Том 31, № 19 (2024)

Anti-Infectives and Infectious Diseases

Multimodality Cardiac Imaging Biomarkers and Atrial Fibrillation Substrate: Are they Worthwhile?

Androulakis E., Ahsan S., Papageorgiou N.
Current Medicinal Chemistry. 2024;31(19):2661-2662
pages 2661-2662 views

The Development of Non-natural Type Nucleoside to Stabilize Triplex DNA Formation against CG and TA Inversion Site

Wang L., Ling Y., Tian Y., Wang X., Sasaki S., Taniguchi Y.

Аннотация

Based on the sequence-specific recognition of target duplex DNA by triplexforming oligonucleotides (TFOs) at the major groove side, the antigene strategy has been exploited as a gene-targeting tool with considerable attention. Triplex DNA is formed via the specific base triplets by the Hoogsteen or reverse Hoogsteen hydrogen bond interaction between TFOs and the homo-purine strand from the target duplex DNA, leading to the established sequence-specificity. However, the presence of inversion sites, which are known as non-natural nucleosides that can form satisfactory interactions with 2′- deoxythymidine (dT) and 2′-deoxycytidine (dC) in TA and CG base pairs in the target homo-purine DNA sequences, drastically restricts the formation of classically stable base triplets and even the triplex DNA. Therefore, the design of non-natural type nucleosides, which can effectively recognize CG or/and TA inversion sites with satisfactory selectivity, should be of great significance to expanding the triplex-forming sequence. Here, this review mainly provides a comprehensive review of the current development of novel nonnatural nucleosides to recognize CG or/and TA inversion sites in triplex DNA formation against double-strand DNA (dsDNA).

Current Medicinal Chemistry. 2024;31(19):2663-2686
pages 2663-2686 views

Hybrids Diazine: Recent Advancements in Modern Antimicrobial Therapy

Mangalagiu V., Danac R., Diaconu D., Zbancioc G., Mangalagiu I.

Аннотация

Nowadays, antimicrobial therapies have become a very challenging issue because of a large diversity of reasons such as antimicrobial resistance, over consumption and misuse of antimicrobial agents, etc. A modern, actual and very useful approach in antimicrobial therapy is represented by the use of hybrid drugs, especially combined five and six-membered ring azaheterocycles. In this review, we present an overview of the recent advanced data from the last five years in the field of hybrid diazine compounds with antimicrobial activity. In this respect, we highlight here essential data concerning the synthesis and antimicrobial activity of the main classes of diazine hybrids: pyridazine, pyrimidine, pyrazine, and their fused derivatives.

Current Medicinal Chemistry. 2024;31(19):2687-2705
pages 2687-2705 views

Biology of Tenascin C and its Role in Physiology and Pathology

Abedsaeidi M., Hojjati F., Tavassoli A., Sahebkar A.

Аннотация

Tenascin-C (TNC) is a multimodular extracellular matrix (ECM) protein hexameric with several molecular forms (180-250 kDa) produced by alternative splicing at the pre-mRNA level and protein modifications. The molecular phylogeny indicates that the amino acid sequence of TNC is a well-conserved protein among vertebrates. TNC has binding partners, including fibronectin, collagen, fibrillin-2, periostin, proteoglycans, and pathogens. Various transcription factors and intracellular regulators tightly regulate TNC expression. TNC plays an essential role in cell proliferation and migration. Unlike embryonic tissues, TNC protein is distributed over a few tissues in adults. However, higher TNC expression is observed in inflammation, wound healing, cancer, and other pathological conditions. It is widely expressed in a variety of human malignancies and is recognized as a pivotal factor in cancer progression and metastasis. Moreover, TNC increases both pro-and anti-inflammatory signaling pathways. It has been identified as an essential factor in tissue injuries such as damaged skeletal muscle, heart disease, and kidney fibrosis. This multimodular hexameric glycoprotein modulates both innate and adaptive immune responses regulating the expression of numerous cytokines. Moreover, TNC is an important regulatory molecule that affects the onset and progression of neuronal disorders through many signaling pathways. We provide a comprehensive overview of the structural and expression properties of TNC and its potential functions in physiological and pathological conditions.

Current Medicinal Chemistry. 2024;31(19):2706-2731
pages 2706-2731 views

A Review on the Efficacy and Safety of Intrathecal Administration of Novel Medications for Leptomeningeal Metastases in Solid Cancers

Jafari F., Nodeh M., Hosseinjani H., Baharara H., Azad S., Arasteh O., Johnston T., Sahebkar A.

Аннотация

Leptomeningeal disease (LMD) is a rare and lethal manifestation that may occur in the advanced stages of solid tumors and hematological malignancies. With advances in diagnostic techniques, the detection and confirmation of the presence of LMD have increased. Although its optimal treatment remains a challenge, the use of the intrathecal route for the delivery of novel therapeutics is now considered a promising drug delivery strategy to complement radiation and systemic-based therapies. Although methotrexate, cytarabine, and thiotepa have a long history in the treatment of LMD, other medications have also been shown to be beneficial. In this article, we have reviewed the effects of novel medications administered via the intrathecal route for the treatment of solid tumors. We have searched PubMed, Scopus, and Google Scholar databases till the end of September 2021 using the following keywords: "leptomeningeal disease", "leptomeningeal carcinomatosis", "leptomeningeal metastases", "solid tumors", "solid cancers", and "intrathecal". Our literature findings have uncovered that most studies on LMD, which occurs secondary to solid cancers, are available as ‘case reports’, and few clinical trials have been conducted to date. Single-drug (monotherapy) or combination drug therapy, administered via the intrathecal route, especially in metastatic breast and lung cancer, has been shown to improve patients' symptoms and overall lifespan, while exhibiting a low and acceptable prevalence of side effects. However, judgments/conclusions about the effectiveness and safety of these drugs still require further clinical evaluation.

Current Medicinal Chemistry. 2024;31(19):2732-2750
pages 2732-2750 views

Crosstalk between Oxidative Stress and Inflammation Induced by Ionizing Radiation in Healthy and Cancerous Cells

Mohammadgholi M., Hosseinimehr S.

Аннотация

Radiotherapy (RT) is a unique modality in cancer treatment with no replacement in many cases and uses a tumoricidal dose of various ionizing radiation (IR) types to kill cancer cells. It causes oxidative stress through reactive oxygen species (ROS) production or the destruction of antioxidant systems. On the other hand, RT stimulates the immune system both directly and indirectly by releasing danger signals from stress-exposed and dying cells. Oxidative stress and inflammation are two reciprocal and closely related mechanisms, one induced and involved by the other. ROS regulates the intracellular signal transduction pathways, which participate in the activation and expression of pro-inflammatory genes. Reciprocally, inflammatory cells release ROS and immune system mediators during the inflammation process, which drive the induction of oxidative stress. Oxidative stress or inflammation-induced damages can result in cell death (CD) or survival mechanisms that may be destructive for normal cells or beneficial for cancerous cells. The present study has focused on the radioprotection of those agents with binary effects of antioxidant and anti-inflammatory mechanisms IR-induced CD.

Current Medicinal Chemistry. 2024;31(19):2751-2769
pages 2751-2769 views

An Update on Parkinson’s Disease and its Neurodegenerative Counterparts

Adam H., Gopinath S., Arshad M., Adam T., Subramaniam S., Hashim U.

Аннотация

Introduction:Neurodegenerative disorders are a group of diseases that cause nerve cell degeneration in the brain, resulting in a variety of symptoms and are not treatable with drugs. Parkinson's disease (PD), prion disease, motor neuron disease (MND), Huntington's disease (HD), spinal cerebral dyskinesia (SCA), spinal muscle atrophy (SMA), multiple system atrophy, Alzheimer's disease (AD), spinocerebellar ataxia (SCA) (ALS), pantothenate kinase-related neurodegeneration, and TDP-43 protein disorder are examples of neurodegenerative diseases. Dementia is caused by the loss of brain and spinal cord nerve cells in neurodegenerative diseases.

Background:Even though environmental and genetic predispositions have also been involved in the process, redox metal abuse plays a crucial role in neurodegeneration since the preponderance of symptoms originates from abnormal metal metabolism.

Method:Hence, this review investigates several neurodegenerative diseases that may occur symptoms similar to Parkinson's disease to understand the differences and similarities between Parkinson's disease and other neurodegenerative disorders based on reviewing previously published papers.

Results:Based on the findings, the aggregation of alpha-synuclein occurs in Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. Other neurodegenerative diseases occur with different protein aggregation or mutations

Conclusion:We can conclude that Parkinson's disease, Multiple system atrophy, and Dementia with Lewy bodies are closely related. Therefore, researchers must distinguish among the three diseases to avoid misdiagnosis of Multiple System Atrophy and Dementia with Lewy bodies with Parkinson's disease symptoms.

Current Medicinal Chemistry. 2024;31(19):2770-2787
pages 2770-2787 views

Emodin Alcohols: Design, Synthesis, Biological Evaluation and Multitargeting Studies with DNA, RNA, and HSA

Wang H., Zhang H.

Аннотация

Objective:A series of novel emodin alcohols were designed and prepared in an effort to overcome the increasing microorganism resistance.

Methods:Novel emodin alcohols were prepared from commercial emodin and different nitrogen-containing heterocycles via different synthetic strategies, such as O-alkylation and N-alkylation. The antimicrobial activity of synthesized emodin compounds was evaluated in vitro by a two-fold serial dilution technique. The interaction of emodin compound 3d with biomolecule was researched using UV-vis spectroscopic method and fluorescence spectroscopy.

Results:Emodin compound 3d containing 2-methyl-5-nitro imidazole ring showed relatively good antimicrobial activity. Notably, it exhibited equivalent activity against S. aureus in comparison to the reference drug norfloxacin (MIC = 4 µg/mL). The combination of strong active compound 3d with reference drugs showed better antimicrobial activity with less dosage and a broader antimicrobial spectrum than their separate use. Further research displayed that emodin compound 3d could intercalate into S. aureus DNA to form the 3d–DNA complex, which might correlate with the inhibitory activity. The hydrogen bonds were found between S. aureus DNA gyrase and strong active compound 3d during the docking research, which were in accordance with the spectral experiment results. The interaction with yeast RNA of compound 3d could also form a complex via hydrogen bonds. The hydrogen bonds were found to play a major role in the transportation of emodin compound 3d by human serum albumin (HSA), as confirmed by molecular simulation.

Conclusion:This work provides a promising starting point to optimize the structures of emodin derivatives as potent antimicrobial agents.

Current Medicinal Chemistry. 2024;31(19):2788-2808
pages 2788-2808 views

Potential Role of Bone Metabolism Markers in Kidney Transplant Recipients

Vigil F., Castro P., Hasparyk U., Bartolomei V., Silva A.

Аннотация

Background:The impact of treatments, suppressing the immune system, persistent hyperparathyroidism, and other risk factors on mineral and bone disorder (MBD) after kidney transplantation is well-known. However, there is limited knowledge about their effect on bone metabolism biomarkers. This study aimed to investigate the influence of kidney transplant on these markers, comparing them to patients undergoing hemodialysis and healthy individuals.

Methods:In this cross-sectional study, three groups were included: kidney transplant patients (n = 57), hemodialysis patients (n = 26), and healthy controls (n = 31). Plasma concentrations of various bone metabolism biomarkers, including Dickkopf-related protein 1, osteoprotegerin, osteocalcin, osteopontin, sclerostin, and fibroblast growth factor 23, were measured. Associations between these biomarkers and clinical and laboratory data were evaluated.

Results:A total of 114 patients participated. Transplant recipients had significantly lower levels of Dickkopf-related protein 1, osteoprotegerin, osteocalcin, osteopontin, sclerostin, and fibroblast growth factor 23 compared to hemodialysis patients. Alkaline phosphatase levels positively correlated with osteopontin (r = 0.572, p < 0.001), while fibroblast growth factor 23 negatively correlated with 25-hydroxyvitamin D (r = -0.531, p = 0.019). The panel of bone biomarkers successfully predicted hypercalcemia (area under the curve [AUC] = 0.852, 95% confidence interval [CI] = 0.679-1.000) and dyslipidemia (AUC = 0.811, 95% CI 0.640-0.982) in transplant recipients.

Conclusion:Kidney transplantation significantly improves mineral and bone disorders associated with end-stage kidney disease by modulating MBD markers and reducing bone metabolism markers, such as Dickkopf-related protein 1, osteoprotegerin, osteocalcin, osteopontin, and sclerostin. Moreover, the panel of bone biomarkers effectively predicted hypercalcemia and dyslipidemia in transplant recipients.

Current Medicinal Chemistry. 2024;31(19):2809-2820
pages 2809-2820 views

Modulation of the HIF-1α-NCOA4-FTH1 Signaling Axis Regulating Ferroptosis-induced Hepatic Stellate Cell Senescence to Explore the Anti-hepatic Fibrosis Mechanism of Curcumol

Zheng Y., Wang L., Wang J., Zhao T., Wang J.

Аннотация

Introduction:Senescence of activated hepatic stellate cells (HSC) reduces extracellular matrix expression to reverse liver fibrosis. Ferroptosis is closely related to cellular senescence, but its regulatory mechanisms need to be further investigated. The iron ions weakly bound to ferritin in the cell are called labile iron pool (LIP), and together with ferritin, they maintain cellular iron homeostasis and regulate the cell's sensitivity to ferroptosis.

Methods:We used lipopolysaccharide (LPS) to construct a pathological model group and divided the hepatic stellate cells into a blank group, a model group, and a curcumol 12.5 mg/L group, a curcumol 25 mg/L group, and a curcumol 50 mg/L group. HIF-1α-NCOA4- FTH1 signalling axis, ferroptosis and cellular senescence were detected by various cellular molecular biology experiments.

Result:We found that curcumol could induce hepatic stellate cell senescence by promoting iron death in hepatic stellate cells. Curcumol induced massive deposition of iron ions in hepatic stellate cells by activating the HIF-1α-NCOA4-FTH1 signalling axis, which further led to iron overload and lipid peroxidation-induced ferroptosis. Interestingly, our knockdown of HIF-1α rescued curcumol-induced LIP and iron deposition in hepatic stellate cells, suggesting that HIF-1α is a key target of curcumol in regulating iron metabolism and ferroptosis. We were able to rescue curcumol-induced hepatic stellate cell senescence when we reduced LIP and iron ion deposition using iron chelators.

Conclusion:Overall, curcumol induces ferroptosis and cellular senescence by increasing HIF-1α expression and increasing NCOA4 interaction with FTH1, leading to massive deposition of LIP and iron ions, which may be the molecular biological mechanism of its anti-liver fibrosis.

Current Medicinal Chemistry. 2024;31(19):2821-2837
pages 2821-2837 views