SMYD2-Methylated PPARγ Facilitates Hypoxia-Induced Pulmonary Hypertension by Activating Mitophagy.

BACKGROUND: Hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs) and consequent pulmonary vascular remodeling are the crucial pathological features of pulmonary hypertension (PH). Protein methylation has been shown to be critically involved in PASMC proliferation and PH, but the underlying mechanism remains largely unknown. METHODS: PH animal models were generated by treating mice/rats with chronic hypoxia for 4 weeks. SMYD2-vTg mice (vascular smooth muscle cell-specific suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 (deformed epidural auto-regulatory factor-1) domain-containing protein 2 transgenic) or wild-type rats and mice treated with LLY-507 (3-cyano-5-{2-[4-[2-(3-methylindol-1-yl)ethyl]piperazin-1-yl]-phenyl}-N-[(3-pyrrolidin-1-yl)propyl]benzamide) were used to investigate the function of SMYD2 (suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 domain-containing protein 2) on PH development in vivo. Primary cultured rat PASMCs with SMYD2 knockdown or overexpression were used to explore the effects of SMYD2 on proliferation and to decipher the underlying mechanism. RESULTS: We demonstrated that the expression of the lysine methyltransferase SMYD2 was upregulated in the smooth muscle cells of pulmonary arteries from patients with PH and hypoxia-exposed rats/mice and in the cytoplasm of hypoxia-induced rat PASMCs. More importantly, targeted inhibition of SMYD2 by LLY-507 significantly attenuated hypoxia-induced pulmonary vascular remodeling and PH development in both male and female rats in vivo and reduced rat PASMC hyperproliferation in vitro. In contrast, SMYD2-vTg mice exhibited more severe PH phenotypes and related pathological changes than nontransgenic mice after 4 weeks of chronic hypoxia treatment. Furthermore, SMYD2 overexpression promoted, while SMYD2 knockdown suppressed, the proliferation of rat PASMCs by affecting the cell cycle checkpoint between S and G2 phases. Mechanistically, we revealed that SMYD2 directly interacted with and monomethylated PPARγ (peroxisome proliferator-activated receptor gamma) to inhibit the nuclear translocation and transcriptional activity of PPARγ, which further promoted mitophagy to facilitate PASMC proliferation and PH development. Furthermore, rosiglitazone, a PPARγ agonist, largely abolished the detrimental effects of SMYD2 overexpression on PASMC proliferation and PH. CONCLUSIONS: Our results demonstrated that SMYD2 monomethylates nonhistone PPARγ and inhibits its nuclear translocation and activation to accelerate PASMC proliferation and PH by triggering mitophagy, indicating that targeting SMYD2 or activating PPARγ are potential strategies for the prevention of PH.

Photoreceptor-Mimetic Microflowers for Restoring Light Responses in Degenerative Retina through a 2D Nanopetal/Cell Biointerface.

Retinitis pigmentosa is the main cause of inherited human blindness and is associated with dysfunctional photoreceptors (PRs). Compared with traditional methods, optoelectronic stimulation can better preserve the structural integrity and genetic content of the retina. However, enhancing the spatiotemporal accuracy of stimulation is challenging. Quantum dot-doped ZnIn2S4 microflowers (MF) are utilized to construct a biomimetic photoelectric interface with a 0D/3D heterostructure, aiming to restore the light response in PR-degenerative mice. The MF bio interface has dimensions similar to those of natural PRs and can be distributed within the curved spatial region of the retina, mimicking cellular dispersion. The soft 2D nano petals of the MF provide a large specific surface area for photoelectric activation and simulate the flexibility interfacing between cells. This bio interface can selectively restore the light responses of seven types of retina ganglion cells that encode brightness. The distribution of responsive cells forms a pattern similar to that of normal mice, which may reflect the generation of the initial "neural code" in the degenerative retina. Patch-clamp recordings indicate that the bio interface can induce spiking and postsynaptic currents at the single-neuron level. The results will shed light on the development of a potential bionic subretinal prosthetic toolkit for visual function restoration.

A zinc-air battery assisted self-powered electrochemical sensor for sensitive detection of microcystin-RR.

Building a high-performance sensing platform is the key to developing sensitive sensors. Herein, a highly sensitive self-powered electrochemical sensor (SPES) was constructed using a WO3·H2O film as the cathode prepared by a hydrothermal method and Zn as the anode, and it could be applied to sensitive detection of microcystin (MC-RR). The WO3·H2O film with a larger specific surface area could boost the oxygen reduction reaction (ORR), which could achieve signal amplification and significantly increase the sensitivity of the sensors. Under the optimal conditions, there was a good linear relationship between the increased electrical power density and the logarithm of MC-RR concentration with a detection limit of 1.31 × 10-15 M (S/N = 3). This method had good anti-interference ability and stability when applied to the determination of MC-RR content in actual samples, which could boost the potential application of electrochemical sensors in the field of environmental monitoring.

A novel electrochemiluminescent sensor based on AgMOF@N-CD composites for sensitive detection of trilobatin.

In this study, a novel electrochemiluminescent (ECL) sensor for highly sensitive detection of trilobatin (Tri) was developed based on silver metal-organic frameworks (AgMOFs) and nitrogen-doped carbon quantum dots (N-CDs). N-CDs exhibited high ECL intensity but poor ECL stability, while AgMOFs had a large specific surface area, high porosity, and good adsorption properties. Compositing both of them not only improved the ECL stability of N-CDs, but also enhanced the ECL strength of materials, so AgMOF@N-CD composites were used as the luminophore of the sensor. Under the optimized conditions, the ECL sensor showed a linear range of 1.0 × 10-7 M to 1.0 × 10-3 M for the detection of Tri, and the detection limit was as low as 5.99 × 10-8 M (S/N = 3). In addition, the sensor had excellent reproducibility, stability, and anti-interference ability. It could be utilized for the detection of Tri in real samples with recoveries of 95.78-102.26%, indicating that the constructed ECL sensor for detecting Tri possessed better application prospects.

A bulit-in self-calibration ratiometric self-powered photoelectrochemical sensor for high-precision and sensitive detection of microcystin-RR.

A novel high-precision aptasensor of microcystin-RR (MC-RR) is developed based on a ratiometric self-powered photoelectrochemical platform. In detail, the defective MoS2/Ti3C2 nanocomposite with good photoelectric activity was designed to serve as the photoanode of the sensor for enhancing the signal and improving the detection sensitivity. In order to effectively eliminate external interferences, the key point of this ratiometric device is the introduction of the spatial-resolved technique, which includes the detection section and the reference section, generating reference signals and response signals, respectively. Moreover, output power was used as the detection signal, instead of the traditional photocurrent or photovoltage. Further, potassium persulfate was introduced as electron acceptor, which was beneficial for improving the electron transport efficiency, hindering electron-hole recombination, and significantly promoting the performance of the sensor. Finally, aptamer was adopted as recognition element to capture MC-RR molecules. The prepared sensor had a linear range from 10-12 to 10-6 M, and the detection limit was 5.6 × 10-13 M (S/N = 3). It has good precision, selectivity, and sensitivity, which shows great prospects in the on-site accurate analysis of samples with high energy output in the self-powered sensing field.

Histone acetyltransferase P300 deficiency promotes ferroptosis of vascular smooth muscle cells by activating the HIF-1α/HMOX1 axis.

BACKGROUND: E1A-associated 300-kDa protein (P300), an endogenous histone acetyltransferase, contributes to modifications of the chromatin landscape of genes involved in multiple cardiovascular diseases. Ferroptosis of vascular smooth muscle cells (VSMCs) is a novel pathological mechanism of aortic dissection. However, whether P300 regulates VSMC ferroptosis remains unknown. METHODS: Cystine deprivation (CD) and imidazole ketone erastin (IKE) were used to induce VSMC ferroptosis. Two different knockdown plasmids targeting P300 and A-485 (a specific inhibitor of P300) were used to investigate the function of P300 in the ferroptosis of human aortic smooth muscle cells (HASMCs). Cell counting kit-8, lactate dehydrogenase and flow cytometry with propidium iodide staining were performed to assess the cell viability and death under the treatment of CD and IKE. BODIPY-C11 assay, immunofluorescence staining of 4-hydroxynonenal and malondialdehyde assay were conducted to detect the level of lipid peroxidation. Furthermore, co-immunoprecipitation was utilized to explore the interaction between P300 and HIF-1α, HIF-1α and P53. RESULTS: Compared with normal control, the protein level of P300 was significantly decreased in HASMCs treated with CD and IKE, which was largely nullified by the ferroptosis inhibitor ferrostatin-1 but not by the autophagy inhibitor or apoptosis inhibitor. Knockdown of P300 by short-hairpin RNA or inhibition of P300 activity by A-485 promoted CD- and IKE-induced HASMC ferroptosis, as evidenced by a reduction in cell viability and aggravation of lipid peroxidation of HASMCs. Furthermore, we found that hypoxia-inducible factor-1α (HIF-1α)/heme oxygenase 1 (HMOX1) pathway was responsible for the impacts of P300 on ferroptosis of HASMCs. The results of co-immunoprecipitation demonstrated that P300 and P53 competitively bound HIF-1α to regulate the expression of HMOX1. Under normal conditions, P300 interacted with HIF-1α to inhibit HMOX1 expression, while reduced expression of P300 induced by ferroptosis inducers would favor HIF-1α binding to P53 to trigger HMOX1 overexpression. Furthermore, the aggravated effects of P300 knockdown on HASMC ferroptosis were largely nullified by HIF-1α knockdown or the HIF-1α inhibitor BAY87-2243. CONCLUSION: Thus, our results revealed that P300 deficiency or inactivation facilitated CD- and IKE-induced VSMC ferroptosis by activating the HIF-1α/HMOX1 axis, which may contribute to the development of diseases related to VSMC ferroptosis.

Hydrovoltaic Effect Coupling with Capacitor Amplification: A Mode for Sensitive Self-Powered Electrochemical Sensing.

Self-powered electrochemical sensors, which can function without external electricity, are incredibly valuable in the realm of sensing. However, most of the present testing methods are normally confined to high environmental requirements, restricted lighting conditions, and temperature differences. Herein, an innovative self-powered electrochemical sensor was successfully developed based on hydrovoltaic effect coupling with capacitor amplification. Due to the combined merits from the two-dimensional transition metal carbides and nitrides (MXene)-polyaniline (PANI) with high surface potential and good hydrophilicity, and the capacitor amplification strategy, the device could harvest electric energy from water evaporation and displayed a high short circuit current value. Under optimal conditions, the proposed self-powered electrochemical sensor presented excellent sensitivity and high specificity for enrofloxacin (ENR) detection in the concentration range from 1 fM to 1 nM with a detection limit of 0.585 fM. Such a proposed sensor also has the advantages of environmental friendliness and ease of use, which is an ideal choice for accurately and precisely detecting ENR in real samples. The mode of such electrochemical detection outlined in this technical note implements a breakthrough in designing self-powered electrochemical sensors, providing a rational basis for development of a diversified sensing platform.

A metal-organic framework regulated graphdiyne-based electrochemiluminescence sensor with a electrocatalytic self-acceleration effect for the detection of di-(2-ethylhexyl) phthalate.

In this work, a super-sensitive electrochemiluminescence (ECL) aptamer sensor was constructed using a multiple signal amplification strategy to realize ultra-sensitive detection of di-(2-ethylhexyl) phthalate (DEHP). The incorporation of a highly efficient electrocatalytic metal-organic framework (NH2-Zr-MOF) and graphdiyne (GDY) composite has significantly enhanced the overall electrochemically active surface area, facilitating electron transfer during the entire electrochemical reaction process, and the large number of pores in graphdiyne and NH2-Zr-MOF limited a series of redox reactions within a certain range. This resulted in the generation of a greater number of SO4˙- radicals, thereby boosting the ECL intensity of the GDY in the K2S2O8 system. To increase the performance of the sensor even further, sodium ascorbate (NaAsc) as an accelerator was added to the co-reactant system. Additionally, nitrogen micro-nano bubbles with higher stability and stronger mass transfer have been introduced into the ECL system for the first time. Based on these, the aptamer as the recognition element realized the ultra-sensitive detection of DEHP in the linear range of 1.0 × 10-12 to 1.0 × 10-4 mg mL-1 with the limit of detection (LOD) of 2.43 × 10-13 mg mL-1. In summary, we have utilized the electrocatalytic activity of the porous MOF and the reducing capability of sodium ascorbate to enhance the ECL emission of GDY, which has been successfully applied to the detection of DEHP in water samples.

A molecularly imprinted polypyrrole electrochemiluminescence sensor based on a novel zinc-based metal-organic framework and chitosan for determination of enrofloxacin.

Nowadays, bacterial resistance caused by the abuse of antibiotics has become a worldwide problem. In this work, a quinolone antibiotic, enrofloxacin (ENR), was rapidly monitored by combining a selective molecular imprinting polymer (MIP) with the electrochemiluminescence (ECL) method. Zn-PTC, a novel zinc-based metal-organic framework (MOF) that has a large specific surface area and ultra-high luminous efficiency, was used as the ECL luminophore. Chitosan (CHIT) was used to contact the specific surface area of molecularly imprinted polymer films and further improved the detection sensitivity. Subsequently, the molecularly imprinted polypyrrole was electropolymerized on the surface of the Zn-PTC and CHIT modified glassy carbon electrode (GCE). The specific sites that could target recombining ENR were shaped on the surface of MIP after extracting the ENR templates. The specific concentrations of ENR could be detected according to the difference in ECL intensity (ΔECL) between the eluting and rebinding of ENR. After optimization, a good linear response of ΔECL and a logarithm of specific ENR concentrations could be obtained in the range of 1.0 × 10-12-1.0 × 10-4 mol L-1, with a detection limit of 9.3 × 10-13 mol L-1 (S/N = 3). Notably, this study provided a rapid, convenient, and cheap method for the detection of ENR in actual samples.

Apatinib combined with SOX regimen for conversion therapy in advanced gastric cancer patients: a retrospective cohort study.

BACKGROUND: Recently, many studies have shown that the progress of conversion therapy can provide surgical opportunities for patients with advanced gastric cancer (GC) and bring survival benefits. However, the results of the current study show that the regimen used in conversion therapy is still controversial. Apatinib, as the standard third-line treatment for GC, has an inconclusive status in conversion therapy. METHODS: This study retrospectively analyzed GC patients admitted to Zhejiang Provincial People's Hospital from June 2016 to November 2019. All patients were pathologically diagnosed, had unresectable factors, and received SOX regimen with or without apatinib as conversion therapy. RESULTS: A total of 50 patients were enrolled in the study. Altogether 33 patients (66%) received conversion surgery and 17 patients (34%) received conversion therapy without surgery. The median progression-free survival (PFS) between surgery group and non-surgery group were 21.0 versus 4.0 months (p < 0.0001), and the median overall survival (OS) were 29.0 versus 14.0 months (p < 0.0001). In conversion surgery group, 16 patients (16/33) were treated with SOX plus apatinib, and the R0 resection rate was 81.3%; 17 patients (17/33) were treated with SOX regimen along, and the R0 resection rate was 41.2% (p = 0.032). The PFS in the SOX combined with apatinib group was significantly longer than that of SOX group (25.5 versus 16 months, p = 0.045), and the median OS were 34.0 versus 23.0 months (p = 0.048). The addition of apatinib did not increase the incidence of serious adverse reactions throughout the preoperative therapy period. CONCLUSIONS: Patients with advanced inoperable gastric cancer could benefit probably from conversion chemotherapy and subsequence conversion surgery. Apatinib-targeted therapy combined with SOX chemotherapy may be a safe and feasible option for conversion therapy.