A retrospective real-world study: the efficacy of immune-related combination therapies in advanced non-small cell lung cancer after resistance to EGFR-TKIs.

BACKGROUND: Whether patients with advanced non-small cell lung cancer (NSCLC) should choose an immune-combination therapy regimen after EGFR-tyrosine kinase inhibitors (EGFR-TKIs) resistance is currently unclear. METHODS: We evaluated 118 NSCLC patients treated by immune checkpoint inhibitors (ICIs) + chemotherapy (I + C), ICIs + chemotherapy + antiangiogenic therapy (I + C + A), chemotherapy + antiangiogenic therapy (C + A) after inefficacy of EGFR-TKIs. We assessed the objective remission rate (ORR), disease control rate (DCR), and progression-free survival (PFS) of these treatments. RESULTS: The ORR was 26.1% vs 38.2% vs 16.3% in the three groups (P = 0.093). The divergence in DCR was also statistically significant (65.2% vs 85.3% vs 74.4%, P = 0.209). The median PFS was no statistically significant difference in PFS (3.09 vs 6.31 vs 5.91 months, P = 0.809), but the Kaplan-Meier survival curve of 12-month-PFS indicated an apparent survival advantage in the I + C + A group (P = 0.001). In addition, the I + C/I + C + A group showed higher median PFS than the C + A group in patients with brain metastases (median PFS, 6.44 vs 4.21 months, P = 0.022). The divergence in ORR of patients in the brain group was also statistically significant (P = 0.045). The I + C + A group showed superior efficacy in patients with liver metastases (median PFS, 0.95 vs 6.44 vs 3.48 months, P < 0.0001). The Cox proportional hazard modeling analysis suggested that the age, brain metastases, and liver metastases were all connected with the prognosis. CONCLUSIONS: This study suggests that advanced NSCLC patients after resistance to EGFR-TKIs may achieve better outcomes from triple therapy. Patients with brain metastases favor ICIs-related combination therapies and patients with liver metastases prefer I + C + A therapy.

Relationship between plasma circulating cell-free DNA concentration and treatment outcomes including prognosis in patients with advanced non-small cell lung cancer.

BACKGROUND: Some research found that elevated plasma cell-free DNA (cfDNA) concentrations and poor prognosis are associated in non-small cell lung cancer (NSCLC). However, more studies need to be carried out to verify this conclusion. Therefore, this study investigated the relationship between cfDNA concentration and treatment outcomes including prognosis in patients with advanced NSCLC. METHODS: We retrospectively collected medical records and cfDNA data from 160 patients with advanced NSCLC. Progression-free survival (PFS) were calculated using the Kaplan-Meier method and were compared between groups using the log rank test. Cox regression analysis was used for estimating the independent predictors of PFS. And we used logistic regression to evaluate the relationship between baseline biomarkers and efficacy. In our study, BT1 cfDNA, BT2 cfDNA, and BT3 cfDNA were defined as cfDNA concentration before the first treatment (baseline cfDNA concentration), cfDNA concentration before the second treatment, and cfDNA concentration before the third treatment, respectively. RESULTS: Patients with low cfDNA (BT1 cfDNA < 15 (ng/mL)) were reported a significantly prolonged median progression-free survival (mPFS) compared with patients with patients with high cfDNA (BT1 cfDNA ≥ 15(ng/mL)) (mPFS: 14.6 vs. 8.3 months, P = 0.002), as well as patients with neutrophil/lymphocyte ratio (NLR)<2.98 (mPFS: 13.1 vs. 7.9 months, P = 0.023). In addition, Cox proportional hazards regression analysis identified independent indicators associated with PFS including BT1 cfDNA ≥ 15 (ng/mL), NLR ≥ 2.98 and extrapulmonary metastasis. The best cut-off value for BT3 cfDNA for predicting disease progression is 41.46 (ng/mL) (Area Under the Curve (AUC): 0.652, 95%CI: 0.516-0.788), achieving 90.7% sensitivity and 37.5% specificity for the prediction of disease progression. BT3 cfDNA (OR = 6.08, 95% CI: 1.94-19.57, P = 0.002) was an independent factor for disease progression in patients with advanced NSCLC. CONCLUSIONS: BT1 cfDNA may be a biomarker to assess the prognosis of advanced NSCLC. Patients with advanced NSCLC with lower cfDNA and NLR before treatment had a better prognosis. Increased BT3 cfDNA concentration was an independent factor of disease progression in advanced NSCLC patients. These findings may assist in identifying high-risk patients and guiding treatment strategies.

MicroRNA-381 in human cancer: Its involvement in tumour biology and clinical applications potential.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. MiRNAs are involved in the development and progression of a wide range of cancers. Among such cancer-associated miRNAs, miR-381 has been a major focus of research. The expression pattern and role of miR-381 vary among different cancer types. MiR-381 modulates various cellular behaviours in cancer, including proliferation, apoptosis, cell cycle progression, migration and invasion. MiR-381 is also involved in angiogenesis and lymphangiogenesis, as well as in the resistance to chemotherapy and radiotherapy. MiR-381 itself is regulated by several factors, such as long noncoding RNAs, circular RNAs and cytokines. Aberrant expression of miR-381 in blood samples indicates that it can be used as a diagnostic marker in cancer. Tissue miR-381 expression may serve as a prognostic factor for the clinicopathological characteristics of cancers and survival of patients. Metformin and icaritin regulate miR-381 expression and present anticancer properties. This review comprehensively summarizes the effect of miR-381 on tumour biological behaviours, as well as the clinical application potential of miR-381 for the treatment of cancer.

Exosomal miR-409-3p secreted from activated mast cells promotes microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway.

OBJECTIVE: Neuroinflammation plays a critical role in central nervous system diseases. Exosomal miRNAs released from various cells are implicated in cell-to-cell communication. Prior studies have placed substantial emphasis on the role of cytokines in mast cell-microglia interactions during neuroinflammation. However, it has never been clearly determined whether exosomal miRNAs participate in the interaction between mast cells and microglia and thus mediate neuroinflammation. METHODS: The characteristics of exosomes isolated from cell culture supernatants were confirmed by transmission electron microscopy (TEM), nanoparticle-tracking analysis (NTA) and Western blot. The transfer of PKH67-labelled exosomes and Cy3-labelled miR-409-3p was observed by fluorescence microscopy. Migration and activation of murine BV-2 microglial cells were evaluated through Transwell assays and immunofluorescence staining for Iba1 and CD68. CD86, IL-1ß, IL-6 and TNF-α were assessed via qRT-PCR and ELISA. MiR-409-3p was detected by qRT-PCR. Nr4a2 and NF-κB levels were measured by western blot. Regulatory effects were identified by luciferase reporter assays. RESULTS: Lipopolysaccharide (LPS)-stimulated murine P815 mast cells secreted exosomes that were efficiently taken up by murine BV-2 cells, which promoted murine BV-2 cell migration and activation. LPS-P815 exosomes increased the CD86, IL-1ß, IL-6 and TNF-α levels in murine BV-2 microglia. Furthermore, activated mast cells delivered exosomal miR-409-3p to murine BV-2 microglia. Upregulated miR-409-3p promoted murine BV-2 microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway. CONCLUSION: Exosomal miR-409-3p secreted from activated mast cells promotes microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway, which provides evidence that not only cytokines but also exosomal miRNAs participate in neuroinflammation. In the future, targeting exosomal miRNAs may provide new insights into neuroinflammation.

PiRNA-DQ541777 Contributes to Neuropathic Pain via Targeting Cdk5rap1.

Piwi-Interacting RNA (piRNA) is the largest class of small noncoding RNA and is involved in various physiological and pathological processes. However, whether it has a role in pain modulation remains unknown. In the present study, we found that spinal piRNA-DQ541777 (piR-DQ541777) was significantly increased in the male mouse model of sciatic nerve chronic constriction injury (CCI)-induced neuropathic pain. Knockdown of spinal piR-DQ541777 alleviated CCI-induced thermal hyperalgesia and mechanical allodynia and spinal neuronal sensitization. However, the overexpression of spinal piR-DQ541777 in naive mice produced pain behaviors and increased spinal neuron sensitization. Furthermore, we found that piR-DQ541777 regulates pain behaviors by targeting CDK5 regulatory subunit-associated protein 1 (Cdk5rap1). CCI increased the methylation level of CpG islands in the cdk5rap1 promoter and consequently reduced the expression of Cdk5rap1, which was reversed by the knockdown of piR-DQ541777 and mimicked by the overexpression of piR-DQ541777 in naive mice. Finally, piR-DQ541777 increased the methylation level of CpG islands by recruiting DNA methyltransferase 3A (DNMT3a) to cdk5rap1 promoter. In conclusion, this study represents a novel role of piR-DQ541777 in the regulation of neuropathic pain through the methylation of cdk5rap1SIGNIFICANCE STATEMENT Chronic pain affects ∼20% of the population of the world and is a major global public health problem. Although we have studied the neurobiological mechanism of neuropathic pain for decades, there is still no ideal drug available to treat it. This work indicates that a novel role of Piwi-interacting RNA (piRNA) DQ541777 in the regulation of neuropathic pain through the methylation of cdk5rap1 Our findings provide the first evidence of the regulatory effect of piRNAs on neuropathic pain, which may improve our understanding of pain mechanisms and lead to the discovery of novel drug targets for the prevention and treatment of neuropathic pain.

Histamine 2/3 receptor agonists alleviate perioperative neurocognitive disorders by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway in aged rats.

BACKGROUND: Microglia, the principal sentinel immune cells of the central nervous system (CNS), play an extensively vital role in neuroinflammation and perioperative neurocognitive disorders (PND). Histamine, a potent mediator of inflammation, can both promote and prevent microglia-related neuroinflammation by activating different histamine receptors. Rat microglia express four histamine receptors (H1R, H2R, H3R, and H4R), among which the histamine 1 and 4 receptors can promote microglia activation, whereas the role and cellular mechanism of the histamine 2 and 3 receptors have not been elucidated. Therefore, we evaluated the effects and potential cellular mechanisms of histamine 2/3 receptors in microglia-mediated inflammation and PND. METHODS: This study investigated the role of histamine 2/3 receptors in microglia-induced inflammation and PND both in vivo and in vitro. In the in vivo experiments, rats were injected with histamine 2/3 receptor agonists in the right lateral ventricle and were then subjected to exploratory laparotomy. In the in vitro experiments, primary microglia were pretreated with histamine 2/3 receptor agonists before stimulation with lipopolysaccharide (LPS). Cognitive function, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotypes, cell migration, and Toll-like receptor-4 (TLR4) expression were assessed. RESULTS: In our study, the histamine 2/3 receptor agonists inhibited exploratory laparotomy- or LPS-induced cognitive decline, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotype transformation, cell migration, and TLR4 expression through the PI3K/AKT/FoxO1 pathway. CONCLUSION: Based on our findings, we conclude that histamine 2/3 receptors ameliorate PND by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway. Our results highlight histamine 2/3 receptors as potential therapeutic targets to treat neurological conditions associated with PND.

CRNDE: an oncogenic long non-coding RNA in cancers.

Colorectal neoplasia differentially expressed (CRNDE) is a long non-coding RNA which has been proved upregulated in various cancers. Meanwhile, CRNDE has been demonstrated to be involved in multiple biological processes of different cancers according to previous study. Moreover, recent studies suggested CRNDE might be a potential diagnostic biomarker and prognostic predictor due to its high sensitivity and specificity in cancer tissues and plasma. In this review, we summarize the biological function of CRNDE and the relevant mechanisms in cancers to establish a molecular basis for the clinical use of CRNDE in the future.

The Mast Cell Is an Early Activator of Lipopolysaccharide-Induced Neuroinflammation and Blood-Brain Barrier Dysfunction in the Hippocampus.

Neuroinflammation contributes to or even causes central nervous system (CNS) diseases, and its regulation is thus crucial for brain disorders. Mast cells (MCs) and microglia, two resident immune cells in the brain, together with astrocytes, play critical roles in the progression of neuroinflammation-related diseases. MCs have been demonstrated as one of the fastest responders, and they release prestored and newly synthesized mediators including histamine, ß-tryptase, and heparin. However, temporal changes in MC activation in this inflammation process remain unclear. This study demonstrated that MC activation began at 2 h and peaked at 4 h after lipopolysaccharide (LPS) administration. The number of activated MCs remained elevated until 24 h after LPS administration. In addition, the levels of histamine and ß-tryptase in the hippocampus markedly and rapidly increased within 6 h and remained higher than the baseline level within 24 h after LPS challenge. Furthermore, mast cell-deficient KitW-sh/W-sh mice were used to investigate the effects of MCs on microglial and astrocytic activation and blood-brain barrier (BBB) permeability at 4 h after LPS stimulation. Notably, LPS-induced proinflammatory cytokine secretion, microglial activation, and BBB damage were inhibited in KitW-sh/W-sh mice. However, no detectable astrocytic changes were found in WT and KitW-sh/W-sh mice at 4 h after LPS stimulation. Our findings indicate that MC activation precedes CNS inflammation and suggest that MCs are among the earliest participants in the neuroinflammation-initiating events.

High mobility group box-1 mediates hippocampal inflammation and contributes to cognitive deficits in high-fat high-fructose diet-induced obese rats.

High-fat high-sugar diet-induced obesity can lead to hippocampal inflammation and cognitive deficits, but the detailed underlying mechanism is still not clear. We aim to investigate the role of HMGB1 in hippocampal inflammatory responses and cognitive impairment in high-fat high-fructose diet (HFHFD)-induced obesity. Rats were fed with a normal control diet or an HFHFD diet for 14 weeks. In the last 6 weeks on the diets, the rats were treated with control, or an HMGB1 inhibitor glycyrrhizin, or an anti-HMGB1 neutralizing monoclonal antibody (mAb). Obesity was induced in the HFHFD-fed rats, which had higher body weight, epididymal white adipose tissue (EWAT) weight and caloric efficiency, and lower brain/body weight ratio, glucose tolerance and insulin sensitivity than the ones on normal diets. In the HFHFD-induced obese rats, the HMGB1 levels in plasma and hippocampus were increased, and the nucleus-to-cytoplasm translocation of HMGB1 was promoted. The hippocampal inflammatory responses were enhanced in the HFHFD-induced obesity, including the activation of TLR4 and NF-κB, the production of IL-1ß, TNF-α and IL-6, as well as the activation of microglia and astrocytes. In addition, the hippocampal cell apoptosis and cognitive impairment were observed in the HFHFD-fed rats. The treatment with glycyrrhizin or HMGB1 mAb successfully decreased the HMGB1 levels in plasma and hippocampus, and prevented the HMGB1 translocation from the nucleus to cytoplasm. Inhibiting HMGB1 by glycyrrhizin or HMGB1 mAb suppressed the hippocampal inflammatory, alleviated the apoptosis and ameliorated the cognitive impairment in HFHFD-fed rats. These findings indicate that HMGB1 mediates the hippocampal inflammation and contributes to the cognitive deficits in HFHFD-induced obesity. Therefore, inhibition of HMGB1 may have beneficial effect in protecting against hippocampal inflammation and cognitive deficits in dietary obesity.

MiR-138: A promising therapeutic target for cancer.

MicroRNAs are small noncoding RNAs which regulate gene expressions at post-transcriptional level by binding to the 3'-untranslated region of target messenger RNAs. Growing evidences highlight their pivotal roles in various biological processes of human cancers. Among them, miR-138, generating from two primary transcripts, pri-miR-138-1 and pri-miR-138-2, expresses aberrantly in different cancers and is extensively studied in cancer network. Importantly, studies have shown that miR-138 acts as a tumor suppressor by targeting many target genes, which are related to proliferation, apoptosis, invasion, and migration. Additionally, some researches also discover that miR-138 can sensitize tumors to chemotherapies. In this review, we summarize the expression of miR-138 on regulatory mechanisms and tumor biological processes, which will establish molecular basis on the usage of miR-138 in clinical applications in the future.

Genome-wide profiling of micro-RNA expression in gefitinib-resistant human lung adenocarcinoma using microarray for the identification of miR-149-5p modulation.

To understand the mechanism involved in gefitinib resistance, we established gefitinib-resistant human HCC827/GR-8-1 cell line from the parental HCC827 cell line. We compared the micro-RNA expression profiles of the HCC827 cells HCC827/GR-8-1 using Agilent micro-RNA microarrays. The micro-RNAs, such as the miR-149-5p, were up- or downregulated and associated with acquired gefitinib resistance. Quantitative real-time polymerase chain reaction was then performed to verify the expression patterns of different micro-RNAs. The result showed that miR-149-5p was upregulated in the HCC827/GR-8-1 cell line. To investigate the biological function of miR-149-5p in non-small cell lung cancer cells acquired gefitinib resistance, we examined cell proliferation using a cell counting kit-8 assay. Cell viability was evaluated after the miR-149-5p mimics, inhibitors, and negative control were separately transfected into the non-small cell lung cancer cells. The results showed that the non-small cell lung cancer cells transfected with miR-149-5p mimics exhibited reduced cell motility. The drug-sensitivity assay results revealed that the overexpression of miR-149-5p effectively evaluates the half maximal inhibitory concentration values of the cell in response to gefitinib, and the downregulation of miR-149-5p can attenuate the half maximal inhibitory concentration values of the cell lines in response to gefitinib. Furthermore, the levels of miR-149-5p in the HCC827 and HCC827/GR-8-1 cells were inversely correlated with caspase-3 expression. In conclusion, this study revealed that miR-149-5p is upregulated in the HCC827/GR-8-1 cells and involved in the acquired gefitinib resistance.

NBDHEX re-sensitizes adriamycin-resistant breast cancer by inhibiting glutathione S-transferase pi.

PURPOSE: Adriamycin is a novel chemotherapeutic agent of great benefit for treating breast cancer. However, adriamycin -resistance remains a major obstacle. The vital Glutathione transferase P1 (GSTPi) inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX) has recently shown antitumor activity in various cancers. In this study, we analyzed the effect of NBDHEX and adriamycin combination against breast cancer in vitro and in vivo. METHODS: CCK-8 assay was performed to test cell viability. The location and expression level of GSTpi was determined by immunofluorescence and Western blot in cells and immunohistochemistry staining in tissues. The enzyme activity test was applied to detect the effect of NBDHEX on the activity of GSTpi. The apoptosis related proteins' expression was tested using Western blot. The phosphorylation sites of GSTpi were detected by mass spectrometry. Antitumor effects of single treatment or co-administration of adriamycin and NBDHEX were evaluated in nude mice. RESULTS: NBDHEX treatment inhibited GSTpi enzyme activity and co-administration of adriamycin and NBDHEX promoted apoptosis of adriamycin-resistance breast cancer cell. Moreover, drug combination of NBDHEX and adriamycin significantly enhanced tumor growth inhibition compared with single agent. CONCLUSION: NBDHEX serves as a good candidate for combination with adriamycin, offering new insights for breast cancer treatment.

To be, or not to be: the dilemma of immunotherapy for non-small cell lung cancer harboring various driver mutations.

INTRODUCTION: Lung cancer is one of primary cancer type with high incidence and mortality, non-small cell lung cancer (NSCLC) is the most common type of lung cncer. For advanced lung cancer, traditional chemotherapy and targeted therapy become difficult to solve the dilemma of further progress. In recent years, with the clinical application of immunotherapy, the therapeutic strategy of lung cancer has changed dramatically. At present, immunotherapy has shown conspicuous efficacy in NSCLC patients with high expression of programmed death-ligand 1 (PD-L1) and high tumor mutational burden (TMB). The discovery of driver mutations brings delightful hope for targeted cancer therapy. However, it remains controversial whether immunotherapy can be used in NSCLC patients with these specific driver mutations. METHOD: This article summarized the latest research progresses of immunotherapy in advanced NSCLC. We paid close attention to the relevance of various driver mutations and immunotherapy in NSCLC patients, and summarized the predictive effects of several driver mutations and immunotherapy. RESULTS: The mutations of KRAS, KRAS+TP53, EPHA (especially EPHA5), ZFHX3, ZFHX3+TP53, NOTCH, BRAF and LRP1B+FAT3 have potential to be used as biomarkers to predict the positive effectiveness of immunotherapy. ZFHX3, ZFHX3+TP53, STKII/LKB1+KEAP1+SMARCA4+PBRM1 mutations in LUAD patients get more positive effect in immunotherapy. While the mutations of EGFR, KEAP1, STKII/LKB1+KRAS, EML4-ALK, MET exon 14 skipping mutation, PBRM1, STKII/LKB1+KEAP1+SMARCA4+PBRM1, ERBB2, PIK3CA and RET often indicate poor benefit from immunotherapy. CONCLUSION: Many gene mutations have been shown to be associated with immunotherapy efficacy. Gene mutations should be combined with PD-L1, TMB, etc. to predict the effect of immunotherapy.

A case report: A new promising treatment for pulmonary sarcomatoid carcinoma - Tislelizumab and Anlotinib combined with local radiotherapy.

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare pathological type of non-small cell lung cancer, only occurs in 0.1%-0.4 % of lung cancer patients. It has a poor prognosis and shows low response to conventional chemotherapy. Target therapy, immunotherapy, and other new approaches are worth exploring in PSC. Recently, patients with MET ex14 skipping mutation can obtain good therapeutic efficacy through target therapy. But there was no definitive treatment for patients without this special mutation. Case description: Now, we report a female PSC patient without MET ex14 skipping mutation in the cT4N2M1 stage treated with Tislelizumab and Anlotinib obtained remarkable effect for more than 2 years. Significantly, in this case, immunotherapy and antiangiogenic therapy continued to prolong the survival time of more than 10 months for the patient after being treated by local radiotherapy. This is the first case that reported the effectiveness of immunotherapy and antiangiogenic therapy combined with local radiotherapy in treating PSC and achieved more long-term clinical efficacy than other treatments. Conclusions: Thus, immunotherapy and antiangiogenic therapy combined with local radiotherapy may bring new hope to advanced PSC patients and is worth conducting further research. It provided an effective reference for the treatment of advanced PSC patients without METex14 skipping mutation. Moreover, this case also demonstrated the synergistic effect of radiotherapy and immunotherapy.

Aldolase A Promotes Colorectal Cancer Progression through Targeting COPS6 and Regulating MAPK Signaling Pathway.

Colorectal cancer (CRC) is a serious threat to human health, and its underlying mechanisms remain to be further explored. Aldolase A (ALDOA) has received increasing attention for its reported association with multiple cancers, but the role and mechanisms of ALDOA in CRC are still unclear. In the current study, high expression levels and enzymatic activity of ALDOA were detected in CRC tissues and cell lines, indicating the clinical significance of ALDOA in human CRC. In addition, silencing ALDOA significantly impaired the proliferation and metastasis of CRC cells in vitro and in vivo. Mechanistically, immunoprecipitation assays and mass spectrometry analysis identified the binding protein COPS6 of ALDOA. Furthermore, the promoting effects of upregulated ALDOA on CRC cell proliferation and metastasis were inhibited by COPS6 depletion, demonstrating COPS6 was required for ALDOA in mediating CRC progress. Moreover, the epithelial-mesenchymal transition (EMT) program and MAPK signaling pathway were found to be activated by ALDOA overexpression as well. In summary, our findings suggested that ALDOA facilitated the proliferation and metastasis of CRC by binding and regulating COPS6, inducing EMT, and activating the mitogen-activated protein kinase (MAPK) signaling pathway. The present study provided evidence for ALDOA as a promising potential biomarker for CRC.

Research Progress on Mono-ADP-Ribosyltransferases in Human Cell Biology.

ADP-ribosylation is a well-established post-translational modification that is inherently connected to diverse processes, including DNA repair, transcription, and cell signaling. The crucial roles of mono-ADP-ribosyltransferases (mono-ARTs) in biological processes have been identified in recent years by the comprehensive use of genetic engineering, chemical genetics, and proteomics. This review provides an update on current methodological advances in the study of these modifiers. Furthermore, the review provides details on the function of mono ADP-ribosylation. Several mono-ARTs have been implicated in the development of cancer, and this review discusses the role and therapeutic potential of some mono-ARTs in cancer.

Laparotomy-Induced Peripheral Inflammation Activates NR2B Receptors on the Brain Mast Cells and Results in Neuroinflammation in a Vagus Nerve-Dependent Manner.

Background: The pathophysiological mechanisms underlying postoperative cognitive dysfunction (POCD) remain unclear over the years. Neuroinflammation caused by surgery has been recognized as an important element in the development of POCD. Many studies also suggest that the vagus nerve plays an important role in transmitting peripheral injury signals to the central nervous system (CNS) and the resultant neuroinflammation. Previously, we have demonstrated that brain mast cells (BMCs), as the "first responders", play a vital role in neuroinflammation and POCD. However, how the vagus nerve communicates with BMCs in POCD has not yet been clarified. Methods: In the current study, we highlighted the role of the vagus nerve as a conduction highway in surgery-induced neuroinflammation for the first time. In our model, we tested if mice underwent unilateral cervical vagotomy (VGX) had less neuroinflammation compared to the shams after laparotomy (LP) at an early stage. To further investigate the roles of mast cells and glutamate in the process, we employed KitW-sh mice and primary bone marrow-derived MCs to verify the glutamate-NR2B axis on MCs once again. Results: Our results demonstrated that there were higher levels of glutamate and BMCs activation as early as 4 h after LP. Meanwhile, vagotomy could partially block the increases and reduce neuroinflammation caused by peripheral inflammation during the acute phase. Excitingly, inhibition of NR2B receptor and knockout of mast cells can attenuateneuroinflammation induced by glutamate. Conclusion: Taken together, our findings indicate that the vagus is a high-speed pathway in the transmission of peripheral inflammation to the CNS. Activation of BMCs triggered a neuroinflammatory cascade. Inhibition of NR2B receptor on BMCs can reduce glutamate-induced BMCs activation, neuroinflammation, and memory impairment, suggesting a novel treatment strategy for POCD.

ErbB4 in Spinal PV Interneurons Regulates Mechanical Allodynia in Neuropathic Pain via Modulation of Glycinergic Inhibitory Tone.

BACKGROUND: Mechanical allodynia is the most common and challenging symptom associated with neuropathic pain; however, the underlying mechanisms are still unclear. The aim of this study was to investigate whether ErbB4, a receptor for neuregulin-1 (NRG1), participates in the modulation of mechanical allodynia. METHODS: Radiant heat and von Frey filaments were applied to assess nociceptive behaviors. Real-time quantitative polymerase chain reaction, Western blotting, immunofluorescence, and small interfering RNA were used to identify the likely mechanisms. RESULTS: ErbB4 was rapidly and persistently activated in spinal parvalbumin (PV) interneurons after chronic constriction injury (CCI) in mice. Knockdown of ErbB4 in the spinal cord prevented and reversed CCI-induced mechanical allodynia, and activation of ErbB4 by spinal application of NRG1 induced mechanical allodynia in naïve mice. Furthermore, we found that activation of ErbB4 decreased the glycine concentration in the spinal cord, contributing to modulation of mechanical allodynia. CONCLUSION: ErbB4 in spinal PV interneurons gates mechanical allodynia in neuropathic pain via regulation of glycinergic inhibitory tone, suggesting that a possible ErbB4-mediated process participates in the development of neuropathic pain.

Research Advances in the Role of the Poly ADP Ribose Polymerase Family in Cancer.

Poly ADP ribose polymerases (PARPs) catalyze the modification of acceptor proteins, DNA, or RNA with ADP-ribose, which plays an important role in maintaining genomic stability and regulating signaling pathways. The rapid development of PARP1/2 inhibitors for the treatment of ovarian and breast cancers has advanced research on other PARP family members for the treatment of cancer. This paper reviews the role of PARP family members (except PARP1/2 and tankyrases) in cancer and the underlying regulatory mechanisms, which will establish a molecular basis for the clinical application of PARPs in the future.

RNF128 suppresses the malignancy of colorectal cancer cells via inhibition of Wnt/ß-catenin signaling.

PURPOSE: Colorectal cancer (CRC) is one of the most frequent tumors and causes of mortality worldwide. Ubiquitin ligase was reported to regulate multiple cellular processes, including tumorigenesis. As ubiquitin E3 ligases, RING-finger proteins play a key role in physiological and pathophysiological processes. METHODS: We compared the expression levels of RNF128 in CRC tissues by western-blotting and qRT-PCR. Knockdown and overexpression of RNF128 were performed to examine its effect on proliferation and metastasis of CRC cells. Using western blot and co-immunoprecipitation assays, we explored the possible mechanisms underlying the effect of RNF128 in CRC cells. RESULTS: We found that the expression level of RNF128 was correlated with the CRC tumorigenicity. Overexpression or knockdown of RNF128 suppressed or elevated CRC cell proliferation, migration and invasion, respectively. We further determined that RNF128 regulated ß-catenin ubiquitination and thus inhibited Wnt/ß-catenin signaling in CRC cells. CONCLUSION: Our research demonstrated that RNF128 inhibited cell proliferation and metastasis of CRC cells via Wnt/ß-catenin signaling-mediated deubiquitination.