Current Medicinal Chemistry - Volume 32, Issue 7, 2025

Kisspeptin was initially known as metastin for its role in suppressing metastasis in melanoma and breast cancer. Later, based on its ability to stimulate GPR54, its importance in maintaining an intact hypothalamic-pituitary-ovarian axis was recognised, which is the basis for the widespread application of the drug in several conditions such as secondary amenorrhea, regulation of puberty onset, ovarian function, trophoblast invasion, fertility regulation, parturition, and lactation. This systematic study aims to evaluate the current status of kisspentin in clinical trials.

The keywords 'kisspeptin' or 'metastin' were used in the clinicaltrials.gov website and Clinical Trial Registry of India (CTRI) to find eligible clinical trials or records carried out without time constraints until February 26, 2023.

A total of 33 records were identified through clinical trial databases. All records were screened, and four trials were rejected as they failed to meet the inclusion criteria. Finally, 29 (87.9%) reports of interventional clinical trials with kisspeptin were reviewed.

Kisspeptin can be viewed as a multipurpose drug with considerably fewer side effects due to its effects simulating normal physiological processes in our body.

Statins are primarily used to decrease elevated LDL-cholesterol and thus prevent atherosclerotic cardiovascular disease. Portal hypertension is one of the most important complications of chronic liver disease. Several studies indicated that statins might be beneficial for portal hypertension as well but there is still no clear answer whether this is true or not.

A literature search of the major databases was performed to find eligible randomized controlled trials (RCTs) analyzing the effect of statins on portal hypertension from inception to February 5^th, 2021. Six RCTs with 442 patients who received statin or statin plus carvedilol were finally included. Meta-analysis was performed using the Comprehensive Meta-Analysis V2 software.

Reduction of portal hypertension after statin treatment was not significant (WMD: -0.494, 95% CI: -1.239, 0.252, p=0.194; I²:0%). The reduction of portal hypertension was robust in the leave-one-out sensitivity analysis.

Treatment with statins did not decrease significantly portal hypertension.

Selective Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) have revolutionized the treatment of breast cancer and have potential in other cancers, being manageable drugs yet with some bone marrow toxicity. Selective CDK9 inhibitors (CDK9i) never advanced into clinical use, partly due to side effects, including gastrointestinal toxicity, and a small window between activity and cytotoxicity, which results in a narrow therapeutic index (TI).

To overcome the drawbacks of CDK4/6 and CDK9 inhibitors, we have developed myrtleciclib, a selective CDK4/6/9 inhibitor with few non-critical molecular off-targets.

Myrtleciclib appears to bind to an allosteric site, unlike all other CDK4/6i and CDK9i acting by an ATP-competitive mechanism, which supports target specificity. Myrtleciclib's anti-proliferative effects are greater and its Therapeutic Index (TI) is broader than CDK9 and CDK4/6-only inhibitors. This can be explained by a moderate target inhibition, resulting in limited cytotoxicity. Moreover, we documented a synergy between CDK9 and CDK4/6 pathways inhibition, justifying increased drug efficacy, yet such synergy can only be achieved when the inhibition of both CDK9 and CDK4/6 is embedded within the same molecule and balanced within a certain ratio, as it is the case with myrtleciclib. Unlike CDK4/6i, myrtleciclib also induces cell death and apoptosis selectively on cancer cell lines, not on bystander cells. Synergy between myrtleciclib and other drugs with complementary Mechanism of Action (MoA) has also been documented.

CDK4/6/9i might represent a new frontier in cancer treatment to overcome the limitations of CDK4/6i and CDK9i for the treatment of cancers, including aggressive cancers with high unmet needs.

The hallmark of non-alcoholic fatty liver disease (NAFLD) is aberrant buildup of triglycerides (TGs) in hepatocytes. Many genes promote NAFLD development. Using bioinformatics tools, we investigated the possible effect of statins on genes involved in NAFLD progression.

Protein interactions of statins and NAFLD were searched in gene-drug and gene-disease databases. A Protein-Protein interaction (PPI) network was constructed to find hub genes and Molecular Complex Detection (MCODE) of NAFLD-related genes. Shared protein targets between protein targets of statins and NAFLD-associated genes were identified. Next, targets of each statin were assayed with all modular clusters in the MCODEs related to NAFLD. Biological process and pathway enrichment analysis for shared proteins was performed.

Screening protein targets for conventional statins and curated NAFLD-related genes identified 343 protein targets and 70 genes, respectively. A Venn diagram of NAFLD-related genes and protein targets of statins showed 24 shared proteins. The biological pathways on KEGG enrichment associated with the 24 shared protein sets were evaluated and included cytokine-cytokine receptor interaction, adipocytokine, PPAR, TNF and AMPK signaling pathways. Gene Ontology analysis showed major involvement in lipid metabolic process regulation and inflammatory response. PPI network analysis of 70 protein targets indicated 13 hub genes (PPARA, IL4, CAT, LEP, SREBF1, PRKCA, CYP2E1, NFE2L2, PTEN, NR1H4, ADIPOQ, GSTP1 and TGFB1). Comparing all seven statins with the three MCODE clusterings and 13 hub genes revealed that simvastatin as the most associated statin with NAFLD.

Simvastatin has the most impact on NAFLD-related genes versus other statins.

Peptide nucleic acid (PNA) plays an important role in antimicrobial activity, but its cellular permeability is poor. To overcome this limitation, we constructed biomimetic nanoparticles by using extracellular vesicle (EV)-coated mesoporous silicon nanoparticles (MSNs) to deliver PNA to Staphylococcus aureus (S. aureus) and improve its antisense therapeutic effect.

MSN was prepared by the sol-gel method, and EV was extracted by affinity resin chromatography. EV was coated on MSN by simple sonication (50 W, 3 mins) to prepare biomimetic nanoparticles with PNA-loaded MSN as the core and EV isolated from S. aureus as the shell.

The MSN prepared by the sol-gel method had a uniform particle size (100 nm) and well-defined pore size for loading PNA with good encapsulation efficiency (62.92%) and drug loading (7.74%). The concentration of EV extracted by affinity resin chromatography was about 1.74 mg/mL. EV could be well coated on MSN through simple ultrasonic treatment (50 W, 3 mins), and the stability and blood compatibility of MSN@EV were good. Internalization experiments showed that EV could selectively enhance the uptake of biomimetic nanoparticles by S. aureus. Preliminary in vitro antibacterial tests revealed that PNA@MSN@EV exhibited enhanced antibacterial activity against S. aureus and had stronger bactericidal activity than free PNA and PNA@MSN at equivalent PNA concentrations (8 µM).

Biomimetic nanoparticles based on EV-coated MSN offer a new strategy to improve the efficacy of PNA for the treatment of bacterial infections, and the technology holds promise for extension to the delivery of antibiotics that are traditionally minimally effective or prone to resistance.

Alcohol intoxication leads to multiple degenerative disorders in the structure and function of mitochondria. The mechanisms underlying these disorders, as well as ways to prevent them, are an urgent task in biomedicine. We investigate the mechanism of the positive effect of AX on rat liver mitochondria after chronic alcohol administration and suggest the targets of its effects. In this work, we continued our studies of astaxanthin (AX) as a possible protector of mitochondria from the toxic effects of ethanol.

In our experiments, we used the Lieber-DeCarly model of chronic alcohol intoxication, which allows high-dose alcohol intake. Four groups of animals were used in the experiments: group 1 (control), group 2 (treated with AX), group 3 (treated with ethanol), and group 4 (treated with ethanol and AX together). Rat liver mitochondria (RLM) were isolated by the standard method modified in our laboratory. A multifunctional chamber with built-in electrodes was used to determine mitochondrial functions. Electrophoresis followed by Western blot analysis was used to detect mitochondrial proteins. Statistical significance was calculated using t-test Student-Newman- Keuls test.

AX has been shown to have a positive effect on the functioning of the mitochondrial permeability transition pore (mPTP), the regulation of signaling pathways, as well as mitochondrial dynamics. It was found that AX is able to suppress the degenerative effect of alcohol on liver mitochondria. Targets for the protective action of AX in rat liver mitochondria (RLM) have been proposed.

The discovered protective effect of AX on liver mitochondria during alcohol damage may contribute to the development of new strategies for the treatment of alcohol-induced damage.

Methamphetamine (METH) is an illicit psychoactive substance that can damage various organs in the body, especially the nervous system. We hypothesized that expression of homocysteine-inducible endoplasmic reticulum-resident with ubiquitin-like domain member 1 (Herpud1) protein would alleviate the induction of apoptosis following METH administration.

To test this hypothesis, we analysed the changes in Herpud1 expression and apoptosis in PC12 cells under different concentrations and exposure times of METH. Moreover, we examined the effects of Herpud1 knockdown on METH-induced neuronal apoptosis. Flow cytometry and Western blot analyses were used to evaluate apoptosis levels and the expression of apoptotic markers (cleaved caspase-3) in PC12 cells following Herpud1 knockdown by synthetic small interfering RNA (siRNA).

Our results showed that Herpud1 expression was upregulated in PC12 cells following METH treatment, while endoplasmic reticulum stress (ERS) and apoptosis were also increased. Conversely, Herpud1 knockdown reduced METH-induced ERS and apoptosis levels in vitro.

These results suggest that Herpud1 plays an essential role in METH-induced neuronal ERS and apoptosis and may represent a potential therapeutic gene target in METH-induced neurotoxicity.

Lung cancer is a frequent malignancy with a poor prognosis. Extensive metabolic alterations are involved in carcinogenesis and could, therefore, serve as a reliable prognostic phenotype.

Our study aimed to develop a prognosis signature and explore the relationship between metabolic characteristic-related signature and immune infiltration in lung adenocarcinoma (LUAD).

TCGA-LUAD and GSE31210 datasets were used as a training set and a validation set, respectively.

A total of 513 LUAD samples collected from The Cancer Genome Atlas database (TCGA-LUAD) were used as a training dataset. Molecular subtypes were classified by consensus clustering, and prognostic genes related to metabolism were analyzed based on Differentially Expressed Genes (DEGs), Protein-Protein Interaction (PPI) network, the univariate/multivariate- and Lasso- Cox regression analysis.

Two molecular subtypes with significant survival differences were divided by the metabolism gene sets. The DEGs between the two subtypes were identified by integrated analysis and then used to develop an 8-gene signature (TTK, TOP2A, KIF15, DLGAP5, PLK1, PTTG1, ECT2, and ANLN) for predicting LUAD prognosis. Overexpression of the 8 genes was significantly correlated with worse prognostic outcomes. RiskScore was an independent factor that could divide LUAD patients into low- and high-risk groups. Specifically, high-risk patients had poorer prognoses and higher immune escape. The Receiver Operating Characteristic (ROC) curve showed strong performance of the RiskScore model in estimating 1-, 3- and 5-year survival in both training and validation sets. Finally, an optimized nomogram model was developed and contributed the most to the prognostic prediction in LUAD.

The current model could help effectively identify high-risk patients and suggest the most effective drug and treatment candidates for patients with LUAD.