PHARMACEUTICALS (ISSN 1424-8247) 是药物化学和相关药物科学的国际科学期刊。

PHARMACEUTICALS is an international scientific journal that focuses on the field of pharmaceutical chemistry and related drug sciences, dedicated to publishing high-quality research findings.

《Pharmaceuticals》是一本国际科学期刊，专注于药物化学及相关药物科学领域，致力于发表高质量的研究成果。

Pharmaceuticals

Kynurenic acid (KYNA) is an endogenous compound with a multidirectional effect. It possesses antiapoptotic, anti-inflammatory, and antioxidative properties that may be beneficial in the treatment of corneal injuries. Moreover, KYNA has been used successfully to improve the healing outcome of skin wounds. The aim of the present study is to evaluate the effects of KYNA on corneal and conjunctival cells in vitro and the re-epithelization of corneal erosion in rabbits in vivo. Normal human corneal epithelial cell (10.014 pRSV-T) and conjunctival epithelial cell (HC0597) lines were used. Cellular metabolism, cell viability, transwell migration, and the secretion of IL-1β, IL-6, and IL-10 were determined. In rabbits, after corneal de-epithelization, eye drops containing 0.002% and 1% KYNA were applied five times a day until full recovery. KYNA decreased metabolism but did not affect the proliferation of the corneal epithelium. It decreased both the metabolism and proliferation of conjunctival epithelium. KYNA enhanced the migration of corneal but not conjunctival epithelial cells. KYNA reduced the secretion of IL-1β and IL-6 from the corneal epithelium, leaving IL-10 secretion unaffected. The release of all studied cytokines from the conjunctival epithelium exposed to KYNA was unchanged. KYNA at higher concentration accelerated the healing of the corneal epithelium. These favorable properties of KYNA suggest that KYNA containing topical pharmaceutical products can be used in the treatment of ocular surface diseases.

Anna Matysik-Woźniak

Waldemar A. Turski

Monika Turska

Roman Paduch

Mirosław Łańcut

Paweł Piwowarczyk

Mirosław Czuczwar

Robert Rejdak

Kynurenic Acid Accelerates Healing of Corneal Epithelium In Vitro and In Vivo

Background: Ergothioneine (ERGO) is a unique antioxidant and a rare amino acid available in fungi and various bacteria but not in higher plants or animals. Substantial research data indicate that ERGO is a physiological antioxidant cytoprotectant. Different from other antioxidants that need to breach the blood-brain barrier to enter the brain parenchyma, a specialized transporter called OCTN1 has been identified for transporting ERGO to the brain. Purpose: To assess whether consumption of ERGO can prevent the progress of Alzheimer's disease (AD) on young (4-month-old) 5XFAD mice. Methods and materials: Three cohorts of mice were tested in this study, including ERGO-treated 5XFAD, non-treated 5XFAD, and WT mice. After the therapy, the animals went through various behavioral experiments to assess cognition. Then, mice were scanned with PET imaging to evaluate the biomarkers associated with AD using [11C]PIB, [11C]ERGO, and [18F]FDG radioligands. At the end of imaging, the animals went through cardiac perfusion, and the brains were isolated for immunohistology. Results: Young (4-month-old) 5XFAD mice did not show a cognitive deficit, and thus, we observed modest improvement in the treated counterparts. In contrast, the response to therapy was clearly detected at the molecular level. Treating 5XFAD mice with ERGO resulted in reduced amyloid plaques, oxidative stress, and rescued glucose metabolism. Conclusions: Consumption of high amounts of ERGO benefits the brain. ERGO has the potential to prevent AD. This work also demonstrates the power of imaging technology to assess response during therapy.

Clayton A. Whitmore

Justin R. Haynes

William J. Behof

Adam J. Rosenberg

Mohammed N. Tantawy

Brian C. Hachey

Brian E. Wadzinski

Benjamin W. Spiller

Todd E. Peterson

Krista C. Paffenroth

Fiona E. Harrison

Robert B. Beelman

Printha Wijesinghe

Joanne A. Matsubara

Wellington Pham

Longitudinal Consumption of Ergothioneine Reduces Oxidative Stress and Amyloid Plaques and Restores Glucose Metabolism in the 5XFAD Mouse Model of Alzheimer’s Disease

This study aims to determine the antiobesity activity of Calophyllum soulattri leaves extract (CSLE) on high fat diet-fed rats (HFD) and to predict the molecular docking and pharmacokinetics of selected compounds of Calophyllum soulattri to fat mass and obesity-associated protein (FTO). Daily body weight, organ, carcass fat (renal and anal), body mass index, total cholesterol, and total triglyceride levels were observed after CSLE was given orally for 50 days. Furthermore, body mass index of a CSLE dose of 50 mg/kgbw, 100 mg/kgbw and orlistat (120 mg/kgbw) group are 0.68, 0.57 and 0.52, respectively. The total body weight of the CLSE dose of 100 mg/kgbw group showed the lowest percentage change, followed by a CLSE dose of 50 mg/kgbw compared to the normal and positive control group. The carcass fat index of CSLE dose of 100 mg/kgbw was not significantly different from orlistat, which was in line with its total cholesterol level and triglyceride (p < 0.05). The binding affinity of selected compounds from Calophyllum soulattri (friedelin, caloxanthone B, macluraxanthone, stigmasterol, trapezifolixanthone, dombakinaxanthone, and brasixanthone B) to FTO are -8.27, -9.74, -8.48, -9.34, -8.85, -8.68 and -9.39 kcal/mol, which are better than that of orlistat at -4.80 kcal/mol. The molecular dynamics simulation showed that the interaction between Caloxanthone B compounds and obesity receptors was relatively stable. Lipinski's rule determined the absorption percentage of all compounds above 90% with good drug-likeness. The results showed the potential of CSLE as an antiobesity drug candidate.

Inarah Fajriaty

Hariyanto Ih

Irda Fidrianny

Neng Fisheri Kurniati

Muhammad Andre Reynaldi

I Ketut Adnyana

Rommy Rommy

Fransiska Kurniawan

Daryono Hadi Tjahjono

In Vivo Pharmacodynamics of Calophyllum soulattri as Antiobesity with In Silico Molecular Docking and ADME/Pharmacokinetic Prediction Studies

This study aimed to explore the mechanism through which Tibetan medicine Liuwei Muxiang (LWMX) pills acts against colorectal cancer (CRC). We firstly retrieved the active ingredients and the correlated targets of LWMX pills from public databases. The CRC-related targets were determined through bioinformatic analysis of a public CRC dataset. By computing the intersection of the drug-specific and disease-related targets, LWMX pill–CRC interaction networks were constructed using the protein–protein interaction (PPI) method and functional enrichment analysis. Subsequently, we determined the hub genes using machine learning tools and further verified their critical roles in CRC treatment via immune infiltration analysis and molecular docking studies. We identified 81 active ingredients in LWMX pills with 614 correlated targets, 1877 differentially expressed genes, and 9534 coexpression module genes related to CRC. A total of 5 target hub genes were identified among the 108 intersecting genes using machine learning algorithms. The immune infiltration analysis results suggested that LWMX pills could affect the CRC immune infiltration microenvironment by regulating the expression of the target hub genes. Finally, the molecular docking outcomes revealed stable binding affinity between all target hub proteins and the primary active ingredients of LWMX pills. Our findings illustrate the anti-CRC potential and the mechanism of action of LWMX pills and provide novel insights into multitarget medication for CRC treatment.

Shaochong Qi

Xinyu Liang

Zijing Wang

Haoran Jin

Liqun Zou

Jinlin Yang

Potential Mechanism of Tibetan Medicine Liuwei Muxiang Pills against Colorectal Cancer: Network Pharmacology and Bioinformatics Analyses

Furin cleavage of the SARS-CoV-2 spike protein results in a polybasic terminal sequence termed the C-end rule (CendR), which is responsible for the binding to neuropilin 1 (NRP1), enhancing viral infectivity and entry into the cell. Here we report the identification of 20 small-molecule inhibitors that emerged from a virtual screening of nearly 950,000 drug-like compounds that bind with high probability to the CendR-binding pocket of NRP1. In a spike NRP1 binding assay, two of these compounds displayed a stronger inhibition of spike protein binding to NRP1 than the known NRP1 antagonist EG00229, for which the inhibition of the CendR peptide binding to NRP1 was also experimentally confirmed. These compounds present a good starting point for the design of small-molecule antagonists against the SARS-CoV-2 viral entry.

Anja Kolarič

Marko Jukič

Urban Bren

Novel Small-Molecule Inhibitors of the SARS-CoV-2 Spike Protein Binding to Neuropilin 1

The p53 protein has attracted huge research interest over several decades due to its role as one of the most important tumor suppressors in mammals, which orchestrates a synchronous response from normal cells in the body to various forms of stress. The diverse cellular activities of the p53 protein are regulated mainly via its post-translational modifications (PTMs). PTMs affect p53 on several levels: at the level of the assembly of tetrameric complexes on DNA to transactivate its target genes, at the level of the assembly of tetrameric complexes on DNA to transactivate its target genes; at the level of proteolysis in the absence of stress; and on the contrary, at the level of augmented protein stability in response to stress signals. Disruptions in these regulatory mechanisms can lead to deviations from normal cellular function, boosting tumor initiation and progression. Conversely, targeted interventions in these pathways could prove beneficial for the development of antitumor therapies. Advancing our understanding of p53 modifiers and the proteins involved in its regulation equips researchers with an expanded toolkit for studying cellular processes and for developing biologically active molecules that influence p53-mediated responses.

Tatiana A. Grigoreva

Angelina A. Romanova

Vyacheslav G. Tribulovich

Nikolay B. Pestov

Ruslan A. Oganov

Diana K. Kovaleva

Tatyana V. Korneenko

Nickolai A. Barlev

p53: The Multifaceted Roles of Covalent Modifications in Cancer

p53：共价修饰在癌症中的多方面作用

Background: A potential strategy to maintain the efficacy of carbapenems against carbapenemase-producing Klebsiella pneumoniae (CPKP) is their combination with carbapenemase inhibitors. To address these issues, the effectiveness of a novel combination of meropenem with avibactam against CPKP was studied. Additionally, the applicability of a pharmacokinetically-based approach to antibiotic/inhibitor minimum inhibitory concentration (MIC) determinations to better predict efficacy was examined. Methods: CPKP strains were exposed to meropenem alone or in combination with avibactam in an in vitro hollow-fiber infection model. Treatment effects were correlated with simulated antibiotic and antibiotic/inhibitor combination ratios of the area under the concentration–time curve (AUC) to the MIC (AUC/MIC). All MICs were determined at standard and at high inocula; combination MICs were determined using the conventional approach with fixed avibactam concentration or using the pharmacokinetic (PK)-based approach with a fixed meropenem-to-avibactam concentration ratio, equal to the respective drug therapeutic AUC ratios. Results: Meropenem alone was not effective even against a “susceptible” CPKP strain. The addition of avibactam significantly improved both meropenem MICs and its effectiveness. The effects of meropenem alone and in combination with avibactam (merged data) correlated well with AUC/MIC ratios only when MICs were determined at high inocula and using the PK-based approach (r2 0.97); the correlation was worse with the conventional approach (r2 0.73). Conclusions: The effectiveness of meropenem/avibactam against CPKP is promising. A single “effect–AUC/MIC” relationship useful for predicting meropenem efficacy (alone or in combination with avibactam) was obtained using MICs at high inocula and combination MICs determined using a PK-based approach.

Elena N. Strukova

Yury A. Portnoy

Maria V. Golikova

Stephen H. Zinner

In Vitro Dynamic Model Evaluation of Meropenem Alone and in Combination with Avibactam Against Carbapenemase-Producing Klebsiella pneumoniae

碳青霉烯酶产生肺炎克雷伯菌对美罗培南单独及与阿维巴坦联合使用的体外动态模型评估

Medicinal plants are increasingly being explored due to their possible pharmacological properties and minimal adverse effects. However, low bioavailability and stability often limit efficacy, necessitating high oral doses to achieve therapeutic levels in the bloodstream. Mesoporous silica nanoparticles (MSNs) offer a potential solution to these limitations. Due to their large surface area, substantial pore volume, and ability to precisely control pore size. MSNs are also capable of efficiently incorporating a wide range of therapeutic substances, including herbal plant extracts, leading to potential use for drug containment and delivery systems. Therefore, this review aimed to discuss and summarize the successful developments of herbal plant extracts loaded into MSN, focusing on preparation, characterization, and the impact on efficacy. Data were collected from publications on Scopus, PubMed, and Google Scholar databases using the precise keywords “mesoporous silica nanoparticle” and “herbal extract”. The results showed that improved phytoconstituent bioavailability, modified release profiles, increased stability, reduced dose and toxicity are the primary benefits of this method. This review offers insights on the significance of integrating MSNs into therapeutic formulations to improve pharmacological characteristics and effectiveness of medicinal plant extracts. Future prospects show favorable potential for therapeutic applications using MSNs combined with herbal medicines for clinical therapy.

Diah Lia Aulifa

Bunga Amarilis

Luthfia Nur Ichsani

Devita Salsa Maharani

Ayunda Myela Shabrina

Hanifah Hanifah

Rizky Prasiska Wulandari

Agus Rusdin

Laila Subra

Arif Budiman

A Comprehensive Review: Mesoporous Silica Nanoparticles Greatly Improve Pharmacological Effectiveness of Phytoconstituent in Plant Extracts

综合评述：介孔二氧化硅纳米颗粒显著提升植物提取物中植物成分的药理效果

Background/Objectives: Vitamin D receptor (VDR) agonists are commonly used in clinical practice for their roles in calcium regulation and potential benefits in various diseases. However, their safety profiles, particularly for compounds available as food supplements, remain underexplored in real-world settings. This study aimed to analyze the safety profiles of VDR agonists using the EudraVigilance database, focusing on adverse drug reactions (ADRs) reported between 1 January 2004 and 23 June 2024. Methods: Data for ten VDR agonists were collected, de-duplicated, and analyzed to identify specific safety signals. Risk factors for specific ADRs were assessed using multiple logistic regression. Results: This study analyzed 5,369,581 reports in the EudraVigilance system, from which 17,947 reports (0.33%) involving 80,050 ADRs were linked to VDR agonists. The most-reported drugs were cholecalciferol (12,944 cases) and calcitriol (1355 cases). Serious ADRs were more prevalent with paricalcitol, alfacalcidol, and calcitriol than with cholecalciferol (p &lt; 0.05). Hypercalcemia was a hallmark ADR for all VDR agonists, with the highest risk linked to dihydrotachysterol (ROR = 5668; 95%CI = 3332 to 9641; p &lt; 0.0001), alfacalcidol (ROR = 965.7; 95%CI = 843.6 to 1106; p &lt; 0.0001), and calcitriol (ROR = 726.0; 95%CI = 634.6 to 830.5; p &lt; 0.0001). Logistic regression highlighted dehydration, overdose, and concomitant administration of calcium salts as major predictors of hypercalcemia. The co-administration of multiple VDR agonists was also found to increase hypercalcemia risk. However, the disproportionality analysis showed that only active VDR agonists (e.g., calcitriol, alfacalcidol) were associated with severe complications like renal and urinary disorders and cardiac issues due to hypercalcemia. Natural precursors (cholecalciferol, ergocalciferol) were more often linked to non-calcemic ADRs such as gastrointestinal symptoms, which were more prevalent in infants and children compared to adults. Conclusions: The safety profiles of VDR agonists differ significantly between compounds. Active derivatives require close monitoring for serious calcemia-related complications, whereas cholecalciferol is associated with less severe ADRs, primarily in at-risk populations. These findings highlight the need for targeted safety monitoring and further research into the real-world uses of VDR agonists.

Zsolt Gáll

Melinda Kolcsar

Comparative Analyses of the Safety Profiles of Vitamin D Receptor Agonists: A Pharmacovigilance Study Based on the EudraVigilance Database

维生素D受体激动剂安全性特征的比较分析：基于EudraVigilance数据库的药物警戒研究

Background: Non-insulin-dependent diabetes mellitus, or type 2 diabetes, is one of the diseases of greatest concern worldwide, and research into natural compounds that are capable of regulating glycemia and insulin resistance is therefore gaining importance. In the preclinical stages, Caenorhabditis elegans is considered a promising in vivo model for research into this disease. Most studies have been carried out using daf-2 mutant strains and observing changes in their phenotype rather than directly measuring the effects within the worms. Methods: We evaluated the in vitro α-glucosidase inhibition of two oral formulations of Origanum vulgare before and after a simulated gastrointestinal digestion process. After confirming this activity, we developed a method to measure α-glucosidase inhibition in vivo in the C. elegans wild-type strain. Results: The crude extract showed a similar IC50 value to that of acarbose (positive control), before and after gastrointestinal digestion. Formulation 1 also showed no differences with the positive control after digestion (111.86 ± 1.26 vs. 110.10 ± 1.00 µL/mL; p = 0.282). However, formulation 2 showed a higher hypoglycemic activity (59.55 ± 0.85 µL/mL; p &lt; 0.05). The IC50 values obtained in the in vivo assays showed results that correlated well with the in vitro results, so the proposed new method of direct quantification of the in vivo activity seems suitable for directly quantifying the effects of this inhibition without the need to measure changes in the phenotype. Conclusion: A novel, simple and reliable method has been developed to directly determine pharmacological activities in an in vivo model of wild-type C. elegans. This allows the hypoglycemic activity to be directly attributed to in vivo treatment without quantifying phenotypic changes in mutant strains that may arise from other effects, opening the door to a simple analysis of in vivo pharmacological activities.

María Pilar de Torre

José Luis Vizmanos

Rita Yolanda Cavero

María Isabel Calvo

A Novel In Vivo Method Using Caenorhabditis elegans to Evaluate α-Glucosidase Inhibition by Natural Products for Type 2 Diabetes Treatment

一种利用秀丽隐杆线虫体内方法评估天然产物对2型糖尿病治疗的α-葡萄糖苷酶抑制作用的新方法

Abbreviation
Journal Impact	4.41
Quartiles(Global)	PHARMACOLOGY & PHARMACY(Q1)

Publication Information	Publisher: Multidisciplinary Digital Publishing Institute (MDPI)，Publishing cycle: ，Journal Type: journal，Open Access Journals: Yes
Basic data	Year of publication: 2009，Proportion of original research papers: 79.07%，Self Citation Rate:4.70%， Gold OA Rate: 99.70%
Journal Fees	$Details
Average review cycle	网友分享经验：6 Weeks

Pharmaceuticals

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