Ischemic stroke as an initial performance of polycythemia vera in young adults: A case report and literature review.

INTRODUCTION: As the second leading cause of death and disability worldwide, stroke is mainly caused by atherosclerosis and cardiac embolism, particularly in older individuals. Nevertheless, in young and otherwise healthy individuals, the causes of stroke can be more diverse and may include conditions such as patent foramen ovale, vasculitis, coagulopathies, genetic factors, or other undetermined causes. Although these other causes of stroke account for a relatively small proportion compared to ischemic stroke, they are becoming increasingly common in clinical practice and deserve attention. Here, we present a rare female patient with polycythemia vera (PV) who was admitted to the hospital as a stroke patient without any previous medical history. PATIENT CONCERNS: A 40-year-old young woman felt sudden dizziness and slow response. After 4 days of being admitted, she developed blurry vision on the right. DIAGNOSES: Cranial magnetic resonance imaging revealed aberrant signals in the left temporal and parietal lobe, as well as multiple small focal signal abnormalities were observed in the left frontal lobe. Magnetic resonance angiography revealed partial stenosis of the left internal carotid artery. The patient's blood routine examination revealed a significant elevation in complete blood counts, particularly the increase in red blood cells, as well as prolonged clotting time. An abdominal ultrasound and abdomen computed tomography showed splenomegaly. The outcome of the genetic testing was positive for the Janus kinase JAK2 exon V617F mutation (JAK2/V617F). The patient was diagnosed with PV-related stroke. INTERVENTIONS: The patient was treated with phlebotomy, cytoreductive therapy, and low-dose aspirin antiplatelet therapy and was regularly followed up in hematology and neurology clinics after discharge. OUTCOMES: The patient's red blood cell, leukocyte, and thrombocyte counts had fully normalized, with her hemoglobin level measuring at 146 g/L and hematocrit value at 43%. Furthermore, there had been a significant improvement in neurological symptoms. LESSONS: PV, a rare hematological disorder, can present with ischemic stroke as the initial performance, and the diagnosis mainly relies on routine blood tests, bone marrow biopsies, and genetic test. Therefore, clinicians should pay attention to PV, a low-prevalence disease, when encountering stroke in youth.

The application of approaches in detecting ferroptosis.

Ferroptosis is a regulatory cell death (RCD) caused by iron-dependent lipid peroxidation, which is the backbone of regulating various diseases such as tumor, nervous system diseases and so on. Despite ferroptosis without specific detection methods currently, there are numerous types of detection technology commonly used, including flow cytometry, cell activity assay, microscopic imaging, western blotting, quantitative polymerase chain reaction (qPCR). In addition, ferroptosis could be detected by quantifying oxygen-free radicals reactive oxygen species (ROS), the lipid metabolite (malondialdehyde ((MDA)), related pathways and observing mitochondrial damage. In the face of numerous detection methods, how to choose appropriate detection methods based on experimental purposes has become a problem that needs to be solved at present. In this review, we summarized the commonly used detection methods of the critical substances in the process of ferroptosis, in the hope of facilitating the comprehensive study of ferroptosis, with a view to providing a guidance for subsequent related research.

Bioinformatics analysis of the prognosis and biological significance of N6 methyladenine regulators in oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a common type of cancer. We performed the present study to explore the function and specific regulatory mechanism of m6A in OSCC and to find a new diagnosis and treatment strategy for OSCC. METHODS: Using bioinformatics, we examined the associations between 20 genes associated with methylation and the epidemiological data about OSCC tumor samples. RESULTS: We created two subgroup curves based on the gene expression levels related to m6A methylation. In total, 14 genes were found to be differentially expressed. Significant differences in terms of survival rates, Grade and gender were found among subgroups with different m6A expression levels. Nine genes had areas under the curves greater than 0.7. Therefore, these genes may be utilized for the clinical diagnosis and prognosis of OSCC. Because of their high individual predictive value, HNRNPC and IGF2BP2 were chosen as the two potential predictors. The two regulatory elements were used to create the prognostic signals for OSCC. The developed prognostic signals made it possible to discern between the samples with good and poor prognoses without potential confounding factors. Four genes (HNRNPC, METTL14, YTHDF2 and ALKBH5) combined well with compounds, which had an anti-cancer effect. CONCLUSIONS: Our findings suggested that OSCC-related genes with m6A methylation could be beneficial treatment targets or prognostic indicators.

Enhanced focal cortical dysplasia detection in pediatric frontal lobe epilepsy with asymmetric radiomic and morphological features.

Objective: Focal cortical dysplasia (FCD) is the most common pathological cause for pediatric epilepsy, with frontal lobe epilepsy (FLE) being the most prevalent in the pediatric population. We attempted to utilize radiomic and morphological methods on MRI and PET to detect FCD in children with FLE. Methods: Thirty-seven children with FLE and 20 controls were included in the primary cohort, and a five-fold cross-validation was performed. In addition, we validated the performance in an independent site of 12 FLE children. A two-stage experiments including frontal lobe and subregions were employed to detect the lesion area of FCD, incorporating the asymmetric feature between the left and right hemispheres. Specifically, for the radiomics approach, we used gray matter (GM), white matter (WM), GM and WM, and the gray-white matter boundary regions of interest to extract features. Then, we employed a Multi-Layer Perceptron classifier to achieve FCD lesion localization based on both radiomic and morphological methods. Results: The Multi-Layer Perceptron model based on the asymmetric feature exhibited excellent performance both in the frontal lobe and subregions. In the primary cohort and independent site, the radiomics analysis with GM and WM asymmetric features had the highest sensitivity (89.2 and 91.7%) and AUC (98.9 and 99.3%) in frontal lobe. While in the subregions, the GM asymmetric features had the highest sensitivity (85.6 and 79.7%). Furthermore, relying on the highest sensitivity of GM and WM asymmetric features in frontal lobe, when integrated with the subregions results, our approach exhibited overlaps with GM asymmetric features (55.4 and 52.4%), as well as morphological asymmetric features (54.4 and 53.8%), both in the primary cohort and at the independent site. Significance: This study demonstrates that a two-stage design based on the asymmetry of radiomic and morphological features can improve FCD detection. Specifically, incorporating regions of interest for GM, WM, GM, and WM, and the gray-white matter boundary significantly enhances the localization capabilities for lesion detection within the radiomics approach.

Catalpol ameliorates inflammation and oxidative stress via regulating Sirt1 and activating Nrf2/HO-1 signaling against acute kidney injury.

BACKGROUND: Septic acute kidney injury (SAKI) is usually caused by sepsis. It has been shown that catalpol (Cat) impairs sepsis-evoked organ dysfunction to a certain degree. The current work aims to evaluate the protective effects of Cat on SAKI and potential mechanisms in vivo and in vitro. METHODS: SAKI cellular and murine model were set up using lipopolysaccharide (LPS) in vitro and in vivo. Cell apoptosis in cells was determined by TUNEL assay. Levels of inflammatory cytokines were detected by enzyme-linked immunosorbent assay (ELISA). The levels of the markers of oxidative injury were evaluated by corresponding commercial kits. Protein levels were assayed via western blotting and immunohistochemistry (IHC) staining. RESULTS: The results demonstrated that LPS upregulated TNF-α, IL-6, and malondialdehyde levels, and downregulated superoxide dismutase, whereas Cat treated cells have the opposite results. Functional assays displayed that Cat remarkably reversed the LPS-challenged damage as the impairment of TNF-α and IL-6 levels, oxidative stress, and the apoptosis in HK-2 cells. Moreover, knockdown of Sirtuin 1 (Sirt1) counteracted the suppressive impact of Cat on LPS-triggered inflammatory response, oxidative stress, and renal damage. Further, Cat elevated Sirt1 expression and activated the Nrf2/HO-1 signaling in LPS-engendered SAKI in vivo and in vitro. CONCLUSION: Our study clearly proved that Cat protected against LPS-induced SAKI via synergic antioxidant and anti-inflammatory actions by regulating Sirt1 and Nrf2/HO-1 signaling pathways.

Diagnostic value of matrix metalloproteinases 2, 7 and 9 in urine for early detection of colorectal cancer.

BACKGROUND: A noninvasive biomarker with high diagnostic performance is urgently needed for the early diagnosis of colorectal cancer (CRC). AIM: To evaluate the diagnostic value of matrix metalloproteinases (MMPs) 2, 7 and 9 in urine for CRC. METHODS: Of 59 healthy controls, 47 patients with colon polyps and 82 patients with CRC were included in this study. Carcinoembryonic antigen (CEA) in serum and MMP2, MMP7, and MMP9 in urine were detected. The combined diagnostic model of the indicators was established by binary logistic regression. The receiver operating characteristic curve (ROC) of the subjects was used to evaluate the independent and combined diagnostic value of the indicators. RESULTS: The MMP2, MMP7, MMP9, and CEA levels in the CRC group differed significantly from levels in the healthy controls (P < 0.05). The levels of MMP7, MMP9, and CEA also differed significantly between the CRC group and the colon polyps group (P < 0.05). The area under the curve (AUC) distinguishing between the healthy control and the CRC patients using the joint model with CEA, MMP2, MMP7 and MMP9 was 0.977, and the sensitivity and specificity were 95.10% and 91.50%, respectively. For early-stage CRC, the AUC was 0.975, and the sensitivity and specificity were 94.30% and 98.30%, respectively. For advanced stage CRC, the AUC was 0.979, and the sensitivity and specificity were 95.70% and 91.50%, respectively. Using CEA, MMP7 and MMP9 to jointly established a model distinguishing the colorectal polyp group from the CRC group, the AUC was 0.849, and the sensitivity and specificity were 84.10% and 70.20%, respectively. For early-stage CRC, the AUC was 0.818, and the sensitivity and specificity were 76.30% and 72.30%, respectively. For advanced stage CRC, the AUC was 0.875, and the sensitivity and specificity were 81.80% and 72.30%, respectively. CONCLUSION: MMP2, MMP7 and MMP 9 may exhibit diagnostic value for the early detection of CRC and may serve as auxiliary diagnostic markers for CRC.

Environmental risk assessment near a typical spent lead-acid battery recycling factory in China.

In recent years, environmental pollution and public health incidents caused by the recycling of spent lead-acid batteries (LABs) has becoming more frequent, posing potential risk to both the ecological environment and human health. Accurately assessing the environmental risk associated with the recycling of spent LABs is a prerequisite for achieving pollution control. In this study, a spent LABs recycling factory in Chongqing was investigated through on-site investigation, sample analysis. Exposure assessment and health risk assessment were also conducted. The results showed that: firstly, Pb and As concentrations exceeding the standard limit values were found in the environmental air and vegetables near the spent LABs recycling factory. Secondly, exposure assessment results showed that total average daily exposure to hazardous substances for children (3.46 × 10-2 mg/kg) is higher than for adults (4.80 × 10-2 mg/kg). The main exposure pathways for Pb, Cr, Ni, Cu, Zn, and Hg are ingestion of vegetables, while those for Cd, As, and Sb are through inhalation. Thirdly, health risk assessment results indicate that environmental exposure poses unacceptable non-carcinogenic and carcinogenic risk to both adults and children near the spent LABs recycling factory, with children facing higher risk than adults. Pb and As are the main contributors to non-carcinogenic risk, and Ni and As are the main contributors to unacceptable carcinogenic risk. In particular, As, has a greater contribution to total carcinogenic risk index through inhalation than vegetable ingestion. Overall, vegetable ingestion and inhalation are the main exposure pathways for non-carcinogenic and carcinogenic risk. Consequently, future risk assessment should focus on the impact of hazardous substances on children, as well as the health risk associated with ingestion of vegetables and inhalation. Our findings will provide basic information for proposing measures of environmental risk prevention during the recycling of spent LABs, for example, controlling of As in exhaust gas emissions.

Combination of immune checkpoint blockade and targeted gene regulation of angiogenesis for facilitating antitumor immunotherapy.

The rapid development of tumor immunotherapy has improved the management of patients with cancer. However, several key problems of tumor immunotherapy, including the insufficient activation of effector T cells, poor tumor invasion, and poor immune killing ability, lead to a low response rate. In the present study, a synergistic strategy was developed by combining in situ tumor vaccines, gene-mediated downregulation of tumor angiogenesis, and anti-PD-L1 therapy. In situ tumor vaccines and antitumor angiogenesis were achieved by codelivering unmethylated cytosine-phosphate-guanine (CpG) and vascular endothelial growth factor (VEGF)-silencing gene (shVEGF) via a hyaluronic acid (HA)-modified HA/PEI/shVEGF/CpG system. Necrotic tumor cells and CpG adjuvants formed in situ tumor vaccines and activated the host immune response. Moreover, VEGF silencing reduced tumor angiogenesis and prompted the homogeneous distribution of tumor blood vessels to facilitate immune cell infiltration. Meanwhile, anti-angiogenesis also improved the immunosuppressive tumor microenvironment. To further improve the specific tumor-killing effect, an anti-PD-L1 antibody was introduced for immune checkpoint blockade, thereby boosting antitumor immune responses. The combination therapy strategy presented in the present study could act in the multiple stages of the tumor immunotherapy cycle, which is expected to offer a new avenue for clinical tumor immunotherapy.

Effectiveness and Safety of Histamine H2 Receptor Antagonists: An Umbrella Review of Meta-Analyses.

Histamine H2 receptor antagonists (H2RAs) were widely used to inhibit gastric acid secretion, but its association with adverse events remains controversial and unclear. We conducted an umbrella review of meta-analyses to systematically assess the quality and credibility of the correlations between H2RA use with the risk of adverse outcomes through searching 4 major databases from inception to April 30, 2022. Forty-six individual meta-analyses were identified, including 29 meta-analyses of observation studies with 32 unique outcomes and 19 meta-analyses of randomized controlled trials with 3 unique outcomes for comparing the H2RA versus non-H2RA group. A Measurement Tool to Assess Systematic Reviews 2 rating for the included meta-analyses showed that 4 of 46 meta-analyses were assigned as high scores, 3 were assigned as "moderate," and 25 were assigned as low scores. Grading of Recommendations Assessment, Development and Evaluation assessment for combined results demonstrated that 6 outcomes were rated as "moderate," 9 outcomes were rated as "low," and 17 outcomes were rated as "very low." We confirmed significant associations of H2RA use with pneumonia, peritonitis, necrotizing enterocolitis, Clostridium difficile infection, liver cancer, gastric cancer, and hip fracture diseases. No associations for colorectal cancer, melanoma, kidney cancer, lung cancer, or common reproductive system cancer or renal, neurological, and cardiovascular system diseases were observed. We found a variety of evidence for the associations between H2RAs and adverse outcomes, which would give clinicians more positive guidance on prescription of H2RAs in clinical practice.

The potential of Valeriana as a traditional Chinese medicine: traditional clinical applications, bioactivities, and phytochemistry.

Valeriana plants are members of the Caprifoliaceae family, which include more than 200 species worldwide. We summarized previous reports on traditional clinical applications, bioactivities, and phytochemistry of Valeriana by searching electronic databases of Science Direct, Web of Science, PubMed, and some books. Some Valeriana species have been used as traditional medicines, demonstrating calming fright and tranquilizing mind, promoting Qi and blood, activating blood circulation and regulating menstruation, dispelling wind and eliminating dampness, regulating Qi-flowing to relieve pain, and promoting digestion and checking diarrhea, and treating diseases of the nervous, cardiovascular, and digestive systems, inflammation, gynecology, and others. Pharmacology studies revealed the effects of Valeriana, including sedative, hypnotic, antispasmodic, analgesic, antidepressant, anxiolytic, anticonvulsant, antiepileptic, neuroprotective, antibacterial, antiviral, cytotoxic, and antitumor effects as well as cardiovascular and cerebrovascular system improvements. More than 800 compounds have been isolated or identified from Valeriana, including iridoids, lignans, flavonoids, sesquiterpenoids, alkaloids, and essential oils. Constituents with neuroprotective, anti-inflammatory, cytotoxic, and sedative activities were also identified. However, at present, the developed drugs from Valeriana are far from sufficient. We further discussed the pharmacological effects, effective constituents, and mechanisms directly related to the traditional clinical applications of Valeriana, revealing that only several species and their essential oils were well developed to treat insomnia. To effectively promote the utilization of resources, more Valeriana species as well as their different medicinal parts should be the focus of future related studies. Clinical studies should be performed based on the traditional efficacies of Valeriana to facilitate their use in treating diseases of nervous, cardiovascular, and digestive systems, inflammation, and gynecology. Future studies should also focus on developing effective fractions or active compounds of Valeriana into new drugs to treat diseases associated with neurodegeneration, cardiovascular, and cerebrovascular, inflammation and tumors. Our review will promote the development and utilization of potential drugs in Valeriana and avoid wasting their medicinal resources.

Proton Pump Inhibitors and Cancer Risk: An Umbrella Review and Meta-analysis of Observational Studies.

OBJECTIVES: Increasing evidence suggested that proton pump inhibitors (PPIs) use might affect the development of cancers, but previous conclusions remain controversial. Therefore, an umbrella review was performed to clarify the associations between PPIs and various types of cancer by summarizing the existing meta-analyses and systematic reviews. METHODS: We searched PubMed, Cochrane Library, Embase, CNKI, Wanfang, and VIP database up to June 2022 for eligible meta-analyses or systematic reviews. The summary effect size, 95% CI, heterogeneity, small study effect, and 95% prediction interval were considered in the present study. A Measurement Tool to Assess Systematic Review 2 and grading of recommendation, assessment, development, and evaluation were used to assess methodological quality and evidence. RESULTS: The umbrella review included 21 meta-analyses containing 65 studies and 10 cancer types with 6.8 million subjects. The results showed that PPI use was significantly associated with increased risks of certain types of cancer, including gastric cancer (odds ratio [OR]: 2.07; 95% CI, 1.30 to 3.29), pancreatic cancer (OR: 1.73; 95% CI, 1.23 to 2.44), colorectal cancer (OR: 1.84; 95% CI, 1.26 to 2.67), and liver cancer (OR: 1.80; 95% CI, 1.27 to 2.54), but was not associated with esophageal cancer. In addition, PPI use was associated with decreased risk of breast cancer (OR: 0.69; 95% CI, 0.50 to 0.96). CONCLUSIONS: These findings suggested that clinicians should pay more attention to the occurrence of gastric cancer, pancreatic cancer, colorectal cancer, and liver cancer in patients who used PPIs, and PPI prescription should be written only when an accurate specific diagnosis has been made. Furthermore, additional PPIs to the treatment regimen may be benefit for women with a higher-than-average risk of breast cancer.

17ß-estradiol reduces NF-κB expression induced by increased crosstalk between KLF5 and ERα in murine vascular smooth muscle cells.

Pathological vascular remodeling and cell proliferation play vital roles in many proliferative vascular diseases. Estrogen can protect the cardiovascular system, but its exact molecular mechanism is unknown. Here we report that 17ß-estradiol (E2) suppressed vascular smooth muscle cells (VSMCs) proliferation and inflammation. qRT-PCR and Western blot demonstrated that E2 decreased NF-κB p50 expression and reduced VSMCs proliferation and inflammation. Mechanistically, a dual luciferase reporter assay and chromatin immunoprecipitation suggested that KLF5 promoted NF-κB p50 expression by binding to the NF-κB p50 promoter, whereas E2 reduced the effect of KLF5 binding to the NF-κB p50 promoter and inhibited NF-κB p50 expression. Furthermore, a coimmunoprecipitation assay and immunofluorescence staining showed that the interaction between KLF5 and ERα increased in VSMCs treated with E2, which in turn decreased NF-κB p50 expression levels. Altogether, we reveal that E2 inhibits VSMCs proliferation and inflammation by reducing NF-κB expression induced by an increased interaction between KLF5 and ERα. These data provide further insights into how E2 inhibits vascular proliferation and inflammation.

microRNA-181a Promotes Mitochondrial Dysfunction and Inflammatory Reaction in a Rat Model of Intensive Care Unit-Acquired Weakness by Inhibiting IGFBP5 Expression.

This study investigated mechanisms by which microRNA (miR)-181a orchestrates mitochondrial dysfunction and inflammation in a rat model of intensive care unit-acquired weakness (ICU-AW). Expression of miR-181a and insulin-like growth factor binding protein 5 (IGFBP5) was detected and then miR-181a was overexpressed or inhibited and IGFBP5 was overexpressed in the ICU-AW rats. The expression of UCP-3, metaphase chromosome protein 1 (MCP1), mitochondrial DNA (mtDNA), inflammatory factors, phosphorylation (p)-JAK1, p-STAT1, and p-STAT2 were measured in skeletal muscle tissues; binding of miR-181a to IGFBP5 was evaluated by a dual-luciferase reporter assay. The results demonstrated high expression of miR-181a and low expression of IGFBP5 in ICU-AW versus control rats; IGFBP5 was identified as a target gene of miR-181a. Further experiments demonstrated that ICU-AW rats suffered from marked loss of grip strength and decreased adenosine triphosphate production, mtDNA content, and UCP-3 mRNA expression in skeletal muscles; this was accompanied by elevated TNF-α, IL-6, IL-1ß, MCP1, p-JAK1, p-STAT1, and p-STAT2 levels. Importantly, miR-181a suppression alleviated strength loss, inflammatory reaction, and mitochondrial dysfunction and diminished the phosphorylation levels of JAK1, STAT1, and STAT2 whereas IGFBP5 upregulation rescued the effect of miR-181a overexpression in ICU-AW rats. These results indicate that miR-181a promotes mitochondrial dysfunction and inflammation by activating the JAK/STAT pathway via IGFBP5 in ICU-AW model rats.

Apigenin, a Single Active Component of Herbal Extract, Alleviates Xerostomia via ERα-Mediated Upregulation of AQP5 Activation.

Xerostomia is a common symptom in menopausal women, suggesting the role of sex steroids in disease development. Shreds of literature had reported the potential use of herbal extracts to relieve xerostomia. However, a cocktail of multiple components in herbal extract makes it difficult to understand the exact mechanism of action. Aquaporin5 (AQP5), the specific aquaporin expressed in salivary glands, plays an important role in salivary secretion as a downstream of estrogen signaling. In this study, we aimed to unravel a single active herbal component as a therapeutic for xerostomia and investigate its mechanism of action. The effects of apigenin (flavonoid), dauricine (alkaloids), protopine (alkaloids), and lentinan (polysaccharides) on AQP5 transcription were screened in vitro. Only apigenin robustly induced AQP5 transcription and expression, and this effect was even robust compared to the effect of estradiol (E2, a positive control). Overexpression of estrogen receptor α (ERα) in the human salivary gland cell line (HSG) upregulated the AQP5 transcription and expression and the knockdown ERα reversed this effect, suggesting the role of ERα signaling on AQP5 activation in HSG cells. Docking results showed apigenin-specific binding sites in ERα. We further analyzed the therapeutic effect of apigenin on ovariectomized mice as a xerostomia model. The saliva secretion in the xerostomia group was reduced to one-third of the sham group, whereas the apigenin or E2 treatment for 12 weeks reversed this effect. Meanwhile, the water consumption in the xerostomia group was augmented obviously compared to the sham group, whereas the water consumption in the apigenin and E2 group was declined to the level of the sham group. Immunohistochemistry of submandibular glands revealed the downregulation of AQP5 expression in xerostomia mice compared to control. Apigenin, or E2 treatment, upregulated AQP5 expression in xerostomia mice. In conclusion, apigenin, a single active component of herbal extract, upregulated AQP5 expression in HSG cells via activation of ERα signaling and restored saliva flow rates in OVX mice. These results revealed apigenin as a single active component of herbal extract with the potential to treat xerostomia.

Long non-coding RNA profiles in plasma exosomes of patients with gastric high-grade intraepithelial neoplasia.

Long non-coding (lnc) RNAs in circulating exosomes are a new class of promising cancer biomarkers; however, their expression in exosomes derived from gastric high-grade intraepithelial neoplasia (GHGIN) has not been reported. In the present study, differentially expressed (DE) lncRNAs were analyzed in the peripheral blood collected from 5 patients with GHGIN and 5 healthy donors using high-throughput sequencing. Reverse transcription-quantitative PCR analysis was performed on 6 randomly selected DE lncRNAs to validate the reliability of the sequencing results. The potential roles of the DE lncRNAs in GHGIN were investigated using Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analyses. A total of 25,145 lncRNAs were identified in all the samples and 83 DE lncRNAs were further screened, including 76 upregulated and 7 downregulated DE lncRNAs. GO and KEGG analyses predicted that the DE lncRNAs played notable roles in 'protein/macromolecule glycosylation', 'regulation of protein ubiquitination', 'renin-angiotensin system' and 'MAPK signaling pathways'. A lncRNA-micro (mi)RNA-mRNA interaction network was constructed and used to perform association analyses. It was found that 83 lncRNAs were abnormally expressed in GHGIN, with some potential functions associated with gastric cancer. Furthermore, the lncRNA-miRNA-mRNA interaction network indicated that 7 DE lncRNAs may play a notable role in the occurrence and development of GHGIN. The results of the present study showed the expression profiles of lncRNAs in human GHGIN, elucidated some of the molecular changes associated with GHGIN and improved the understanding of the molecular mechanisms underlying GHGIN and gastric cancer.

Inflammatory and Cytotoxic Activities of Abietane Terpenoids from Nepeta bracteata Benth.

Nepeta bracteata Benth. is used clinically to treat tracheal inflammation, coughs, asthma, colds, fevers, adverse urination, and other symptoms, along with functions in clearing heat and removing dampness. However, there have been few studies characterizing the material basis of its efficacy. Therefore, the aim of this study was to screen for compounds with anti-inflammatory activities in N. bracteata Benth. Using silica gel, ODS C18, and Sephadex LH-20 column chromatography, as well as semipreparative HPLC, 10 compounds were separated from N. bracteata Benth. extract, including four new diterpenoids (1-4), one amide alkaloid (5), and five known diterpenoids (6-10). The structures of all the isolates were elucidated by HR-ESI-MS, NMR, and CD analyses. Using lipopolysaccharide (LPS)-stimulated RAW 264.7 cells, we investigated the anti-inflammatory activities of compounds 1-10. It is worth noting that all were able to inhibit nitric oxide (NO) production with IC50 values < 50 µM and little effect on RAW 264.7 macrophage viability. Compounds 2 and 4 displayed remarkable inhibition with IC50 values of 19.2 and 18.8 µM, respectively. Meanwhile, screening on HCT-8 cells demonstrated that compounds 2 and 4 also had moderate cytotoxic activities with IC50 values of 36.3 and 41.4 µM, respectively, which is related to their anti-inflammatory effects.

17ß-Estradiol Attenuates LPS-Induced Macrophage Inflammation In Vitro and Sepsis-Induced Vascular Inflammation In Vivo by Upregulating miR-29a-5p Expression.

Excessive release of cytokines such as IL-1ß and other inflammatory mediators synthesized and secreted by macrophages is the fundamental link of uncontrolled inflammatory response in sepsis. 17ß-Estradiol (E2) plays anti-inflammatory and vascular protective effects by regulating leukocyte infiltration and the expression of chemokines or cytokines induced by injury. However, the role of E2 in the inflammatory response of macrophages in sepsis and its mechanism are still not fully understood. In the present study, we show that E2 alleviates vascular inflammation in sepsis mice induced by cecal ligation puncture (CLP). E2 significantly decreases RAW 264.7 cell inflammation response by downregulating the expression of NLRP3. Furthermore, we found that miR-29a-5p was significantly downregulated in LPS-treated macrophages. Treating RAW 264.7 cells with E2 markedly upregulated the miR-29a-5p expression level. More importantly, we demonstrated that miR-29a-5p repressed NLRP3 expression by directly targeting its 3'-UTR. Loss- and gain-of-function experiments revealed that transfection of the miR-29a-5p mimic abrogates LPS-induced macrophage inflammation. Moreover, depletion of miR-29a-5p by its inhibitor largely promotes LPS-induced macrophage inflammation. In summary, miR-29a-5p upregulation induced by E2 alleviated RAW 264.7 cell inflammation response by aggravating miR-29a-5p repression of NLRP3 expression. E2 exerts significant anti-inflammatory efficacy in macrophages by regulating the miR-29a-5p/NLRP3 axis. Targeting miR-29a-5p may be a novel therapeutic strategy to suppress sepsis-induced vascular inflammation.

Role of Exosomal Non-coding RNAs in Gastric Cancer: Biological Functions and Potential Clinical Applications.

Gastric cancer (GC) is one of the most common fatal cancers worldwide. The communication between GC and other cells in the GC microenvironment directly affects GC progression. Recently, exosomes have been revealed as new players in intercellular communication. They play an important role in human health and diseases, including cancer, owing to their ability to carry various bioactive molecules, including non-coding RNAs (ncRNAs). NcRNAs, including micro RNAs, long non-coding RNAs, and circular RNAs, play a significant role in various pathophysiological processes, especially cancer. Increasing evidence has shown that exosomal ncRNAs are involved in the regulation of tumor proliferation, invasion, metastasis, angiogenesis, immune regulation, and treatment resistance in GC. In addition, exosomal ncRNAs have promising potential as diagnostic and prognostic markers for GC. Considering the biocompatibility of exosomes, they can also be used as biological carriers for targeted therapy. This review summarizes the current research progress on exosomal ncRNAs in gastric cancer, focusing on their biological role in GC and their potential as new biomarkers for GC and therapeutics. Our review provides insight into the mechanisms involved in GC progression, which may provide a new point cut for the discovery of new diagnostic markers and therapeutic strategies.

Combined exome sequencing and deep phenotyping in highly selected fetuses with skeletal dysplasia during the first and second trimesters improves diagnostic yield.

OBJECTIVE: To investigate the genetic etiology of skeletal dysplasia in highly selected fetuses during the first and second trimesters using deep phenotyping and exome sequencing (ES). METHOD: Fetuses with short femurs were identified using the established prenatal diagnostic approach. A multidisciplinary team reviewed fetal phenotypic information (prenatal ultrasound findings, fetal postmortem, and radiographs) in a cohort of highly selected fetuses with skeletal dysplasia during the first and second trimesters. The affected families underwent multiplatform genetic tests. RESULTS: Of the 27 affected fetuses, 21 (77.8%) had pathogenic or potential pathogenic variations in the following genes: COL1A1, FGFR3, COL2A1, COL1A2, FLNB, DYNC2LI1, and TRIP11. Two fetuses had compound heterozygous mutations in DYNC2LI1 and TRIP11, respectively, and the other 19 carried de novo autosomal dominant variants. Novel variants were identified in COL1A1, COL2A1, COL1A2, DYNC2LI1, and TRIP11 in 11 fetuses. We also included the first description of the phenotype of odontochondrodysplasia in a prenatal setting. CONCLUSIONS: ES or panel sequencing offers a high diagnostic yield for fetal skeletal dysplasia during the first and second trimesters. Comprehensive and complete phenotypic information is indispensable for genetic analysis and the expansion of genotype-phenotype correlations in fetal skeletal abnormalities.

Imbalance of Molecular Module of TINCR-miR-761 Promotes the Metastatic Potential of Early Triple Negative Breast Cancer and Partially Offsets the Anti-Tumor Activity of Luteolin.

BACKGROUND: Triple negative breast cancer (TNBC) poses a great threat to patient prognosis. LncRNA-miRNA is a molecular module formed by a long non-coding RNA (LncRNA) and a microRNA (miRNA) that mediates the metastatic potential of tumours such as TNBC, and luteolin (LU) is a natural compound with anti-TNBC activity. OBJECTIVE: We aim to explore the regulatory mechanism of terminal differentiation-induced non-coding RNA (TINCR)-miR-761 molecular module in early TNBC, as well as its influence on anti-tumor activity of LU. METHODS: The serum was collected from TNBC patients in early stage to detect the expression of TINCR and miR-761 using RT-PCR. Transwell method was applied for the determination of cell migration and invasion, Western blot for epithelial-mesenchymal transition (EMT), flow cytometry (FCM) for cell apoptosis, and dual luciferase reporter and RNA pull-down experiment for the verification of the targeted relationship between TINCR and miR-761. RESULTS: Both TINCR and miR-761 were up-regulated in the serum of patients with early TNBC and the area under the curve (AUC) of the two for distinguishing TNBC from BC was not less than 0.850. In the cell function tests, down-regulation of TINCR or miR-761 notably suppressed the metastatic potentials (cell migration, invasion and EMT) of TNBC cells were remarkably inhibited, while up-regulation of TINCR or miR-761 notably promoted the metastatic potentials. We also confirmed that TINCR acts as the molecular sponge of miR-761, and has positive regulation on it. Besides, LU can significantly down-regulate TINCR and miR-761, and partially offset the anti-TNBC activity of LU when they were abnormally up-regulated, which was mainly reflected in the decrease of anti-proliferation and pro-apoptotic ability of LU against TNBC. CONCLUSION: There is an imbalance of TINCR-miR-761 molecular module in early TNBC, which may be a potential new therapeutic target of TNBC.