes on the T2-weighted images in the C6 vertebral body, with significant contrast-enhanced infiltration signals. Furthermore, in positron emission tomography-computed tomography (PET-CT), focal hypermetabolism and abnormal uptake signals were seen only in the C6 vertebral body. The patient underwent an anterior cervical corpectomy with instrumented fusion. The histopathological results confirmed the diagnosis of LCH. The patient reported significant pain relief on postoperative day one. Moreover, she was treated by local RT at postoperative one month. Good clinical outcomes were achieved in the form of no pain and recovery in neck mobility up to postoperative six months. No evidence of recurrence was observed at the final follow-up. Conclusions: This case report describes a treatment option for a solitary C6 collapse with LCH managed by anterior corpectomy and instrumented fusion, followed by local RT, with a good clinical outcome at postoperative six months. More studies are needed to elucidate whether such a treatment strategy is superior to surgery or RT alone. [ABSTRACT FROM AUTHOR]

Background: Whipple's disease is a chronic infection due to Tropheryma whipplei, commonly reported in the Caucasian but not in the Chinese population. Case presentation: A 52-year-old female with good past health, was diagnosed with Whipple's disease, presenting with constipation, unintentional weight gain, and fleeting polyarthralgia. Investigations prior to admission showed raised CA125 and computed tomography of the abdomen showed multiple retroperitoneal mesenteric lymphadenopathies. Extensive investigations performed on secondary causes of weight gain were unrevealing. Subsequent PET-CT scan revealed generalized lymphadenopathy involving the left deep cervical, supraclavicular, and retroperitoneal mesenteric area. Excisional biopsy of the left supraclavicular lymph node was performed, with histology showing infiltrations of Periodic acid-Schiff positive foamy macrophages. T. whipplei DNA was detected in her serum, saliva, stool, and lymph node by PCR targeting the 16S ribosomal RNA gene. She was started on intravenous ceftriaxone, and then stepped down to oral antibiotics for a total of 44 months. The recurrence of fever after 12 days of ceftriaxone raised the suspicion of Immune Reconstitution Inflammatory Syndrome (IRIS). Serial imaging showed a gradual reduction in the size of retroperitoneal lymphadenopathies. Literature review on Whipple's disease in the Chinese population identified 13 reports of detectable T. whipplei DNA in clinical specimens. The majority of the cases were pneumonia, followed by culture-negative endocarditis, encephalitis, and skin and soft tissue infection. However, most patients with pneumonia were diagnosed based on next generation sequencing alone, with the resolution of pulmonary infiltrates without adequate duration of antibiotics, suggesting the possibility of colonization instead of infection. The recommendation of long-term doxycycline suppression after treatment may be supported by the slow response of retroperitoneal lymphadenopathies to antibiotics in our patient. Conclusions: Unintentional weight gain and constipation could be atypical presentations of Whipple's disease. It is a rare disease in the Chinese population despite the advancement of molecular techniques in the diagnosis of infections. A prolonged course of antibiotics may be required due to slow clinical response as documented by serial imaging in our case. The possibility of IRIS should be considered in patients with breakthrough fever during treatment of Whipple's disease. [ABSTRACT FROM AUTHOR]

Background: Opportunistic infection is an under-recognized complication of Cushing's syndrome, with infection due to atypical mycobacterium rarely reported. Mycobacterium szulgai commonly presents as pulmonary infection, with cutaneous infection seldom reported in the literature. Case Presentation: 48-year-old man with a newly-diagnosed Cushing's syndrome secondary to adrenal adenoma presented with a subcutaneous mass on the dorsum of his right hand, was diagnosed with cutaneous Mycobacterium szulgai infection. The most likely source of the infection was through minor unnoticed trauma and inoculation from a foreign body. The patient's Cushing's syndrome, high serum cortisol levels and secondary immune suppression facilitated mycobacterial replication and infection. The patient was successfully treated with adrenalectomy, surgical debridement of cutaneous lesion, and a combination of rifampicin, levofloxacin, clarithromycin, and ethambutol for 6 months. There were no signs of relapse one year after cessation of anti-mycobacterial treatment. A literature review on cutaneous M. szulgai infection to further characterize the clinical characteristics of this condition, identified 17 cases of cutaneous M. szulgai infection in the English literature. Cutaneous M. szulgai infections with subsequent disease dissemination are commonly reported in immunocompromised hosts (10/17, 58.8%), as well as in immunocompetent patients with a history of breached skin integrity, such as invasive medical procedures or trauma. The right upper extremity is the most commonly involved site. Cutaneous M. szulgai infection is well controlled with a combination of anti-mycobacterial therapy and surgical debridement. Disseminated infections required a longer duration of therapy than localized cutaneous infections. Surgical debridement may shorten the duration of antibiotics. Conclusions: Cutaneous M. szulgai infection is a rare complication of adrenal Cushing's syndrome. Further studies are needed to provide evidence-based guidelines on the best combination of anti-mycobacterial and surgical therapy for managing this rare infective complication. [ABSTRACT FROM AUTHOR]

Background: Previous reports have indicated that disrupting the Wnt/β-catenin pathway in dendritic cells (DCs) may affect the progression of autoimmune inflammation; however, the factors and timing that regulate Wnt/β-catenin signaling have not been clearly understood. Methods: Experimental autoimmune uveitis (EAU) mice and Vogt–Koyanagi–Harada disease (VKH) patient samples were used to detect the expression of Wnt/β-catenin pathway genes. Western blot, real-time PCR, flow cytometry, and ELISA were performed to examine the expression of components of the Wnt/β-catenin pathway and inflammatory factors. DC-specific β-catenin knockout mice and 6-bromoindirubin-3′-oxime (BIO) administered mice were used to observe the effect of disrupting the Wnt pathway on EAU pathogenesis. Results: Wnt/β-catenin signaling was inhibited in DCs during the induction phase of EAU. The inhibition was mediated by pertussis toxin (PTX), which promoted DC maturation, in turn promoting pathogenic T cell proliferation and differentiation. In vivo experiments confirmed that deleting β-catenin in DCs enhanced EAU severity, and pre-injection of PTX advanced EAU onset. Administration of a Wnt activator (BIO) limited the effects of PTX, in turn ameliorating EAU. Conclusions: Our results demonstrate that PTX plays a key role as a virulence factor in initiating autoimmune inflammation via DCs by inhibiting Wnt/β-catenin signaling in EAU, and highlight the potential mechanism by which infection can trigger apparent autoimmunity. [ABSTRACT FROM AUTHOR]

Background: Autoimmune uveitis is a sight-threatening intraocular inflammation mainly caused by immune dysregulation. The development of safe and effective therapeutic approaches is urgently needed. Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have been demonstrated to inhibit autoimmune responses; however, the immunosuppressive effect of MSC-sEVs is too weak for clinical transfer. In the current study, we investigated the therapeutic effect of IL-10-overexpressing MSC-sEVs (sEV-IL10) on experimental autoimmune uveitis (EAU) and studied the underlying mechanism. Methods: Mice were randomly grouped and received a single tail vein injection of different sEVs (50 μg) or PBS on day 11 post-immunization. The clinical and histological scores were graded, and the percentage of T helper cell was measured. To investigate the effect of sEVs on the proliferation of T-cells and the differentiation of Th1, Th17 and Treg cells, T-cells were cocultured with sEVs under the corresponding culture conditions. After labeled with PKH-26, sEVs were traced both in vivo and in vitro. Results: Compared with normal or vector sEV-treated groups, mice in the sEV-IL10-treated group had lower clinical and histological scores with lower percentages of Th1 and Th17 cells in the eyes and higher percentages of Treg cells in the spleen and draining lymph nodes (LN). Furthermore, sEV-IL10 enhanced the suppressive effect of MSC-sEVs on the proliferation of T-cells and differentiation of Th1 and Th17 cells, whereas upregulated the differentiation of Treg cells. Both in vivo and in vitro experiments demonstrated that MSC-sEVs were rapidly enriched in target tissues and internalized by T-cells. Conclusion: These results suggested that sEV-IL10 effectively ameliorates EAU by regulating the proliferation and differentiation of T-cells, indicating sEVs as a potential novel therapy for autoimmune uveitis or other autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background: Intervertebral disc degeneration (IDD) has become a serious public health problem, the mechanism of which is complex and still unclear. We aimed to construct a ceRNA network related to IDD to explore its pathogenesis. Methods: We downloaded the GSE67566, GSE63492, GSE116726 and GSE124272 datasets from GEO database, and obtained the differentially expressed RNAs. Then, we constructed a ceRNA network and the KEGG and GO enrichment analysis were performed. Finally, we performed immune cell infiltration analysis on the GSE124272 dataset and analysed the correlation between immune cell abundance and hub genes expression levels. Results: The ceRNA network included three down-regulated circRNAs: hsa_circ_0074817, hsa_circ_0002702, hsa_circ_0003600, three up-regulated miRNAs: hsa-miR-4741, hsa-miR-3158-5p, hsa-miR-508-5p, and 57 down-regulated mRNAs, including six hub genes: IGF1, CHEK1, CCNB1, OIP5, BIRC5, AR. GO and KEGG analysis revealed that the network is involved in various biological functions. Immune infiltration analysis showed that IDD was closely related to immune cell infiltration, and hub genes could further affect the development of IDD by affecting immune cell infiltration. Conclusion: This study identified the hsa_circ_0074817-hsa-miR-508-5p-IGF1/CHEK1/CCNB1, the hsa_circ_0003600-hsa-miR-4741-BIRC5/OIP5/AR and the hsa_circ_0002702-hsa-miR-3158-5p-IGF1/AR as important regulatory axis of IDD, which will help us gain further insight into the pathogenesis of IDD and determine potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel diseases (IBD) are chronic relapsing–remitting inflammatory diseases of the gastrointestinal tract that are typically categorized into two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). Although MSCs therapy has achieved encouraging outcomes in IBD therapy, objective responses are limited in colon fibrosis stenosis owing to the complicated microenvironment of CD and MSCs heterogeneity of quality. Here, we chose IFN-γ and kynurenic acid (KYNA) to overcome the low response and heterogeneity of human adipose-derived MSCs (hADSCs) to treat IBD and expand the therapeutic effects based on the excellent ability of IFN-γ and KYNA to promote indoleamine 2,3-dioxygenase-1 (IDO-1) signaling, providing a potential protocol to treat IBD and fibrosis disease. Methods: hADSCs were isolated, cultured, and identified from human abdominal adipose tissue. The CD pathology-like acute colitis and chronic colon fibrosis rat model was induced by 2,4,6-trinitrobenzen sulfonic acid (TNBS). hADSCs were pretreated in vitro with IFN-γ and KYNA and then were transplanted intravenously at day 1 and 3 of TNBS administration in colitis along with at day 1, 15, and 29 of TNBS administration in chronic colonic fibrosis. Therapeutic efficacy was evaluated by body weights, disease activity index, pathological staining, real-time PCR, Western blot, and flow cytometry. For knockout of IDO-1, hADSCs were transfected with IDO-1-targeting small gRNA carried on a CRISPR-Cas9-lentivirus vector. Results: hADSCs treated with IFN-γ and KYNA significantly upregulated the expression and secretion of IDO-1, which has effectively ameliorated CD pathology-like colitis injury and fibrosis. Notably, the ability of hADSCs with IDO-1 knockout to treat colitis was significantly impaired and diminished the protective effects of the primed hADSCs with IFN-γ and KYNA. Conclusion: Inflammatory cytokines IFN-γ- and KYNA-treated hADSCs more effectively alleviate TNBS-induced colitis and colonic fibrosis through an IDO-1-dependent manner. Primed hADSCs are a promising new strategy to improve the therapeutic efficacy of MSCs and worth further research. [ABSTRACT FROM AUTHOR]

Background: Autoimmune uveitis is a sight-threatening intraocular inflammation mainly caused by immune dysregulation. The development of safe and effective therapeutic approaches is urgently needed. Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have been demonstrated to inhibit autoimmune responses; however, the immunosuppressive effect of MSC-sEVs is too weak for clinical transfer. In the current study, we investigated the therapeutic effect of IL-10-overexpressing MSC-sEVs (sEV-IL10) on experimental autoimmune uveitis (EAU) and studied the underlying mechanism. Methods: Mice were randomly grouped and received a single tail vein injection of different sEVs (50 μg) or PBS on day 11 post-immunization. The clinical and histological scores were graded, and the percentage of T helper cell was measured. To investigate the effect of sEVs on the proliferation of T-cells and the differentiation of Th1, Th17 and Treg cells, T-cells were cocultured with sEVs under the corresponding culture conditions. After labeled with PKH-26, sEVs were traced both in vivo and in vitro. Results: Compared with normal or vector sEV-treated groups, mice in the sEV-IL10-treated group had lower clinical and histological scores with lower percentages of Th1 and Th17 cells in the eyes and higher percentages of Treg cells in the spleen and draining lymph nodes (LN). Furthermore, sEV-IL10 enhanced the suppressive effect of MSC-sEVs on the proliferation of T-cells and differentiation of Th1 and Th17 cells, whereas upregulated the differentiation of Treg cells. Both in vivo and in vitro experiments demonstrated that MSC-sEVs were rapidly enriched in target tissues and internalized by T-cells. Conclusion: These results suggested that sEV-IL10 effectively ameliorates EAU by regulating the proliferation and differentiation of T-cells, indicating sEVs as a potential novel therapy for autoimmune uveitis or other autoimmune diseases. [ABSTRACT FROM AUTHOR]

Aim: Previous studies have reported that circular RNA (circRNA) is associated with the pathogenesis of CRC. This study was designed to reveal the mechanism of circ-ring finger protein 121 (circ-RNF121) in colorectal cancer (CRC). Materials and methods: The levels of circ-RNF121, microRNA-1224-5p (miR-1224-5p) and forkhead box M1 (FOXM1) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Protein level was detected by western blot. Cell proliferation was analyzed by 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and cell colony formation assays. Flow cytometry analysis was performed to investigate cell apoptosis. Cell migration and invasion were investigated by transwell and wound-healing assays. Cell glycolysis was detected using glucose, lactate and ADP/ATP ratio assay kits. The binding relationship between miR-1224-5p and circ-RNF121 or FOXM1 was predicted by starBase online database, and identified by dual-luciferase reporter assay. The impacts of circ-RNF121 silencing on tumor formation in vivo were disclosed by in vivo tumor formation assay. Key findings: Circ-RNF121 and FOXM1 expression were dramatically upregulated, while miR-1224-5p expression was downregulated in CRC tissues or cells compared with control groups. Circ-RNF121 silencing repressed cell proliferation, migration, invasion and glycolysis but induced cell apoptosis in CRC, which were attenuated by miR-1224-5p inhibitor. Additionally, circ-RNF121 acted as a sponge of miR-1224-5p and miR-1224-5p bound to FOXM1. Circ-RNF121 silencing inhibited tumor growth in vivo. Furthermore, circ-RNF121 was secreted through being packaged into exosomes. Significance: The finding provided a novel insight into studying circRNA-mediated CRC therapy. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is a common malignant tumor. Circular RNAs (circRNAs) have been reported to take part in the progression of CRC. However, the functions of circ_0084615 in CRC development are still undefined. In this study, we aimed to explore the functions and underlying mechanisms of circ_0084615 in CRC. Methods: qRT-PCR, western blot assay and IHC assay were utilized for the levels of circ_0084615, miR-599, ONECUT2 or EIF4A3. 5-ethynyl-2'-deoxyuridine (EdU) assay and colony formation assay were conducted for cell proliferation ability. Wound-healing assay and transwell assay were applied to evaluate cell migration and invasion. Tube formation assay was used to analyze angiogenesis ability. RNA immunoprecipitation (RIP) assay, RNA pull down assay and dual-luciferase reporter assay were used to analyze the relationships of circ_0084615, miR-599, ONECUT2 and EIF4A3. Murine xenograft model assay was employed for the role of circ_0084615 in vivo. Results: Circ_0084615 was elevated in CRC tissues and was linked to TNM stages, lymph node metastasis, differentiation and overall survival rate. Circ_0084615 knockdown inhibited CRC cell proliferation, migration, invasion and angiogenesis in vitro and hampered tumorigenesis in vivo. Circ_0084615 sponged miR-599 and miR-599 inhibition reversed circ_0084615 knockdown-mediated effects on CRC cell growth, motility and angiogenesis. ONECUT2 was identified as the target gene of miR-599. ONECUT2 overexpression recovered the effects of miR-599 on CRC malignant behaviors. Additionally, EIF4A3 induced circ_0084615 expression. Conclusions: EIF4A3-induced circ_0084615 played an oncogenic role in CRC development via miR-599/ONECUT2 axis. [ABSTRACT FROM AUTHOR]

Background: Liver fibrosis (LF) is a common pathological process characterized by the activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix. Severe LF causes cirrhosis and even liver failure, a major cause of morbidity and mortality worldwide. Transplantation of human placental mesenchymal stem cells (hPMSCs) has been considered as an alternative therapy. However, the underlying mechanisms and the appropriate time window for hPMSC transplantation are not well understood. Methods: We established mouse models of CCl4-injured LF and administered hPMSCs at different stages of LF once a week for 2 weeks. The therapeutic effect of hPMSCs on LF was investigated, according to histopathological and blood biochemical analyses. In vitro, the effect of hPMSCs and the secretomes of hPMSCs on the inhibition of activated HSCs was assessed. RNA sequencing (RNA-seq) analysis, real-time PCR array, and western blot were performed to explore possible signaling pathways involved in treatment of LF with hPMSCs. Results: hPMSC treatment notably alleviates experimental hepatic fibrosis, restores liver function, and inhibits inflammation. Furthermore, the therapeutic effect of hPMSCs against mild-to-moderate LF was significantly greater than against severe LF. In vitro, we observed that the hPMSCs as well as the secretomes of hPMSCs were able to decrease the activation of HSCs. Mechanistic dissection studies showed that hPMSC treatment downregulated the expression of fibrosis-related genes, and this was accompanied by the upregulation of Caveolin-1 (Cav1) (p < 0.001). This suggested that the amelioration of LF occurred partly due to the restoration of Cav1 expression in activated HSCs. Upregulation of Cav1 can inhibit the TGF-β/Smad signaling pathway, mainly by reducing Smad2 phosphorylation, resulting in the inhibition of activated HSCs, whereas this effect could be abated if Cav1 was silenced in advance by siRNAs. Conclusions: Our findings suggest that hPMSCs could provide multifaceted therapeutic benefits for the treatment of LF, and the TGF-β/Cav1 pathway might act as a therapeutic target for hPMSCs in the treatment of LF. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with poor prognosis and high incidence. The clinical data analysis of liver hepatocellular carcinoma samples downloaded from The Cancer Genome Atlas reveals that the THO Complex 1 (THOC1) is remarkable upregulated in HCC and associated with poor prognosis. However, the underlying mechanism remains to be elucidated. We hypothesize that THOC1 can promote the proliferation of HCC. The present study aims to identify THOC1 as the target for HCC treatment and broaden our sights into therapeutic strategy for this disease. Methods: Quantitative RT-PCR, Western blot, immunofluorescence and immunohistochemistry were used to measure gene and protein expression. Colony formation and cell cycle analysis were performed to evaluate the proliferation. The gene set enrichment analysis were performed to identify the function which THOC1 was involved in. The effects of THOC1 on the malignant phenotypes of hepatocellular cells were examined in vitro and in vivo. Results: The gene set enrichment analysis reveals that THOC1 can promote the proliferation and G2/M cell cycle transition of HCC. Similarly, experimental results demonstrate that THOC1 promotes HCC cell proliferation and cell cycle progression. The knockdown of THOC1 leads to R-loop formation and DNA damage and confers sensitivity to cisplatin. In addition, in vivo data demonstrate that THOC1 can enhance tumorigenesis by increasing tumor cell proliferation. Furthermore, virtual screening predicts that THOC1 as a direct target of luteolin. Luteolin can induce DNA damage and suppress the proliferation of HCC by targeting THOC1. Furthermore, the inhibition of THOC1 activity by luteolin enhances the chemosensitivity of HCC tumor cells to cisplatin. Conclusions: THOC1 was identified as a predictive biomarker vital for HCC-targeted treatments and improvement of clinical prognosis. Luteolin combined with cisplatin can effectively suppress HCC tumor growth, indicating a potential and effective therapeutic strategy that uses luteolin in combination with conventional cytotoxic agents for HCC treatment. [ABSTRACT FROM AUTHOR]

Background: Esophageal cancer (EC) represents one of the most aggressive digestive neoplasms globally, with marked geographical variations in morbidity and mortality. Chemoprevention is a promising approach for cancer therapy, while acquired chemoresistance is a major obstacle impeding the success of 5-fluorouracil (5-FU)-based chemotherapy in EC, with the mechanisms underlying resistance not well-understood. In the present study, we focus on exploring the role of long non-coding RNA (lncRNA) HOTAIR in EC progression and sensitivity of EC cells to 5-FU. Methods: Paired cancerous and pre-cancerous tissues surgically resected from EC patients were collected in this study. Promoter methylation of the MTHFR was assessed by methylation-specific PCR. RIP and ChIP assays were adopted to examine the interaction of DNA methyltransferases (DNMTs) with lncRNA HOTAIR and MTHFR, respectively. EC cells resistant to 5-FU were induced by step-wise continuous increasing concentrations of 5-FU. The sensitivity of EC cells to 5-FU in vivo was evaluated in nude mice treated with xenografts of EC cells followed by injection with 5-FU (i.p.). Results: We found reciprocal expression patterns of lncRNA HOTAIR and MTHFR in EC tissues and human EC cells. Interference with lncRNA HOTAIR enhanced 5-FU-induced apoptosis, exhibited anti-proliferative activity, and reduced promoter methylation of the MTHFR in EC cells. Besides, overexpression of MTHFR attenuated the acquired chemoresistance induced by overexpression of lncRNA HOTAIR in EC cells. At last, enhanced chemosensitivity was observed in vivo once nude mice xenografted with lncRNA HOTAIR-depleted EC cells. Conclusion: Together, our study proposes that pharmacologic targeting of lncRNA HOTAIR sensitizes EC cells to 5-FU-based chemotherapy by attenuating the promoter hypermethylation of the MTHFR in EC. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies suggest synergistic effectiveness of ascorbic acid (AA, vitamin C) and cytotoxic agents in gastrointestinal malignancies. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AA combined with mFOLFOX6 or FOLFIRI regimens in patients with metastatic colorectal cancer (mCRC) or gastric cancer (mGC).Methods: In the dose-escalation phase, patients received AA (0.2-1.5 g/kg, 3-h infusion, once daily, days 1-3) with mFOLFOX6 or FOLFIRI in a 14-day cycle until the MTD was reached. In the speed-expansion phase, AA was administered at the MTD or at 1.5 g/kg if the MTD was not reached at a fixed rate of 0.6, 0.8 or 1 g/min. Pharmacokinetics and preliminary efficacy were also assessed.Results: Thirty-six patients were enrolled. The MTD was not reached. The RP2D was established as AA at 1.5 g/kg/day, days 1-3, with mFOLFOX6 or FOLFIRI. No dose-limiting toxicity (DLT) was detected during dose escalation. The most common treatment-emergent adverse events (TRAEs) were sensory neuropathy (50%), nausea (38.9%), vomiting (36.1%) and neutropenia (27.8%). Grade 3-4 TRAEs were neutropenia (13.9%), sensory neuropathy (2.8%), vomiting (2.8%), diarrhea (2.8%) and leukopenia (2.8%). AA exposure was dose-proportional. The objective response rate was 58.3%, and the disease control rate was 95.8%. No difference in efficacy was found between mCRC patients with wild-type RAS/BRAF and mutant RAS or BRAF.Conclusions: The favorable safety profile and preliminary efficacy of AA plus mFOLFOX6/FOLFIRI support further evaluation of this combination in mCRC or mGC.Trial Registration: ClinicalTrial.gov Identifier: NCT02969681 . [ABSTRACT FROM AUTHOR]

Background: Inflammatory micro-environment has been proposed to play a critical role in lung tumorigenesis. NLRP3 is known as an intracellular receptor involving inflammation and has been reported which is increasingly associated with tumor development, but the role in inflammation-driven lung cancer has not been fully clarified. In this study, we investigated whether lipopolysaccharide (LPS)-induced pulmonary inflammation could contribute to lung tumorigenesis induced by benzo(a)pyrene [B(a)p] in C57BL/6J mice and the role of NLRP3 in the pathogenesis.Methods: NLRP3-/- mice and C57BL/6J mice (wide-type, WT) were instilled intratracheally with B(a)p (1 mg/mouse) once a week for 4 times [the week of the last time of B(a)p treatment named Week 0], and mice were then instilled intratracheally with LPS at Week 3, 2.5 μg/mouse, once every three weeks for 5 times. At Week 30, the incidence, number, size and histopathology of lung tumor were analyzed.Results: Mice exposed to B(a)p or B(a)p plus LPS could induce lung tumors, whereas LPS or vehicles treatment could not induce lung tumorigenesis. In WT mice, B(a)p plus LPS exposure significantly increased tumor incidence, mean tumor count and tumor size of visible tumors of lungs compared with B(a)p treatment alone, and NLRP3 deletion inhibited lung tumorigenesis induced by B(a)p or B(a)p plus LPS. Histopathological examination found LPS-induced pulmonary inflammatory changes enhanced lung tumorigenesis induced by B(a)p in WT mice, deletion of NLRP3 improved the inflammatory changes induced by LPS and the number and size of pathological tumor nests induced by B(a)p or B(a)p plus LPS. In addition, we found B(a)p treatment and B(a)p plus LPS treatment predominately induced the development of adenoma.Conclusion: LPS enhanced B(a)p-induced lung tumorigenesis in WT and NLRP3-/- mice of C57BL/6J strain, and NLRP3 deletion inhibits lung tumorigenesis induced by B(a)p or B(a)p plus LPS. [ABSTRACT FROM AUTHOR]

Background: G protein-coupled receptors (GPR) are involved in a wide range of physiological processes, some of which, however, can be hijacked by tumor cells. Over-expression of G protein-coupled receptors 137 (GPR137) are associated with the growth of tumor cells, but under-expression of GPR137 has shown to inhibit cell proliferation in several different types of cancers. Currently, the role of GPR137 in leukemia is still unclear. In this study, the effect of under-expression of GPR137 on inhibiting the proliferation of leukemia cells is explored, to identify a novel target for leukemia treatment. Materials and methods: In this study, lentivirus-mediated RNA interference (RNAi) was employed to investigate the role of GPR137 in two leukemia cell lines K562 and HL60. The gene expression of GPR137 was analyzed by RT-PCR and its protein expression was determined by Western blot. Flow cytometry and Annexin V/7-AAD Apoptosis Detection Kit was used respectively in cell cycle and apoptosis analysis. The protein expression of CyclinD1, CDK4, BCL-2 and caspase-3 were also determined. Results: There was high level of constitutive expression of GPR137 in leukemia cancer cell lines K562 and HL60. Lentivirus-mediated RNAi could significantly down-regulate gene and protein expression of GPR137 in both cell lines. Down regulation of GPR137 was associated with the reduction in proliferation rate and colony forming capacity. In addition, down regulation of GPR137 arrested cells in the G0/G1 phase of cell cycle and induced apoptosis in both leukemia cell lines K562 and HL60. Conclusions: The expression of GPR137 is associated with the proliferation of leukemia cell lines. Down regulation of GPR137 could inhibit proliferation and promote apoptosis in leukemia cells, which makes it a promising bio-marker and therapeutic target to treat patients with leukemia. [ABSTRACT FROM AUTHOR]

Background: Elevated plasma homocysteine (Hcy) levels have been indicated as a strong and modifiable risk factor of ischemic stroke; the previous studies have shown that exposure to Hcy activates cultured microglia. However, whether neurotoxicity of Hcy involves microglia activation following brain ischemia and the underlying mechanisms remains incompletely understood.Methods: The cerebral damage was evaluated by staining with 2,3,5-triphenyltetrazolium chloride, hematoxylin-eosin, and Fluoro Jade B. The activation state of microglia was assessed via immunoreaction using the microglial markers Iba1 and OX-42. Then, the inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) were examined by Western blot analysis and fluorescence immunohistochemistry.Results: Elevated Hcy level augmented brain damage and neural cell toxicity in the brain cortex and the dentate gyrus region of the hippocampus after cerebral ischemia/reperfusion. Meanwhile, Hcy activated microglia and induced the expression of the inflammatory factors such as TNF-α and IL-6. Moreover, Hcy caused an increase in pSTAT3 expression which occurs in microglial cells. AG490, a JAK2-STAT3 inhibitor, effectively inhibited the phosphorylation of STAT3, microglial cell activation and the secretion of IL-6, TNF-α raised by Hcy treatment.Conclusions: STAT3 signaling pathway located in microglia plays a critical role in mediating Hcy-induced activation of microglia and neuroinflammation in rat MCAO model. This suggests the feasibility of targeting the JAK2/STAT3 pathway as an effective therapeutic strategy to alleviate the progression of Hcy-associated ischemia stroke. [ABSTRACT FROM AUTHOR]

Background: Expression of the long non-coding mRNA LINC00152 has been reported to correlate with cancer cell resistance to oxaliplatin (L-OHP). However, little is known regarding the molecular mechanism of LINC00152 in esophageal cancer (EC). Hence, we intended to characterize the role of LINC00152 in EC, with a special focus on epithelial-mesenchymal transition (EMT) and L-OHP resistance. Methods: We collected EC tissues and identified EC cell lines with higher L-OHP resistance, and then characterized expression patterns of LINC00152, Zeste Homologue 2 (EZH2), Zinc finger e-box binding homeobox (ZEB1) and EMT-related genes using RT-qPCR and Western blot analysis. Furthermore, their functional significance was identified by gain and loss-of-function experiments. The relationship among LINC00152, EZH2 and ZEB1 was examined using RIP, RNA pull-down and ChIP assays. Additionally, resistance of EC cells to L-OHP was reflected by CCK-8 assay to detect cell viability. Animal experiments were also conducted to detect the effects of the LINC00152/EZH2/ZEB1 on EMT and L-OHP resistance. Results: LINC00152, EZH2 and ZEB1 were highly expressed in EC tissues and Kyse−150/TE-1 cells. As revealed by assays in vitro and in vivo, LINC00152 positively regulated ZEB1 expression through interaction with EZH2 to enhance EMT and L-OHP resistance in EC cells. In contrast, silencing of LINC00152 contributed to attenuated EMT and drug resistance of EC cells to L-OHP. Conclusions: Our study demonstrates that LINC00152/EZH2/ZEB1 axis can regulate EMT and resistance of EC cells to L-OHP, thus presenting a potential therapeutic target for EC treatment. [ABSTRACT FROM AUTHOR]

Background: Anti-angiogenic therapies demonstrate anti-tumor effects by decreasing blood supply to tumors and inhibiting tumor growth. However, anti-angiogenic therapy may leads to changes in tumor microenvironment and increased invasiveness of tumor cells, which in turn promotes distant metastasis and increased drug resistance. Methods: The CO-IP assays, N-STORM and cytoskeleton analysis were used to confirm the mechanism that p-VEGFR2/VE-cadherin/β-catenin/actin complex regulates vascular remodeling and improves the tumor microenvironment. 6-gingerol (6G), the major bioactive component in ginger, stabilized this complex by enhancing the binding of VEGFa to VEGFR2 with non-pathway dependent. Biacore, pull down and molecular docking were employed to confirm the interaction between 6G and VEGFR2 and enhancement of VEGFa binding to VEGFR2. Results: Here, we report that microvascular structural entropy (MSE) may be a prognostic factor in several tumor types and have potential as a biomarker in the clinic. 6G regulates the structural organization of the microvascular bed to decrease MSE via the p-VEGFR2/VE-cadherin/β-catenin/actin complex and inhibit tumor progression. 6G promotes the normalization of tumor vessels, improves the tumor microenvironment and decreases MSE, facilitating the delivery of chemotherapeutic agents into the tumor core and thereby reducing tumor growth and metastasis. Conclusions: This study demonstrated the importance of vascular normalization in tumor therapy and elucidated the mechanism of action of ginger, a medicinal compound that has been used in China since ancient times. [ABSTRACT FROM AUTHOR]

Background: Tumor cells transfer into endothelial cells by epithelial–endothelial transition (EET), which is characterized by vasculagenic mimicry (VM) in morphology. VM can change tumor microcirculation, progression, and metastasis. However, the molecular mechanisms of endothelial-like transition remain unclear. EET is a subtype of epithelial–mesenchymal transition (EMT). Twist1, a transcriptional regulatory factor of EMT, is an important factor that induces EET in hepatocellular carcinoma(HCC), but the upstream signal of Twist1 is unclear. Methods: Expression plasmids, Ca mobilization, and three-dimensional cultures were evaluated. Western blot assay, reporter gene assay, and immunofluorescence staining were conducted. A murine xenograft model was established. Analyses of immunohistochemistry, patient samples, and complementary DNA (cDNA) microarrays were also performed. Results: This study demonstrated that protease-activated receptor-1 (PAR1) can increase the expression of endothelial markers and enhance VM formation by upregulating Twist1 both in vitro and in vivo through thrombin binding. Thrombin not only activates PAR1 but also promotes PAR1 internalization in a time-dependent manner. Clinical pathological analysis further confirms that PAR1 expression is directly correlated with the endothelial marker expression, VM formation, and metastasis and indicates poor survival rate of patients with tumors. Conclusion: PAR1 promotes EET through Twist1 in HCC. [ABSTRACT FROM AUTHOR]

Background: RIP3 (Receptor-interacting protein 3) pathway was mainly described as the molecular mechanism of necroptosis (programmed necrosis). But recently, non-RIP3 pathways were found to mediate necroptosis. We deliberate to investigate the effect of calpain, a molecule to induce necroptosis as reported (Cell Death Differ 19:245-256, 2012), in RGC-5 following elevated hydrostatic pressure.Results: First, we identified the existence of necroptosis of RGC-5 after insult by using necrostatin-1 (Nec-1, necroptosis inhibitor) detected by flow cytometry. Immunofluorescence staining and western blot were used to detect the expression of calpain. Western blot analysis was carried out to describe the truncated AIF (tAIF) expression with or without pretreatment of ALLN (calpain activity inhibitor). Following elevated hydrostatic pressure, necroptotic cells pretreated with or without ALLN was stained by Annexin V/PI, The activity of calpain was also examined to confirm the inhibition effect of ALLN. The results showed that after cell injury there was an upregulation of calpain expression. Upon adding ALLN, the calpain activity was inhibited, and tAIF production was reduced upon injury along with the decreased number of necroptosis cells.Conclusion: Our study found that calpain may induce necroptosis via tAIF-modulation in RGC-5 following elevated hydrostatic pressure. [ABSTRACT FROM AUTHOR]