IL-17A mediates pyroptosis via the ERK pathway and contributes to steroid resistance in CRSwNP.

BACKGROUND: Pyroptosis is closely related to inflammation. However, the molecular mechanisms and pathologic contributions of pyroptotic epithelial cell are not yet fully understood. OBJECTIVE: This study aimed to explore the function and molecular mechanisms of IL-17A on human nasal epithelial cell (hNEC) pyroptosis. METHODS: The expression of pyroptosis-related biomarkers and IL-17A was assessed in sinonasal mucosa from control individuals, patients with chronic rhinosinusitis without nasal polyps, and patients with chronic rhinosinusitis with nasal polyps (CRSwNP) by using quantitative RT-PCR. Their localization was analyzed via immunohistochemistry and immunofluorescence. The ultrastructural characteristics of IL-17A-induced pyroptosis in hNECs were visualized by using electron microscopy. IL-17A functional assays were performed on hNECs and airway epithelial cell lines. Cytokine levels were quantified via ELISA. The signaling pathways involved in IL-17A-induced pyroptosis were studied via unbiased RNA sequencing and Western blotting. RESULTS: The expression of IL-17A and the pyroptotic biomarkers NOD-like receptor family, pyrin domain containing 3 (NLRP3), caspase-1, gasdermin D, and IL-1ß was increased in nasal mucosa from patients with CRSwNP compared with in those with chronic rhinosinusitis without nasal polyps and the control subjects. IL-17A was positively correlated and colocalized with the pyroptotic biomarkers. IL-17A treatment induced pyroptosis in the hNECs and cell lines analyzed, primarily through the extracellular signal-regulated kinase (ERK)-NLRP3/caspase-1 signaling pathway, and increased IL-1ß and IL-18 secretion in hNECs. Moreover, IL-17A-induced pyroptosis contributed to steroid resistance by affecting glucocorticoid receptor-α and glucocorticoid receptor-ß expression, and the inhibition of pyroptotic proteins partially abolished IL-17A-induced steroid resistance in hNECs. CONCLUSION: Elevated IL-17A level promotes pyroptosis in hNECs through the ERK-NLRP3/caspase-1 signaling pathway and contributes to glucocorticoid resistance by affecting glucocorticoid receptor homeostasis in patients with CRSwNP.

Angiogenic circular RNAs: A new landscape in cardiovascular diseases.

Angiogenesis refers to the formation of new blood vessels from existing blood vessels, including endothelial progenitor cells differentiation and cytokine regulation. Circular RNAs, a type of non-coding RNA, are a stable and conservative endogenous transcriptional product with a circular structure that is produced by the reverse and scrambled splicing of mRNA precursors. They can be used as microRNA sponges, are involved in transcription and protein translation, and regulate the pathophysiological processes of various diseases. Recent studies have shown that circRNAs can regulate angiogenesis by regulating vascular endothelial cell function. In this review, we summarize the angiogenic mechanism; the biogenesis, properties and biological function of circRNAs; and their roles in regulating angiogenesis. We also discuss their potential implications for clinical applications.

Retraction Note: Resveratrol rescues hyperglycemia-induced endothelial dysfunction via activation of Akt.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Effects of mTOR/NF-κB signaling pathway and high thoracic epidural anesthesia on myocardial ischemia-reperfusion injury via autophagy in rats.

We investigated the role of mammalian target of rapamycin/nuclear factor-kappa B (mTOR/NF-κB) signaling pathway in high thoracic epidural anesthesia (HTEA) against myocardial ischemia-reperfusion (I/R) injury in rats. The rat model of myocardial I/R injury was established. Ninety rats were divided into the normal, sham, I/R, eHTEA, the PDTC, and HTEA + PDTC groups. ELISA was applied to detect cardiac function indexes. HE staining was conducted to observe histopathological changes of myocardial tissues, and TTC staining was performed to detect the myocardial infarction size. TUNEL staining was adopted to detect the cell apoptosis rate. The mRNA and protein levels of mTOR, NF-κB, Fasl, Bcl-2 and Bax, and LC3-I, LC3-II, BNIP3, and Atg5 were detected by RT-qPCR and Western blotting, respectively. The findings indicated that compared with the normal and sham groups, the I/R, PDTC, and HTEA groups showed the larger myocardial infarction size and increased cell apoptosis rate, while the results in the HTEA + PDTC group were opposite. Compared with the normal and sham groups, the I/R group showed reduced mRNA and protein levels of Bcl-2, LC3, BNIP3, and Atg5, and elevated mRNA and protein levels of mTOR, p50, p65, Bax, and Fasl, while the HTEA + PDTC group revealed the opposite results, and the PDTC and HTEA group revealed the increased mRNA and protein levels of Bcl-2, LC3, BNIP3, Atg5, mTOR, p50, p65, Bax, and Fasl. These results prove that the inhibition of mTOR/NF-κB signaling pathway potentiates HTEA against myocardial IR injury by autophagy and apoptosis in rats.

Protective Effects of Microrna-22 Against Endothelial Cell Injury by Targeting NLRP3 Through Suppression of the Inflammasome Signaling Pathway in a Rat Model of Coronary Heart Disease.

BACKGROUND/AIMS: This study aimed to identify the role of microRNA-22 (miR-22) in endothelial cell (EC) injury in coronary heart disease (CHD) by targeting NLRP3 through the inflammasome signaling pathway. METHODS: A total of 24 healthy male Sprague-Dawley (SD) rats were divided into normal and atherosclerosis groups. The atherosclerosis rats were assigned into blank, negative control (NC), miR-22 mimic, miR-22 inhibitor and miR-22 inhibitor + siNLRP3 groups. A luciferase reporter gene assay was used to detect the relationship between miR-22 and NLRP3. MiR-22 expression as well as NLRP3 and caspase-1 mRNA and protein expression were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The activity and apoptosis of coronary arterial endothelial cells (CAECs) were determined by MTT and Hoechst 33258. CAEC lumen formation was detected by a lumen formation assay. An enzyme-linked immunosorbent assay (ELISA) was used to detect IL-1ß, IL-6, IL-10 and IL-18 levels. RESULTS: The results indicated that the atherosclerosis group significantly decreased miR-22 expression but increased NLRP3 and caspase-1 mRNA and protein expression. The cell survival rate was significantly increased in the miR-22 mimic group and significantly reduced in the miR-22 inhibitor group. The miR-22 mimic group displayed a lower apoptosis rate and more cells with obvious lumen walls and numerous tubular structures, while cells in the miR-22 inhibitor group were unable to form lumen walls and had a scattered distribution compared to the blank group. The ELISA showed that IL-1ß, IL-6 and IL-18 levels were markedly decreased, while IL-10 was clearly increased in the miR-22 mimic group. In contrast, in the miR-22 inhibitor group, IL-1ß, IL-6 and IL-18 levels were significantly increased, and IL-10 levels were decreased. CONCLUSION: Our findings indicated that miR-22 could lower the levels of pro-inflammatory cytokines by inhibiting the NLRP3 inflammasome pathway, which suppresses CAEC apoptosis and protects CAECs in rats with CHD.

Is the concomitant use of clopidogrel and Proton Pump Inhibitors still associated with increased adverse cardiovascular outcomes following coronary angioplasty?: a systematic review and meta-analysis of recently published studies (2012 - 2016).

BACKGROUND: Controversies were previously observed with the concomitant use of clopidogrel and Proton Pump Inhibitors (PPIs), especially omeprazole, following coronary angioplasty. Even though several studies showed no interaction between clopidogrel and PPIs, questions have been raised about the decrease in antiplatelet effects of clopidogrel with PPIs. A previously published meta-analysis showed concomitant use of clopidogrel and PPIs to be associated with higher adverse cardiovascular outcomes. However, data which were used were extracted from studies published before the year 2012. Whether these controversies still exist in this new era is not clear. Therefore, we aim to show if the concomitant use of clopidogrel and PPIs is still associated with higher adverse outcomes following Percutaneous Coronary Intervention (PCI) using data obtained from recently published studies (2012 to 2016). METHODS: Electronic databases were searched for recent publications (2012-2016) comparing (clopidogrel plus PPIs) versus clopidogrel alone following PCI. Adverse cardiovascular outcomes were considered as the clinical endpoints. Odds Ratios (OR) with 95% Confidence Intervals (CI) were used as the statistical parameters and the pooled analyses were performed with RevMan 5.3 software. RESULTS: Eleven studies with a total number of 84,729 patients (29,235 patients from the PPIs group versus 55,494 patients from the non-PPIs group) were included. Results of this analysis showed that short term mortality and Target Vessel Revascularization (TVR) significantly favored the non-PPIs group with OR: 1.55; 95% CI: 1.43-1.68, P < 0.00001 and OR: 1.26; 95% CI: 1.06-1.49, P = 0.009 respectively. Long-term Major Adverse Cardiac Events (MACEs), Myocardial Infarction (MI), Stent Thrombosis (ST) and TVR significantly favored patients who did not use PPIs with OR: 1.37; 95% CI: 1.23-1.53, P < 0.00001, OR: 1.41; 95% CI: 1.26-1.57, P < 0.00001 and OR: 1.38; 95% CI: 1.13-1.70, P = 0.002 and OR: 1.28; 95% CI: 1.01-1.61, P = 0.04 respectively. However, the result for long term mortality was not statistically significant. CONCLUSION: The combined use of clopidogrel with PPIs is still associated with significantly higher adverse cardiovascular events such as MACEs, ST and MI following PCI supporting results of the previously published meta-analysis. However, long-term mortality is not statistically significant warranting further analysis with randomized patients.

Does infection with human immunodeficiency virus have any impact on the cardiovascular outcomes following percutaneous coronary intervention?: a systematic review and meta-analysis.

BACKGROUND: A direct link between human immunodeficiency virus (HIV)-infected patients and the risk of cardiovascular diseases (CVD) has been shown in recent scientific research. However, this issue is controversial since other previous reports showed no apparent impact of HIV or its anti-retroviral drugs on the cardiovascular system. We aimed to systematically compare the postinterventional adverse cardiovascular outcomes which were observed in patients with and without HIV infection during a mean follow up period ranging from 1 year to 3 years. METHODS: Common electronic databases were searched for studies which compared postinterventional adverse cardiovascular outcomes [mortality, myocardial infarction (MI), cardiac death, target vessel revascularization (TVR), target lesion revascularization (TLR), stroke and major adverse cardiac events (MACEs)] in patients with and without HIV infection. Statistical analysis was carried out by the RevMan 5.3 software whereby Odds Ratios (OR) and 95% Confidence Intervals (CIs) were generated. RESULTS: Two thousand two hundred and sixty-eight (2268) patients (821 patients were HIV positive and 1147 patients were HIV negative) were analyzed. The current results showed that mortality was not significantly increased among patients who were HIV positive with OR: 1.13, 95% CI: 0.65-1.96; P = 0.66. Cardiac death was also similarly reported with OR: 1.16, 95% CI: 0.50-2.68; P = 0.74. However, even if recurrent MI, TVR, TLR, MACEs and stroke were higher in patients who were HIV positive, with OR: 1.32, 95% CI: 0.88-2.12; P = 0.18, OR: 1.36, 95% CI: 0.88-2.12; P = 0.17, OR: 1.22, 95% CI: 0.72-2.06; P = 0.46, OR: 1.29, 95% CI: 0.89-1.85; P = 0.17 and OR: 1.47, 95% CI: 0.44-4.89; P = 0.53 respectively, these results were not statistically significant. CONCLUSION: Patients who were infected with HIV had similar mortality post coronary intervention compared to patients who were not infected by the virus, during a mean follow-up period of 1-3 years. In addition, no significant increase in MI, TVR, TLR, MACEs and stroke were observed during this follow up period. Therefore, it might be concluded that no apparent impact of HIV on the cardiovascular outcomes was observed post coronary intervention.

Comparing Stent Thrombosis associated with Zotarolimus Eluting Stents versus Everolimus Eluting Stents at 1 year follow up: a systematic review and meta-analysis of 6 randomized controlled trials.

BACKGROUND: Two thousand fifteen has been a winning year for Drug Eluting Stents (DES). Increase in the number of patients with cardiovascular diseases treated by Percutaneous Coronary Intervention (PCI) has resulted to a high demand for second generation DES. This current analysis aimed to compare the different types of Stent Thrombosis (ST) associated with Zotarolimus Eluting Stents (ZES) versus Everolimus Eluting Stents (EES) at 1 year follow up. METHODS: Electronic databases were searched for studies comparing ZES with EES. Different types of ST reported at 1 year follow up were considered as the primary endpoints in this analysis. Odds Ratios (OR) with 95% Confidence Intervals (CIs) were used as the statistical parameters and the pooled analyses were carried out by the RevMan 5 · 3 software. RESULTS: A total number of 10,512 patients were included in this analysis. No significant difference in any definite ST, acute definite ST, subacute definite ST, and late definite ST were observed between ZES and EES, at 1 year follow up with OR: 1.70, 95% CI: 0.92 - 3.16; P = 0.09, OR: 3.44, 95% CI: 0.82 - 14.43; P = 0.09, OR: 1.13, 95% CI: 0.43 - 2.95; P = 0.80 and OR: 2.39, 95% CI: 0.83 - 6.85; P = 0.11 respectively. Moreover, any definite or probable ST and definite/probable/possible ST were also not significantly different with OR: 1.39, 95% CI: 0.89 - 2.17; P = 0.15 and OR: 1.19, 95% CI: 0.84 - 1.70; P = 0.33 respectively. In addition, any probable ST, acute probable ST, late probable ST and possible ST were also not significantly different at 1 year follow up with OR: 1.11, 95% CI: 0.60 - 2.05; P = 0.75, OR: 0.53, 95% CI: 0.12 - 2.40; P = 0.41, OR: 1.67, 95% CI: 0.35 - 7.86; P = 0.52 and OR: 1.08, 95% CI: 0.64 - 1.82; P = 0.78 respectively. CONCLUSION: At 1 year follow up, ZES were not associated with significantly lower or higher definite and probable ST compared to EES. In addition, no significant difference was observed in acute, subacute and late definite or probable ST. However, further trials are recommended to assess the effects of these second-generation DES during the long-term.

Bleeding outcomes associated with rivaroxaban and dabigatran in patients treated for atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND: Warfarin is commonly used as a secondary prevention of stroke in patients with atrial fibrillation (AF). However, limitations have been observed even with the use of this medication. Recently, several newer direct oral anticoagulants (DOACs) have been approved for use by the food and drug administrations. Unfortunately, these newer drugs have seldom been compared directly with each other. Therefore, this study aimed to compare the bleeding events associated with rivaroxaban and dabigatran in patients treated for non-valvular AF. METHODS: EMBASE, Medline (National Library of Medicine) and the Cochrane Central Registry of Controlled Trials were searched for studies comparing rivaroxaban with dabigatran using the terms 'rivaroxaban, dabigatran and atrial fibrillation'. Primary endpoints were: any bleeding outcomes, intracranial bleeding and gastro-intestinal (GI) bleeding. Secondary outcomes included stroke/systemic embolism (SE)/transient ischemic attack (TIA), venous thromboembolism and mortality. Odds ratios (OR) with 95% confidence intervals (CIs) were calculated. The pooled analyses were carried out with RevMan 5.3 software. All the authors had full access to the data and approved the manuscript as written. RESULTS: A total number of 4895 patients were included. This analysis showed that rivaroxaban was not associated with a significantly higher bleeding event when compared to dabigatran (OR: 1.28, 95% CI: 0.95-1.72; P = 0.11). GI bleeding was similarly manifested between these two DOACs (OR: 0.98, 95% CI: 0.43-2.25; P = 0.97). Even if intracranial bleeding was higher with the use of rivaroxaban, (OR: 2.18, 95% CI: 0.51-9.25; P = 0.29), the result was not statistically significant. Moreover, stroke/SE/TIA and venous thromboembolism were also not significantly different (OR: 0.81, 95% CI: 0.53-1.23; P = 0.32) and (OR: 2.06, 95% CI: 0.73-5.82; P = 0.17) respectively. However, even if mortality favored dabigatran (OR: 1.42, 95% CI: 0.99-2.06; P = 0.06), this result only approached statistical significance. CONCLUSION: Head to head comparison showed that rivaroxaban was not associated with significantly higher bleeding events compared to dabigatran. Intracranial bleeding, GI bleeding, stroke/SE/TIA, venous thromboembolism and mortality were also not significantly different between these two DOACs. However, due to the limited number of patients analyzed, and which were mainly obtained from observational studies, this hypothesis might only be confirmed in future randomized trials. Furthermore, the CHADS2-VASC and HAS-BLED score which might play an important role in predicting bleeding risks should also not be ignored.

Resveratrol rescues hyperglycemia-induced endothelial dysfunction via activation of Akt.

Resveratrol (RSV), a phytoalexin, has shown to prevent endothelial dysfunction and reduce diabetic vascular complications and the risk of cardiovascular diseases. The aim of this study was to investigate the signaling mechanisms underlying the protecting effects of RSV against endothelial dysfunction during hyperglycemia in vitro and in vivo. Human umbilical vein endothelial cells (HUVECs) were treated with RSV, and then exposed to high glucose (HG, 30 mmol/L). Akt-Ser473 phosphorylation, eNOS-Ser1177 phosphorylation, and PTEN protein levels in the cells were detected using Western blot. For in vivo studies, WT and Akt-/- mice were fed a normal diet containing RSV (400 mg·kg-1·d-1) for 2 weeks, then followed by injection of STZ to induce hyperglycemia (300 mg/dL). Endothelial function was evaluated using aortic rings by assessing ACh-induced vasorelaxation. RSV (5-20 µmol/L) dose-dependently increased Akt-Ser473 phosphorylation, accompanied by increased eNOS-Ser1177 phosphorylation in HUVECs; these effects were more prominent under HG stimulation. Transfection with Akt siRNA abolished RSV-enhanced eNOS phosphorylation and NO release. Furthermore, RSV (5-20 µmol/L) dose-dependently decreased the levels of PTEN, which was significantly increased under HG stimulation, and PTEN overexpression abolished RSV-stimulated Akt phosphorylation in HG-treated HUVECs. Moreover, RSV dramatically increased 26S proteasome activity, which induced degradation of PTEN. In in vivo studies, pretreatment with RSV significantly increased Akt and eNOS phosphorylation in aortic tissues and ACh-induced vasorelaxation, and improved diabetes-induced endothelial dysfunction in wild-type mice but not in Akt-/- mice. RSV attenuates endothelial function during hyperglycemia via activating proteasome-dependent degradation of PTEN, which increases Akt phosphorylation, and consequentially upregulation of eNOS-derived NO production.

Adverse clinical outcomes associated with a low dose and a high dose of aspirin following percutaneous coronary intervention: a systematic review and meta-analysis.

BACKGROUND: Guidelines from the American Heart Association/American College of Cardiology recommend a higher dosage of aspirin daily following Percutaneous Coronary Intervention (PCI), whereas guidelines from the European Society of Cardiology recommend a lower dosage. This study aimed to compare the adverse clinical outcomes associated with a low dose and a high dose of aspirin following PCI. METHODS: Electronic databases were searched for studies comparing a low dose with a high dose aspirin following PCI. Adverse clinical outcomes were considered as the endpoints in this study. We calculated Odds Ratios (OR) with 95 % Confidence Intervals (CIs) for categorical variables. The pooled analyses were performed with RevMan 5.3 software. RESULTS: A total number of 25,083 patients were included. Results from this analysis showed that the combination of Cardiovascular (CV) death/Myocardial Infarction (MI) or stroke was not significantly different between a low and high dose of aspirin with OR: 1.08, 95 % CI: 0.98-1.18; P = 0.11. Mortality and MI were also not significantly different between these two treatment regimens following PCI with OR: 0.95, 95 % CI: 0.74-1.23; P = 0.71 and OR: 1.17, 95 % CI: 0.97-1.41; P = 0.09 respectively. However, a high dose of aspirin was associated with a significantly higher rate of Major Adverse Cardiac Events (MACEs) with OR: 1.20, 95 % CI: 1.02-1.41; P = 0.03. Thrombolysis In Myocardial Infarction (TIMI) defined minor bleeding was also significantly higher with a high dose aspirin with OR: 1.22, 95 % CI: 1.02-1.47; P = 0.03. When Stent thrombosis (ST) was compared, no significant difference was found with OR: 1.28, 95 % CI: 0.59-2.58; P = 0.53. Even if TIMI defined major bleeding favored a low dose of aspirin, with OR: 1.42, 95 % CI: 0.95-2.13; P = 0.09, or even if major bleeding was insignificantly higher with a high dose aspirin, with OR: 1.78, 95 % CI: 1.01-3.13; P = 0.05; I(2) = 94 %, higher levels of heterogeneity observed in these subgroups could not be considered significant to any extent. CONCLUSION: According to the results of this analysis, a high dose of aspirin following PCI was not associated with any significantly higher rate of CV death/MI/stroke, mortality or MI. However, MACEs significantly favored a low dose of aspirin. In addition, TIMI defined minor bleeding was significantly higher with a high dose of aspirin whereas the results for the major bleeding outcomes were not statistically significant. However, due to limited data availability and since the subgroups analyzing major bleeding were highly heterogeneous, further studies are recommended to completely solve this issue.

Nanogalvanic Cells Release Highly Reactive Electrons in Tumors to Effectively Eliminate Tumors.

External stimuli triggering chemical reactions in cancer cells to generate highly reactive chemical species are very appealing for cancer therapy, in which external irradiation activating sensitizers to transfer energy or electrons to surrounding oxygen or other molecules is critical for generating cytotoxic reactive species. However, poor light penetration into tissue, low activity of sensitizers, and reliance on oxygen supply restrict the generation of cytotoxic chemical species in hypoxic tumors, which lowers the therapeutic efficacy. Here, this work presents galvanic cell nanomaterials that can directly release highly reactive electrons in tumors without external irradiation or photosensitizers. The released reactive electrons directly react with surrounding biomolecules such as proteins and DNA within tumors to destroy them or react with other surrounding (bio)molecules to yield cytotoxic chemical species to eliminate tumors independent of oxygen. Administering these nanogalvanic cells to mice results in almost complete remission of subcutaneous solid tumors and deep metastatic tumors. The results demonstrate that this strategy can further arouse an immune response even in a hypoxic environment. This method offers a promising approach to effectively eliminate tumors, similar to photodynamic therapy, but does not require oxygen or irradiation to activate photosensitizers.

Significant increase of the photoresponse range and conductivity for a chalcogenide semiconductor by viologen coating through charge transfer.

Widening the photoresponse range while enhancing the electrical properties of semiconductors could reduce the complexity and cost of photodetectors or increase the power conversion efficiency of solar cells. Surface doping through charge transfer with organic species is one of the most effective and widely used approaches to achieve this aim. It usually features easier preparation over other doping methods but is still limited by the low physicochemical stability and high cost of the used organic species or low improvement of electrical properties. This work shows unprecedented surface doping of semiconductors with highly stable, easily obtained, and strong electron-accepting viologen components, realizing the significant improvement of both the photoresponse range and conductivity. Coating the chalcogenide semiconductor KGaS2 with dimethyl viologen dichloride (MV) yields a charge-transfer complex (CTC) on the surface, which broadens the photoresponse range by nearly 300 nm and improves the conductivity by 5 orders of magnitude. The latter value surpasses all records obtained by surface doping through charge transfer with organic species.

Clinical efficacy of robotic spine surgery: an updated systematic review of 20 randomized controlled trials.

Purpose: To determine whether using robots in spine surgery results in more clinical advantages and fewer adverse consequences. Methods: Between October 1990 and October 2022, a computer-based search was conducted through the databases of PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure, China Biology Medicine, VIP databases, and WAN FANG. The study only included randomized controlled trials (RCTs) comparing the clinical efficacy and safety of robot-assisted surgery with those of conventional spine surgery. The review was conducted following PRISMA 2020, and AMSTAR-2 was used to evaluate the methodological quality. R version 4.2.1 was used in the meta-analysis. The Cochrane Collaboration Tool was used for evaluating the risk of bias. Results: This study analyzed 954 participants from 20 RCTs involving cervical spondylosis, lumbar degenerative disease, scoliosis, etc. The robot-assisted group outperformed the freehand group in terms of intraoperative blood loss, number of screws in grade A position, grade A + B position, radiation dose, and hospital stay. Operation duration, visual analog scale scores of low back pain, Oswestry disability index, and radiation exposure time did not significantly differ between the two groups. Conclusions: Although robotic spine surgery is more accurate in pedicle screw placement than conventional methods, the robot group did not demonstrate an advantage in terms of clinical efficacy. Studies of complications and cost-effectiveness are still very rare.

Tumor Microenvironment Triggered the In Situ Synthesis of an Excellent Sonosensitizer in Tumor for Sonodynamic Therapy.

An ultrasound-triggered sonodynamic therapy has shown great promise for cancer therapy. However, its clinical applications are very limited because the traditional sonosensitizers tend to suffer from very poor efficiency combined with low retention in cancer cells and low tumor selectivity. Therefore, sonosensitizers with higher effectivity, higher tumor cell retention, and higher tumor cell specificity are highly required. Herein, we constructed a Ti2C(OH)X nanosheet, which was a poor sonosensitizer but had a long circulation in the blood system. However, it was very interesting to find that the tumor microenvironment could in situ turn Ti2C(OH)X nanosheet into a novel and excellent sonosensitizer with a nanofiber structure in tumors, exhibiting excellent ability to generate reactive oxygen species (ROS) under ultrasound. Moreover, the nanofiber structure made it very difficult to get out of cancer cells, highly enhancing the retention of the sonosensitizer in the tumor, thereby enabling it to effectively and selectively kill cancer cells in vivo. Our findings demonstrate that the strategy of the tumor microenvironment triggering the in situ synthesis of an effective sonosensitizer in tumor provided a promising means to simultaneously increase the efficiency, sonosensitizer retention in cancer cells, and cancer selectivity, thereby effectively killing cancer cells but causing little damage to healthy tissues via the sonodynamic therapy.

Angiogenic Exosome-Derived microRNAs: Emerging Roles in Cardiovascular Disease.

Angiogenesis is the process of growing endothelial capillary cells. Exosomes are extracellular vesicles that are rich in miRNAs. Studies have shown that exosomes can carry communication between cells and various tissues by delivering miRNAs to their target organs and cells. It has been repeatedly proven that miRNAs regulate the expression of growth factors and other proteins in endothelial cells through paracrine signalling and participate in the physiological and pathological processes of angiogenesis. In the diagnosis and treatment of diseases, exosome-derived microRNAs can play important roles as biomarkers and drug carriers. In this review, we introduce the characteristics of miRNAs and exosomes and their interactions. Then, we specifically summarize the exosome-derived miRNAs related to angiogenesis, and we discuss the potential uses of exosome-derived miRNAs for diagnosing and treating cardiovascular diseases. Graphical abstract.

Single nanosheet can sustainably generate oxygen and inhibit respiration simultaneously in cancer cells.

In a tumor, the abnormal cancer cell proliferation results in an insufficient O2 supply, and meanwhile cancer cells consume O2 very fast. The imbalance between a low oxygen supply and overwhelming oxygen consumption results in a low oxygen concentration in solid tumors. Therefore, in order to relieve hypoxia in tumors, it is necessary to not only sustainably generate O2, but also inhibit mitochondrial respiration simultaneously. Here, we found that a single Ti2C(OH)2 nanomaterial not only can sustainably generate O2 but also simultaneously highly inhibits mitochondrial respiration via binding phosphorylation proteins onto the surface in cancer cells. Ce6 was linked onto Ti2C(OH)2, forming Ti2C(OH)2-Ce6. Ti2C(OH)2-Ce6 could highly relieve hypoxia in tumors via the combination of sustainable O2 generation and respiration inhibition, produce enough 1O2 to kill cancer cells via PDT, and also effectively convert the absorbed light energy into thermal energy to kill cancer cell via PTT, thereby highly enhancing the cancer therapy.

Correction: Single nanosheet can sustainably generate oxygen and inhibit respiration simultaneously in cancer cells.

Correction for 'Single nanosheet can sustainably generate oxygen and inhibit respiration simultaneously in cancer cells' by Wei-Qiang Huang et al., Mater. Horiz., 2021, DOI: .

[Myocardial inflammation and injury induced by coronary microembolization in rats: role of ERK1/2 signaling pathway].

OBJECTIVE: To determine the role of extracellular signal-regulated kinases1/2 (ERK1/2) signaling pathway in regulating myocardial inflammation and cardiac function in a rat model of coronary microembolization (CME). METHODS: The Sprague-Dawley rats were randomly divided into three groups: sham-operated group (n = 15), coronary microembolization group (n = 15) and PD98059 group (n = 15). CME model was established by injection of 42 microm microspheres 0.1 ml (3 x 10(4)/ml, 3000)into left ventricle while occluding the ascending aorta. At 30 minutes pre-operation, rats of PD98059 group were injected with PD98059 IV, a specific ERK1/2 inhibitor. Western blot and immunochemical analysis were used to determine the activation and distribution of ERK1/2. Echocardiography was employed to evaluate cardiac functions. The hematoxylin-eosin staining was used to assay myocardial inflammation. Expression of TNF-alpha and MIF mRNA was determined by RT-PCR analysis and activity of NF-kappaB assessed by electrophoretic mobility shift assay. RESULTS: In comparison with sham-operated group, CME increased phosphorylation of ERK1/2 (0.92 +/- 0.10 vs 0.61 +/- 0.04), local myocardial inflammatory cells (455 +/- 16 vs 47 +/- 7), expression of TNF-alpha mRNA (0.94 +/- 0.04 vs 0.60 +/- 0.09) and MIF mRNA(1.30 +/- 0.44 vs 0.63 +/- 0.25) and activity of NF-kappaB (541 +/- 25 vs 311 +/- 65) in myocardium(all P < 0.05). All of these dramatically induced cardiac dysfunction [LVEF (73 +/- 3)% vs (83 +/- 4)%, P < 0.05]. To compare with CME group, treatment of specific ERK1/2 inhibitor PD98059 blocked the activation of ERK1/2 (0.48 +/- 0.11 vs 0.92 +/- 0.10, P < 0.05), decreased inflammatory cells (401 +/- 12 vs 455 +/- 16, P < 0.05), decreased expression of TNF-alpha mRNA (0.42 +/- 0.06 vs 0.94 +/- 0.04, P < 0.05) and suppressed activity of NF-kappaB (105 +/- 14 vs 541 +/- 25, P < 0.05). Most importantly, PD98059 treatment ameliorated cardiac functions dramatically [LVEF (76 +/- 4)% vs (73 +/- 3)%, P < 0.05]. However there was no significant change in the expression of MIF mRNA (1.17 +/- 0.37 vs 1.30 +/- 0.44, P > 0.05). CONCLUSION: The present study demonstrates a novel role of ERK1/2 signaling pathway in promoting myocardial inflammation in CME. And ERK1/2 may be a novel drug target for CME therapy.

Rhodanine-based Knoevenagel reaction and ring-opening polymerization for efficiently constructing multicyclic polymers.

Cyclic polymers have a number of unique physical properties compared with those of their linear counterparts. However, the methods for the synthesis of cyclic polymers are very limited, and some multicyclic polymers are still not accessible now. Here, we found that the five-membered cyclic structure and electron withdrawing groups make methylene in rhodanine highly active to aldehyde via highly efficient Knoevenagel reaction. Also, rhodanine can act as an initiator for anionic ring-opening polymerization of thiirane to produce cyclic polythioethers. Therefore, rhodanine can serve as both an initiator for ring-opening polymerization and a monomer in Knoevenagel polymerization. Via rhodanine-based Knoevenagel reaction, we can easily incorporate rhodanine moieties in the backbone, side chain, branched chain, etc, and correspondingly could produce cyclic structures in the backbone, side chain, branched chain, etc, via rhodanine-based anionic ring-opening polymerization. This rhodanine chemistry would provide easy access to a wide variety of complex multicyclic polymers.