Angiotensin-converting enzyme 2-at the heart of the COVID-19 pandemic.

ACE2 is the indispensable entry receptor for SARS-CoV and SARS-CoV-2. Because of the COVID-19 pandemic, it has become one of the most therapeutically targeted human molecules in biomedicine. ACE2 serves two fundamental physiological roles: as an enzyme, it alters peptide cascade balance; as a chaperone, it controls intestinal amino acid uptake. ACE2's tissue distribution, affected by co-morbidities and sex, explains the broad tropism of coronaviruses and the clinical manifestations of SARS and COVID-19. ACE2-based therapeutics provide a universal strategy to prevent and treat SARS-CoV-2 infections, applicable to all SARS-CoV-2 variants and other emerging zoonotic coronaviruses exploiting ACE2 as their cellular receptor.

Uptake of SGLT2i and Outcomes in Patients with Diabetes and Heart Failure: A Population-Based Cohort and a Specialized Clinic Cohort.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are effective in adults with diabetes mellitus (DM) and heart failure (HF) based on randomized clinical trials. We compared SGLT2 inhibitor uptake and outcomes in two cohorts: a population-based cohort of all adults with DM and HF in Alberta, Canada and a specialized heart function clinic (HFC) cohort. METHODS: The population-based cohort was derived from linked provincial healthcare datasets. The specialized clinic cohort was created by chart review of consecutive patients prospectively enrolled in the HFC between February 2018 and August 2022. We examined the association between SGLT2 inhibitor use (modeled as a time-varying covariate) and all-cause mortality or deaths/cardiovascular hospitalizations. RESULTS: Of the 4,885 individuals from the population-based cohort, 64.2% met the eligibility criteria of the trials proving the effectiveness of SGLT2 inhibitors. Utilization of SGLT2 inhibitors increased from 1.2% in 2017 to 26.4% by January 2022. In comparison, of the 530 patients followed in the HFC, SGLT2 inhibitor use increased from 9.8% in 2019 to 49.1 % by March 2022. SGLT2 inhibitor use in the population-based cohort was associated with fewer all-cause mortality (aHR 0.51, 95%CI 0.41-0.63) and deaths/cardiovascular hospitalizations (aHR 0.65, 95%CI 0.54-0.77). However, SGLT2 inhibitor usage rates were far lower in HF patients without DM (3.5% by March 2022 in the HFC cohort). CONCLUSIONS: Despite robust randomized trial evidence of clinical benefit, the uptake of SGLT2 inhibitors in patients with HF and DM remains low, even in the specialized HFC. Clinical care strategies are needed to enhance the use of SGLT2 inhibitors and improve implementation.

Synthesis and biological evaluation of novel 1,2,3,4-tetrahydro-ß-carboline derivatives as potential antibacterial agents.

The quest for novel antibacterial agents is imperative in the face of escalating antibiotic resistance. Naturally occurring tetrahydro-ß-carboline (THßC) alkaloids have been highlighted due to their significant biological derivatives. However, these structures have been little explored for antibacterial drugs development. In this study, a series of 1,2,3,4-THßC derivatives were synthesized and assessed for their antibacterial prowess against both gram-positive and gram-negative bacteria. The compounds exhibited moderate to good antibacterial activity, with some compounds showing superior efficacy against gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), to that of Gentamicin. Among these analogs, compound 3k emerged as a hit compound, demonstrating rapid bactericidal action and a significant post-antibacterial effect, with significant cytotoxicity towards human LO2 and HepG2 cells. In addition, compound 3k (10 mg/kg) showed comparable anti-MRSA efficacy to Ciprofloxacin (2 mg/kg) in a mouse model of abdominal infection. Overall, the present findings suggested that THßC derivatives based on the title compounds hold promising applications in the development of antibacterial drugs.

Design, synthesis, and evaluation of formylpiperazine analogs of Ferrostatin-1 as novel improved ferroptosis inhibitors.

In this study, a series of new formylpiperazine-derived ferroptosis inhibitors were designed and synthesized based on the structure of a known ferroptosis inhibitor, ferrostatin-1 (Fer-1). The anti-ferroptosis activity of these synthetic compounds in human umbilical vein endothelial cells (HUVECs) induced by Erastin was evaluated. It was found that some of the new compounds, especially compound 26, showed potent anti-ferroptosis activity, as evidenced by its ability to restore cell viability, reduce iron accumulation, scavenge reactive oxygen species, maintain mitochondrial membrane potential, increase GSH levels, decrease LPO and MDA content, and upregulate GPX4 expression. Moreover, compound 26 exhibited superior microsomal stability than Fer-1. The present results suggest that compound 26 is a promising lead compound for the development of new ferroptosis inhibitors for the treatment of vascular diseases.

New cycloalkyl[b]thiophenylnicotinamide-based α-glucosidase inhibitors as promising anti-diabetic agents: Synthesis, in silico study, in vitro and in vivo evaluations.

In the present study, a series of cycloalkyl[b]thiophenylnicotinamide derivatives against α-glucosidase were synthesized, and evaluated for their in vitro and in vivo anti-diabetic potential. Most of the synthetic analogues exhibited superior α-glucosidase inhibitory effects than the standard drug acarbose (IC50 = 258.5 µM), in which compound 11b with cyclohexyl[b]thiophene core demonstrated the highest activity with an IC50 value of 9.9 µM and showed higher selectivity towards α-glucosidase over α-amylase by 7.4-fold. Fluorescence quenching experiment confirmed the direct binding of 11b with α-glucosidase, kinetics study revealed that 11b was a mixed-type inhibitor, and its binding mode was analyzed using molecular docking. Moreover, analogs compounds 6a-9b, 11b, 12b did not show in vitro cytotoxicity against LO2 and HepG2 cells. Finally, compound 11b exhibited in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-loaded rats.

Discovery of marine phidianidine-based Nrf2 activators and their potential against oxLDL- and HG-induced injury in HUVECs.

One effective strategy for treating atherosclerosis is to inhibit the injury of vascular endothelial cells (VECs) induced by oxidized low-density lipoprotein (oxLDL) and high glucose (HG). This study synthesized and evaluated a series of novel Nrf2 activators derived from the marine natural product phidianidine for their ability to protect human umbilical VECs against oxLDL- and HG-induced injury. The results of in vitro bioassays demonstrated that compound D-36 was the most promising Nrf2 activator, effectively inhibiting the apoptosis of HUVECs induced by oxLDL and HG. Furthermore, Nrf2 knockdown experiments confirmed that compound D-36 protected against oxLDL- and HG-induced apoptosis in HUVECs by activating the Nrf2 pathway. These findings provide important insights into a new chemotype of marine-derived Nrf2 activators that could potentially be optimized to develop effective anti-atherosclerosis agents.

Photocatalyst-free visible light driven synthesis of gem-dihaloenones from alkynes, tetrahalomethanes and water.

Photocatalytic reactions, in particular, processes without photosensitisers, have attracted increased attention due to their green aspect and high economic value and are considered valuable tools in organic synthesis. A new practical photocatalytic system was investigated in this study, and it can efficiently produce gem-dihaloenones by combining terminal alkynes with tetrahalomethanes (BrCCl3 and CBr4) and water without a photocatalyst, and the yield can reach up to 87%. The catalytic system is straightforward, the raw materials are inexpensive and easy to obtain, and the operation is simple.

miR-100-5p Regulates Skeletal Muscle Myogenesis through the Trib2/mTOR/S6K Signaling Pathway.

MicroRNAs (miRNAs) are endogenous small non-coding RNAs that play crucial regulatory roles in many biological processes, including the growth and development of skeletal muscle. miRNA-100-5p is often associated with tumor cell proliferation and migration. This study aimed to uncover the regulatory mechanism of miRNA-100-5p in myogenesis. In our study, we found that the miRNA-100-5p expression level was significantly higher in muscle tissue than in other tissues in pigs. Functionally, this study shows that miR-100-5p overexpression significantly promotes the proliferation and inhibits the differentiation of C2C12 myoblasts, whereas miR-100-5p inhibition results in the opposite effects. Bioinformatic analysis predicted that Trib2 has potential binding sites for miR-100-5p at the 3'UTR region. A dual-luciferase assay, qRT-qPCR, and Western blot confirmed that Trib2 is a target gene of miR-100-5p. We further explored the function of Trib2 in myogenesis and found that Trib2 knockdown markedly facilitated proliferation but suppressed the differentiation of C2C12 myoblasts, which is contrary to the effects of miR-100-5p. In addition, co-transfection experiments demonstrated that Trib2 knockdown could attenuate the effects of miR-100-5p inhibition on C2C12 myoblasts differentiation. In terms of the molecular mechanism, miR-100-5p suppressed C2C12 myoblasts differentiation by inactivating the mTOR/S6K signaling pathway. Taken together, our study results indicate that miR-100-5p regulates skeletal muscle myogenesis through the Trib2/mTOR/S6K signaling pathway.

Circular Intronic RNA circTTN Inhibits Host Gene Transcription and Myogenesis by Recruiting PURB Proteins to form Heterotypic Complexes.

Muscle cell growth plays an important role in skeletal muscle development. Circular RNAs (circRNAs) have been proven to be involved in the regulation of skeletal muscle growth and development. In this study, we explored the effect of circTTN on myoblast growth and its possible molecular mechanism. Using C2C12 cells as a functional model, the authenticity of circTTN was confirmed by RNase R digestion and Sanger sequencing. Previous functional studies have showed that the overexpression of circTTN inhibits myoblast proliferation and differentiation. Mechanistically, circTTN recruits the PURB protein on the Titin (TTN) promoter to inhibit the expression of the TTN gene. Moreover, PURB inhibits myoblast proliferation and differentiation, which is consistent with circTTN function. In summary, our results indicate that circTTN inhibits the transcription and myogenesis of the host gene TTN by recruiting PURB proteins to form heterotypic complexes. This work may act as a reference for further research on the role of circRNA in skeletal muscle growth and development.

Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2.

ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1-7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.

Trajectory of left ventricular ejection fraction in response to therapies in patients with muscular dystrophy.

BACKGROUND: Patients with muscular dystrophy (MD) are at elevated risk of serious cardiac complications and clinical assessment is limited due to inherent physical limitations. We assessed the utility of left ventricular ejection fraction (LVEF) derived from transthoracic echocardiogram (TTE) as a prognostic marker for major adverse cardiac events (MACE) in a mixed adult MD cohort. METHODS: One hundred and sixty-five MD patients (median age: 36 (interquartile range [IQR]: 23.0-49.0) years; 65 [39.4%] females) were enrolled in our prospective cohort study. Diagnoses included dystrophinopathies (n = 42), limb-girdle MD (n = 31), type 1 myotonic dystrophy (n = 71), and facioscapulohumeral MD (n = 21). Left ventricular ejection fraction, ventricular dimensions at end-diastole and end-systole, and serial measures (n = 124; follow-up period: 2.19 [IQR: 1.05-3.32] years) stratified patients for MACE risk. RESULTS: Cardiomyopathy was diagnosed in 60 (36.4%) patients of the broader cohort (median LVEF: 45.0 [IQR: 35.0-50.0] %). Ninety-eight MACE occurred over the 7-year study period. At baseline, patients with a LVEF < 55.0% had a high risk of MACE (adjusted odds ratio: 8.30; 95% confidence interval [CI]: 3.18-21.7), concordant with the analysis of LV dimensions. Forty-one percent of these patients showed an improvement in LVEF with the optimization of medical and device therapies. Relative to patients with preserved LVEF, patients with reduced LVEF were at an elevated risk of MACE (adjusted hazard ratio [aHR]: 7.21; 95% CI: 1.99-26.1), and improved LVEF resulted in comparable outcomes (aHR: 1.84; 95% CI: .49-6.91) associated with optimization of medical and device therapies. Reduction in QRS duration by CRT therapy was associated with an improvement in LVEF (average improvement: 12.8 [± 2.30] %; p = .04). CONCLUSIONS: Reduction in LVEF indicates an increased risk of cardiovascular events in patients with MD. Baseline and serial LVEF obtained by TTE can prognosticate patients for MACE and guide clinical management.

Research on Self-Noise Characteristics of Nine Types of Seismometers Obtained by PDF Representation Using Continuous Seismic Data from the Malingshan Seismic Station, China.

The self-noise level of a seismometer can determine the performance of the seismic instrument and limit the ability to use seismic data to solve geoscience problems. Accurately measuring and simultaneously comparing the self-noise models from different types of seismometers has long been a challenging task due to the constraints of observation conditions. In this paper, the self-noise power spectral density (PSD) values of nine types of seismometers are calculated using four months of continuous seismic waveforms from Malingshan seismic station, China, and nine self-noise models are obtained based on the probability density function (PDF) representation. For the seismometer STS-2.5, the self-noise levels on the horizontal channels (E−W and N−S) are significantly higher than that on the vertical channel (U−D) in the microseism band (0.1 Hz to 1 Hz), which is a computing bias caused by the misalignment between the sensors in the horizontal direction, while the remarkably elevated noise on the horizontal channels at the low frequencies (<0.6 Hz) may originate from the local variation of atmospheric pressure. As for the very broadband seismometers Trillium-Horizon-120 and Trillium-120PA, and the ultra-broadband seismometers Trillium-Horizon-360 and CMG-3T-360, there is a trade-off between the microseism band range and low-frequency range in the PSD curves of the vertical channel. When the level of self-noise in the microseism band is high, the self-noise at low frequencies is relatively low. Although compared with the other very broadband seismometers, the self-noise level of the vertical component of the STS-2.5 is 3 dB to 4 dB lower at frequencies less than 1 Hz, the self-noise level of the STS-2.5 at high frequencies (>2 Hz) is slightly higher than others. From our observations, we conclude that the nine seismometers cannot reach the lowest noise level in all frequency bands within the working range.

Co-culture with Sirt1-overexpressed chondrocytes delays the nucleus pulposus cells degeneration.

Nucleus pulposus cells (NPCs) degeneration is an essential pathological basis of intervertebral disc diseases, and autologous cell transplantation is a means of regeneration of NPCs. This study aimed to evaluate the effects of autologous facet joint chondrocytes (CHs) with Sirtuin 1 (sirt1)-overexpression on NPCs degeneration. We used human NPCs and CHs isolated from the patients' tissue and transduced CHs with the plasmid vector to overexpress the sirt1 gene. Further, NPCs were seeded as monolayers and treated with IL-1ß to obtain the degeneration, and the sirt1-overexpressed CHs (sirt1-CHs) in the transwell insert were co-cultured in the same well. The NPCs' degenerated degree was determined by the levels of living cells, proliferation, p16, and collagen I/II, and aggrecan expression at the time point of 1, 3, or 5 days. Besides, the ROS accumulation, antioxidative enzymes, sirt1, and inflammatory factors gene expression were also tested. After IL-1ß treatment, when co-cultured with sirt1-CHs, NPCs accumulated more living cells, proliferation, collagen II, aggrecan, but less p16 and collagen I expression than cultured without sirt1-CHs. Additionally, SOD1, CAT, and TIMP4 mRNA were protected, and the production of TNF-α, IL-6, MMP3, and ROS were alleviated with the presence of sirt1-CHs. Thus, co-culture with sirt1-CHs delays NPCs' degeneration via the suppression of ROS accumulation and inflammatory response. Transplanting autologous CHs with sirt1-overexpressed into the NP tissue might be a novel treatment for intervertebral disc degeneration.

Design, synthesis and biological evaluation of novel (E)-2-benzylidene-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)hydrazine-1-carboxamide derivatives as α-glucosidase inhibitors.

In this present study, a series of novel (E)-2-benzylidene-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)hydrazine-1-carboxamide derivatives against α-glucosidase were designed and synthesized, and their biological activities were evaluated in vitro and in vivo. Most of the designed analogues exhibited better inhibitory activity than the marketed acarbose, especially the most potent compound 7 with an IC50 value of 9.26 ± 1.84 µM. The direct binding of 7 and 8 with α-glucosidase was confirmed by fluorescence quenching experiments, and the kinetic and molecular docking studies revealed that 7 and 8 inhibited α-glucosidase in a non-competitive manner. Cytotoxicity bioassay indicated compounds 7 and 8 were non-toxic towards LO2 and HepG2 at 100 µM. Furthermore, both compounds were demonstrated to have in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-treated rats.

Characteristics of hepatic solitary necrotic nodules on contrast-enhanced ultrasonography.

BACKGROUND: To summarize the characteristics of solitary necrotic nodules (SNN) in the liver observed under contrast-enhanced ultrasonography (CEUS). METHODS: Conventional ultrasonography (US) and CEUS were performed in 24 patients who were confirmed to have SNN by pathological assessment. The US data and dynamic enhancement patterns of CEUS were recorded and retrospectively analyzed. RESULTS: Ten of 24 patients underwent surgical resection, while the other 14 patients underwent a puncture biopsy to be confirmed as SNN. Among the 24 patients, 13 patients had a single lesion and 11 patients had multiple lesions. The largest lesion was selected for CEUS examination for patients with multiple lesions. Eleven patients presented no enhancement in all three phases, while the other 13 patients presented with a peripheral thin rim-like enhancement in the arterial phase, an iso-enhancement in the portal phase and delayed phase. However, no enhancement in the interior of the lesions was detected during three phases of CEUS. CONCLUSIONS: SNN has characteristic findings on the CEUS, which play an important role in the differential diagnoses of liver focal lesions.

Discovery of new 2-phenyl-1H-benzo[d]imidazole core-based potent α-glucosidase inhibitors: Synthesis, kinetic study, molecular docking, and in vivo anti-hyperglycemic evaluation.

In the present study, a series of 2-phenyl-1H-benzo[d]imidazole-based α-glucosidase inhibitors were synthesized and evaluated for their in vitro and in vivo anti-diabetic potential. Screening of an in-house library revealed a moderated α-glucosidase inhibitor, 6a with 3-(1H-benzo[d]imidazol-2-yl)aniline core, and then the structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased activity than 6a, and the most promising inhibitors were found to be compounds 15o and 22d with IC50 values of 2.09 ± 0.04 and 0.71 ± 0.02 µM, respectively. Fluorescence quenching experiment confirmed the direct binding of compounds 15o and 22d with α-glucosidase. Kinetic study revealed that both compounds were non-competitive inhibitors, that was consistent with the result of molecular docking studies where they located at the allosteric site of the enzyme. Cell viability evaluation demonstrated the non-cytotoxicity of 15o and 22d against LO2 cells. Furthermore, the in vivo pharmacodynamic study revealed that compound 15o showed significant hypoglycemic activity and improved oral sucrose tolerance, comparable to the positive control acarbose.

Interaction between the apelinergic system and ACE2 in the cardiovascular system: therapeutic implications.

The apelinergic system is widely expressed and acts through autocrine and paracrine signaling to exert protective effects, including vasodilatory, metabolic, and inotropic effects on the cardiovascular (CV) system. The apelin pathway's dominant physiological role has delineated therapeutic implications for coronary artery disease, heart failure (HF), aortic aneurysm, pulmonary arterial hypertension (PAH), and transplant vasculopathy. Apelin peptides interact with the renin-angiotensin system (RAS) by promoting angiotensin converting enzyme 2 (ACE2) transcription leading to increased ACE2 protein and activity while also antagonizing the effects of angiotensin II (Ang II). Apelin modulation of the RAS by increasing ACE2 action is limited due to its rapid degradation by proteases, including ACE2, neprilysin (NEP), and kallikrein. Apelin peptides are hence tightly regulated in a negative feedback manner by ACE2. Plasma apelin levels are suppressed in pathological conditions, but its diagnostic and prognostic utility requires further clinical exploration. Enhancing the beneficial actions of apelin peptides and ACE2 axes while complementing existing pharmacological blockade of detrimental pathways is an exciting pathway for developing new therapies. In this review, we highlight the interaction between the apelin and ACE2 systems, discuss their pathophysiological roles and potential for treating a wide array of CV diseases (CVDs).

Is endoscopic treatment beneficial in patients with clinically suspicious of common bile duct stones but no obvious filling defects during the ERCP examination?

BACKGROUND: Sometimes, no definite filling defect could be found by cholangiogram (ERC) during the endoscopic retrograde cholangio-pancreatiographic (ERCP) exam; even prior images had evidence of common bile duct stones (CBDS). We aimed in estimating the positive rate of extraction of CBDS who had treated by endoscopic sphincterotomy/endoscopic papillary balloon dilation (EST/EPBD) with negative ERC finding. METHODS: One hundred forty-one patients with clinically suspicious of CBDS but negative ERC, who had received EST/EPBD treatments was enrolled. Potential factors for predicting CBDS, as well as the treatment-related complications were analyzed. RESULTS: Nearly half of the patients with negative ERC, had a positive stone extraction. Only patients with high probability of CBDS were significantly associated with positive stone extraction. Moreover, patients with intermediate probability of CBDS had higher rates of overall complications, including post-ERCP pancreatitis. In addition, no significant difference of post-ERCP pancreatitis was found between EST and EPBD groups in any one group of patients with the same probability of CBDS. CONCLUSIONS: Regarding patients with negative ERC, therapeutic ERCP is beneficial and safe for patients present with high probability of CBDS. Moreover, under the same probability of CBDS, there was no significance difference in post-ERCP pancreatitis between EST and EPBD.