Semaglutide inhibits ischemia/reperfusion-induced cardiomyocyte apoptosis through activating PKG/PKCε/ERK1/2 pathway.

Apoptosis is a major pathophysiological change following myocardial ischemia/reperfusion (I/R) injury. Glucagon-like peptide 1 (GLP-1) and its receptor GLP-1R are widely expressed in the cardiovascular system and GLP-1/GLP-1R activates the protein kinase G (PKG)-related signaling pathway. Therefore, this study tested whether semaglutide, a new GLP-1 analog, inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. We induced myocardial I/R injury in rats and hypoxia/reoxygenation (H/R) injury in H9C2 cells and detected the effects of semaglutide, a PKG analog (8-Br-cGMP), and a PKG inhibitor (KT-5823) on the PKG/PKCε/ERK1/2 pathway and cardiomyocyte apoptosis. We found that semaglutide upregulated GLP-1R levels, and both semaglutide and 8-Br-cGMP activated the PKG/PKCε/ERK1/2 pathway, inhibited myocardial infarction (MI), decreased hs-cTNT levels, increased NT-proBNP levels, and suppressed cardiomyocyte apoptosis in I/R rats and H/R H9C2 cells. However, KT-5823 exerted contrasting effects with semaglutide and 8-Br-cGMP, and KT-5823 weakened the cardioprotective effects of semaglutide. In conclusion, semaglutide inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. The beneficial effect of GLP-1/GLP-1R, involved in the activation of the PKG/PKCε/ERK1/2 pathway, may provide a novel treatment method for myocardial I/R injury.

Efficacy and safety of weekly versus triweekly cisplatin treatment concomitant with radiotherapy for locally advanced nasopharyngeal carcinoma: A systematic review and pooled analysis.

Background: Most nasopharyngeal carcinoma cases are diagnosed at an advanced stage due to their hidden anatomical structure and atypical clinical symptoms and often require chemoradiotherapy. Here, we present a systematic review and pooled analysis to synthesize existing research on the efficacy and adverse effects of weekly versus triweekly cisplatin chemotherapy concomitant with radiotherapy for locally advanced nasopharyngeal carcinoma (LANPC). Methods: We searched the PubMed, Embase, and Cochrane Library databases from inception to 1 September 2021, for relevant original research articles published in English. The literature search and data extraction were done independently by two investigators. We used random-effects models to provide point estimates [95% confidence interval (CI)] of overall response rate (ORR), overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and the incidence rate of adverse effects (AEs) and with subgroup analysis according to each study type. The primary endpoints were ORR, OS, and PFS; LRFS, DMFS, and grade ≥3 acute AEs were secondary endpoints. Results: In total, 2,305 patients of eight studies were included in this review. We found that patients who were administered cisplatin weekly or triweekly had no differences in ORR, OS, PFS, DMFS, LRFS, severe mucositis, dermatitis, nausea/vomiting or nephrotoxicity. Patients who were administered weekly cisplatin were at a higher risk of hematological toxicity compared with patients who received the chemotherapy triweekly. Conclusion: Our findings suggest that both regimens could be recommended as the standard of care for the chemoradiotherapy treatment of LANPC, the perceived benefit of lower toxicity with weekly cisplatin could not be established.

How far are the new wave of mRNA drugs from us? mRNA product current perspective and future development.

mRNA products are therapies that are regulated from the post-transcriptional, pre-translational stage of a gene and act upstream of protein synthesis. Compared with traditional small molecule drugs and antibody drugs, mRNA drugs had the advantages of simple design, short development cycle, strong target specificity, wide therapeutic field, and long-lasting effect. mRNA drugs were now widely used in the treatment of genetic diseases, tumors, and viral infections, and are expected to become the third major class of drugs after small molecule drugs and antibody drugs. The delivery system technology was the key to ensuring the efficacy and safety of mRNA drugs, which plays an important role in protecting RNA structure, enhancing targeting ability, reducing the dose of drug delivery, and reducing toxic side effects. Lipid nanoparticles (LNP) were the most common delivery system for mRNA drugs. In recent years, mRNA drugs have seen rapid development, with the number of drugs on the market increasing each year. The success of commercializing mRNA vaccines has driven a wave of nucleic acid drug development. mRNA drugs were clinically used in genetic diseases, oncology, and infectious diseases worldwide, while domestic mRNA clinical development was focused on COVID-19 vaccines, with more scope for future indication expansion.

Histone Methylation and Oxidative Stress in Cardiovascular Diseases.

Oxidative stress occurs when ROS overproduction overwhelms the elimination ability of antioxidants. Accumulated studies have found that oxidative stress is regulated by histone methylation and plays a critical role in the development and progression of cardiovascular diseases. Targeting the underlying molecular mechanism to alter the interplay of oxidative stress and histone methylation may enable creative and effective therapeutic strategies to be developed against a variety of cardiovascular disorders. Recently, some drugs targeting epigenetic modifiers have been used to treat specific types of cancers. However, the comprehensive signaling pathways bridging oxidative stress and histone methylation need to be deeply explored in the contexts of cardiovascular physiology and pathology before clinical therapies be developed. In the present review, we summarize and update information on the interplay between histone methylation and oxidative stress during the development of cardiovascular diseases such as atherosclerosis, coronary artery disease, pulmonary hypertension, and diabetic macro- and microvascular pathologies.

A Novel Serum Biomarker Model to Discriminate Aortic Dissection from Coronary Artery Disease.

Background: The misdiagnosis of aortic dissection (AD) can lead to a catastrophic prognosis. There is currently a lack of stable serological indicators with excellent efficacy for the differential diagnosis of AD and coronary artery disease (CAD). A recent study has shown an association between AD and iron metabolism. Thus, we investigated whether iron metabolism could discriminate AD from CAD. Methods: This retrospective and multicenter cross-sectional study investigated the efficacy of biomarkers of iron metabolism for the differential diagnosis of AD. We collected biomarkers of iron metabolism, liver function, kidney function, and other biochemistry test, and further, logistic regression analysis was applied. Results: Between Oct. 8, 2020, and Mar. 1, 2021, we recruited 521 patients diagnosed with AD, CAD, and other cardiovascular diseases (OCDs) with the main symptoms of chest and back pain and assigned them to discovery set (n = 330) or validation set (n = 191). We found that six serum biomarkers, including serum iron, low-density lipoprotein, uric acid, transferrin, high-density lipoprotein, and estimated glomerular filtration rate, can serve as a novel comprehensive indicator (named FLUTHE) for the differential diagnosis of AD and CAD with a sensitivity of 0.954 and specificity of 0.905 to differentially diagnose AD and CAD more than 72 h past symptom onset. Conclusion: Our findings provide insight into the role of iron metabolism in diagnosing and distinguishing AD, which might in the future be a key component in AD diagnosis. Furthermore, we establish a novel model named "FLUTHE" with higher efficiency, safety, and economy, especially for patients with chest pain for more than 72 h.

Durable Clinical Response to Immune and Targeted Therapies in an Elderly Man with Synchronous Gastric (HER2+) and Bladder Cancers: Case Report and Literature Review.

Synchronous occurrences of gastric cancer positive for human epidermal growth factor receptor 2 (HER2+) and bladder cancer are rarely encountered in clinical practice. When and how to effectively treat both tumors, without compounding adverse effects, must be addressed. Herein, we describe an elderly man who presented with both gastric cancer (HER2+) and bladder cancer. Due to enlarged and fused lymph nodal metastasis, he was ill-suited for stomach resection. After transurethral resection of the bladder tumor, we administered both chemotherapy and the targeted agent trastuzumab. Gastric cancer showed partial response however bladder cancer recurred following two cycles of this regimen, the adverse effects were prohibitive, prompting refusal of further chemotherapy and radiotherapy. He then received the immune checkpoint inhibitor (ICI) nivolumab and trastuzumab in combination. This particular regimen successfully controlled both cancers and substantially improved the patient's quality of life. Its long-term use did not intensify adverse reactions, enabling a progression-free survival of 21 months to date. We have also reviewed other published clinical strategies applied in rare instances of multiple primary malignancies as a reference for treating such patients.

One-pot regiospecific synthesis of imidazo[1,2-a]pyridines: a novel, metal-free, three-component reaction for the formation of C-N, C-O, and C-S bonds.

A novel transition-metal-free three-component reaction for the construction of imidazo[1,2-a]pyridines has been developed. It represents a facile approach for the formation of C-N, C-O, and C-S bonds from ynals, pyridin-2-amines, and alcohols or thiols.

Copper-catalyzed C-O bond formation: an efficient one-pot highly regioselective synthesis of furans from (2-furyl)carbene complexes.

A convenient one-pot Cu(I)-catalyzed strategy for regioselective synthesis of trisubstituted furan derivatives has been developed via (2-furyl) carbene complexes. This process has opened a new synthetic route to a variety of α-carbonyl furans using air as the oxidant affording furans in good yields.