m6A/HOXA10-AS/ITGA6 axis aggravates oxidative resistance and malignant progression of laryngeal squamous cell carcinoma through regulating Notch and Keap1/Nrf2 pathways.

As the second most prevalent malignant tumor of head and neck, laryngeal squamous cell carcinoma (LSCC) imposes a substantial health burden on patients worldwide. Within recent years, resistance to oxidative stress and N6-methyladenosine (m6A) of RNA have been proved to be significantly involved in tumorigenesis. In current study, we investigated the oncogenic role of m6A modified long non coding RNAs (lncRNAs), specifically HOXA10-AS, and its downstream signaling pathway in the regulation of oxidative resistance in LSCC. Bioinformatics analysis revealed that heightened expression of HOXA10-AS was associated with the poor prognosis in LSCC patients, and N (6)-Methyladenosine (m6A) methyltransferase-like 3 (METTL3) was identified as a factor in promoting m6A modification of HOXA10-AS and further intensify its RNA stability. Mechanistically, HOXA10-AS was found to play as a competitive endogenous RNA (ceRNA) by sequestering miR-29 b-3p and preventing its downregulation of Integrin subunit alpha 6 (ITGA6), ultimately enhancing the oxidative resistance of tumor cells and promoting the malignant progression of LSCC. Furthermore, our research elucidated the mechanism by which ITGA6 accelerates Keap1 proteasomal degradation via enhancing TRIM25 expression, leading to increased Nrf2 stability and exacerbating its aberrant activation. Additionally, we demonstrated that ITGA6 enhances γ-secretase-mediated Notch signaling activation, ultimately promoting RBPJ-induced TRIM25 transcription. The current study provides the evidence supporting the effect of m6A modified HOXA10-AS and its downstream miR-29 b-3p/ITGA6 axis on regulating oxidative resistance and malignant progression in LSCC through the Notch and Keap1/Nrf2 pathways, and proposed that targeting this axis holds promise as a potential therapeutic approach for treating LSCC.

Comprehensive Landscape of Prognostic Significance and Immune Characteristics of Myosins in Squamous Cell Carcinoma of the Head and Neck.

Myosin superfamily, a large and diverse family of molecular motors important for cell motility and migration, has been illustrated to play contradictory roles during the development of several kinds of tumors. However, the function and prognostic values of MYOs in head and neck squamous cell carcinoma (HNSCC) still remain largely unknown. In the current manuscript, the expression levels and clinical data of MYOs in HNSCC were investigated by online databases, including Oncomine, GEPIA, GEO, TCGA, HPA, UALCAN, Kaplan-Meier plotter, and CancerSEA; we found that the expression levels of MYO1B, MYO5A, and MYO10 were significantly elevated in HNSCC tissues, which were also correlated with the unfavorable overall survival (OS) of the patients. Furthermore, MYO1B/MYO5A/MYO10 interacting genes were identified, and the protein-protein interaction (PPI) networks were constructed by STRING and GeneMANIA. The enrichment analysis revealed that MYO1B/MYO5A/MYO10 associated genes mainly participated in cell metastasis and EMT processes, which were also confirmed by cell functional experiments. At last, the ssGSEA method was conducted to investigate the extent of immune cell infiltration, and we found that both the expression of MYO1B/MYO5A/MYO10 were closely correlated with the infiltration of immune cells in HNSCC. These findings implied that MYO1B, MYO5A, and MYO10 as novel prognostic factors for HNSCC and provided new strategy for HNSCC treatment.

lncRNA LEF1-AS1 Acts as a Novel Biomarker and Promotes Hypopharyngeal Squamous Cell Carcinoma Progression and Metastasis by Targeting the miR-221-5p/GJA1 Axis.

Hypopharyngeal squamous cell carcinoma (HSCC) is highly malignant and extremely aggressive, making it one of the worst prognoses among all kinds of head and neck squamous cell carcinoma (HNSCC); therefore, gaining insight into molecular mechanisms of HSCC is of profound significance. In the current manuscript, we revealed the elevated expression of long noncoding RNA (lncRNA) LEF1-AS1 in HNSCC which was associated with the poor prognosis by bioinformatic analysis. Moreover, we noticed that LEF1-AS1 dramatically accelerated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process in HSCC cell line FaDu. Most importantly, we illustrated that LEF1-AS1 played as a competitive endogenous RNA (ceRNA) via sponging miR-221-5p and thereby positively regulated gap junction protein alpha 1 (GJA1) expression, thus aggravated tumor progression and EMT. In conclusion, for the first time, we demonstrated lncRNA LEF1-AS1 as a novel biomarker for HNSCC and suggested LEF1-AS1/miR-221-5p/GJA1 axis as promising diagnostic and therapeutic target for HSCC treatment.

Upregulation of Beta4 subunit of BKCa channels in the anterior cingulate cortex contributes to mechanical allodynia associated anxiety-like behaviors.

The anterior cingulate cortex (ACC) serves as a critical hub for the anxiety and pain perception. The large-conductance Ca2+-activated potassium channels, or BKCa channels, are ubiquitously expressed throughout the central nervous system including the cingulate cortex. However, what changes of cortical BKCa channels undergo in the ACC remains unknown in pain-related anxiety. In the present study, a significant upregulation of synaptic and non-synaptic BKCa channel accessory ß4 subunits in the ACC was accompanied with pain-associated anxiety-like behaviors in the chronic compression of multiple dorsal root ganglia (mCCD) of the rat. NS1619, an opener of BKCa channels, significantly rescued the alteration of fAHP and AP duration of ACC pyramidal neurons in mCCD rats. The mRNA expression of BKCa ß4 subunits was extremely upregulated in the ACC after mCCD with the increased amount of both synaptic and non-synaptic BKCa ß4 subunit protein. Meanwhile, NS1619 reversed the enhanced AMPA receptor-mediated spontaneous excitatory postsynaptic current (sEPSC) frequency and the attenuated PPR of ACC neurons in mCCD rats. Local activation of BKCa channels in the ACC reversed mechanical allodynia and anxiety-like behaviors. These results suggest that the upregulation of postsynaptic and presynaptic BKCa ß4 subunit may contribute to neuronal hyperexcitability and the enhanced synaptic transmission in the ACC in neuropathic pain state, and then may result in anxiety-like behavior induced by neuropathic pain.

Acute glycemic variability on admission predicts the prognosis in hospitalized patients with coronary artery disease: a meta-analysis.

PURPOSE: Increased glycemic variability has been related with poor prognosis in patients with coronary artery disease (CAD). However, whether diabetic status or subtype of CAD could affect the association remains unknown. We performed a meta-analysis to systematically evaluate the association between the mean amplitude of glycemic excursions (MAGE) on continuous glucose monitoring and the incidence of major adverse cardiovascular events (MACEs) in CAD patients. METHODS: Relevant prospective cohort studies were identified through search of PubMed, Embase, WanFang, and CNKI databases. A random-effect model was used to pool the results. Subgroup analyses were performed to evaluate the influences of the predefined study characteristics on the outcome. RESULTS: Eleven cohort studies with 2666 hospitalized patients with acute coronary syndrome (ACS) or stable CAD for percutaneous coronary intervention were included. Pooled results showed that higher MAGE at admission was associated with higher incidence of MACEs during follow-up (adjusted relative risk [RR]: 1.84, p < 0.001; I2 = 12%). Stratified analyses showed that the association between higher MAGE and higher risk of MACEs in CAD patients were consistent in patients with or without diabetes, and in those with ACS or stable CAD (p for subgroup difference both >0.05). Significant publication bias was detected (p = 0.041). Trim-and-fill analysis retrieved three studies to generate symmetrical funnel plots. Meta-analysis that incorporated these studies showed similar results (RR: 1.80, p < 0.001). CONCLUSIONS: Increased glycemic variability may be associated with poor prognosis in CAD patients regardless of the diabetic status and the subtype of CAD.

Effects of ANRIL polymorphisms on the likelihood of coronary artery disease: A meta-analysis.

BACKGROUND: Whether antisense noncoding RNA in the INK4 locus (ANRIL) polymorphisms are associated with the likelihood of coronary artery disease (CAD) remains controversial. Therefore, we performed this study to explore correlation between ANRIL polymorphisms and CAD. METHODS: Literature retrieve was conducted in PubMed, Medline and Embase. Odds ratios and 95% confidence intervals were calculated. RESULTS: Nineteen studies were enrolled for analyses. Pooled overall analyses showed that rs1333040 (dominant model: P < 0.0001; recessive model: P < 0.0001; allele model: P < 0.0001), rs1333049 (dominant model: P = 0.02; allele model: P = 0.02) and rs2383207 (additive model: P = 0.004; allele model: P = 0.03) polymorphisms were significantly associated with the likelihood of CAD. Further subgroup analyses revealed that rs1333040, rs1333049, rs2383206, rs2383207, rs10757274, and rs10757278 polymorphisms were all significantly correlated with the likelihood of CAD in East Asians. Additionally, rs2383206, rs10757274, and rs10757278 polymorphisms were also significantly correlated with the likelihood of CAD in Caucasians and West Asians. CONCLUSIONS: Our findings indicated that rs1333040, rs1333049, rs2383206, rs2383207, rs10757274, and rs10757278 polymorphisms may serve as genetic biomarkers of CAD in East Asians. Moreover, rs2383206, rs10757274, and rs10757278 polymorphisms may also serve as genetic biomarkers of CAD in Caucasians and West Asians.

Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization.

Macrophages play essential roles in the generation and resolution of inflammation. Ischemia-reperfusion injury (IRI) triggers a systemic inflammatory response and leads to cellular injury and organ failure. During surgical procedures of the liver, such as hepatic resection and liver transplantation, IRI leads to the dysfunction of the liver. Rho-associated protein kinase (ROCK) inhibitors were reported protecting the liver from IRI. However, the systematic administration of ROCK inhibitors causes severe hypotension. Here, using Fasudil carried liposomes, we specifically inhibited the ROCK-II expression in Kupffer cells and blood monocytes. Through this macrophage/monocyte specific treatment of Fasudil, we successfully protected the liver from IRI by shifting Kupffer cells/monocytes from M1/classical to M2/patrolling phenotype in the liver and peripheral blood. Our finding provides novel insights into the macrophage/monocyte-specific drug delivery and the treatment of liver IRI.

Synaptic Plasticity, a Prominent Contributor to the Anxiety in Fragile X Syndrome.

Fragile X syndrome (FXS) is an inheritable neuropsychological disease caused by expansion of the CGG trinucleotide repeat affecting the fmr1 gene on X chromosome, resulting in silence of the fmr1 gene and failed expression of FMRP. Patients with FXS suffer from cognitive impairment, sensory integration deficits, learning disability, anxiety, autistic traits, and so forth. Specifically, the morbidity of anxiety in FXS individuals remains high from childhood to adulthood. By and large, it is common that the change of brain plasticity plays a key role in the progression of disease. But for now, most studies excessively emphasized the one-sided factor on the change of synaptic plasticity participating in the generation of anxiety during the development of FXS. Here we proposed an integrated concept to acquire better recognition about the details of this process.

Insular Cortex is Critical for the Perception, Modulation, and Chronification of Pain.

An increasing body of neuroimaging and electrophysiological studies of the brain suggest that the insular cortex (IC) integrates multimodal salient information ranging from sensation to cognitive-affective events to create conscious interoception. Especially with regard to pain experience, the IC has been supposed to participate in both sensory-discriminative and affective-motivational aspects of pain. In this review, we discuss the latest data proposing that subregions of the IC are involved in isolated pain networks: the posterior sensory circuit and the anterior emotional network. Due to abundant connections with other brain areas, the IC is likely to serve as an interface where cross-modal shaping of pain occurs. In chronic pain, however, this mode of emotional awareness and the modulation of pain are disrupted. We highlight some of the molecular mechanisms underlying the changes of the pain modulation system that contribute to the transition from acute to chronic pain in the IC.