Small extracellular vesicles-transported lncRNA TDRKH-AS1 derived from AOPPs-treated trophoblasts initiates endothelial cells pyroptosis through PDIA4/DDIT4 axis in preeclampsia.

BACKGROUND: Substantial studies have demonstrated that oxidative stress placenta and endothelial injury are considered to inextricably critical events in the pathogenesis of preeclampsia (PE). Systemic inflammatory response and endothelial dysfunction are induced by the circulating factors released from oxidative stress placentae. As a novel biomarker of oxidative stress, advanced oxidation protein products (AOPPs) levels are strongly correlated with PE characteristics. Nevertheless, the molecular mechanism underlying the effect of factors is still largely unknown. METHODS: With the exponential knowledge on the importance of placenta-derived extracellular vesicles (pEVs), we carried out lncRNA transcriptome profiling on small EVs (sEVs) secreted from AOPPs-treated trophoblast cells and identified upregulated lncRNA TDRKH-AS1 as a potentially causative factor for PE. We isolated and characterized sEVs from plasma and trophoblast cells by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting. The expression and correlation of lncRNA TDRKH-AS1 were evaluated using qRT-PCR in plasmatic sEVs and placentae from patients. Pregnant mice injected with TDRKH-AS1-riched trophoblast sEVs was performed to detect the TDRKH-AS1 function in vivo. To investigate the potential effect of sEVs-derived TDRKH-AS1 on endothelial function in vitro, transcriptome sequencing, scanning electron Microscopy (SEM), immunofluorescence, ELISA and western blotting were conducted in HUVECs. RNA pulldown, mass spectrometry, RNA immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP) and coimmunoprecipitation (Co-IP) were used to reveal the latent mechanism of TDRKH-AS1 on endothelial injury. RESULTS: The expression level of TDRKH-AS1 was significantly increased in plasmatic sEVs and placentae from patients, and elevated TDRKH-AS1 in plasmatic sEVs was positively correlated with clinical severity of the patients. Moreover, pregnant mice injected with TDRKH-AS1-riched trophoblast sEVs exhibited a hallmark feature of PE with increased blood pressure and systemic inflammatory responses. Pyroptosis, an inflammatory form of programmed cell death, is involved in the development of PE. Indeed, our in vitro study indicated that sEVs-derived TDRKH-AS1 secreted from AOPPs-induced trophoblast elevated DDIT4 expression levels to trigger inflammatory response of pyroptosis in endothelial cells through interacting with PDIA4. CONCLUSIONS: Herein, results in the present study supported that TDRKH-AS1 in sEVs isolated from oxidative stress trophoblast may be implicated in the pathogenesis of PE via inducing pyroptosis and aggravating endothelial dysfunction.

Association of Hashimoto's thyroiditis and anti-thyroid antibodies with oral lichen planus: A cross-sectional study.

Hashimoto's thyroiditis (HT) and its autoantibodies may be associated with oral lichen planus (OLP). In this cross-sectional study, we aimed to assess the relationship among HT, auto-anti-thyroid antibodies, and OLP in a Chinese population of 247 patients with oral lichen planus. Clinical manifestations of OLP were evaluated using the Thongprasom scoring system and clinical type. The diagnosis of HT was based on thyroid function, anti-thyroid peroxidase antibody (anti-TPOAb) and anti-thyroglobulin antibody (anti-TgAb) detection, and ultrasonography. The prevalence of HT in all patients with OLP was 39.68% (98/247); the prevalence in females with OLP was 46.24% (86/186), which was higher than that in males with OLP 19.67% (12/61) (P < 0.01). The titers of the two HT autoantibodies in females with OLP were higher than those in males (P < 0.01). The clinical manifestations of OLP, regardless of being evaluated using the Thongprasom system or clinical type, were not significantly associated with HT development or TPOAb (P = 0.864) or TgAb titers (P = 0.745). In this population-based southern Chinese cohort, the prevalence of HT in patients with OLP, particularly in female patients with OLP, was significantly higher than that in the general population. Female patients had higher HT autoantibody titers than male patients. However, the clinical manifestations of OLP were not significantly correlated with either HT development or auto-anti-thyroid antibody levels. The findings could help further elucidate the factors involved in the relationship between oral lichen planus and Hashimoto's thyroiditis.

RIOX1-demethylated cGAS regulates ionizing radiation-elicited DNA repair.

Exposure to radiation causes DNA damage; hence, continuous surveillance and timely DNA repair are important for genome stability. Epigenetic modifications alter the chromatin architecture, thereby affecting the efficiency of DNA repair. However, how epigenetic modifiers coordinate with the DNA repair machinery to modulate cellular radiosensitivity is relatively unknown. Here, we report that loss of the demethylase ribosomal oxygenase 1 (RIOX1) restores cell proliferation and reduces cell death after exposure to ionizing radiation. Furthermore, RIOX1 depletion enhances homologous recombination (HR) repair but not nonhomologous end-joining (NHEJ) repair in irradiated bone marrow cells and oral mucosal epithelial cells. Mechanistic study demonstrates that RIOX1 removes monomethylation at K491 of cyclic GMP-AMP synthase (cGAS) to release cGAS from its interaction with the methyl-lysine reader protein SAGA complex-associated factor 29 (SGF29), which subsequently enables cGAS to interact with poly(ADP-ribosyl)ated poly(ADP-ribose) polymerase 1 (PARP1) at DNA break sites, thereby blocking PARP1-mediated recruitment of Timeless. High expression of RIOX1 maintains cGAS K491me at a low level, which impedes HR repair and reduces cellular tolerance to ionizing radiation. This study highlights a novel RIOX1-dependent mechanism involved in the non-immune function of cGAS that is essential for the regulation of ionizing radiation-elicited HR repair.

Comparison of topical antifungal agents for oral candidiasis treatment: a systematic review and meta-analysis.

OBJECTIVE: To compare the efficacy and safety of topical antifungal drugs for oral candidiasis in adults and children. STUDY DESIGN: Databases were searched from their inception to December 2020. The inclusion criterion was randomized controlled trials comparing topical antifungal agents. The primary outcomes were clinical response and mycological cure rates. The secondary outcomes were adverse reaction incidence and relapse rate. RESULTS: In adults with oral candidiasis, fluconazole showed a better clinical response rate than clotrimazole (P = 0.001; risk ratio [RR], 1.14), but a similar mycological cure rate (P = 0.57; RR, 1.03). There was no significant difference in clinical response and mycological cure rates with either fluconazole and amphotericin B (clinical: P = 0.47, RR, 0.96; mycological: P = 0.99, RR, 1.00) or with either itraconazole and clotrimazole (clinical: P = 0.51, RR, 1.06; mycological: P = 0.45, RR, 1.32). For immunocompetent patients, fluconazole was superior to clotrimazole in terms of clinical response rate. For immunosuppressed patients, clotrimazole and itraconazole presented similar clinical response and mycological cure rates, but the relapse rate with itraconazole was lower than that with clotrimazole. In infants, miconazole and nystatin showed similar clinical response rates (P = 0.36; RR, 1.23), whereas miconazole presented a superior mycological cure rate (P = 0.03; RR, 4.03). CONCLUSIONS: Fluconazole and amphotericin B are recommended as topical antifungal agents for adults with oral candidiasis. Existing studies tend to recommend fluconazole for immunocompetent patients and itraconazole for immunosuppressed patients, whereas miconazole is recommended for infants.

Innate immune response orchestrates phosphoribosyl pyrophosphate synthetases to support DNA repair.

Ionizing radiation-induced DNA damages cause genome instability and are highly cytotoxic. Deoxyribonucleotide metabolism provides building blocks for DNA repair. Nevertheless, how deoxyribonucleotide metabolism is timely regulated to coordinate with DNA repair remains elusive. Here, we show that ionizing radiation results in TBK1-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2 at T228, thereby enhancing PRPS1/2 catalytic activity and promoting deoxyribonucleotide synthesis. DNA damage-elicited activation of cGAS/STING axis and ATM-mediated PRPS1/2 S16 phosphorylation are required for PRPS1/2 T228 phosphorylation under ionizing radiation. Furthermore, T228 phosphorylation overrides allosteric regulator-mediated effects and preserves PRPS1/2 with high activity. The expression of non-phosphorylatable PRPS1/2 mutants or inhibition of cGAS/STING axis counteracts ionizing radiation-induced PRPS1/2 activation, deoxyribonucleotide synthesis, and DNA repair, and further impairs cell viability. This study highlights a novel and important mechanism underlying an innate immune response-guided deoxyribonucleotide metabolism, which supports DNA repair.

Epigenetic regulation of ion channels in the sense of taste.

There are five fundamental tastes discovered so far: sweet, bitter, umami, sour and salty. Taste is mediated by the specialized neuroepithelial cells mainly located at the tongue papillae, namely taste receptor cells, which can be classified into type I, type II, type III and type IV. Ion channels are necessary for diverse cell physiological activities including taste sensing, smell experience and temperature perception. Existing evidences have demonstrated distinct structures and working models of ion channels. Epigenetic modifications regulate gene expression mainly through histone modifications, DNA methylation and non-coding RNA-mediated regulation, without altering DNA sequence. This review summarizes how ion channels work during the transduction of multiple tastes, as well as the recent progressions in the epigenetic regulation of ion channels.

Metabolic enzymes function as epigenetic modulators: A Trojan Horse for chromatin regulation and gene expression.

Epigenetic modification is a fundamental biological process in living organisms, which has significant impact on health and behavior. Metabolism refers to a set of life-sustaining chemical reactions, including the uptake of nutrients, the subsequent conversion of nutrients into energy or building blocks for organism growth, and finally the clearance of redundant or toxic substances. It is well established that epigenetic modifications govern the metabolic profile of a cell by modulating the expression of metabolic enzymes. Strikingly, almost all the epigenetic modifications require substrates produced by cellular metabolism, and a large proportion of metabolic enzymes can transfer into nucleus to locally produce substrates for epigenetic modification, thereby providing an alternative link between metabolism, epigenetic modification and gene expression. Here, we summarize the recent literature pertinent to metabolic enzymes functioning as epigenetic modulators in the regulation of chromatin architecture and gene expression.

FGF8 induces epithelial-mesenchymal transition and promotes metastasis in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide, and with 354 864 new cases each year. Cancer metastasis, recurrence, and drug resistance are the main causes to cripples and deaths of OSCC patients. As potent growth factors, fibroblast growth factors (FGFs) are frequently susceptible to being hijacked by cancer cells. In this study, we show that FGF8 is upregulated in OSCC tissues and high FGF8 expression is related with a set of clinicopathologic parameters, including age, drinking, and survival time. FGF8 treatment enhances the invasive capability of OSCC cells. Lentivirus-based FGF8 expression promotes OSCC metastasis in a mouse lung metastasis model. Further, mechanistic study demonstrates that FGF8 induces epithelial-mesenchymal transition (EMT) in OSCC cells. These results highlight a pro-metastatic function of FGF8, and underscore the role of FGF8 in OSCC development.

SOX2-dependent expression of dihydroorotate dehydrogenase regulates oral squamous cell carcinoma cell proliferation.

Oral squamous cell carcinoma (OSCC) become a heavy burden of public health, with approximately 300 000 newly diagnosed cases and 145 000 deaths worldwide per year. Nucleotide metabolism fuel DNA replication and RNA synthesis, which is indispensable for cell proliferation. But how tumor cells orchestrate nucleotide metabolic enzymes to support their rapid growth is largely unknown. Here we show that expression of pyrimidine metabolic enzyme dihydroorotate dehydrogenase (DHODH) is upregulated in OSCC tissues, compared to non-cancerous adjacent tissues. Enhanced expression of DHODH is correlated with a shortened patient survival time. Inhibition of DHODH by either shRNA or selective inhibitors impairs proliferation of OSCC cells and growth of tumor xenograft. Further, loss of functional DHODH imped de novo pyrimidine synthesis, and disrupt mitochondrial respiration probably through destabilizing the MICOS complex. Mechanistic study shows that transcriptional factor SOX2 plays an important role in the upregulation of DHODH in OSCC. Our findings add to the knowledge of how cancer cells co-opt nucleotide metabolism to support their rapid growth, and thereby highlight DHODH as a potential prognostic and therapeutic target for OSCC treatment.