Inhibition of Cardiac Kv4.3/KChIP2 Channels by Sulfonylurea Drug Gliquidone.

The Kv4.3 channel features fast N-type inactivation and also undergoes a slow C-type inactivation. The gain-of-function mutations of Kv4.3 channels cause an inherited disease called Brugada syndrome (BrS), characterized by a shortened duration of cardiac action potential repolarization and ventricular arrhythmia. The sulfonylurea drug gliquidone, an ATP-dependent K+ channel antagonist, is widely used for the treatment of type 2 diabetes. Here, we report a novel role of gliquidone in inhibiting Kv4.3 and Kv4.3/KChIP2 channels that encode the cardiac transient outward K+ currents responsible for the initial phase of action potential repolarization. Gliquidone results in concentration-dependent inhibition of both Kv4.3 and Kv4.3/KChIP2 fast or steady-state inactivation currents with an IC50 of approximately 8 µM. Gliquidone also accelerates Kv4.3 channel inactivation and shifts the steady-state activation to a more depolarizing direction. Site-directed mutagenesis and molecular docking reveal that the residues S301 in the S4 and Y312A and L321A in the S4-S5 linker are critical for gliquidone-mediated inhibition of Kv4.3 currents, as mutating those residues to alanine significantly reduces the potency for gliquidone-mediated inhibition. Furthermore, gliquidone also inhibits a gain-of-function Kv4.3 V392I mutant identified in BrS patients in voltage- and concentration-dependent manner. Taken together, our findings demonstrate that gliquidone inhibits Kv4.3 channels by acting on the residues in the S4 and the S4-S5 linker. Therefore, gliquidone may hold repurposing potential for the therapy of Brugada syndrome. SIGNIFICANCE STATEMENT: We describe a novel role of gliquidone in inhibiting cardiac Kv4.3 currents and the channel gain-of-function mutation identified from patients with Brugada syndrome, suggesting its repurposing potential for therapy for the heart disease.

Cascading Detection of Hydrogen Sulfide and N-Acetyltransferase 2 in Hepatocellular Carcinoma Cells Using a Two-Photon Fluorescent Probe.

Hydrogen sulfide (H2S), a critical gas signaling molecule, and N-acetyltransferase 2 (NAT2), a key enzyme in drug metabolism, are both known active biomarkers for liver function. However, the interactions and effects of H2S and NAT2 in living cells or lesion sites remain unknown due to the lack of imaging tools to achieve simultaneous detection of these two substances, making it challenging to implement real-time imaging and precise tracking. Herein, we report an activity-based two-photon fluorescent probe, TPSP-1, for the cascade detection of H2S and NAT2 in living liver cells. Continuous conversion from TPSP-1 to TPSP-3 was achieved in liver cells and tissues. Significantly, leveraging the outstanding optical properties of this two-photon fluorescent probe, TPSP-1, has been effectively used to identify pathological tissue samples directly from clinical liver cancer patients. This work provides us with this novel sensing and two-photon imaging probe, which can be used as a powerful tool to study the physiological functions of H2S and NAT2 and will help facilitate rapid and accurate diagnosis and therapeutic evaluation of hepatocellular carcinoma.

Pure Laparoscopic Anatomic Resection of Liver Segment 4 with Middle Hepatic Vein Involvement Using Indocyanine Green Fluorescence Staining.

BACKGROUND: Laparoscopic anatomic resection of liver segment 4 is a technically challenging operation, which is rarely reported owing to the difficulty of defining the demarcation of a hepatic segment 4 on a monitor.1 The portal territory staining method is technically feasible to identify tumors and segment boundaries during hepatectomy.2 Herein, we describe the laparoscopic hepatectomy of segment 4 using the fluorescent-positive staining method. METHODS: A 72-year-old man recurred colorectal liver metastases after colectomy, positron emission tomography (PET)/computed tomography (CT) showed metastases located in segment 4 with involvement of the middle hepatic vein (MHV) and caudate lobe; no other organ metastasis or recurrence occurred. We performed an anatomical hepatectomy 4 with MHV and parenchymal resection of segment 1 (H1'/4-MHV).3 The key point of the procedure was dividing and clamping Glisson's branches for segment 2 and segment 3 using the hepatic round ligament approach; the G2 and G3 were dissected along the right side of round ligament via the extrahepatic Glissonian approach, then the left hepatic artery (LHA) was divided and injected with ICG in the left portal vein (LPV). Finally, transection was performed along the fluorescent stain location line and ischemic demarcation line. RESULTS: The operation time was 263 min; the Pringle lasted 110 min, and the estimated blood loss was 400 g. The patient was discharged on postoperative day 5 without complications. Sigmoid carcinoma and R0 margin were confirmed by histopathology. CONCLUSIONS: Laparoscopic anatomic hepatectomy 4 with middle hepatic vein invasion using indocyanine green (ICG) fluorescence staining is a feasible and effective technique.

Incremental prognostic utility of left ventricular and left atrial strains in coronary artery disease patients with reduced systolic function.

OBJECTIVE: This study aimed to investigate the predictive value of left ventricular global longitudinal strain (GLS) and left atrial reservoir strain (LARS) on adverse events in chronic coronary artery disease (CAD) patients with reduced systolic function. METHODS: A total of 192 consecutive patients clinically diagnosed with chronic CAD and left ventricular ejection fraction (LVEF) ≤ 50% were finally included. Multiple strain parameters were analyzed with speckle tracking echocardiography. The composite endpoint included all-cause mortality, rehospitalization due to heart failure, myocardial infarction, and stroke. RESULTS: Patients experiencing the endpoint showed lower LVEF, lower absolute GLS and LARS than those without events. Both GLS (AUC = 0.82 [GLS] vs. 0.58 [LVEF], p < 0.001) and LARS (AUC = 0.71 [LARS] vs. 0.58 [LVEF], p = 0.033) were superior to LVEF in predicting adverse events. Multivariate cox regression analysis showed that both GLS (hazard ratio, 0.71; 95% CI, 0.63-0.79; p < 0.001) and LARS (hazard ratio, 0.96; 95% CI, 0.93-0.98; p < 0.001) were independent predictors for the endpoint. The addition of LARS (global chi-squared, 35.7 vs. 17.4; p < 0.05), GLS (global chi-squared, 58.6 vs. 17.4; p < 0.05) or both LARS and GLS (global chi-squared, 79.6 vs. 17.4; p < 0.05) to LVEF in the prediction model significantly improved its performance. The same significant improvement was also shown in the subgroups of mild (30% < LVEF ≤ 50%) and severe (LVEF ≤ 30%) reduced systolic function. CONCLUSIONS: Regarding CAD patients with reduced LVEF, both GLS and LARS are superior to LVEF in predicting adverse events, providing significant incremental value to LVEF.

Association between gout and the risk of osteoporosis and fractures: a meta-analysis.

OBJECTIVE: The relationship between gout and osteoporosis is poorly clarified, and the association between gout and fractures incidence remains controversial. Hence, in the present study, we aimed to comprehensively evaluate the available literature to elucidate whether gout is associated with an increased risk of both osteoporosis and fractures. MATERIALS AND METHODS: We conducted an exhaustive search of pertinent literature published until 20 March 2023, in well-recognized databases, namely Medline, Embase and Cochrane Library, focusing on examining the association between gout and the risk of osteoporosis or fracture. Meta-analysis was performed to aggregate the relative risks (RR) using random- or fixed-effects models. Sensitivity analyses were conducted iteratively, whereby each study was removed sequentially to gauge its impact on the overall outcome. Publication bias was assessed using Egger's and Begg's tests. This study was registered with PROSPERO (registry number: CRD42022376822). RESULTS: Herein, we included 10 observational studies comprising a total of 1,606,095 participants. An independent population sample of four studies validated the significant association between gout and osteoporosis (RR = 1.25, 95% confidence interval [CI] 1.05-1.48), with the results demonstrating robustness. However, our analysis did not detect any association between gout and fracture risk when compared with the control group (RR = 1.09, 95%CI 0.99-1.19), along with high heterogeneity (p for heterogeneity = 0.000; I2 = 79.7%). Further subgroup analysis revealed that gout is positively associated with fracture risk in the Chinese population (RR = 1.17, 95%CI 1.14-1.21), with no evidence of heterogeneity (p for heterogeneity = 0.420; I2 = 0.00%). CONCLUSION: Our meticulous evaluation of the available literature indicates that gout has no discernible impact on fracture incidence, although it is positively associated with an enhanced risk of osteoporosis. Therefore, it is imperative to prioritize preventive measures to prevent osteoporotic complications in individuals diagnosed with gout.

A Novel Role of Uricosuric Agent Benzbromarone in BK Channel Activation and Reduction of Airway Smooth Muscle Contraction.

The uricosuric drug benzbromarone, widely used for treatment of gout, hyperpolarizes the membrane potential of airway smooth muscle cells, but how it works remains unknown. Here we show a novel role of benzbromarone in activation of large conductance calcium-activated K+ channels. Benzbromarone results in dose-dependent activation of macroscopic big potassium (BK) currents about 1.7- to 14.5-fold with an EC50 of 111 µM and shifts the voltage-dependent channel activation to a more hyperpolarizing direction about 10 to 54 mV in whole-cell patch clamp recordings. In single-channel recordings, benzbromarone decreases single BKα channel closed dwell time and increases the channel open probability. Coexpressing ß1 subunit also enhances BK activation by benzbromarone with an EC50 of 67 µM and a leftward shift of conductance-voltage (G-V) curve about 44 to 138 mV. Site-directed mutagenesis reveals that a motif of three amino acids 329RKK331 in the cytoplasmic linker between S6 and C-terminal regulator of potassium conductance (RCK) gating ring mediates the pharmacological activation of BK channels by benzbromarone. Further ex vivo assay shows that benzbromarone causes reduction of tracheal strip contraction. Taken together, our findings demonstrate that uricosuric benzbromarone activates BK channels through molecular mechanism of action involving the channel RKK motif of S6-RCK linker. Pharmacological activation of BK channel by benzbromarone causes reduction of tracheal strip contraction, holding a repurposing potential for asthma and pulmonary arterial hypertension or BK channelopathies. SIGNIFICANCE STATEMENT: We describe a novel role of uricosuric agent benzbromarone in big potassium (BK) channel activation and relaxation of airway smooth muscle contraction. In this study, we find that benzbromarone is an activator of the large-conductance Ca2+- and voltage-activated K+ channel (BK channel), which serves numerous cellular functions, including control of smooth muscle contraction. Pharmacological activation of BK channel by the FDA-approved drug benzbromarone may hold repurposing potential for treatment of asthma and pulmonary arterial hypertension or BK channelopathies.

Design, synthesis, and biological evaluation of acyl sulfonamide derivatives with spiro cycles as NaV1.7 inhibitors for antinociception.

Chronic pain, as an unmet medical need, severely impacts the quality of life. The voltage-gated sodium channel NaV1.7 preferentially expressed in sensory neurons of dorsal root ganglia (DRG) serves a promising target for pain therapy. Here, we report the design, synthesis, and evaluation of a series of acyl sulfonamide derivatives targeting Nav1.7 for their antinociceptive activities. Among the derivatives tested, the compound 36c was identified as a selective and potent NaV1.7 inhibitor in vitro and exhibited antinociceptive effects in vivo. The identification of 36c not only provides a new insight into the discovery of selective NaV1.7 inhibitors, but also may hold premise for pain therapy.

Calculation of excited states of monolayer TPPA-COF based on first principles.

Two-dimensional covalent organic frameworks (COFs) have always been a hot topic in condensed matter physics. Herein, the first 100 excited states of the TPPA-COF are calculated to investigate the optical absorption properties of the materials in the interval. The stable molecular structure of monolayer TPPA-COF is obtained by first-principles calculation, which can be regarded as a hexagon with an aperture size of 18.25 Å. By means of the band structure and density of state analysis, it is found that the monolayer band gap width of the TPPA-COF is 1.52 eV. All excited states of the TPPA-COF exhibit obvious pi → pi* (delocalized π to anti π) local excitation characteristics through analysing the spatial distribution of the electron-hole pairs of the 10 excited states with the highest oscillator strength among the first 100 excited states. In addition, the simulated UV-vis spectra show that the maximum absorption intensity of the TPPA-COF is about 357 684 mol-1 cm-1, indicating that the TPPA-COF is a potential light-absorbing material.

Association of hyperhomocysteinemia and chronic kidney disease in the general population: a systematic review and meta-analysis.

BACKGROUND: Increasing evidence shows that an elevated homocysteine(Hcy) level is associated with an increased risk of chronic kidney disease (CKD). This study systematically evaluated the correlation between homocysteine level and the incidence of CKD reported in cohort and cross-sectional studies. METHODS: We searched electronic databases and reference lists for relevant articles. 4 cohort studies and 7 cross-sectional studies including 79,416 patients were analyzed in a meta-analysis. Hyperhomocysteinemia was defined as a Hcy level > 15 µmol/L, which was the criterium used in previous studies. Meta-analyses were conducted of literature searches from online databases such as PubMed, Embase, Cochrane and Scopus. Computed pooled adjusted odds ratios with corresponding 95% confidence intervals (95% CI) were used to estimate the risk of new-onset CKD according to Hcy levels in the general population. RESULTS: People with high Hcy levels were more likely to suffer from CKD than people with normal Hcy levels (pooled OR, 2.09; 95% CI, 1.72-2.55). This positive relationship persisted across different study types such as cohort studies (summary OR, 2.2; 95% CI, 1.55-3.13) and cross-sectional studies (summary OR, 2.07; 95% CI, 1.63-2.63). CONCLUSIONS: People with hyperhomocysteinemia have a higher incidence of CKD, Hyperhomocysteinemia may also be an independent risk factor for CKD in the general population.

Ultrasound-assisted biomimetic nanobubbles for targeted treatment of atherosclerosis.

Cardiovascular disease caused by atherosclerosis remains the main reason of death in the worldwide scale. Although oxidative stress plays a key role in the initiation and progression of atherosclerosis, current antioxidant drugs have limited efficacy. To resolve this problem, we constructed Nox2 siRNA-loaded nanobubbles (PNBs-siNox2) coated with platelet membranes to utilize their antioxidant stress activity and targeting effect for atherosclerosis treatment. After platelet membranes modification, the capacity of PNBs-siNox2 to target collagen, foam cells, or human umbilical vein endothelial cells (HUVECs) was significantly increased. Moreover, our study demonstrated that under ultrasonic irradiation, biomimetic nanobubbles were more effective at targeting atherosclerotic plaques and delivering genes into cells. In the present study, we provided a biomimetic gene loading strategy based on nanoplatform for noninvasive, precise and efficient therapy of atherosclerosis, which further improved the efficiency of gene transfection and effectively slowed the progression of atherosclerotic plaques when combined with ultrasound.

Epileptic brain fluorescent imaging reveals apigenin can relieve the myeloperoxidase-mediated oxidative stress and inhibit ferroptosis.

Myeloperoxidase (MPO)-mediated oxidative stress has been suggested to play an important role in the pathological dysfunction of epileptic brains. However, there is currently no robust brain-imaging tool to detect real-time endogenous hypochlorite (HClO) generation by MPO or a fluorescent probe for rapid high-throughput screening of antiepileptic agents that control the MPO-mediated chlorination stress. Herein, we report an efficient two-photon fluorescence probe (named HCP) for the real-time detection of endogenous HClO signals generated by MPO in the brain of kainic acid (KA)-induced epileptic mice, where HClO-dependent chlorination of quinolone fluorophore gives the enhanced fluorescence response. With this probe, we visualized directly the endogenous HClO fluxes generated by the overexpression of MPO activity in vivo and ex vivo in mouse brains with epileptic behaviors. Notably, by using HCP, we have also constructed a high-throughput screening approach to rapidly screen the potential antiepileptic agents to control MPO-mediated oxidative stress. Moreover, from this screen, we identified that the flavonoid compound apigenin can relieve the MPO-mediated oxidative stress and inhibit the ferroptosis of neuronal cells. Overall, this work provides a versatile fluorescence tool for elucidating the role of HClO generation by MPO in the pathology of epileptic seizures and for rapidly discovering additional antiepileptic agents to prevent and treat epilepsy.

The impact of stoma management education on the self-care abilities of individuals with an intestinal stoma.

An intestinal stoma is a surgically formed exteriorisation of the large or small bowel on to the anterior abdomen wall, to enable faeces to be excreted from the body. Patients living with a stoma may encounter physical, psychological, and social barriers and challenges. Stoma self-management education is essential to improving self-care competence, and patients who perceive the benefits of self-management education show a better adjustment to living with a stoma. This literature review explored the effectiveness of patient education interventions in improving the self-care knowledge and skills of patients living with an ostomy. The findings from the nine studies reviewed showed that self-management education approaches are effective in improving patients' self-care. The application of different approaches to ostomy self-management education, such as a transtheoretical model, chronic care model, telehealth and multimedia-based programmes - helped improve patients' self-care ability. The review also found that patients needed at least 3 months to develop the skills and maintain their ability to self-care. In addition, two education sessions provided to patients in hospital pre-discharge appeared sufficient for improving and maintaining self-care abilities. Where patients received education in hospital post-surgery, 2 or 3 sessions over 7 days were found to be sufficient to provide them with stoma care skills. Education sessions based on the transtheoretical model and chronic care model or telehealth helped maintain and reinforce self-care behaviours following discharge.

Ultrarapid Nanomanufacturing of High-Quality Bimetallic Anode Library toward Stable Potassium-Ion Storage.

Bimetallic alloy nanomaterials are promising anode materials for potassium-ion batteries (KIBs) due to their high electrochemical performance. The most well-adopted fabrication method for bimetallic alloy nanomaterials is tube furnace annealing (TFA) synthesis, which can hardly satisfy the trade-off among granularity, dispersity and grain coarsening due to mutual constraints. Herein, we report a facile, scalable and ultrafast high-temperature radiation (HTR) method for the fabrication of a library of ultrafine bimetallic alloys with narrow size distribution (≈10-20 nm), uniform dispersion and high loading. The metal-anchor containing heteroatoms (i.e., O and N), ultrarapid heating/cooling rate (≈103  K s-1 ) and super-short heating duration (several seconds) synergistically contribute to the successful synthesis of small-sized alloy anodes. As a proof-of-concept demonstration, the as-prepared BiSb-HTR anode shows ultrahigh stability indicated by negligible degradation after 800 cycles. The in situ X-ray diffraction reveals the K+ storage mechanism of BiSb-HTR. This study can shed light on the new, rapid and scalable nanomanufacturing of high-quality bimetallic alloys toward extended applications of energy storage, energy conversion and electrocatalysis.

Superconductivity in Layered van der Waals Hydrogenated Germanene at High Pressure.

The emergence of superconductivity in two-dimensional (2D) materials has attracted tremendous research efforts because the origins and mechanisms behind the unexpected and fascinating superconducting phenomena remain unclear. In particular, the superconductivity can survive in 2D systems even with weakened disorder and broken spatial inversion symmetry. Here, structural and superconducting transitions of 2D van der Waals (vdW) hydrogenated germanene (GeH) are observed under compression and decompression processes. GeH possesses a superconducting transition with a critical temperature (Tc) of 5.41 K at 8.39 GPa. A crystalline to amorphous transition occurs at 16.80 GPa, while superconductivity remains. An abnormal increase of Tc up to 6.11 K was observed during the decompression process, while the GeH remained in the 2D amorphous phase. A combination study of in situ high-pressure synchrotron X-ray diffraction, in situ high-pressure Raman spectroscopy, transition electron microscopy, and density functional theory simulations suggests that the superconductivity in 2D vdW GeH is attributed to the increased density of states at the Fermi level as well as the enhanced electron-phonon coupling effect under high pressure even in the form of an amorphous phase. The unique pressure-induced phase transition of GeH from 2D crystalline to 2D amorphous metal hydride provides a promising platform to study the mechanisms of amorphous hydride superconductivity.

A novel, simple and reliable method for the determination of hydronidone and its metabolites M3 and M4 in human plasma and urine by HPLC-MS/MS and its application to a pharmacokinetic study in health Chinese subjects.

In this study, a novel, simple and reliable high-performance liquid chromatography with tandem mass spetrometry method (HPLC-MS/MS) was developed for the determination of hydronidone and its metabolites M3 and M4 in human plasma and urine so as to study the clinical pharmacokinetics of hydronidone. By effectively inhibiting the proliferation of hepatic stellate cells (HSC), hydronidone can reduce collagen synthesis and curbs the process of liver fibrosis, and is currently in the stage of clinical research for anti-liver fibrosis. Hydronidone and its metabolites M3, M4 were extracted from human plasma by protein precipitation, and the urine samples were directly diluted with acetonitrile and analyzed by HPLC-MS/MS. The quantification ranges in plasma were 1.00-1000 ng/mL, 2.00-2000 ng/mL and 4.00-4000 ng/mL, respectively and in urine were 10.0-2000 ng/L, 100-25000 ng/L and 300-75000 ng/L, respectively. Coefficients of variation of less than 15% between intraday and interday accuracy and precision values were observed for hydronidone, M3 and M4. The S/N (signal-to-noise ratio) of the analyte in each Low limit of quantification sample in the analytical batch was greater than 5, indicating good sensitivity. The recovery rates were above 50% for all analytes. The parameters such as linearity, selectivity, lower precision, accuracy, recovery, stability and matrix effects were validated by the methodology and met the requirements specified by the FDA and the European Medicines Agency. The method has been successfully applied to the pharmacokinetics of hydronidone and its metabolites M3 and M4 in healthy Chinese volunteers.

Comparison of different strategies towards the chemical synthesis of long-chain scorpion toxin AaH-II.

Long-chain scorpion toxin AaH-II isolated from Androctonus australis Hector can selectively inhibit mammalian voltage-gated sodium ion channel Nav 1.7 responsible for pain sensation. Efficient chemical synthesis of AaH-II and its derivatives is beneficial to the study of the function and mechanism of Nav 1.7 and the development of potential peptide inhibitors. Herein, we compared three different strategies, namely, direct solid-phase peptide synthesis, hydrazide-based two-segment native chemical ligation, and hydrazide-based three-segment native chemical ligation for the synthesis of AaH-II. The hydrazide-based two-segment native chemical ligation affords the target toxin with the optimal efficiency, which provides a practically robust procedure for the preparation of tool molecules derived from AaH-II to study the biological functions and modulation of Nav 1.7. Our work highlights the importance of selecting suitable segment condensation approach in the chemical synthesis of protein toxins.

Unravelling the role of GntR on the regulation of alkane hydroxylase AlkB2 in Pseudomonas aeruginosa DN1 based on transcriptome analysis.

AIMS: The purpose of this study is to acquire a comprehensive understanding of the involvement of the gene alkB2 in alkane degradation. METHODS AND RESULTS: The changes of gene expression in the wild-type and alkB2 knockout strains of Pseudomonas aeruginosa DN1 were characterized based on transcriptional profiling, when grown in a medium containing eicosane (C20 n-alkane) as the sole carbon source. Compared to wild-type, approximately 7% of the genes in the knockout mutant was significantly differentially expressed, including 344 upregulated genes and 78 downregulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that numerous differentially expressed genes (DEGs) were potentially associated with degradation or physiological response to n-alkane, including genes encoding methyl-accepting chemotaxis proteins (MCPs), an outer membrane fatty acid transport protein (FadL), a membrane receptor protein (FptA), oprin and transcriptional regulators. Notably, the transcriptional regulator gene gntR (RS18845) located upstream of alkB2 (RS18850) was upregulated. The possible regulatory function of this transcriptional regulator on alkB2 was investigated using a gene knockout approach and quantitative reverse transcriptase PCR (RT-qPCR) combined with electrophoretic mobility shift assay (EMSA) experiments. The RT-qPCR results showed that in the gntR mutant, alkB2 expression was independent of the presence of eicosane, while its expression was significantly induced by the substrate when GntR was produced. Based on the EMSA analysis, the palindromic DNA motif 5'-ATTGTCAGACAAT-3' was verified as being recognized by GntR, and two copies of GntR were able to bind this sequence. However, the interaction between GntR and DNA was altered in the presence of eicosane, suggesting that GntR could bind with eicosane to regulate the expression of alkB2 . CONCLUSION: These findings indicate that GntR plays a key role in the transcriptional regulation of alkB2 , which affects the degradation of C20 n-alkane in P. aeruginosa DN1. SIGNIFICANCE AND IMPACT OF THE STUDY: This report presents insights into the significance of GntR in the regulation of alkane degradation by alkB2 , and increases our understanding of the complex regulatory network involved in alkane degradation.

Biomimetic calcium carbonate nanoparticles delivered IL-12 mRNA for targeted glioblastoma sono-immunotherapy by ultrasound-induced necroptosis.

Glioblastoma (GBM) is the most aggressive brain tumor, which owns the characteristics of high recurrence, low survival rate and poor prognosis because of the existence of blood brain barrier (BBB) and complicated brain tumor microenvironment. Currently, immunotherapy has attracted much attention on account of favorable therapeutic effect. In this study, we designed a cRGD-modified cancer cell membrane (CM) coated calcium carbonate nanoparticle to deliver interleukin-12 messenger RNA (IL-12 mRNA@cRGD-CM-CaCO3 NPs). The cRGD-modified CM as the shell can endow the nanoparticles with BBB crossing and tumor homing/homotypic targeting effect in the brain tumor microenvironment. IL-12 mRNA-loaded calcium carbonate nanoparticles as the core allow synergistic immunotherapy of necroptosis-induced immune response and IL-12 mRNA transfection under ultrasound irradiation. The as-prepared biomimetic nanoparticles showed superior target and immunotherapeutic outcomes, suggesting that this biomimetic nanoplatform provides a feasible strategy for promoting BBB-penetrating and antitumor immunity.

Quantitative assessment of right ventricular size and function with multiple parameters from artificial intelligence-based three-dimensional echocardiography: A comparative study with cardiac magnetic resonance.

AIMS: This study aimed to explore the validation and the diagnostic value of multiple right ventricle (RV) volumes and functional parameters derived from a novel artificial intelligence (AI)-based three-dimensional echocardiography (3DE) algorithm compared to cardiac magnetic resonance (CMR). METHODS AND RESULTS: A total of 51 patients with a broad spectrum of clinical diagnoses were finally included in this study. AI-based RV 3DE was performed in a single-beat HeartModel mode within 24 hours after CMR. In the entire population, RV volumes and right ventricular ejection fraction (RVEF) measured by AI-based 3DE showed statistically significant correlations with the corresponding CMR analysis (p < 0.05 for all). However, the Bland-Altman plots indicated that these parameters were slightly underestimated by AI-based 3DE. Based on CMR derived RVEF < 45% as RV dysfunction, end-systolic volume (ESV), end-systolic volume index (ESVi), stroke volume (SV), and RVEF showed great diagnostic performance in identifying RV dysfunction, as well as some non-volumetric parameters, including tricuspid annular systolic excursion (TAPSE), fractional area change (FAC), and free-wall longitudinal strains (LS) (p < 0.05 for all). The cutoff value was 43% for RVEF with a sensitivity of 94% and specificity of 67%. CONCLUSION: AI-based 3DE could provide rapid and accurate quantitation of the RV volumes and function with multiple parameters. Both volumetric and non-volumetric measurements derived from AI-based 3DE contributed to the identification of the RV dysfunction.

Identification of a Partial and Selective TRPV1 Agonist CPIPC for Alleviation of Inflammatory Pain.

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, predominantly expressed in a subset of peripheral sensory neurons for pain signaling. Topical application of agonist capsaicin for desensitizing TRPV1 currents has been approved for relief of chronic pain. However, the potent TRPV1 capsaicin is not ingestible and even topical capsaicin causes common side effects such as skin irritation, swelling, erythema and pruritus, suggesting that a mild TRPV1 agonist might be helpful for reducing side effects while reliving pain. In this study, we reported on a partial and selective TRPV1 agonist 4-(5-chloropyridin-2-yl)-N-(1H-indazol-6-yl)piperazine-1-carboxamide named CPIPC that was modified based on targeting the residue Arg557, important for conversion between the channel antagonism and agonism. Whole-cell patch clamp recordings indicated a concentration-dependent activation of TRPV1 currents by CPIPC with an EC50 of 1.56 ± 0.13 µM. The maximum efficacy of CPIPC (30 µM) was about 60% of saturated capsaicin (10 µM). Repetitive additions of CPIPC caused TRPV1 current desensitization in both TRPV1-expressing HEK293 cells and dorsal root ganglion (DRG) sensory neurons. Oral administration of CPIPC dose-dependently alleviated inflammatory pain in mice. Further site-directed mutagenesis combined with molecular docking revealed that residue Arg557 is critical for TRPV1 activation by CPIPC. Taken together, we identified a novel partial and selective TRPV1 agonist CPIPC that exhibits antinociceptive activity in mice.