Current Medicinal Chemistry - Online First

Escherichia coli strains are known to cause various gastrointestinal disorders, with Shiga toxin 2, a potent cytotoxin, being a key virulence factor contributing to disease severity. Targeting Shiga toxin 2 presents a promising approach for therapeutic intervention in controlling E. coli O157 infections. This study aims to explore natural and synthetic inhibitors as potential therapeutic agents against Shiga toxin 2 through in-silico molecular docking and drug-likeness predictions.

An in-silico molecular docking study was conducted using AutoDock Vina and Chimera to assess the binding affinity of various natural and synthetic inhibitors against Shiga toxin 2. The selected inhibitors were evaluated for their drug-likeness based on adsorption, distribution, metabolism, and excretion (ADME) properties, applying Lipinski's rule of five and the Boiled-Egg technique to predict their suitability as potential drugs in biological systems.

During the screening process, luteolin, a natural flavonoid, exhibited the highest binding affinity to Shiga toxin 2, with a notable negative binding energy of -8.7 kcal/mol, indicating strong interaction potential.

The findings suggest that luteolin holds promise as a lead molecule for further development as a therapeutic agent against E. coli infections, warranting additional studies to validate its efficacy and safety.

Hyperuricemia (HUA) is a condition characterized by excessive uric acid production and/or inadequate uric acid excretion due to abnormal purine metabolism in the human body. Uric acid deposits resulting from HUA can lead to complications such as renal damage. Currently, drugs used to treat HUA lack specificity and often come with specific toxic side effects.

This study aimed to investigate the renal protective effects of an optimized tea polyphenol formula and allopurinol in a rat model of hyperuricemia following renal resection. The goal was to explore the mechanisms underlying these effects.

Initially, a blend was formulated based on the distinctive functions of catechins, thearubigins, tea polysaccharides, and theanine. Orthogonal experiments were then employed to select a rational combination. A 5/6 renal resection rat model was successfully established, and the animals were fed a 2% oxonic acid diet to induce hyperuricemia. Urinary protein content was measured using the biuret method, and serum levels of uric acid, creatinine, and urea nitrogen were determined biochemically. Kidney pathology was examined through HE staining and renal tubulointerstitial pathological scoring. The expression of α-SMA, CD34, PCNA, and TGF-β in renal tissue was detected using immunohistochemistry. Apoptosis of renal tubular epithelial cells was assessed using the TUNEL method.

Hyperuricemia markedly worsens renal damage in rats following nephrectomy, while tea polyphenols demonstrate the ability to reduce levels of blood uric acid, urea nitrogen, creatinine, and urinary protein. Additionally, tea polyphenols enhance smooth muscle proliferation in renal glomerular arterioles, prevent the loss of interstitial capillaries, alleviate apoptosis of renal tubular epithelial cells, promote their proliferation, and reduce interstitial fibrosis. A significant improvement in the severity of renal damage is observed in rats subjected to nephrectomy combined with hyperuricemia, and this effect surpasses that of allopurinol.

Tea polyphenols could effectively alleviate renal damage in rats with nephrectomy combined with hyperuricemia. They demonstrate high cost-effectiveness and minimal side effects, positioning them as a promising new therapeutic option for hyperuricemia-induced renal damage.

To build an innovative telomere-associated scoring model to predict prognosis and treatment responsiveness in acute myeloid leukemia (AML).

AML is a highly heterogeneous malignant hematologic disorder with a poor prognosis. While telomere maintenance is frequently observed in tumors, investigations into telomere-related genes (TRGs) in AML remain limited.

This study aimed to identify prognostic TRGs using the least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression, evaluate their predictive value, explore the association between TRG scores and immune cell infiltration, and assess the sensitivity of high-scoring AML patients to chemotherapeutic agents.

Univariate Cox regression analysis was conducted on the TCGA cohort to identify prognostic TRGs and to develop the TRG scoring model using LASSO-Cox and multivariate Cox regression. Validation was performed on the GSE37642 cohort. Immune cell infiltration patterns were assessed through computational analysis, and the sensitivity to chemotherapeutic agents was evaluated.

Thirteen prognostic TRGs were identified, and a seven-TRG scoring model (including NOP10, OBFC1, PINX1, RPA2, SMG5, MAPKAPK5, and SMN1) was developed. Higher TRG scores were associated with a poorer prognosis, as confirmed in the GSE37642 cohort, and remained an independent prognostic factor even after adjusting for other clinical characteristics. The high-score group was characterized by elevated infiltration of B cells, T helper cells, natural killer cells, tumor-infiltrating lymphocytes, regulatory T (Treg) cells, M2 macrophages, neutrophils, and monocytes, along with reduced infiltration of gamma delta T cells, CD4- T cells, and resting mast cells. Moreover, high infiltration of M2 macrophages and Tregs was associated with poor overall survival compared to low infiltration. Notably, high-risk AML patients were resistant to Erlotinib, Parthenolide, and Nutlin-3a, but sensitive to AC220, Midostaurin, and Tipifarnib. Additionally, using RT-qPCR, we observed significantly higher expression of two model genes, OBFC1 and SMN1, in AML tissues compared to control tissues.

This innovative TRG scoring model demonstrates considerable predictive value for AML patient prognosis, offering valuable insights for optimizing treatment strategies and personalized medicine approaches. The identified TRGs and associated scoring models could aid in risk stratification and guide tailored therapeutic interventions in AML patients.

Astaxanthin (AXT), a natural antioxidant recognized for its therapeutic potential in cancer and cardiovascular diseases, holds promise in mitigating adriamycin-induced cardiotoxicity (AIC). Nevertheless, the underlying mechanisms of AXT in AIC mitigation remain to be elucidated. Consequently, this study endeavors to elucidate the mechanism of AXT against AIC, employing an integrated approach.

Network pharmacology, molecular docking, and molecular dynamics simulations were harnessed to explore the molecular mechanism underlying AXT's action against AIC. Furthermore, the in-vitro AIC model was established with the H9c2 cell to generate transcriptome data for validation.

A total of 533 putative AXT targets and 1478 AIC-related genes were initially screened by database retrieval and bioinformatics analysis. A total of 248 potential targets of AXT against AIC and several signaling pathways were identified by network pharmacology and enrichment analysis. Two core genes (CCL2 and NOS3) and the AGE-RAGE signaling pathway in diabetic complications were further highlighted by transcriptome validation based on the AIC in-vitro model. Additionally, molecular docking and dynamics analyses supported the robust binding affinity of AXT with the core targets.

The study suggested that AXT might ameliorate AIC through the inhibition of CCL2 and NOS3 as well as AGE-RAGE signaling, which provide a theoretical basis for the development of a strategy against AIC.

Prosopis juliflora has been employed in many traditional treatments. As evidenced by our earlier research, Prosopis juliflora leaf methanol extract (PJME) has a promising future in the fight against lung cancer. It may also be used in conjunction with other treatments to effectively manage lung cancer. Aims and objective: The main objective of this study was to explore the potential of PJME to inhibit lung cancer in A549 cells, along with its underlying mechanisms of action.

The antiproliferative effects were determined using MTT and LDH tests. Apoptosis-inducing capacity was evaluated using the DAPI staining, caspase-3 test, cytochrome C assay, PARP cleavage, and qRT-PCR. To investigate the mechanism of action of PJME in lung cancer, the levels of ROS, MMP, GSH, MDA, and specific ferroptosis indicators were measured.

The experimental data of the current study indicated that exposure of A549 cells to PJME reduced cell viability and increased cellular cytotoxicity. The apoptosis-inducing ability of PJME in A549 cells was validated by enhanced nuclear condensation, level of the caspase-3, cytochrome C, and PARP release. In addition, qRT-PCR investigations verified that the administration of PJME led to a decrease in the expression of anti-apoptotic gene Bcl2 while enhancing the mRNA level of pro-apoptotic genes, such as Bax and caspase-3, in A549 cells.

The study also found that PJME has the ability to activate ferroptosis pathways, as evidenced by elevated reactive oxygen species (ROS) generation, changes in the levels of antioxidant markers (MDA and GSH), and decreased expression of SLC7A11 and GPX4. The results of the present study clearly showed that PJME inhibited the proliferation of A549 cells and induced ferroptosis by reducing the expression of the important targets SLC7A11 and GPX4. Further research is necessary to fully understand the clinical efficacy of PJME before it can be investigated as supplemental or adjuvant therapy for lung cancer.

Menopause symptoms may be distressing, especially when they appear at a time when women are expected to play significant responsibilities in society. Numerous biological systems are influenced by the hormonal changes that start during the menopausal transition. This review attempts to decipher the complex relationship between obesity, menopause, and depression, citing some recent longitudinal and cross-sectional studies. Additionally, this study provides a summary of the different phytoestrogens, their sources, and probable mechanisms of action in addition to available therapeutic alternatives.

For this review purpose, the authors have gone through a vast number of articles from various scientific databases like PubMed, Google Scholar, and Web of Science.

It is becoming clear that the physiological basis for these menopausal symptoms is complicated and connected to estrogen deficiency, but not alone. Other hormones like FSH, LH, progesterone, and inhibin B are the major ones that are both directly and indirectly responsible for most of the menopausal symptoms. Numerous longitudinal and cross-sectional studies have found a direct relationship between the incidence of menopause and depression as well as obesity. Phytoestrogens like stilbene, lignans, isoflavone, and coumestan have been reported to be the alternatives to synthetic estrogen with lesser side effects, as reported in various studies.

The complex relationship between depression, menopause, and obesity presents a complex obstacle to women's health and overall well-being. There might be a lot of promising prospects for revolutionary advancements in women's health during the menopausal stage in the future. Promising drug development that targets not just one but also the three conditions -obesity, menopause, and depression - as well as more thorough research are needed to improve the healthcare system for women who suffer from these conditions.

Atherosclerosis is a complex cardiovascular disease often associated with mitochondrial dysfunction, which can lead to various cellular and metabolic abnormalities. Within the mitochondrial genome, specific mutations have been implicated in contributing to mitochondrial dysfunction. Atherosclerosis-associated m.15059G>A mutation has been of particular interest due to its potential role in altering mitochondrial function and cellular health.

This study aims to investigate the role of the atherosclerosis-associated m.15059G>A mutation in the development of mitochondrial dysfunction in monocyte-like cells.

Monocyte-like cytoplasmic hybrid cell line TC-HSMAM1, which contains the m.15059G>A mutation in mtDNA, was used. The MitoCas9 vector was utilized to eliminate mtDNA copies carrying the m.15059G>A mutation from TC-HSMAM1 cybrids. Mitochondrial membrane potential, generation of reactive oxygen species, and lipid peroxidation levels were assessed using flow cytometry. Cellular reduced glutathione levels were assessed using the confocal microscopy. The oxygen consumption rate was measured using polarographic oxygen respirometry.

The elimination of the m.15059G>A mutation resulted in a significant increase in mitochondrial membrane potential and improved mitochondrial efficiency while also causing a decrease in the generation of reactive oxygen species, lipid peroxidation, as well as cellular bioenergetic parameters, such as proton leak and non-mitochondrial oxygen consumption. At the same time, no changes were found in the intracellular antioxidant system after the mitochondrial genome editing.

The presence of the m.15059G>A mutation contributes to mitochondrial dysfunction by reducing mitochondrial membrane potential, increasing the generation of reactive oxygen species and lipid peroxidation, and altering mitochondrial bioenergetics. Elimination of the mtDNA containing atherogenic mutation leads to an improvement in mitochondrial function.

Aspergillus fumigatus, a significant fungal pathogen, poses a threat to human health, especially in immunocompromised individuals. Addressing the need for novel antifungal strategies, this study employs virtual screening to identify potential inhibitors of Fructosamine oxidase, also known as Amadoriase II, a crucial enzyme in A. fumigatus (PDB ID: 3DJE).

Virtual screening of 81,197 triazole derivatives was subjected to computational analysis, aiming to pinpoint molecules with high binding affinity to the active site of Fructosamine oxidase. Subsequently, an in-depth ADMET analysis assessed the pharmacokinetic properties of lead compounds, ensuring their viability for further development. Molecular dynamics simulations were performed to evaluate the stability of top-ranked compounds over time.

The results unveil a subset of triazole derivatives displaying promising interactions, suggesting their potential as inhibitors for further investigation.

This approach contributes to the development of targeted antifungal agents, offering a rational starting point for experimental validation and drug development against Aspergillus fumigatus infections.