Main active components of Si-Miao-Yong-An decoction (SMYAD) attenuate autophagy and apoptosis via the PDE5A-AKT and TLR4-NOX4 pathways in isoproterenol (ISO)-induced heart failure models.

Heart failure (HF), the main cause of death in patients with many cardiovascular diseases, has been reported to be closely related to the complicated pathogenesis of autophagy, apoptosis, and inflammation. Notably, Si-Miao-Yong-An decoction (SMYAD) is a traditional Chinese medicine (TCM) used to treat cardiovascular disease; however, the main active components and their relevant mechanisms remain to be discovered. Based on our previous ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) results, we identified angoriside C (AC) and 3,5-dicaffeoylquinic acid (3,5-DiCQA) as the main active components of SMYAD. In vivo results showed that AC and 3,5-DiCQA effectively improved cardiac function, reduced the fibrotic area, and alleviated isoproterenol (ISO)-induced myocarditis in rats. Moreover, AC and 3,5-DiCQA inhibited ISO-induced autophagic cell death by inhibiting the PDE5A/AKT/mTOR/ULK1 pathway and inhibited ISO-induced apoptosis by inhibiting the TLR4/NOX4/BAX pathway. In addition, the autophagy inhibitor 3-MA was shown to reduce ISO-induced apoptosis, indicating that ISO-induced autophagic cell death leads to excess apoptosis. Taken together, the main active components AC and 3,5-DiCQA of SMYAD inhibit the excessive autophagic cell death and apoptosis induced by ISO by inhibiting the PDE5A-AKT and TLR4-NOX4 pathways, thereby reducing myocardial inflammation and improving heart function to alleviate and treat a rat ISO-induced heart failure model and cell heart failure models. More importantly, the main active components of SMYAD will provide new insights into a promising strategy that will promote the discovery of more main active components of SMYAD for therapeutic purposes in the future.

Three new tyrosol derivatives from Huangjing wine.

Phytochemical investigation on the concentrate of Huangjing wine, resulted in the isolation of three new tyrosol derivatives 4'''-hydroxyphenethyl 2-(R)-hydroxy-3-phenylpropionate (1), 4'''-hydroxyphenethyl(4'-hydroxy-3'-methoxyphenyl)propionate (2) and 4''-hydroxyphenethyl ethyl succinate (3), together with 5 known compounds, ferulic acid (4), L-phenyllactic acid (5), hydroxytyrosol (6), dihydroferulic acid (7), cyclo(L-Pro-D-Tyr) (8). Their structures were elucidated using spectroscopic analysis and by comparison with the literature data. All compounds displayed antioxidant effect in the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical. Among them, the new compound 2 exhibited obvious antioxidant effect, and new compounds 1 and 3 exhibited medium antioxidant effect.

Dual-Functional Liposomes with Carbonic Anhydrase IX Antibody and BR2 Peptide Modification Effectively Improve Intracellular Delivery of Cantharidin to Treat Orthotopic Hepatocellular Carcinoma Mice.

Liposomal nanotechnology has a great potential to overcome the current major problems of chemotherapy. However, the lack of penetrability and targetability retards the successful delivery of liposomal carriers. Previously, we showed that BR2 peptide modification endowed cantharidin-loaded liposomes with intracellular penetration that enhanced the drug cytotoxic effects. Here, we aimed to improve the targeting delivery of drugs into cancer cells via highly expressed carbonic anhydrase IX (CA IX) receptors by modifying our previous catharidin-loaded BR2-liposomes with anti-CA IX antibody. A higher cellular uptake of dual-functional liposomes (DF-Lp) than other treatments was observed. Induction of CA IX over-expressing resulted in a higher cellular binding of DF-Lp; subsequently, blocking with excess antibodies resulted in a decreased cancer-cell association, indicating a specific targeting property of our liposomes towards CA IX expressed cells. After 3h tracking, most of the liposomes were located around the nucleus which confirmed the involvement of targeting intracellular delivery. Cantharidin loaded DF-Lp exhibited enhanced cytotoxicity in vitro and was most effective in controlling tumor growth in vivo in an orthotopic hepatocellular carcinoma model compared to other groups. Collectively, our results presented the advantage of the BR2 peptide and CA IX antibody combination to elevate the therapeutic potential of cantharidin loaded DF-liposomes.

Surface Functionalization and Targeting Strategies of Liposomes in Solid Tumor Therapy: A Review.

Surface functionalization of liposomes can play a key role in overcoming the current limitations of nanocarriers to treat solid tumors, i.e., biological barriers and physiological factors. The phospholipid vesicles (liposomes) containing anticancer agents produce fewer side effects than non-liposomal anticancer formulations, and can effectively target the solid tumors. This article reviews information about the strategies for targeting of liposomes to solid tumors along with the possible targets in cancer cells, i.e., extracellular and intracellular targets and targets in tumor microenvironment or vasculature. Targeting ligands for functionalization of liposomes with relevant surface engineering techniques have been described. Stimuli strategies for enhanced delivery of anticancer agents at requisite location using stimuli-responsive functionalized liposomes have been discussed. Recent approaches for enhanced delivery of anticancer agents at tumor site with relevant surface functionalization techniques have been reviewed. Finally, current challenges of functionalized liposomes and future perspective of smart functionalized liposomes have been discussed.

Augmented Anticancer Effects of Cantharidin with Liposomal Encapsulation: In Vitro and In Vivo Evaluation.

PEGylated liposomes have received much attention as pharmaceutical carriers to deliver chemotherapeutic agents for therapeutic purpose. The aim of this study was to prepare and characterize PEGylated liposome of cantharidin and investigate its therapeutic effect on human hepatocellular carcinoma treatment in vitro and in vivo. Liposomal cantharidin was evaluated for their anticancer effects in vitro using human hepatocellular carcinoma HepG2 cells and in vivo using HepG2-bearing nude mice compared to free drug. PEGylated liposome of cantharidin had a particle size of 129.9 nm and a high encapsulation efficacy of approximately 88.9%. The liposomal cantharidin had a higher anti-proliferative effect vis-à-vis free cantharidin in inducing G2/M cell cycle arrest and apoptosis. Liposomal cantharidin killed more HepG2 cancer cells at the same concentration equivalent to free cantharidin. Further study in vivo also showed that liposomal cantharidin achieved a higher tumor growth inhibition efficacy than free drug on hepatocellular carcinoma. As our study exhibited enhanced cytotoxicity against HepG2 cells and augmented tumor inhibitory effects in vivo, the results validate the potential value of cantharidin-liposome in improving the therapeutic efficacy of cantharidin for liver cancer.

Drug delivery system targeting advanced hepatocellular carcinoma: Current and future.

Hepatocellular carcinoma (HCC) has a fairly high morbidity and is notoriously difficult to treat due to long latent period before detection, multidrug resistance and severe drug-related adverse effects from chemotherapy. Targeted drug delivery systems (DDS) that can selectively deliver therapeutic drugs into tumor sites have demonstrated a great potential in cancer treatment, which could be utilized to resolve the limitations of conventional chemotherapy. Numerous preclinical studies of DDS have been published, but targeted DDS for HCC has yet to be made for practical clinical use. Since rational targeted DDS design should take cancer-specific properties into consideration, we have reviewed the biological and physicochemical properties of HCC extensively to provide a comprehensive understanding on HCC, and recent DDS studies on HCC, aiming to find some potential targeted DDSs for HCC treatment and a meaningful platform for further development of HCC treatments. FROM THE CLINICAL EDITOR: Hepatocellular carcinoma has a high incidence worldwide and is known to be multidrug resistant. Thus, intensive research is being carried out to find better chemotherapeutic agents as well as new drug delivery systems. In this article, the authors reviewed in depth the current challenges facing new drug designs and also outlined novel targeted drug delivery systems (DDS) in the fight against HCC.

Exploring Different Strategies for Efficient Delivery of Colorectal Cancer Therapy.

Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death in the world. Currently available chemotherapy of CRC usually delivers the drug to both normal as well as cancerous tissues, thus leading to numerous undesirable effects. Much emphasis is being laid on the development of effective drug delivery systems for achieving selective delivery of the active moiety at the anticipated site of action with minimized unwanted side effects. Researchers have employed various techniques (dependent on pH, time, pressure and/or bacteria) for targeting drugs directly to the colonic region. On the other hand, systemic drug delivery strategies to specific molecular targets (such as FGFR, EGFR, CD44, EpCAM, CA IX, PPARγ and COX-2) overexpressed by cancerous cells have also been shown to be effective. This review aims to put forth an overview of drug delivery technologies that have been, and may be developed, for the treatment of CRC.

Medicinal chemistry aspects of fat mass and obesity associated protein: structure, function and inhibitors.

Adiposity and obesity-related proteins (FTO), the earliest identified mRNA N6-methyladenosine (m6A) demethylases, are known to play crucial roles in several biological processes. Therefore, FTO is a promising target for anticancer treatment. Understanding the biological functions and regulatory mechanisms of FTO targets can serve as guidelines for drug development. Despite significant efforts to develop FTO inhibitors, no specific small-molecule inhibitors have entered clinical trials so far. In this manuscript, we review the relationship between FTO and various cancers, the small-molecule inhibitors developed against FTO targets from the perspective of medicinal chemistry and other fields, and describe their structural optimization process and structure-activity relationship, providing clues for their future development direction.

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Insight into small-molecule inhibitors targeting extracellular nucleotide pyrophosphatase/phosphodiesterase1 for potential multiple human diseases.

Extracellular nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has been identified as a type II transmembrane glycoprotein. It plays a crucial role in various biological processes, such as bone mineralization, cancer cell proliferation, and immune regulation. Consequently, ENPP1 has garnered attention as a promising target for pharmacological interventions. Despite its potential, the development of clinical-stage ENPP1 inhibitors for solid tumors, diabetes, and silent rickets remains limited. However, there are encouraging findings from preclinical trials involving small molecules exhibiting favorable therapeutic effects and safety profiles. This perspective aims to shed light on the structural properties, biological functions and the relationship between ENPP1 and diseases. Additionally, it focuses on the structure-activity relationship of ENPP1 inhibitors, with the intention of guiding the future development of new and effective ENPP1 inhibitors.

[Intestinal absorption kinetics of flurbiprofen in rats].

To study the in situ intestinal absorption kinetics of flrubiprofen in rats, the absorption of flurbiprofen in small intestine (duodenum, jejunum and ileum) and colon of rats was investigated using in situ single-pass perfusion method and the drug content was measured by HPLC. The effects of drug concentration on the intestinal absorption were investigated. The K(a) and P(app) values of flurbiprofen in the small intestine and colon had no significant difference (P > 0.05). Drug concentration (4.0, 10.0 and 16.0 mg x L(-1)) had no significant influence on the K(a) values (P > 0.05). However, when concentration was 4.0 mg x L(-1) and 10.0 mg x L(-1), significant effect on the P(app) values (P < 0.05) was found, but significant effect on the P(app) values was not shown between 10.0 mg x L(-1) and 16.0 mg x L(-1) (P > 0.05). The K(a) and P(app) values of flurbiprofen on the perfusion flow rate had significant difference (P < 0.05). Flurbiprofen could be absorbed at all segments of the intestine in rats and had no special absorption window. The absorption of flurbiprofen complies with the facilitated diffusion in the general intestinal segments, and accompany with the cytopsistransport mechanism probably. The perfusion flow rate had significant effect on the K(a) and P(app).

Development of JmjC-domain-containing histone demethylase (KDM2-7) inhibitors for cancer therapy.

Histone methylation is the most common histone modification and a highly dynamic regulator of gene transcription. Methylation of lysine residues can alter the structure of chromatin, helping to regulate DNA-based nuclear activities. Lysine demethylases control and maintain epigenetic factors that affect chromatin structure and cell characteristics. A variety of diseases, including malignant tumors, are connected to their dysregulation. Advances in biochemistry and pathogenesis have prompted the discovery of small molecule inhibitors and tool compounds that disrupt lysine demethylation. In this review, we focus on JmjC-domain-containing histone lysine demethylases (KDM2-7), discussing their structures and biological roles, representative inhibitors, and therapeutic potential in cancer therapy, and aiming to provide unique insights into the development of JmjC-KDM inhibitors.

Quantification of epicardial fat volume using low-dose cardiac scan in patients with low calcium score.

Background: We investigated the accuracy of quantifying epicardial adipose tissue volume (EATV) using low-dose cardiac scan (EATVcardiac scan) and evaluated its clinical utility in predicting coronary heart disease in patients with low or mild calcification. Methods: In total, 204 patients with clinical symptoms of coronary heart disease and coronary artery calcium score (CACS) of <100 AU were enrolled in this retrospective study. After obtaining EATVcardiac scan and EATV measured using computed tomography angiography (EATVCTA), the agreement between the two measurements was evaluated using Pearson correlation coefficient and Bland-Altman analysis. Multivariate logistic regression was used to analyze the utility of EATV in predicting plaque and vulnerable plaque. Receiver operating characteristic curves were constructed. Results: The mean EATVcardiac scan (101.51±41.57 cm3) and EATVCTA (104.57±41.34 cm3) of all patients were similar, and the two measurements were strongly correlated (r=0.9596, P<0.001). The difference between EATVcardiac scan and EATVCTA was -3.0549, with only 4.9% (10/204) of patients having values outside the 95% confidence interval (CI) range (-26.15 to 20.04; P for agreement =0.0003). Further, a significant agreement was observed between EATVcardiac scan and EATVCTA in 126 patients with plaques, with an estimated difference of -3.354, and 6.35% (8/126) of patients had values outside the 95% CI range (-31.37 to 24.66; P for agreement =0.0095). After adjustment for age and sex, EATVcardiac scan and EATVCTA were significantly associated with plaque (all P values <0.001), and the areas under the curve (AUCs) were 0.662 and 0.670 (P=0.4331), respectively. In contrast, EATVcardiac scan and EATVCTA were not associated with vulnerable plaque (P>0.05), with AUCs of 0.550 and 0.530, respectively (P=0.2157). Conclusions: The study results indicate that EATVcardiac scan and EATVCTA are equivalent. In addition, both methods provide comparable values for predicting coronary arteriosclerosis in patients with low-to-mild calcification (CACS of <100 AU).

Targeting glutaminase 1 (GLS1) by small molecules for anticancer therapeutics.

Glutaminase-1 (GLS1) is a critical enzyme involved in several cellular processes, and its overexpression has been linked to the development and progression of cancer. Based on existing research, GLS1 plays a crucial role in the metabolic activities of cancer cells, promoting rapid proliferation, cell survival, and immune evasion. Therefore, targeting GLS1 has been proposed as a promising cancer therapy strategy, with several GLS1 inhibitors currently under development. To date, several GLS1 inhibitors have been identified, which can be broadly classified into two types: active site and allosteric inhibitors. Despite their pre-clinical effectiveness, only a few number of these inhibitors have advanced to initial clinical trials. Hence, the present medical research emphasizes the need for developing small molecule inhibitors of GLS1 possessing significantly high potency and selectivity. In this manuscript, we aim to summarize the regulatory role of GLS1 in physiological and pathophysiological processes. We also provide a comprehensive overview of the development of GLS1 inhibitors, focusing on multiple aspects such as target selectivity, in vitro and in vivo potency and structure-activity relationships.

Novel Medicinal Chemistry Strategies Targeting CDK5 for Drug Discovery.

Cyclin-dependent kinase 5 (CDK5) protein plays an important role not only in the central nervous system but also in the periphery, including immune response, regulation of insulin secretion, and cancer development and progression. Consequently, targeting the CDK5 protein is a potential strategy for the treatment of many diseases, especially cancer and neurodegenerative diseases. To date, numerous pan-CDK inhibitors have entered clinical trials. Nevertheless, limited clinical efficacy and severe adverse effects have prompted the application of new techniques to optimize clinical efficacy and minimize adverse events. In this Perspective, we highlight the protein properties, biofunctions, relevant signaling pathways, and associations with cancer development and proliferation of CDK5, and analyze the clinical status of pan-CDK inhibitors and the preclinical status of CDK5-specific inhibitors. In addition, CDK5-selective inhibitors, protein-protein interaction inhibitors, proteolytic-targeting chimera (PROTAC) degraders, and dual-target CDK5 inhibitors are discussed.

Small-molecule LRRK2 inhibitors for PD therapy: Current achievements and future perspectives.

Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that orchestrates a diverse array of cellular processes, including vesicle transport, autophagy, lysosome degradation, neurotransmission, and mitochondrial activity. Hyperactivation of LRRK2 triggers vesicle transport dysfunction, neuroinflammation, accumulation of α-synuclein, mitochondrial dysfunction, and the loss of cilia, ultimately leading to Parkinson's disease (PD). Therefore, targeting LRRK2 protein is a promising therapeutic strategy for PD. The clinical translation of LRRK2 inhibitors was historically impeded by issues surrounding tissue specificity. Recent studies have identified LRRK2 inhibitors that have no effect on peripheral tissues. Currently, there are four small-molecule LRRK2 inhibitors undergoing clinical trials. This review provides a summary of the structure and biological functions of LRRK2, along with an overview of the binding modes and structure-activity relationships (SARs) of small-molecule inhibitors targeting LRRK2. It offers valuable references for developing novel drugs targeting LRRK2.

Medicinal chemistry strategies targeting PRMT5 for cancer therapy.

Protein arginine methyltransferases 5 (PRMT5), a therapeutic target whose main physiological function is mono- and symmetric dimethylation of arginine, has drawn significant attention from researchers in the field. PRMT5 has been reported to participate in many cellular functions including cell growth, migration, and development. Upregulation of PRMT5 occurs in different kinds of tumors and is strongly associated with poor prognosis. In recent years, several PRMT5 inhibitors have entered clinical trials for the treatment of various cancers, such as advanced or recurrent solid tumors with MTAP deletion. Herein, we reviewed the binding modes and structure-activity relationships of novel PRMT5 inhibitors and discussed prospects of PRMT5 inhibitors in cancer therapy, aiming to provide insights on drug development of PRMT5 inhibitors.

A sulfhydryl blocking reagent BT-4 sensitizes cisplatin-based micelle prodrugs for efficient treatment of breast cancer.

Detoxification of glutathione (GSH) and insufficient cellular uptake of cisplatin (CDDP) severely compromised the therapeutic efficacy of CDDP. Here, a nano-delivery system (BT-4@PtPPNPs) for CDDP prodrug (C16-Pt(Ⅳ)-PEG) based on a novel sulfhydryl blocking reagent methyl 2-(methylsulfonyl) benzothiazole-6-carboxylate (BT-4) was developed. On the one hand, BT-4 can deplete GSH in tumor cells by directly interacting with reactive sulfhydryl group on GSH, thereby increasing the cytotoxicity of CDDP. On the other hand, the CDDP prodrug carrier C16-Pt(IV)-PEG can promote the distribution of CDDP in tumors, reduce the probability of unexpected inactivation of CDDP, and reduce the content of GSH in tumor cells during the conversion to CDDP, thereby making CDDP more effective for treatment. The results showed that the optimized BT-4@PtPPNPs with a small particle size (130 nm) exhibited notable cytotoxicity and apoptosis of 4T1 cells. BT-4@PtPPNPs not only significantly improved the uptake of drugs by tumor cells, but also rapidly targeted and accumulated in the tumors for a long time. Moreover, in vivo efficacy studies showed that BT-4@PtPPNPs could effectively inhibit tumor growth, inhibiting 60.85 % of tumors in a 4T1 breast cancer mice model, showing superior antitumor activity, which can be attributed to GSH-triggered CDDP tolerance reversal. Overall, this study provides an attractive and simple strategy to combine novel sulfhydryl blockers and CDDP prodrugs to potentiate the efficacy of CDDP in breast cancer.

Discovery of physalin biosynthesis and structure modification of physalins in Physalis alkekengi L. var. Franchetii.

Physalins, active ingredients from the Physalis alkekengi L. var. franchetii (P. alkekengi) plant, have shown anti-inflammatory, antioxidant and anticancer activities. Whereas the bioactivity of physalins have been confirmed, their biosynthetic pathways, and those of quite a few derivatives, remain unknown. In this paper, biosynthesis and structure modification-related genes of physalins were mined through transcriptomic and metabolomic profiling. Firstly, we rapidly and conveniently analyzed physalins by UPLC-Q-TOF-MS/MS utilizing mass accuracy, diagnostic fragment ions, and common neutral losses. In all, 58 different physalin metabolites were isolated from P. alkekengi calyxes and berries. In an analysis of the physalin biosynthesis pathway, we determined that withanolides and withaphysalins may represent a crucial intermediate between lanosterol and physalins. and those steps were decanted according to previous reports. Our results provide valuable information on the physalin metabolites and the candidate enzymes involved in the physalins biosynthesis pathways of P. alkekengi. In addition, we further analyzed differential metabolites collected from calyxes in the Jilin (Daodi of P. alkekengi) and others. Among them, 20 physalin metabolites may represent herb quality biomarkers for Daodi P. alkekengi, providing an essential role in directing the quality control index of P. alkekengi.

Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy.

Vascular endothelial growth factor receptors (VEGFRs) are a family of receptor protein tyrosine kinases that play an important role in the regulation of tumor-induced angiogenesis. Currently, VEGFR inhibitors have been widely used in the treatment of various tumors. However, current VEGFR inhibitors are limited to a certain extent due to limited clinical efficacy and potential toxicity, which hinder their clinical application. Thus, the development of new strategies to improve the clinical outcomes and minimize the toxic effects of VEGFR inhibitors is required. Given the synergistic effect of VEGFR and other therapies in tumor development and progression, VEGFR dual-target inhibitors are becoming an attractive approach due to their favorable pharmacodynamics, low toxicity, and anti-resistant effects. This perspective provides an overview of the development of VEGFR dual-target inhibitors from multiple aspects, including rational target combinations, drug discovery strategies, structure-activity relationships and future directions.

Advance cardiac nanomedicine by targeting the pathophysiological characteristics of heart failure.

Heart failure (HF) has continued to be a leading cause of morbidity and mortality worldwide. Nanomedicine, which can deliver therapeutic drugs/biomolecules specifically to damaged myocardium and overcome the limitations of conventional therapies, shows great potential in the treatment of HF. Although a number of preclinical studies of cardiac nanoformulations have been published, targeted nanomedicine for HF is yet to be applied in clinical practice. Therefore, it is meaningful to sum up past experiences and deepen the understanding of nanomedicine and HF. In this review, we first emphasized the key biological barriers to cardiac nanomedicine that hinder its targeting effect. Since the rational design of nanoparticles should take into account the specific characteristics of HF, we then summarized the key pathophysiological changes of HF to provide a clear understanding on HF, as well as the latest examples of nanotechnology-based delivery strategies for different pathophysiological characteristics. Finally, the major challenges are discussed in detail, aiming to provide guidance for future development of cardiac nanomedicine.