Mechanism of lncRNA SNHG16 on kidney clear cell carcinoma cells by targeting miR-506-3p/ETS1/RAS/ERK molecular axis.

Objective: This study aimed to investigate the mechanism of long noncoding ribonucleic acid (lncRNA) SNHG16 on kidney clear cell carcinoma (KIRC) cells by targeting miR-506-3p/ETS proto-oncogene 1, transcription factor (ETS1)/RAS/Extracellular regulated protein kinases (ERK) molecular axis, thus to provide reference for clinical diagnosis and treatment of KIRC in the future. Methods: Thirty-six patients with KIRC were enrolled in this study, and their carcinoma tissues and adjacent tissues were obtained for the detection of SNHG16/miR-506-3p/ETS1/RAS/ERK expression. Then, over-expressed SNHG16 plasmid and silenced plasmid were transfected into KIRC cells to observe the changes of their biological behavior. Results: SNHG16 and ETS1 were highly expressed while miR-506- 3p was low expressed in KIRC tissues; the RAS/ERK signaling pathway was significantly activated in KIRC tissues (P < 0.05). After SNHG16 silence, KIRC cells showed decreased proliferation, invasion and migration capabilities and increased apoptosis rate; correspondingly, increase in SNHG16 expression achieved opposite results (P < 0.05). Finally, in the rescue experiment, the effects of elevated SNHG16 on KIRC cells were reversed by simultaneous increase in miR-506-3p, and the effects of miR-506-3p were reversed by ETS1. Activation of the RAS/ERK pathway had the same effect as increase in ETS1, which further worsened the malignancy of KIRC. After miR-506-3p increase and ETS1 silence, the RAS/ERK signaling pathway was inhibited (P < 0.05). At last, the rescue experiment (co-transfection) confirmed that the effect of SNHG16 on KIRC cells is achieved via the miR-506-3p/ETS1/RAS/ERK molecular axis. Conclusion: SNHG16 regulates the biological behavior of KIRC cells by targeting the miR-506-3p/ETS1/RAS/ERK molecular axis.

Cancer burden attributable to risk factors, 1990-2019: A comparative risk assessment.

An up-to-date comprehensive assessment of the cancer burden attributable to risk factors is essential for cancer prevention. We analyzed the population attributable fraction (PAF) of cancer disability-adjusted life years (DALYs) attributable to 11 level 2 risk factors using data from the Global Burden and Disease Study (GBD) 2019. We highlighted that almost half of the cancer DALYs can be preventable by modifying relevant risk factors. The attributable cancer DALYs increased by 60.42%-105.0 million from 1990 to 2019. Tobacco, dietary risks, alcohol use, high body-mass index, and air pollution were the top five risk factors. The PAFs attributable to high fasting plasma glucose, high body-mass index, and low physical activity have increased worldwide from 1990 to 2019. Unsafe sex was the leading risk factor for women before age of 54. Tailored prevention programs targeted at specific populations should be scaled up to reduce the cancer burden in the future.

Global Burden of Lung Cancer Attributable to Household Fine Particulate Matter Pollution in 204 Countries and Territories, 1990 to 2019.

INTRODUCTION: Household particulate matter (PM) air pollution is substantially associated with lung cancer. Nevertheless, the global burden of lung cancer attributable to household PM2.5 is still uncertain. METHODS: In this study, data from the Global Burden and Disease Study 2019 are used to thoroughly assess the burden of lung cancer associated with household PM2.5. RESULTS: The number of deaths and disability-adjusted life-years (DALYs) attributable to household PM2.5 was found to be 0.08 million and 1.94 million, respectively in 2019. Nevertheless, the burden of lung cancer attributable to household PM2.5 decreased from 1990 to 2019. At the sociodemographic index (SDI) district level, the middle SDI region had the most number of lung cancer deaths and DALYs attributable to household PM2.5. Moreover, the burden of lung cancer was mainly distributed in low-SDI regions, such as Sub-Saharan Africa. Conversely, in high-SDI regions, the age-standardized mortality rate and age-standardized DALY rate of lung cancer attributable to household PM2.5 exhibit the most rapid declines. The burden of lung cancer attributable to household PM2.5 is heavier for men than for women. The sex difference is more obvious in the elderly. CONCLUSIONS: The prevalence of lung cancer attributable to household PM2.5 has exhibited a declining trend from 1990 to 2019 owing to a concurrent decline in household PM2.5 exposure.

Targeting the Main Sources of Reactive Oxygen Species Production: Possible Therapeutic Implications in Chronic Pain.

Humans have long been combating chronic pain. In clinical practice, opioids are first- choice analgesics, but long-term use of these drugs can lead to serious adverse reactions. Finding new, safe and effective pain relievers that are useful treatments for chronic pain is an urgent medical need. Based on accumulating evidence from numerous studies, excess reactive oxygen species (ROS) contribute to the development and maintenance of chronic pain. Some antioxidants are potentially beneficial analgesics in the clinic, but ROS-dependent pathways are completely inhibited only by scavenging ROS directly targeting cellular or subcellular sites. Unfortunately, current antioxidant treatments donot achieve this effect. Furthermore, some antioxidants interfere with physiological redox signaling pathways and fail to reverse oxidative damage. Therefore, the key upstream processes and mechanisms of ROS production that lead to chronic pain in vivo must be identified to discover potential therapeutic targets related to the pathways that control ROS production in vivo. In this review, we summarize the sites and pathways involved in analgesia based on the three main mechanisms by which ROS are generated in vivo, discuss the preclinical evidence for the therapeutic potential of targeting these pathways in chronic pain, note the shortcomings of current research and highlight possible future research directions to provide new targets and evidence for the development of clinical analgesics.

Health burden of unbalanced fatty acids intake from 1990 to 2019: A global analysis.

BACKGROUND: Unbalanced fatty acids intake is associated with a range of health outcomes; however, the impact on human health remains unclear globally. We aim to provide a comprehensive assessment of the health effect of unbalanced fatty acids intake on a global scale. METHODS: We analyzed the trends of summary exposure value (SEV) and the attributable burden of unbalanced fatty acids intake, including diet low in polyunsaturated fatty acids (low PUFAs), diet low in seafood omega-3 fatty acids (low seafood-(ω-3)-PUFAs), and diet high in trans fatty acids (high TFAs) from 1990 to 2019 using data from Global Burden of Disease Study 2019. FINDINGS: The global fatty acids intake was far from the optimal level. High-income North America had the highest SEV of diet of high TFAs, while less-developed regions located in Saharan Africa had the highest SEVs of low PUFAs and low seafood-(ω-3)-PUFAs. The attributable burden was unequally distributed to less-developed regions. Males had lower SEVs but higher attributable burden than females and this gender gap was particularly pronounced before the age of 59. The young population had a higher SEV of diet of low PUFAs, comparable SEV of low seafood-(ω-3)-PUFAs but lower SEV of high TFAs than the elderly population. CONCLUSIONS: This study underpinned the high prevalence of unbalanced fatty acids intake worldwide and provided evidence-based guidance for identifying at-risk populations and developing effective strategies to improve fatty acids intake in the future. FUNDING: The study was funded by Shanxi Province "136" Revitalization Medical Project Construction Funds and the Fundamental Research Funds for the Central Universities.

Effect of PM2.5 air pollution on the global burden of lower respiratory infections, 1990-2019: A systematic analysis from the Global Burden of Disease Study 2019.

Particulate matter (PM) air pollution is closely related to lower respiratory infections (LRIs). However, the global LRI burden attributable to PM remains unclear. Here, we provide a comprehensive assessment of the PM2.5-attributable LRI burden using data from the Global Burden and Disease Study (GBD) 2019. We found that PM2.5 air pollution contributed to approximately 0.7 million deaths and 37.6 million disability-adjusted life years (DALYs) of LRIs in 2019. The LRI burden attributable to PM2.5 has decreased from 1990 to 2019, with a more pronounced decrease in household PM2.5 than in ambient PM2.5. Unlike the decreasing trend in LRI burden due to household PM2.5 worldwide, nearly one fifth of countries experienced an increase of LRI burden due to ambient PM2.5. The burden was unevenly distributed to less developed countries, mainly in Sub-Saharan Africa. All age groups experienced a decrease in the PM2.5-attributable burden, with the most significant decrease in children younger than 10 years. Notably, individuals aged 20-84 years experienced an increase in the LRI burden attributable to ambient PM2.5. Males had higher burden than females in the elder age and higher SDI regions. This study provided an evidence-based guidance for the prevention of LRIs and control of PM2.5 air pollution.

Correlation between color doppler flow pattern and molecular biology in elderly patients with colon cancer.

OBJECTIVE: To investigate the correlation between the grade and type of color Doppler flow imaging (CDFI) and tumor-related cytokines in elderly patients with colon cancer. METHODS: Seventy-six elderly patients with colorectal cancer admitted to Zhejiang Provincial People's Hospital from July 2020 to June 2022 were selected. CDFI was used to analyze the blood flow grade and distribution type of tumor tissues, and ELISA was used to detect the levels of tumor-related cytokines in serum. Preoperative clinical data were collected and analyzed, and the correlation between measured cytokine levels and CDFI analysis results was further explored. RESULTS: CDFI blood flow grade showed significant difference in the different lengths, invasion depths and lymph node metastasis of tumors (all P < 0.001). In addition, serum levels of TNF-α, IL-6 and VEGF also showed statistical difference in all above different tumor-related factors (all P < 0.001). Further Pearson correlation analysis showed that CDFI blood flow grade and distribution types were both significantly positively correlated with above serum cytokine levels (r > 0, all P < 0.001). Kaplan-Meier survival analysis showed that both CDFI blood flow grade and distribution types were poor prognostic factors in elderly patients with colon cancer. Regression analysis showed that serum levels of TNF-α, IL-6 and VEGF were independent risk factors for poor prognosis of colon cancer in elderly patients. CONCLUSION: CDFI blood flow grade and tumor tissue distribution have potential significant correlations with tumor-associated cytokines in the serum of colon cancer patients. CDFI blood flow grading technique provides an important imaging method for dynamic observation of angiogenesis and blood flow changes in elderly patients with colon cancer. Abnormal changes in serum levels of tumor-related factors can be used as sensitive indicators to evaluate the therapeutic effect and prognosis of colon cancer.

Development and Validation of a Radiomics Model Based on 3-Dimensional Endoanal Rectal Ultrasound of Rectal Cancer for Predicting Lymph Node Metastasis.

BACKGROUND: Development of a radiomics model for predicting lymph node metastasis status in rectal cancer patients based on 3-dimensional endoanal rectal ultrasound images. METHODS: This study retrospectively included 79 patients (41 with lymph node metastasis positive and 38 with lymph node metastasis negative) diagnosed with rectal cancer in our hospital from January 2018 to February 2022. The tumor's region of interest is first delineated by radiologists, from which radiomics features are extracted. Radiomics features were then selected by independent samples t-test, correlation coefficient analysis between features, and least absolute shrinkage and regression with selection operator. Finally, a multilayer neural network model is developed using the selected radiomics features, and nested cross-validation is performed on it. These models were validated by assessing their diagnostic performance and comparing the areas under the curve and recall rate curve in the test set. RESULTS: The areas under the curve of radiologist was 0.662 and the F1 score was 0.632. Thirty-four radiomics features were significantly associated with lymph node metastasis (P < .05), and 10 features were finally selected for developing multilayer neural network models. The areas under the curve of the multilayer neural network models were 0.787, 0.761, 0.853, and the mean areas under the curve was 0.800. The F1 scores of the multilayer neural network models were 0.738, 0.740, and 0.818, and the mean F1 score was 0.771. CONCLUSIONS: Radiomics models based on 3-dimensional endoanal rectal ultrasound can be used to identify lymph node metastasis status in rectal cancer patient with good diagnostic performance.

Trends and risk factors of global incidence, mortality, and disability of genitourinary cancers from 1990 to 2019: Systematic analysis for the Global Burden of Disease Study 2019.

Background: The incidence of kidney, bladder, and prostate cancer ranked ninth, sixth, and third in male cancers respectively, meanwhile, the incidence of testicular cancer also increased gradually in the past 30 years. Objective: To study and present estimates of the incidence, mortality, and disability of kidney, bladder, prostate, and testicular cancer by location and age from 1990 to 2019 and reveal the mortality risk factors of them. Materials: The Global Burden of Diseases Study 2019 was used to obtain data for this research. The prediction of cancer mortality and incidence was based on mortality-to-incidence ratios (MIRs). The MIR data was processed by logistic regression and adjusted by Gaussian process regression. The association between the socio-demographic index and the incidence or disease burden was determined by Spearman's rank order correlation. Results: Globally in 2019, there were 371,700 kidney cancer cases with an age-standardized incidence rate (ASIR) of 4.6 per 100,000, 524,300 bladder cancer cases, with an ASIR of 6.5 per 100,000, 1,410,500 prostate cancer cases with an ASIR of 4.6 per 100,000 and 109,300 testicular cancer incident cases with an ASIR of 1.4 per 100,000, the ASIR of these four cancers increased by 29.1, 4, 22, and 45.5% respectively. The incidence rate of the four cancers and the burden of kidney cancer were positively correlated with the socio-demographic index (SDI), regions with a higher SDI faced more of a burden attributable to these four cancers. High body-mass index has surpassed smoking to be the leading risk factor in the past thirty years for kidney cancer mortality. Smoking remained the leading risk factor for cancer-related mortality for bladder cancer and prostate cancer and the only risk factor for prostate cancer. However, the contribution of high fasting plasma glucose to bladder cancer mortality has been increasing. Conclusion: The incidence of bladder, kidney, prostate, and testicular cancer is ever-increasing. High-income regions face a greater burden attributable to the four cancers. In addition to smoking, metabolic risk factors may need more attention.

Global, Regional, and National Burden of CKD due to Glomerulonephritis from 1990 to 2019: A Systematic Analysis from the Global Burden of Disease Study 2019.

BACKGROUND: CKD is becoming a major human health concern. Limited quantitative assessments of the burden of CKD due to glomerulonephritis have been performed. We performed a comprehensive analysis of the disease burden to update the epidemiology of this disease. METHODS: Incidence, prevalence, deaths, and disability-adjusted life-years (DALYs) data and percent changes in these indicators were extracted from Global Burden of Disease Study 2019 to analyze the burden of CKD due to glomerulonephritis. RESULTS: Globally, there were 606,300 (95% uncertainty interval [UI], 560,100 to 658,100) incident patients, 17,300,000 (95% UI, 16,100,000 to 18,600,000) prevalent patients, 183,700 (95% UI, 146,300 to 228,900) deaths, and 6,900,000 (95% UI, 5,900,000 to 8,100,000) DALYs of CKD due to glomerulonephritis in 2019. Compared with those in 1990, the numbers of incident patients, prevalent patients, deaths, and DALYs increased by 77%, 81%, 100%, and 66%, respectively. Most of the disease burden was concentrated in countries with lower sociodemographic index. In Central Latin America, the disease burden was much higher than expected on the basis of its sociodemographic index. Decomposition analysis showed that population aging and growth were the two major drivers of the increase in DALYs. Frontier analysis revealed considerable opportunities to reduce the age-standardized DALYs in the middle of the sociodemographic-index spectrum. Although middle-aged and elderly individuals accounted for the majority of the disease burden, the highest incidence rate was observed in children aged 1-4 years. CONCLUSIONS: The disease burden of CKD due to glomerulonephritis has increased worldwide, especially in regions and countries with lower sociodemographic indexes.

Synthesis, Characterization of Low Molecular Weight Chitosan Selenium Nanoparticles and Its Effect on DSS-Induced Ulcerative Colitis in Mice.

Selenium nanoparticles have attracted extensive attention due to their good bioavailability and activity. In the present study, a new form of selenium nanoparticle (Low molecular weight chitosan selenium nanoparticles (LCS-SeNPs)) were synthesized in a system of sodium selenite and acetic acid. The size, element state, morphology and elementary composition of LCS-SeNPs were characterized by using various spectroscopic and microscopic measurements. The protection of LCS-SeNPs against dextran sulfate sodium (DSS)-induced intestinal barrier dysfunction and the inherent mechanisms of this process were investigated. The results showed that LCS-SeNPs, with an average diameter of 198 nm, zero-valent and orange-red relatively uniform spherical particles were prepared. LCS-SeNPs were mainly composed of C, N, O and Se elements, of which Se accounted for 39.03% of the four elements C, N, O and Se. LCS-SeNPs reduced colon injury and inflammation symptoms and improved intestinal barrier dysfunction. LCS-SeNPs significantly reduced serum and colonic inflammatory cytokines TNF-α and IL-6 levels. Moreover, LCS-SeNPs remarkably increased antioxidant enzyme GSH-Px levels in serum and colonic tissue. Further studies on inflammatory pathways showed that LCS-SeNPs alleviated DSS-induced colitis through the NF-κB signaling pathway, and relieved inflammatory associated oxidative stress through the Nrf2 signaling pathway. Our findings suggested that LCS-SeNPs are a promising selenium species with potential applications in the treatment of oxidative stress related inflammatory intestinal diseases.

Effectiveness of Platelet-Rich Plasma in Anterior Cruciate Ligament Reconstruction: A Systematic Review of Randomized Controlled Trials.

This study aimed to identify the effectiveness of platelet-rich plasma (PRP) for patients operated with anterior cruciate ligament reconstruction (ACLR). Databases of PubMed, Embase, and CENTRAL were independently retrieved by two authors, for identifying the eligible randomized controlled trials (RCTs) comparing the clinical and imaging outcomes of ACL reconstructed patients augmented with or without PRP. The Cochrane Collaboration tool was utilized to assess the risk of bias of the included trials. We qualitatively synthesized the outcomes include the image evaluations on the healing of bone tunnels, graft remodeling, donor site healing and tunnel widening, and clinical evaluations on knee stability and function, pain symptom by visual analogue scale (VAS), inflammatory parameters and so on. A total of 16 RCTs, including 1025 patients, were included for eligibility. Generally, the included studies were of low risk of bias, but the conducting of allocation concealment was not clearly described in many studies. Three imaging techniques, including MRI, CT and ultrasound, were selected in these trials. Significant improvement on graft remodeling, bone tunnel healing, harvest site healing and bone tunnel diameters were demonstrated in one of five (20.0%), three of five (60.0%), two of four (50.0%) and one of five (20.0%) studies respectively, for PRP group. Various clinical outcomes, such as IKDC score, Lysholm score, Tegner score, knee anteroposterior and rotational laxity, range of motion and VAS, could not be improved with PRP application. The PRP is associated with very limited role in improving knee outcomes following ACLR, and there is no indication for PRP procedures in ACLR at this stage.

Naringenin promoted spinal microglia M2 polarization in rat model of cancer-induced bone pain via regulating AMPK/PGC-1α signaling axis.

Cancer-induced bone pain (CIBP) treatment remains a clinical challenge because the pathophysiological mechanisms are not fully understood. Recently, it was verified that shifting microglial polarization toward the M2 phenotype reveals a potential strategy for CIBP treatment. Naringenin, a natural flavone flavonoid, has been reported to have antioxidant, anti-inflammatory and neuroprotective properties. However, the role of naringenin on regulating microglial polarization in CIBP rats and the molecular mechanisms participating in this process have not been fully clarified. Herein, we investigated the potential effect of naringenin on M1/M2 microglial polarization and further explored the potential mechanisms of this action. Our study demonstrated that intraperitoneal administration of naringenin could upregulate the antioxidative molecule glutathione peroxidase 4 (GPx4) level in the spinal cord, as well as bone cancer-induced mechanical allodynia in rats. Moreover, naringenin treatment also suppressed microglia-mediated neuroinflammation by downregulating the phosphorylation of nuclear factor κB (NF-κB) p65 expression and promoting microglial polarization toward the M2 phenotype in CIBP rats. The promoting effects mediated by naringenin on M1/M2 microglial polarization are dependent on the serine/threonine protein kinase adenosine monophosphate-activated protein kinase (AMPK)/proliferator-activated receptor γ coactivator-1α (PGC-1α) signaling pathway. Inhibition of AMPK activation with the classical AMPK inhibitor Compound C attenuated this effect of naringenin. These results improved the understanding of the anti-inflammatory property of naringenin on microglial polarization, which might provide new alternative avenues for CIBP treatment.

Clinical Applications of Liquid Biopsy in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognosis in the world. The low rate of early diagnosis, as well as the high risk of postoperative metastasis and recurrence, led to the poor clinical prognosis of HCC patients. Currently, it mainly depends on serum markers, imaging examination, and tissue biopsy to diagnose and determine the recurrence and metastasis of HCC after treatments. Nevertheless, the accuracy and sensitivity of serum markers and imaging for early HCC diagnosis are suboptimal. Tissue biopsy, containing limited tissue samples, is insufficient to reveal comprehensive tumor biology information and is inappropriate to monitor dynamic tumor progression due to its invasiveness. Thus, low invasive diagnostic methods and novel biomarkers with high sensitivity and reliability must be found to improve HCC detection and prediction. As a non-invasive, dynamic, and repeatable detection method, "liquid biopsy", has attracted much attention to early diagnosis and monitoring of treatment response, which promotes the progress of precision medicine. This review summarizes the clinical applications of liquid biopsy in HCC, including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosome in early diagnosis, prognostic evaluation, disease monitoring, and guiding personalized treatment.

[Molecular mechanism of Ganoderma against gastric cancer based on network pharmacology and experimental test].

This study aims to explore the molecular mechanism of Ganoderma against gastric cancer based on network pharmacology, molecular docking, and cell experiment. The active components and targets of Ganoderma were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), and gastric cancer-related targets from GeneCards and Online Mendelian Inheritance in Man(OMIM). The protein-protein interaction(PPI) network of the common targets was constructed with STRING, followed by Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis of the common genes based on Bioconductor and R language. The medicinal-disease-component-target network and medicinal-disease-component-target-pathway network were established by Cytoscape. Molecular docking was performed between ß-sitosterol(the key component in Ganoderma) and the top 15 targets in the PPI network. Cell experiment was performed to verify the findings. A total of 14 active components and 28 targets of Ganoderma were retrieved, and the medicinal and the disease shared 25 targets, including caspase-3(CASP3), caspase-8(CASP8), caspase-9(CASP9), and B-cell lymphoma-2(BCL2). The common targets involved 72 signaling pathways and apoptosis and p53 signaling pathway may play a crucial role in the effect of Ganoderma against gastric cancer. ß-sitosterol had strong binding activity to the top 15 targets in the PPI network. The in vitro cell experiment demonstrated that ß-sitosterol inhibited gastric cancer AGS cell proliferation by inducing cell apoptosis and cell cycle arrest in the S phase, which might be related to the regulation of the p53 pathway. This study shows the multi-component, multi-target, and multi-pathway characteristics of Ganoderma against gastric cancer, which lays a scientific basis for further research on the molecular mechanism.

Galectin-3 in Microglia-Mediated Neuroinflammation: Implications for Central Nervous System Diseases.

Microglial activation is one of the common hallmarks shared by various central nervous system (CNS) diseases. Based on surrounding circumstances, activated microglia play either detrimental or neuroprotective effects. Galectin-3 (Gal-3), a group of ß-galactoside-binding proteins, has been cumulatively revealed to be a crucial biomarker for microglial activation after injuries or diseases. In consideration of the important role of Gal-3 in the regulation of microglial activation, it might be a potential target for the treatment of CNS diseases. Recently, Gal-3 expression has been extensively investigated in numerous pathological processes as a mediator of neuroinflammation, as well as in cell proliferation. However, the underlying mechanisms of Gal-3 involved in microgliamediated neuroinflammation in various CNS diseases remain to be further investigated. Moreover, several clinical studies support that the levels of Gal-3 are increased in the serum or cerebrospinal fluid of patients with CNS diseases. Thus, we summarized the roles and underlying mechanisms of Gal-3 in activated microglia, thus providing a better insight into its complexity expression pattern, and contrasting functions in CNS diseases.

STING/NF-κB/IL-6-Mediated Inflammation in Microglia Contributes to Spared Nerve Injury (SNI)-Induced Pain Initiation.

Innate immune response acts as the first line of host defense against damage and is initiated following the recognition of pathogen-associated molecular patterns (PAMPs). For double-stranded DNA (dsDNA) sensing, interferon gene stimulator (STING) was discovered to be an integral sensor and could mediate the immune and inflammatory response. Selective STING antagonist C-176 was administered and pain behaviors were assessed following spared nerve injury (SNI)-induced neuropathic pain. The level of serum dsDNA following neuropathic pain was assessed using Elisa analysis. STING signaling pathway, microglia activation, and proinflammatory cytokines were assessed by qPCR, western blots, Elisa, and immunofluorescence staining. STING agonist DMXAA was introduced into BV-2 cells to assess the inflammatory response in microglial cells. dsDNA was significantly increased following SNI and STING/TANK-binding kinase 1 (TBK1)/nuclear factor-kappa B (NF-κB) pathway was activated in vivo and vitro. Early but not the late intrathecal injection of C-176 attenuated SNI-induced pain hypersensitivity, microglia activation, proinflammatory factors, and phosphorylated JAK2/STAT3 in the spinal cord dorsal horn, and the analgesic effect of C-176 was greatly abolished by recombinant IL-6 following SNI. We provided evidence clarifying dsDNA mediated activation of microglia STING signaling pathway, after which promoting expression of proinflammatory cytokines that are required for hyperalgesia initiation in the spinal cord dorsal horn of SNI model. Further analysis showed that microglial STING/TBK1/NF-κB may contribute to pain initiation via IL-6 signaling. Pharmacological blockade of STING may be a promising target in the treatment of initiation of neuropathic pain.

Wnt signaling: A prospective therapeutic target for chronic pain.

Despite the rapid advance over the past decades to design effective therapeutic pharmacological interventions, chronic pain remains to be an unresolved healthcare concern. Long term use of opioids, the first line analgesics, often causes detrimental side effects. Therefore, a profound understanding of the mechanisms underlying the development and maintenance of chronic pain states is urgently needed for the management of chronic pain. Substantial evidence indicates aberrant activation of Wnt signaling pathways in sciatic nerve, dorsal root ganglia and spinal cord dorsal horn in rodent models of chronic pain. Moreover, growing evidence shows that pharmacological blockage of aberrant activation of Wnt signaling pathways attenuates pain behaviors in animal models of chronic pain. Importantly, both intrathecal injection of Wnt agonists and Wnt ligands to naïve rats lead to the development of mechanical allodynia, which was inhibited by Wnt inhibitors. In this review, we summarized and discussed the therapeutic potential of pharmacological inhibitors of Wnt signaling in chronic pain in preclinical studies. These evidence showed that aberrant activation of Wnt signaling pathways contributed to chronic pain via enhancing neuroinflammation, regulating synaptic plasticity and reducing intraepidermal nerve fiber density. However, these findings raise further questions. Overall, despite the future challenges, these pioneering studies suggest that Wnt signaling is a promising therapeutic target for chronic pain.

Glycine Decarboxylase Suppresses the Renal Cell Carcinoma Growth and Regulates Its Gene Expressions and Functions.

Background: Glycine decarboxylase (GLDC), a key metabolic enzyme, participates in the regulation of the glycine metabolic pathway. Differential expression of GLDC is linked to the malignant growth of renal cell carcinoma (RCC) and may regulate tumor progression through other genes. However, the regulatory function of GLDC in RCC is currently unknown. The purpose of this work was to evaluate the roles of GLDC in the invasion, proliferation, and migration of RCC cells and elucidate the processes underlying RCC development. Methods: The expression of GLDC in RCC cell lines and tissues was identified by quantitative reverse transcription polymerase chain reaction (PCR) and western blot. A stably transfected cell line overexpressing GLDC was constructed using a lentiviral vector. Cell proliferation was detected using Cell Counting Kit-8 (CCK8) and EdU experiments, and scratch and transwell assays were used to determine migration and invasion capabilities. Furthermore, differential proteins were identified and obtained using high-performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS) analysis. Finally, these differential proteins were analyzed by bioinformatics, including cluster analysis, subcellular localization, domain annotation, annotation of the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), enrichment analysis, and study of protein-protein interactions. Results: GLDC expression was found to be lower in six RCC cell lines (786-O, A498, Caki-1, 769-P, OSRC-2, and ACHN) than in 293T cells and decreased in kidney cancer tissues compared to neighboring normal tissues. Overexpression of GLDC inhibited the proliferation of RCC cells as well as their migration and invasion abilities. Tandem mass tag analysis showed that 317 and 236 genes were downregulated and upregulated, respectively, when GLDC was overexpressed in A498 cells. Tandem mass tag analysis showed that 317 and 236 genes were downregulated and upregulated, respectively, when GLDC was overexpressed in A498 cells. Volcano plot showed these upregulated and downregulated proteins. Cluster analysis showed that differentially expressed protein screening can represent the effect of biological treatment on samples. Subcellular localization analysis showed differential proteins are mainly distributed in the nucleus, cytoplasm, mitochondria, plasma membrane, extracellular matrix, and lysosome. GO annotation showed many biological processes in the cells were changed, including "positive regulation of histone H3-K4 methylation", "cofactor binding", and "nuclear body". KEGG pathway analysis showed key pathways have all undergone considerable alterations, such as "cell cycle", "glyoxylate and dicarboxylate metabolism", and "threonine, glycine, and serine metabolism". Finally, highly aggregated proteins with the same or similar functions were acquired by analysis of the protein-protein interaction (PPI) network. Conclusions: These studies indicate that GLDC overexpression suppresses the invasion, proliferation, and migration of RCC cells and leads to the upregulation and downregulation of 236 and 317 genes, respectively.