Peptidase inhibitor 16 promotes proliferation of pancreatic ductal adenocarcinoma cells through OASL signaling.

Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive cancer with a poor prognosis and a 5-year survival rate of less than 11%. As a member of the CAP superfamily of proteins, the role of peptidase inhibitor 16 (Pi16) in tumor progression is still unclear. Immunohistochemistry and quantitative RT-PCR methods were used to detect the expression levels of Pi16 protein and mRNA in PDAC patients. CRISPR/Cas9 technology was used to knock out the expression of Pi16 in PDAC cell lines. In vivo and in vitro experiments were used to verify the effect of Pi16 on PDAC proliferation ability. By RNA sequencing, we found that oligoadenylate synthetase L (OASL) can serve as a potential downstream target of Pi16. The expression of Pi16 was higher in PDAC tissues than in matched adjacent tissues. High expression of Pi16 was associated with PDAC progression and poor prognosis. Overexpression of Pi16 could promote the proliferation of PDAC cells in vitro and in vivo. Bioinformatics analysis and coimmunoprecipitation assays showed that Pi16 could bind to OASL. Moreover, the functional recovery test confirmed that Pi16 could promote the proliferation of PDAC via OASL. Our present study demonstrates that Pi16 might participate in the occurrence and development of PDAC by regulating cell proliferation by binding to OASL, indicating that Pi16 might be a promising novel therapeutic target for PDAC.

Exploring the effect of disc displacement on the risk and severity of condylar erosion in adult temporomandibular disorder patients: A CBCT and MRI study.

OBJECTIVE: The objective of the study was to investigate the relationship between types of disc displacement (DD) diagnosed by magnetic resonance imaging (MRI), and the risk (presence or absence) and severity of condylar erosion (CE) graded using cone-beam computed tomography (CBCT) in adult Temporomandibular disorders (TMD) patients. METHODS: A total of 353 TMD patients (283 females, 70 males) underwent MRI scans to categorise DD as normal (NA), anterior displacement with reduction (ADDR), or anterior displacement without reduction (ADDNR). CE severity was graded on a scale of 0-3 (absence, mild, moderate or severe) using CBCT. To establish the plausibility and cut-off points for CE diagnosis, the severity of CE was then further divided into three classifications: Grade 0 versus 1 + 2 + 3; Grades 0 + 1 versus 2 + 3; Grades 0 + 1 + 2 versus 3. Logistic regression analysis was performed, adjusting for age, gender and joint correlation. RESULTS: ADDNR significantly increased the risk of CE compared with NA (OR = 10.04, 95% CI: [6.41, 15.73]) and showed a significant increase in CE severity across all classifications (ORs = 10.04-18.95). The effects of ADDNR were significant in both genders (p < .001) and had a greater impact in females. ADDR was predominantly associated with mild CE. CONCLUSIONS: ADDNR significantly increased the risk and severity of CE independent of gender when compared to NA, whereas ADDR was mainly associated with mild CE. Slight cortical discontinuity may represent a subclinical diagnosis requiring further investigation.

Role of Stat3 in NLRP3/caspase-1-mediated hippocampal neuronal pyroptosis in epileptic mice.

Epilepsy, a fairly common neurological disorder, is linked to various sequelae and greatly impairs the quality of life. Meanwhile, there is evidence to suggest an association between pyroptosis and epilepsy. Accordingly, the current study sought to determine the role of signal transduction activator of transcription 3 (Stat3) in pyroptosis in epileptic mice. First, epileptic mouse models were induced by lithium chloride, atropine, and pilocarpine, and HT22 cells were treated with lipopolysaccharide (LPS) to establish in vitro hippocampal neuronal inflammation models. Subsequently, Stat3, NOD-like receptor protein 3 (NLRP3), cleaved-caspase-1, gasdermin D (GSDMD)-N, activated Stat3 (p-Stat3), and H3K9Ac levels were detected in the mouse hippocampus and HT22 cells. Morris water maze test was further performed to detect changes in the learning and memory abilities of epileptic mice, and hematoxylin-eosin staining and Nissl staining were conducted to detect the pathological injury. HT22 cell proliferation and apoptosis were also detected using a cell counting kit-8 assay and flow cytometry. An enzyme-linked immunosorbent assay was adopted to detect Interleukin (IL)-1ß and IL-18 concentrations in the mouse hippocampus and HT22 cells. Furthermore, the enrichment of H3K9Ac and p-Stat3 in the NLRP3 promoter region was detected with the help of a chromatin immunoprecipitation assay. The obtained findings revealed that Stat3 was highly expressed in the hippocampus of epileptic mice and LPS-treated HT22 cells. Meanwhile, Stat3 silencing brought about improvements in the learning and memory abilities of the mice, in addition to alleviation of hippocampal neuronal damage and pyroptosis-related factors in hippocampal tissue and HT22 cells. We also observed that Stat3 bound to the NLRP3 promoter to promote H3K9 acetylation and NLRP3 transcription. Moreover, increasing H3K9Ac in cells annulled the inhibition of silencing Stat3 on neuronal pyroptosis. To conclude, our findings revealed that Stat3 bound to the NLRP3 promoter to augment H3K9 acetylation, NLRP3 transcription, and NLRP3/caspase-1-mediated neuronal pyroptosis, resulting in aggravation of neuronal damage in epileptic mice.

miR-106b-5p upregulation is associated with microglial activation and inflammation in the mouse hippocampus following status epilepticus.

To investigate the association of miR-106b-5p with neuroinflammation and microglial activation in a status epilepticus (SE) mouse model. We examined changes in the expression of microRNA-106b-5p (miRNA-106b-5p), repulsive guidance molecule A (RGMa), triggering receptor expressed on myeloid cells 2 (TREM2), and the microglia-related markers interleukin (IL)-1ß, IL-4, IL-6, IL-10, inducible nitric oxide synthase (iNOS), and arginase-1 (Arg-1) in the mouse hippocampus of the lithium-pilocarpine-induced SE mouse model. Eighty-four female C57BL/6 mice were randomly divided into a normal control group (n = 12), and six SE groups (n = 12/group), which were monitored at 6 h and at 1, 3, 7, 14, and 21 days (d) post-SE induction. Unlike in the dentate gyrus, immunohistochemical staining revealed prominent neuronal swelling at 6 h, significant neuronal loss and apoptosis on day 3, and recovery by day 14 in the hippocampal cornu ammonis (CA)1 and CA3 pyramidal cells in SE mice. We noted elevated levels of miRNA-106b-5p and all microglia-related markers, which peaked at 3 days post-SE, except IL-4, which peaked at 7 days post-SE, indicating inflammation and microglial activation. RGMa and TREM2 levels decreased at 6 h post-SE. All markers but miRNA-106b-5p, RGMa, and TREM2 returned to baseline levels at 21 days post-SE. Dual luciferase reporter gene assay showed that microRNA-106b-5p can interact with RGMa. We observed that miR-106b-5p level increased while both RGMa and TREM2 levels decreased post-SE and showed associations with microglial activation and inflammation in the mouse hippocampus, suggesting their potential as SE therapeutic targets.

Dental Care Utilization of Hospitalized Persons Living with HIV and Substance Use.

People living with HIV (PLWH) who use drugs experience worse health outcomes than their non-using counterparts. Little is known about how often they seek dental care and the factors that influence their utilization. PLWH with substance use disorders who were inpatients at 11 urban hospitals (n = 801) participated in a National Institute on Drug Abuse Clinical Trials Network study to improve engagement in HIV outcomes. Dental care utilization at each time point during the study period (baseline, 6 months and/or 12 months) was assessed (n = 657). Univariate analysis and logistic regression were used to examine factors associated with dental care utilization. Over half (59.4%) reported not having received any dental care at any timepoint. Participants with less than high school education had lower odds of reporting dental care utilization than those with more than education (aOR = 0.60 [95% CI 0.37-0.99], p = 0.0382). Participants without health insurance also had lower odds of reporting dental care utilization than those with insurance (aOR = 0.50 [95% CI 0.331-0.76], p = 0.0012). Higher food insecurity was associated with having recent dental care utilization (OR = 1.03 [95% CI 1.00, 1.05], p = 0.0359). Additionally, those from Southern states were less likely to report dental care utilization (aOR = 0.55 [95% CI 0.38, 0.79], p = 0.0013). Having health insurance and education are key factors associated with use of dental care for PLWH with substance use disorders. The association between food insecurity and dental care utilization among this population suggests the need for further exploration.

Antineoplastic activity of Newcastle disease virus strain D90 in oral squamous cell carcinoma.

Newcastle disease virus (NDV), an avian paramyxovirus, possesses the ability to kill tumor cells. Here, we report the effects of NDV strain D90, which was isolated in China, against oral squamous cell carcinoma (OSCC) cells. In this study, we showed that the cell death induced by D90 was apoptotic. Furthermore, the apoptosis induced by D90 was dependent on the mitochondrial pathway, and the death receptor pathway may be not involved. Bax and Bcl-2 also played a role in the apoptosis induced by D90. Lymph node metastasis is a serious problem for oral cancer; we therefore evaluated the impact of D90 on the migration and invasion of OSCC cells. NDV D90 affected microtubules and microfilaments to inhibit the motility of OSCC prior to apoptosis. The effects of D90 on the migration and invasion rates of OSCC cells were evaluated by migration and invasion assays. Subsequently, the changes in sp1, RECK, MMP-2, and MMP-9 induced by a low concentration of D90 were detected by western blot and gelatin zymography. D90 significantly inhibited the invasion and metastasis of OSCC cells by decreasing the expression of sp1 and increasing the expression of RECK to suppress the expression and activity of MMP-2 and MMP-9.

Locomotion modulates olfactory learning through proprioception in C. elegans.

Locomotor activities can enhance learning, but the underlying circuit and synaptic mechanisms are largely unknown. Here we show that locomotion facilitates aversive olfactory learning in C. elegans by activating mechanoreceptors in motor neurons, and transmitting the proprioceptive information thus generated to locomotion interneurons through antidromic-rectifying gap junctions. The proprioceptive information serves to regulate experience-dependent activities and functional coupling of interneurons that process olfactory sensory information to produce the learning behavior. Genetic destruction of either the mechanoreceptors in motor neurons, the rectifying gap junctions between the motor neurons and locomotion interneurons, or specific inhibitory synapses among the interneurons impairs the aversive olfactory learning. We have thus uncovered an unexpected role of proprioception in a specific learning behavior as well as the circuit, synaptic, and gene bases for this function.

Cladosporium sphaerospermum extract inhibits quorum sensing associated virulence factors of Serratia marcescens.

Serratia marcescens is now becoming a propensity for its highly antimicrobial-resistant clinical infections. Currently, it provides a novel strategy to prevent and control microbial infection by regulating S. marcescens quorum sensing (QS). Deep-sea-derived fungi are rich in QS bioactive constituents. In this work, the extracts from Cladosporium sphaerospermum SCSGAF0054 showed potent QS-related virulence factors and biofilm-inhibiting activities against S. marcescens NJ01. The swimming motility and multiple virulence factors such as prodigiosin, exopolysaccharide (EPS), lipase, protease and hemolysin were moderately inhibited by the extracts at varied concentrations. The confocal laser scanning microscope (CLSM) and scanning electron microscope (SEM) images revealed that C. sphaerospermum extracts moderately arrested biofilm formation and cell viability. Further, real-time quantitative PCR (RT-qPCR) analysis revealed that expressions of genes associated with virulence factors, flhD, fimA, fimC, bsmA, bsmB, pigA, pigC, and shlA, were significantly down-regulated compared with control. In addition, the extracts combined with imipenem inhibited the QS system of S. marcescens NJ01, disrupted its preformed biofilm, released the intra-biofilm bacteria and killed the bacteria gradually. Therefore, the extracts combined with imipenem can partially restore bacterial drug sensitivity. These results suggest that the extracts from SCSGAF0054 effectively interfere with the QS system to treat S. marcescens infection alone or combining with classical antimicrobial drugs.

Methylene Blue Mitigates Acute Neuroinflammation after Spinal Cord Injury through Inhibiting NLRP3 Inflammasome Activation in Microglia.

The spinal cord injury (SCI) is a detrimental neurological disease involving the primary mechanical injury and secondary inflammatory damage. Curtailing the detrimental neuroinflammation would be beneficial for spinal cord function recovery. Microglia reside in the spinal cord and actively participate in the onset, progression and perhaps resolution of post-SCI neuroinflammation. In the current study, we tested the effects of methylene blue on microglia both in vitro and in a rat SCI model. We found that methylene blue inhibited the protein levels of IL-1ß and IL-18 rather than their mRNA levels in activated microglia. Further investigation indicated that methylene blue deceased the activation of NLRP3 inflammasome and NLRC4 inflammasome in microglia in vitro. Moreover, in the rat SCI model, the similar effect of methylene blue on post-SCI microglia was also observed, except that the activation of NLRC4 inflammasome was not seen. The inhibition of microglia NLRP3 inflammasome was associated with down-regulation of intracellular reactive oxygen species (ROS). The administration of methylene blue mitigated the overall post-SCI neuroinflammation, demonstrated by decreased pro-inflammatory cytokine production and leukocyte infiltrates. Consequently, the neuronal apoptosis was partially inhibited and the hind limb locomotor function was ameliorated by methylene blue treatment. Our research highlights the role of methylene blue in inhibiting post-SCI neuroinflammation, and suggests that methylene blue might be used for SCI therapy.