Current Medicinal Chemistry - Volume 29, Issue 30, 2022

Dihydrochalcones are a class of secondary metabolites, possessing several biological properties such as antitumor, antioxidant, antibacterial, antidiabetic, estrogenic, anti-inflammatory, antithrombotic, antiviral, neuroprotective, and immunomodulatory properties; therefore, they are currently considered promising candidates in the drug discovery process. This review intends to debate their pharmacological actions with particular attention to their antitumor activity against a panel of cancer cell lines and to the description of the inhibition mechanisms of cell proliferation such as the regulation of angiogenesis, apoptosis, etc.

The incidence of malignant tumors is rising rapidly and tends to be in the younger, which has been one of the most important factors endangering the safety of human life. Ultrasound micro/nanobubbles, as a noninvasive and highly specific antitumor strategy, can reach and destroy tumor tissue through their effects of cavitation and acoustic perforation under the guidance of ultrasound. Meanwhile, micro/nanobubbles are now used as a novel drug carrier, releasing drugs at a target region, especially on the prospects of biomaterial-modified micro/nanobubbles as a dual modality for drug delivery and therapeutic monitoring. Successful evaluation of the sonoporation mechanism(s), ultrasound parameters, drug type, and dose will need to be addressed before translating this technology for clinical use. Therefore, this paper collects the literature on the experimental and clinical studies of ultrasound biomaterial-modified micro/nanobubbles therapy in vitro and in vivo in recent years.

Seven-membered heterocyclic compounds are important drug scaffolds because of their unique chemical structures. They widely exist in natural products and show a variety of biological activities. They have been used commonly in central nervous system drugs in the past 30 years. In the past decade, many studies have been conducted on their activities, including antitumor, antibacterial, etc. Herein, we summarize the research advances in different kinds of seven-membered heterocyclic compounds containing nitrogen, oxygen, and sulfur heteroatoms with antitumor, antisepsis, and anti-inflammation activities in the past ten years, which are expected to be beneficial to the development and design of novel drugs for the corresponding indications.

Background: Neuropathic pain (NP) is a complex symptom related to nerve damage. The discovery of new drugs for treating chronic NP has been continuing for several decades, while more progress is still needed because of the unsatisfactory efficacy and the side effects of the currently available drugs. Among all the approved drugs for chronic NP, voltage- gated calcium channel (VGCC) α2δ subunit ligands, also known as gabapentinoids, are among the first-line treatment and represent a class of efficacious and relatively safe therapeutic agents. However, new strategies are still needed to be explored due to the unsatisfied response rate. Objective: The aim of the study is to review the latest status of the discovery and development of gabapentinoids for the treatment of chronic NP by covering both the marketed and the preclinical/clinical ones. Moreover, it aims to analyze the structure-activity relationship (SAR) of gabapentinoids to facilitate the future design of structurally novel therapeutic agents targeting the VGCC α2δ subunit. Methods: We searched PubMed Central, Embase, Cochrane Library, Web of Science, Scopus, and Espacenet for the literature and patents on diabetic peripheral neuropathic pain, postherpetic neuralgia, fibromyalgia, voltage-gated calcium channel α2δ subunit and related therapeutic agents from incipient to June 10, 2021. The SAR of gabapentinoids was analyzed by pharmacophore modeling using the Phase module in the Schrödinger suite. Results: A variety of gabapentinoids were identified as VGCC α2δ ligands that have ever been under development to treat chronic NP. Among them, four gabapentinoids are marketed, one is in the active late clinical trials, and eight have been discontinued. Pharmacophore models were generated using the phase module in the Schrödinger suite, and common pharmacophores were predicted based on pharmacophoric features and analyzed. Conclusion: The latest progress in the discovery and development of gabapentinoids for the treatment of chronic NP was reviewed. Moreover, the structure-activity relationship (SAR) of gabapentinoids has been analyzed by pharmacophore modeling, which will be valuable for the future design of structurally novel therapeutic agents targeting the VGCC α2δ subunit.

Background: Carvacrol, a plant phenolic monoterpene, is largely employed as food additive and phytochemical. Objective: We aimed to assess the lipid lowering and protective effects of carvacrol in vitro using cellular models of hepatic steatosis and endothelial dysfunction. We also investigated if and how the binding of carvacrol to albumin, the physiological transporter for small compounds in the blood, might be altered by the presence of high levels of fatty acids (FAs). Methods: Hepatic FaO cells treated with exogenous FAs mimic hepatosteatosis; endothelial HECV cells exposed to hydrogen peroxide are a model of endothelial dysfunction. In these models, we measured spectrophotometrically lipid accumulation and release, lipoperoxidation, free radical production, and nitric oxide release before and after treatment with carvacrol. The carvacrol binding to albumin in the presence or absence of high levels of FAs was assessed by absorption and emission spectroscopies. Results: Carvacrol counteracted lipid accumulation and oxidative stress in hepatocytes and protected endothelial cells from oxidative stress and dysfunction. Moreover, high levels of FAs reduced the binding of carvacrol to albumin. Conclusion: The results suggest the good potential of carvacrol in ameliorating dysfunction of hepatic and endothelial cells in vitro. High levels of circulating FAs might compete with carvacrol for binding to albumin thus influencing its transport and bio-distribution.

Background: MicroRNAs modify protein expression at the post-transcriptional level, and their circulating levels may help identify the underlying molecular pathways. Objective: The purpose of this study was to assess the differential expression of microRNAs related to myocardial cell energy substrate, autophagy, and ischaemia in chronic and acute heart failure (HF). Methods: In this case-control study, we studied 19 patients with acute HF (AHF) and 19 patients with chronic HF (CHF). Basic demographic and clinical characteristics were collected from the patients upon arrival, at 48 hours, and at 120 hours. Blood samples for microRNAs measurements (miR-22, -92a, and -499), B-type natriuretic peptide (BNP), C reactive protein, and high sensitivity cardiac troponin I, were collected at all study points. In this study, we included subjects with a left ventricular ejection fraction of <40%. Results: At baseline, circulating miR-22 levels were 1.9-fold higher (p<0.001), miR-92a levels were 1.25-fold higher (p=0.003), and miR-499 were 5-times lower (p<0.001) in AHF compared to CHF. Interestingly, circulating miR-499 was found to be associated with BNP levels (r=0.47, p=0.01). At follow-up, there was a stepwise increase in the levels of all three examined microRNAs (miR-22, p=0.001, miR-92a, p=0.001, and miR-499, p<0.001) for AHF but not for CHF subjects. Conclusion: MicroRNAs -22, -92a, and -499 are differentially expressed in chronic and acute HF subjects. MicroRNA signatures are also differentially expressed up to the discharge of the patients. These findings may have important implications for diagnosis, progression, and treatment of patients with chronic and acute heart failure.

Background: Recent studies have indicated that epigallocatechin gallate (EGCG) benefits a variety of neurological insults. This study was performed to investigate the neuroprotective effect of EGCG after brachial plexus root avulsion in SD rats. Methods: One hundred twenty SD rats were randomized into the following three groups: an EGCG group, an Avulsion group, and a Sham group. There were 40 rats in each group. EGCG (100 mg/kg, i.p.) or normal saline was administered to rats immediately following the injuries. The treatment was continued from day 1 to day 7, and the animals were sacrificed on days 3, 7, 14, and 28 post-surgery for the harvesting of spinal cord samples for Nissl staining, immunohistochemistry (caspase-3, p-JNK, p-c-Jun), and western blot analysis (p-JNK, JNK, p-c-Jun, c-Jun). Results: EGCG treatment caused significant increases in the percentage of surviving motoneurons on days 14 and 28 (p<0.05) compared to the control animals. On days 3 and 7 after avulsion, the numbers of caspase-3-positive motoneurons in the EGCG-treated animals were significantly fewer than in the control animals (p<0.05). The numbers of p- JNK-positive motoneurons and the ratio of p-JNK/JNK were no significant differences between the Avulsion group and the EGCG-treated group after injury at any time point. The numbers of p-c-Jun-positive motoneurons and the ratio of p-c-Jun/c-Jun were significantly lower in the EGCG-treated group compared with the Avulsion group at 3d and 7d after injury (p<0.05). Conclusion: Our results indicated that motoneurons were protected by EGCG against the cell death induced by brachial plexus root avulsion, and this effect was correlated with inhibiting c-Jun phosphorylation.