Pharmaceuticals

23 pages, 1895 KiB

Open AccessArticle

Polyphenolic Composition, Mineral Profile, and Biological Activities in Different Organs of Alpine Woundwort—Insights into Antioxidant and Enzyme Inhibitory Potential

by Sabina Lachowicz-Wiśniewska, Ireneusz Ochmian, Jan Oszmiański, Rafał Wiśniewski, Małgorzata Bernatek, Paweł Rubiński and Daniela De Vita

Pharmaceuticals 2025, 18(5), 674; https://doi.org/10.3390/ph18050674 (registering DOI) - 1 May 2025

Abstract

Background: Stachys alpina is a medicinal plant from the Lamiaceae family whose biological potential remains poorly explored. Methods: The aim of this study was to comprehensively assess the pol-yphenol profile, macro- and microelement composition, and the antioxidant, an-ti-diabetic, and anti-obesity activities of [...] Read more.

Background: Stachys alpina is a medicinal plant from the Lamiaceae family whose biological potential remains poorly explored. Methods: The aim of this study was to comprehensively assess the pol-yphenol profile, macro- and microelement composition, and the antioxidant, an-ti-diabetic, and anti-obesity activities of various plant organs (leaves, flowers, stems, and roots). Results: The leaves and flowers exhibited the highest concentration of phenolic compounds, while anthocyanins were detected exclusively in the flowers (215.05 mg/100 g dry matter (dm)) and constituted 3% of the total polyphenols. Verbas-coside and chlorogenic acid were the most abundant polyphenols, reaching 4618.88 and 3277.83 mg/ 100 g dm in the leaves. The highest ABTS and FRAP scavenging activity was observed in leaves (19.30 and 7.62 mmol TE/g dm, respectively). Principal component analysis demonstrated a strong correlation between polyphenol content and antioxidant activity (ABTS-r= 0.87 and FRAP-r = 0.90), which was further confirmed by Pearson’s correlation coefficients. The study also highlighted the significant impact of mineral composition on biological activity—calcium and magnesium dominated in stems (10,100 and 3900 mg/kg) and in roots (9200 and 3100 mg/kg), supporting the functioning of an-tioxidant enzymes, while zinc and manganese in leaves (89.43 and 155.33 mg/kg) con-tributed to intense metabolic processes. Conclusions: S. aplina could serve as a valuable source of natural antioxidants and enzyme inhibitors associated with glucose and lipid metabolism, suggesting its promising application in the prevention and management of metabolic disorders.. Full article

(This article belongs to the Special Issue Natural Products in Drug Discovery in the 21st Century: Challenges and Opportunities)

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18 pages, 4947 KiB

Open AccessArticle

Anticonvulsant Profiles of Three Hemorphin-4 Analogs with Rhodamine B in Mice

by Jana Tchekalarova, Miroslav Rangelov, Ivan Iliev, Nadezhda Todorova, Tsveta Stoyanova, Lian Nedelchev and Petar Todorov

Pharmaceuticals 2025, 18(5), 673; https://doi.org/10.3390/ph18050673 (registering DOI) - 1 May 2025

Abstract

Background/Objectives: Hemorphins, considered to be bioactive atypical oligopeptides, are products of hemoglobin metabolism. Recently, our team reported the synthesis and characterization of three N-modified analogs of hemorphin-4 (H4) with rhodamine B (Rh). In the present study, the Rh-1, Rh-2, and Rh-3 compounds [...] Read more.

Background/Objectives: Hemorphins, considered to be bioactive atypical oligopeptides, are products of hemoglobin metabolism. Recently, our team reported the synthesis and characterization of three N-modified analogs of hemorphin-4 (H4) with rhodamine B (Rh). In the present study, the Rh-1, Rh-2, and Rh-3 compounds were intracerebroventricularly infused at doses of 1, 2.5, 5, and 10 µg/5 µL, respectively, and evaluated for their antiseizure activity in 6-Hz and maximal electroshock (MES) tests and in a pentylenetetrazol (PTZ)-induced kindling model in mice. Phenytoin and diazepam were used as the reference drugs. The role of opioid receptors (ORs) underlying their mechanism of action was also evaluated in silico and pharmacologically. Results: The three Rh-H4 compounds showed a good safety profile at a concentration of 100 µg/mL in the mouse embryonic fibroblasts. They suppressed psychomotor seizures and seizure spreading as follows: Rh-1 at doses of 5 and 10 µg/5 µL, Rh-2 at the highest dose, and Rh-3 at doses of 1–10 µg/5 µL, respectively. Administered at doses of 5 µg/5 µL (Rh-1 and Rh-3) and 10 µg/5 µL (Rh-2), the compounds suppressed clonic seizures in the kindled mice comparable to the reference drug diazepam. A combination of selective delta (DOR), kappa (KOR), and mu (MOR) OR antagonists with the highest doses of the Rh-1, Rh-2, and Rh-3 compounds was used to elucidate the possible role of ORs in the underlying mechanism related to their protective activity against seizure spread. Only the selective DOR antagonist, natrindole, suppressed the effect of the Rh-1 peptide analog on seizures. The OR antagonist naloxone prevented the antiseizure activity of Rh-1 in the kindled mice. The results of docking analysis also showed the model-specific interaction of the three Rh-H4 compounds with the OR. Conclusions: Our results suggest that the antiseizure activity of Rh-1 is mediated by the OR, and in particular by the DOR, while the mechanism underlying the antiseizure effect of Rh-3 is more complex and may involve other receptors. Full article

(This article belongs to the Special Issue Pharmacology and Mechanism of Action of Peptides in the Brain)

23 pages, 1222 KiB

Open AccessArticle

Lanthanides-Based Nanoparticles Conjugated with Rose Bengal for FRET-Mediated X-Ray-Induced PDT

by Batoul Dhaini, Joël Daouk, Hervé Schohn, Philippe Arnoux, Valérie Jouan-Hureaux, Albert Moussaron, Agnès Hagege, Mathilde Achard, Samir Acherar, Tayssir Hamieh and Céline Frochot

Pharmaceuticals 2025, 18(5), 672; https://doi.org/10.3390/ph18050672 (registering DOI) - 1 May 2025

Abstract

In order to find a good candidate for Förster Resonance Energy Transfer (FRET)-mediated X-ray-induced photodynamic therapy (X-PDT) for the treatment of cancer, lanthanide (Ln)-based AGuIX nanoparticles (NPs) conjugated with Rose Bengal (RB) as a photosensitizer (PS) were synthesized. X-PDT overcomes the problem of [...] Read more.

In order to find a good candidate for Förster Resonance Energy Transfer (FRET)-mediated X-ray-induced photodynamic therapy (X-PDT) for the treatment of cancer, lanthanide (Ln)-based AGuIX nanoparticles (NPs) conjugated with Rose Bengal (RB) as a photosensitizer (PS) were synthesized. X-PDT overcomes the problem of the poor penetration of visible light into tissues, which limits the efficacy of PDT in the treatment of deep-seated tumors. It is essential to optimize FRET efficiency by maximizing the overlap integral between donor emission and acceptor absorption and lengthening the duration of the donor emission. In this study, we optimized energy transfer between a scintillator (Sc) as a donor and a PS as an acceptor. Terbium (Tb) and Gadolinium (Gd) as Scs and Rose RB as a PS were chosen. The study of energy transfer between Tb, Gd and RB in solution and chelated on AGuIX NPs proved to be FRET-like. RB was conjugated directly onto AGuIX NPs (i.e., AGuIX Ln@RB), and the use of a spacer arm (i.e., AGuIX Ln@spacer arm-RB) increased FRET efficiency. Singlet oxygen production by these NPs was observed under UV–visible illumination and X-ray irradiation. The in vitro bioassay demonstrated 52% cell death of U-251MG derived from human malignant glioblastoma multiforme at a concentration of 1 μM RB after illumination and irradiation (2 Gy, 320 kV, 10 mA, 3 Gy/min at 47 cm). In addition, the RB-coupled NRP-1-targeting peptide (i.e., K(RB)DKPPR) was conjugated onto AGuIX NPs by a thiol-maleimide click chemistry reaction, and an affinity in the nM range was observed. Full article

(This article belongs to the Special Issue Photodynamic Therapy: 3rd Edition)

19 pages, 1602 KiB

Open AccessReview

Advances in Targeted Autophagy Modulation Strategies to Treat Cancer and Associated Treatment-Induced Cardiotoxicity

by Lauren A. Ling, Asma Boukhalfa, Andrew H. Kung, Vicky K. Yang and Howard H. Chen

Pharmaceuticals 2025, 18(5), 671; https://doi.org/10.3390/ph18050671 (registering DOI) - 1 May 2025

Abstract

Autophagy, an evolutionarily conserved process, plays an important role in cellular homeostasis and human diseases. Cardiovascular dysfunction, which presents during cancer treatment or in cancer-free individuals years after treatment, is a growing clinical challenge. Millions of cancer survivors and patients face an unpredictable [...] Read more.

Autophagy, an evolutionarily conserved process, plays an important role in cellular homeostasis and human diseases. Cardiovascular dysfunction, which presents during cancer treatment or in cancer-free individuals years after treatment, is a growing clinical challenge. Millions of cancer survivors and patients face an unpredictable risk of developing cardiotoxicity. Cardiotoxicity due to cancer treatment, as well as cancer progression, has been linked to autophagy dysregulation. Modulating autophagy has been further proposed as a therapeutic treatment for both cancer and cardiovascular disorders. The safe and effective use of autophagy modulation as a cardioprotective strategy during cancer treatment especially requires careful consideration and experimentation to minimize the impact on cancer treatment. We focus here on recent advances in targeted autophagy modulation strategies that utilize interdisciplinary approaches in biomedical sciences and are potentially translatable to treat cardiotoxicity and improve cancer treatment outcomes. This review highlights non-small molecule autophagy modulators to enhance targeted therapy, nanomedicine for autophagy modulation and monitoring, and in vitro models and future experiments needed to bring novel autophagy discoveries from basic research to clinical translation. Full article

(This article belongs to the Special Issue Emerging Therapeutics for the Prevention of Chemotherapy-Induced Cardiotoxicity: Advances and Future Perspectives)

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24 pages, 650 KiB

Open AccessReview

Exploring the Protective Effects of Traditional Antidiabetic Medications and Novel Antihyperglycemic Agents in Diabetic Rodent Models

by Cosmin Gabriel Tartau, Ianis Kevyn Stefan Boboc, Liliana Mititelu-Tartau, Maria Bogdan, Beatrice Rozalina Buca, Liliana Lacramioara Pavel and Cornelia Amalinei

Pharmaceuticals 2025, 18(5), 670; https://doi.org/10.3390/ph18050670 (registering DOI) - 1 May 2025

Abstract

Type 2 Diabetes (T2D) is a complex metabolic disorder that affects multiple organs, leading to severe complications in the pancreas, kidneys, liver, and heart. Prolonged hyperglycemia, along with oxidative stress and chronic inflammation, plays a crucial role in accelerating tissue damage, significantly increasing [...] Read more.

Type 2 Diabetes (T2D) is a complex metabolic disorder that affects multiple organs, leading to severe complications in the pancreas, kidneys, liver, and heart. Prolonged hyperglycemia, along with oxidative stress and chronic inflammation, plays a crucial role in accelerating tissue damage, significantly increasing the risk of diabetic complications such as nephropathy, hepatopathy, and cardiovascular disease. This review evaluates the protective effects of various antidiabetic treatments on organ tissues affected by T2D, based on findings from experimental animal models. Metformin, a first-line antidiabetic agent, has been widely recognized for its ability to reduce inflammation and oxidative stress, thereby mitigating diabetes-induced organ damage. Its protective role extends beyond glucose regulation, offering benefits such as improved mitochondrial function and reduced fibrosis in affected tissues. In addition to traditional therapies, new classes of antidiabetic drugs, including sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists not only improve glycemic control but also exhibit nephroprotective and cardioprotective properties by reducing glomerular hyperfiltration, oxidative stress, and inflammation. Similarly, GLP-1 receptor agonists have been associated with reduced hepatic steatosis and enhanced cardiovascular function. Preclinical studies suggest that tirzepatide, a dual GLP-1/gastric inhibitory polypeptide receptor agonist may offer superior metabolic benefits compared to conventional GLP-1 agonists by improving β-cell function, enhancing insulin sensitivity, and reducing fatty liver progression. Despite promising preclinical results, differences between animal models and human physiology pose a challenge. Further clinical research is needed to confirm these effects and refine treatment strategies. Future T2D management aims to go beyond glycemic control, emphasizing organ protection and long-term disease prevention. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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14 pages, 719 KiB

Open AccessArticle

Repositioning FDA-Approved Sulfonamide-Based Drugs as Potential Carbonic Anhydrase Inhibitors in Trypanosoma cruzi: Virtual Screening and In Vitro Studies

by Eyra Ortiz-Pérez, Adriana Moreno-Rodríguez, Timoteo Delgado-Maldonado, Jessica L. Ortega-Balleza, Alonzo González-González, Alma D. Paz-González, Karina Vázquez, Guadalupe Avalos-Navarro, Simone Giovannuzzi, Claudiu T. Supuran and Gildardo Rivera

Pharmaceuticals 2025, 18(5), 669; https://doi.org/10.3390/ph18050669 (registering DOI) - 1 May 2025

Abstract

Background/Objectives: α-carbonic anhydrase (α-TcCA) has emerged as a promising drug target in T. cruzi, the causative agent of Chagas disease in the Americas. Sulfonamides, known inhibitors of CAs, bind to the zinc ion on the enzyme’s active site. This study proposes the [...] Read more.

Background/Objectives: α-carbonic anhydrase (α-TcCA) has emerged as a promising drug target in T. cruzi, the causative agent of Chagas disease in the Americas. Sulfonamides, known inhibitors of CAs, bind to the zinc ion on the enzyme’s active site. This study proposes the repositioning of sulfonamide-based drugs to identify new trypanocidal agents. Method: Ligand-based virtual screening and molecular docking analysis were performed on FDA-approved drugs targeting α-TcCA. These compounds were evaluated in vitro and ex vivo against the A1 and NINOA strains, followed by enzymatic assays. Results: Four sulfonylureas were selected: glimepiride (Glim), acetohexamide (Ace), gliclazide (Glic), and tolbutamide (Tol). Ace and Tol had half-maximal inhibitory concentration (IC₅₀) values similar or better than reference drugs against the NINOA strain in the epimastigote and trypomastigote stages, while Glic and Glim had the highest activity against the A1 strain (epimastigotes and amastigotes). Notably, Ace had the highest trypanocidal activity against all stages in NINOA, with IC₅₀ values of 6.5, 46.5, and 46 μM for epimastigotes, trypomastigotes, and amastigotes, respectively. Additionally, Ace inhibited α-TcCA with K_I = 5.6 μM, suggesting that its trypanocidal effect is associated to the enzyme inhibition. Conclusions: This study supports the repositioning of FDA-approved sulfonamide-based hypoglycaemic agents as trypanocidal compounds. Future studies should focus on structural modifications to improve selectivity. Integrating docking, parasitological, and enzymatic data is crucial for optimizing drug candidates for Chagas disease. Full article

(This article belongs to the Special Issue Drug Discovery and Development for Parasitic Diseases)

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19 pages, 538 KiB

Open AccessSystematic Review

The Efficacy and Safety of Tirzepatide in Patients with Diabetes and/or Obesity: Systematic Review and Meta-Analysis of Randomized Clinical Trials

by Ligang Liu, Hekai Shi, Merilyn Xie, Yuxiao Sun and Nahata Milap

Pharmaceuticals 2025, 18(5), 668; https://doi.org/10.3390/ph18050668 (registering DOI) - 30 Apr 2025

Abstract

Background: Obesity and type 2 diabetes (T2D) are major public health concerns. Tirzepatide has shown promise in recent clinical trials. This systematic review and meta-analysis aim to evaluate the efficacy and safety of tirzepatide in adults with obesity or type 2 diabetes, compared [...] Read more.

Background: Obesity and type 2 diabetes (T2D) are major public health concerns. Tirzepatide has shown promise in recent clinical trials. This systematic review and meta-analysis aim to evaluate the efficacy and safety of tirzepatide in adults with obesity or type 2 diabetes, compared to placebo, GLP-1 receptor agonists (GLP-1 RAs), and insulin. Method: PubMed, Embase, and the Cochrane Library were searched on 17 January 2024, focusing on phase II and III randomized controlled trials (RCTs). We included studies involving adults with T2D or obesity, comparing tirzepatide to placebo, GLP-1 RAs, or insulin. The primary outcomes were the proportion of participants achieving ≥5%, ≥10%, and ≥15% weight loss targets. Secondary outcomes included changes in body weight, waist circumference, HbA1c levels, and blood pressure. Safety outcomes focused on adverse event rates. Meta-analyses were performed, and risk of bias was assessed using the Cochrane Risk-of-Bias tool version 2. Results: Fourteen RCTs involving 14,713 patients were included. Tirzepatide significantly increased the proportion of participants achieving weight loss targets, and reduced body weight, waist circumference, HbA1c, and blood pressure versus placebo and insulin. Compared with GLP-1 RAs, tirzepatide provided comparable or better outcomes in weight loss, waist circumference, and glycemic control. The incidence of gastrointestinal adverse events was significantly higher at all doses of tirzepatide compared to placebo and insulin. When compared with GLP-1 RAs, higher doses of tirzepatide were associated with increased risk of nausea, diarrhea, and decreased appetite, but not vomiting. Conclusions: Tirzepatide is an effective option for managing weight and improving metabolic outcomes in patients with T2D or obesity. However, it is associated with an increased risk of gastrointestinal adverse events, especially at higher doses. Therefore, close monitoring should be considered in clinical practice. Registration: PROSPERO CRD42021283449. Full article

(This article belongs to the Section Pharmacology)

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23 pages, 2798 KiB

Open AccessArticle

The Cordyceps Genus as a Potential Source of Bioactive Compounds for Adjuvant Cancer Therapy: A Network Pharmacology Approach

by Jose Luis Gonzalez-Llerena, Daniela Treviño-Almaguer, Jesus Alejandro Leal-Mendez, Gael Garcia-Valdez, Arely Guadalupe Balderas-Moreno, Michel Stéphane Heya, Isaias Balderas-Renteria, María del Rayo Camacho-Corona and Bryan Alejandro Espinosa-Rodriguez

Pharmaceuticals 2025, 18(5), 667; https://doi.org/10.3390/ph18050667 (registering DOI) - 30 Apr 2025

Abstract

Background/Objectives: Cancer remains one of the leading causes of mortality globally, underscoring the need for novel therapeutic strategies capable of targeting multiple molecular pathways simultaneously. Natural products, particularly fungal-derived metabolites from the genus Cordyceps, represent promising candidates due to their diverse biological [...] Read more.

Background/Objectives: Cancer remains one of the leading causes of mortality globally, underscoring the need for novel therapeutic strategies capable of targeting multiple molecular pathways simultaneously. Natural products, particularly fungal-derived metabolites from the genus Cordyceps, represent promising candidates due to their diverse biological activities. Although previous studies have indicated the anticancer potential of Cordyceps species, systematic characterization of their molecular targets has been limited. This study aimed to comprehensively identify and evaluate Cordyceps metabolites as potential multitarget anticancer agents through a network pharmacology approach. Methods: A total of 129 metabolites previously reported in the literature from polar aqueous, alcoholic, and non-polar extracts of Cordyceps were compiled and chemically classified using ChemMine tools. Structure-based target prediction and pathway enrichment analyses were performed to investigate their potential biological targets. Predicted molecular targets were cross-referenced with differentially expressed genes in breast, colorectal, and lung cancers to identify hub proteins. Molecular docking simulations were conducted to assess binding affinities of metabolites to key oncogenic targets, and SwissADME was utilized for pharmacokinetic profiling. Results: The analysis revealed that Cordyceps metabolites targeted critical oncogenic pathways, including cell cycle regulation, DNA replication, and apoptosis. Hub proteins such as TYMS, AURKA, and CDK1 were identified as primary targets. Docking simulations highlighted metabolites such as cordycepsidone A, jiangxienone, and flazin, demonstrating binding affinities comparable or superior to clinically used inhibitors. Pharmacokinetic profiling identified several metabolites with favorable drug-like properties, supporting their potential as lead compounds. Conclusions:Cordyceps extracts contain structurally diverse metabolites capable of modulating multiple cancer-relevant molecular targets, providing a robust foundation for their development into multitarget anticancer therapies. This integrative network pharmacology approach underscores the potential of fungal metabolites in oncology drug discovery. Full article

(This article belongs to the Special Issue Adjuvant Therapies for Cancer Treatment: 2nd Edition)

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22 pages, 6086 KiB

Open AccessArticle

Natural Killer Cell Activation Signature Identifies Cyclin B1/CDK1 as a Druggable Target to Overcome Natural Killer Cell Dysfunction and Tumor Invasiveness in Melanoma

by Linbin Chen, Wanqian Liao, Jing Huang, Qiuyue Ding, Junwan Wu, Qiong Zhang, Ya Ding, Dandan Li, Jingjing Li, Xizhi Wen and Xiaoshi Zhang

Pharmaceuticals 2025, 18(5), 666; https://doi.org/10.3390/ph18050666 (registering DOI) - 30 Apr 2025

Abstract

Background/Objectives: Natural killer (NK) cells play a crucial role in immune surveillance against melanoma, yet they frequently exhibit dysfunction in the tumor microenvironment. This study aims to establish an NK cell activation-related prognostic signature and identify potential druggable targets to overcome NK cell [...] Read more.

Background/Objectives: Natural killer (NK) cells play a crucial role in immune surveillance against melanoma, yet they frequently exhibit dysfunction in the tumor microenvironment. This study aims to establish an NK cell activation-related prognostic signature and identify potential druggable targets to overcome NK cell dysfunction. Methods: A prognostic signature was developed using the TCGA-SKCM cohort and validated across independent datasets. NK cell activation and cytotoxicity were evaluated in melanoma-NK-92MI co-culture systems via flow cytometry. Mechanistic studies employed Western blotting, co-immunoprecipitation, ELISA, and qRT-PCR. Single-cell RNA-seq data were used to analyze cell–cell communication. Results: A four-gene NK cell activation signature was identified and validated for prognostic significance across five independent melanoma datasets. Among the identified genes, cyclin B1 (CCNB1) emerged as a novel therapeutic target for overcoming NK cell resistance. In vivo, pharmacological inhibition of the CCNB1/Cyclin-dependent kinase 1 (CDK1) complex with RO-3306 significantly suppressed melanoma growth by enhancing NK cell infiltration and IFN-γ production. In vitro, CCNB1 knockdown in melanoma cells augmented NK-92MI activation, as evidenced by increased expression of CD69, CD107a, IFN-γ, and NKG2D, thereby improving NK cell-mediated cytotoxicity. Mechanistically, in melanoma cells, the CCNB1/CDK1 complex phosphorylates STAT3, activating the IL-6/STAT3 positive feedback loop, which upregulates PD-L1 and enables resistance to NK cell-mediated cytotoxicity. Beyond its role in immune evasion, CCNB1 also promoted melanoma invasiveness by inducing epithelial–mesenchymal transition (EMT) through the TGF-β-SMAD2/3 signaling. Conclusions: This study establishes CCNB1/CDK1 as a novel immunotherapeutic target and uncovers a new role for CDK1 inhibitors in enhancing NK cell function and suppressing melanoma progression. Full article

(This article belongs to the Topic Kinases in Cancer and Other Diseases, 2nd Edition)

42 pages, 789 KiB

Open AccessReview

New Agents in the Treatment of Psychiatric Disorders: What Innovations and in What Areas of Psychopathology?

by Paola Bozzatello, Roberta Novelli, Rebecca Schisano, Claudio Brasso, Paola Rocca and Silvio Bellino

Pharmaceuticals 2025, 18(5), 665; https://doi.org/10.3390/ph18050665 (registering DOI) - 30 Apr 2025

Abstract

Psychiatric disorders are a major cause of illness in the world. Unfortunately, many patients are resistant to treatment and present serious complications. Schizophrenia is refractory to treatment in about one-third of patients. Antidepressants are effective in about half of patients. Suicidal ideation is [...] Read more.

Psychiatric disorders are a major cause of illness in the world. Unfortunately, many patients are resistant to treatment and present serious complications. Schizophrenia is refractory to treatment in about one-third of patients. Antidepressants are effective in about half of patients. Suicidal ideation is an increasing issue in patients with mixed features in bipolar disorder (BD). Therefore, there is a need to develop and test new drugs or new indications of available medications for the treatment of psychiatric disorders through evidence-based investigations. This narrative review aims to present the molecules approved by the main drug agencies, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), from 2018 to date, along with new indications and new formulations of existing medications. We searched PubMed for new drugs approved for schizophrenia, BD, major depressive disorder (MDD), anxiety disorders, and obsessive-compulsive disorder (OCD). We evaluated their clinical benefits, safety, and tolerability profiles. Finally, we considered studies on the main molecules that have shown initial evidence of efficacy and are in the process of obtaining approval. Our search suggested that a new antipsychotic, lumateperone, and two drug combinations, olanzapine/samidorphan (OLZ/SAM) and xanomeline/trospium (KarXT), were approved for schizophrenia. In addition, some new methods of administration—monthly risperidone administration, subcutaneous risperidone administration, and transdermal asenapine administration—obtained approval from the main drug agencies. Lumateperone and OLZ/SAM were also approved in BD. Esketamine, a compound that modulates glutamatergic transmission, was approved to treat treatment-resistant depression and acute suicidal ideation. The dextromethorphan/bupropion combination was approved for MDD. Two new agents, brexanolone and zuranolone, were approved for treatment of postpartum depression. On the other hand, no new drugs received approval for anxiety disorders or OCD. In summary, some new psychotropic medications have been developed, in particular with the aim to improve the symptoms of resistant patients and to decrease the incidence of adverse effects. It is necessary to continue testing the effectiveness of new compounds in methodologically rigorous studies. Full article

(This article belongs to the Special Issue Recent Advances in Psychopharmacology)

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15 pages, 4463 KiB

Open AccessArticle

Norfloxacin Derivative with Carbazole at C-7 FQB-1 Induces Cytotoxic, Antiproliferative, and Antitumor Effects in an Experimental Lung Carcinoma Model

by Alondra Bocanegra-Zapata, Hiram Hernández-López, Socorro Leyva-Ramos, Rodolfo Daniel Cervantes-Villagrana, Marisol Galván-Valencia, L. Angel Veyna-Hurtado, Norma Guadalupe Ramírez Tovar, Damaris Albores-García, Juan Armando Flores de la Torre and Alberto Rafael Cervantes-Villagrana

Pharmaceuticals 2025, 18(5), 664; https://doi.org/10.3390/ph18050664 (registering DOI) - 30 Apr 2025

Abstract

Background: Cancer remains a leading cause of morbidity and mortality worldwide. According to the World Health Organization (WHO), lung cancer is the most prevalent type of cancer among both men and women. Despite the various pharmacological and biological treatments available for lung cancer, [...] Read more.

Background: Cancer remains a leading cause of morbidity and mortality worldwide. According to the World Health Organization (WHO), lung cancer is the most prevalent type of cancer among both men and women. Despite the various pharmacological and biological treatments available for lung cancer, their effectiveness has often fallen short, and the side effects can be severe. Therefore, there is an ongoing need to identify and develop novel compounds with enhanced anti-tumor efficacy and improved safety profiles. Research has shown that fluoroquinolone derivatives exhibit a broad cytotoxic spectrum comparable to other drugs used in clinical chemotherapy. Objective: The aim of this work was to synthesize and evaluate the cytotoxic, anti-proliferative, and anti-tumor effects of FQB-1, a novel fluoroquinolone derivative. Results: In silico molecular docking analysis demonstrated a strong interaction between FQB-1 and human topoisomerase, with a binding affinity score of –9.8 kcal/mol. In vitro cytotoxicity and anti-proliferative assays were conducted using the Lewis Lung Carcinoma (LLC) cell line. FQB-1 was tested at concentrations of 2.5, 5.0, 25.0, 50.0, 100.0, and 150.0 µg/mL. Significant cytotoxic and anti-proliferative effects were observed at concentrations of 50–150 µg/mL after 24 h of treatment. To evaluate FQB-1′s efficacy in vivo, a syngeneic tumor model was established in C57BL/6 mice. Treatment with FQB-1 (100 mg/kg) resulted in a marked reduction in tumor volume compared to the untreated control group. Histopathological analysis of tumor tissues from treated animals revealed a decrease in mitotic index and an increase in necrotic regions, indicating compromised tumor viability. Conclusions: FQB-1 exhibits cytotoxic and anti-proliferative effects and can reduce tumor growth while compromising tumor viability. Full article

(This article belongs to the Special Issue Fluoroquinolones)

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17 pages, 2797 KiB

Open AccessArticle

Investigation of the Anti-Lung Cancer Mechanisms of Taraxacum officinale Based on Network Pharmacology and Multidimensional Experimental Validation

by Jianing Liu, Hailing Yang, Ran Liu, Dongjin Sun, Yongbao Liu, Jing Lu, Jinbiao Liu and Junrui Lu

Pharmaceuticals 2025, 18(5), 663; https://doi.org/10.3390/ph18050663 (registering DOI) - 30 Apr 2025

Abstract

Background:Taraxacum officinale(commonly known as dandelion) is a medicinal and edible plant, with the entire plant being used for therapeutic purposes. Studies have demonstrated that dandelion exhibits inhibitory effects against various types of cancer. However, research on its potential for lung cancer [...] Read more.

Background:Taraxacum officinale(commonly known as dandelion) is a medicinal and edible plant, with the entire plant being used for therapeutic purposes. Studies have demonstrated that dandelion exhibits inhibitory effects against various types of cancer. However, research on its potential for lung cancer (LC) treatment is limited, and the specific compounds responsible for its anticancer effects, as well as the underlying mechanisms, remain unclear. Methods: This study aimed to elucidate the underlying pharmacological mechanisms by which dandelion exerts therapeutic effects against LC. Initially, active compounds of dandelion and their corresponding targets were retrieved from public databases. Subsequently, network pharmacology approaches were applied to identify LC-associated disease targets. By integrating drug-specific targets and disease-related targets, a comprehensive dandelion–lung cancer interaction network was established. Protein–protein interaction (PPI) analyses and functional enrichment studies were further performed to uncover potential molecular mechanisms. Additionally, molecular docking and molecular dynamics (MD) simulations were conducted to evaluate binding interactions between critical active constituents and core targets. To experimentally validate these findings, in vitro cellular assays combined with scanning electron microscopy (SEM) were employed to investigate the anticancer effects of taraxasterol, a key bioactive sterol compound isolated from dandelion, on LC cells. Results: Our analyses identified 58 active compounds in dandelion linked to 614 potential targets, of which 228 targets were associated with LC. The PPI network highlighted 16 core targets, notably TP53, CASP3 and EGFR. Functional enrichment analysis suggested that dandelion might exert its anticancer effects by modulating the tumor microenvironment through the regulation of these critical targets. Molecular docking results demonstrated stable binding interactions between major active compounds and the identified core targets. Furthermore, the anticancer activity of taraxasterol was experimentally validated through in vitro assays and SEM-based morphological assessments, confirming its inhibitory effects on A549 lung cancer cells. Conclusions: Collectively, our findings reveal a multi-targeted therapeutic mechanism of dandelion against LC and support its potential development as a novel natural candidate for lung cancer treatment. Full article

(This article belongs to the Special Issue Adjuvant Therapies for Cancer Treatment)

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41 pages, 21782 KiB

Open AccessArticle

Isoetin from Isoetaceae Exhibits Superior Pentatransferase Inhibition in Breast Cancer: Comparative Computational Profiling with FDA-Approved Tucatinib

by Abdulaziz H. Al Khzem, Mansour S. Alturki, Ohood K. Almuzaini, Saad M. Wali, Mohammed Almaghrabi, Mohammed F. Aldawsari, Maram H. Abduljabbar, Reem M. Alnemari, Atiah H. Almalki and Thankhoe A. Rants’o

Pharmaceuticals 2025, 18(5), 662; https://doi.org/10.3390/ph18050662 (registering DOI) - 30 Apr 2025

Abstract

Background: Breast cancer, the most prevalent cancer among women globally, develops primarily in the breast’s ducts or lobules. Drug resistance is a significant challenge in treating advanced cases, contributing to over 685,000 breast cancer-related deaths annually, and identifying novel compounds that inhibit key [...] Read more.

Background: Breast cancer, the most prevalent cancer among women globally, develops primarily in the breast’s ducts or lobules. Drug resistance is a significant challenge in treating advanced cases, contributing to over 685,000 breast cancer-related deaths annually, and identifying novel compounds that inhibit key proteins is crucial for developing effective therapies. Methods: In this study, five transferase proteins with PDB IDs were selected due to their involvement in breast cancer: 1A52, 3PP0, 4EJN, 4I23, and 7R9V. Multitargeted docking studies were conducted using three different docking strategies and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) to calculate the binding affinities against the ZINC Natural compound library. Isoetin (ZINC000006523948), found mainly in Isoetaceae, was identified, and the results were compared with the Food and Drug Administration (FDA)-approved drug Tucatinib. In addition, molecular interaction fingerprints and pharmacokinetic profiling were evaluated. We also performed 5 ns WaterMap simulations to identify hydration sites and interactions, followed by 100 ns molecular dynamics (MD) simulations and MM/GBSA to assess the stability of the Isoetin–protein complexes. Results: The docking results indicated that Isoetin demonstrated superior binding and docking scores ranging from −9.901 to −13.903 kcal/mol compared to Tucatinib, which showed values between −4.875 and −10.948 kcal/mol, suggesting Isoetin’s potential efficacy as a therapeutic agent for breast cancer. Interaction fingerprints revealed significant interactions between Isoetin and key residues, including 28LEU, 12MET, 9PHE, 7ASP, 6ASN, and 6THR. The pharmacokinetics and DFT analysis of Isoetin supported its potential as a viable drug candidate. Furthermore, the 5 ns WaterMap simulations identified various hydration sites, and the 100 ns MD simulations showed that the Isoetin–protein complexes exhibited minimal deviations and fluctuations, indicating better stability than Tucatinib, and MM/GBSA confirmed Isoetin’s superior binding stability. Conclusions: Isoetin, a natural compound identified through in silico screening, demonstrates significant promise as a potential therapeutic agent for breast cancer as it outperforms the FDA-approved drug Tucatinib, the respective native and FDA-approved drug. However, experimental validation is necessary before considering Isoetin for clinical use. Full article

(This article belongs to the Collection The Story of Successful Drugs and Recent FDA-Approved Molecules)

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20 pages, 59852 KiB

Open AccessArticle

Gut Microbiota-Targeted Intervention of Hyperlipidemia Using Monascus-Fermented Ginseng

by Qing Zhou, Cuiting Yang, Mingyue Jia, Qingsong Qu, Xinhui Peng, Weishuo Ren, Guoqing Li, Yueyang Xie, Bingxuan Li and Xinyuan Shi

Pharmaceuticals 2025, 18(5), 661; https://doi.org/10.3390/ph18050661 (registering DOI) - 30 Apr 2025

Abstract

Background/Objectives: Hyperlipidemia (HLP) encompasses a spectrum of poorly understood lipid metabolism disorders that are frequently overlooked or misdiagnosed, potentially leading to multiple complications. While the gut microbiota has been implicated in HLP pathogenesis, the causal relationships and molecular mechanisms remain elusive. This study [...] Read more.

Background/Objectives: Hyperlipidemia (HLP) encompasses a spectrum of poorly understood lipid metabolism disorders that are frequently overlooked or misdiagnosed, potentially leading to multiple complications. While the gut microbiota has been implicated in HLP pathogenesis, the causal relationships and molecular mechanisms remain elusive. This study aimed to investigate the therapeutic mechanisms of Monascus-fermented ginseng (MFG) on HLP through gut microbiota modulation and explore treatment potential via fecal microbiota transplantation (FMT). Methods: The MFG-modulated gut microbiota was transplanted into HLP mice. Systemic evaluations, including serum biochemical parameter detection, histopathological section analysis, 16S rRNA sequencing, and fecal metabolomics, were conducted to assess therapeutic efficacy and identify associated metabolic pathways. Results: FMT significantly improved lipid profiles, reduced body weight, and attenuated hepatic lipid accumulation in HLP mice. Mechanistically, it enhanced cholesterol excretion and fatty acid β-oxidation while suppressing lipogenic regulators, concurrently promoting primary-to-secondary bile acid conversion. Gut microbiota analysis revealed that the MFG intervention effectively normalized the Firmicutes/Bacteroidetes ratio and enriched beneficial microbiota. Conclusions: These findings demonstrate FMT’s therapeutic value in HLP management and provide new perspectives on utilizing fermented herbal medicines for metabolic disorders via gut microbiota reprogramming. Full article

(This article belongs to the Special Issue Natural Products in Gut Microbiome Modulation: From Mechanisms to Clinical Applications)

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23 pages, 5379 KiB

Open AccessArticle

Fructose-1,6-Bisphosphate Reduces Chronic Constriction Injury Neuropathic Pain in Mice by Targeting Dorsal Root Ganglia Nociceptive Neuron Activation

by Amanda Martins Dionisio, Paula de Azevedo Oliveira Milanez, Ana Carla Zarpelon-Schutz, Sandra Satie Mizokami, Mariana Marques Bertozzi, Kelly Megumi Yaekashi, Doumit Camilios-Neto, Sergio Marques Borghi, Rubia Casagrande and Waldiceu A. Verri

Pharmaceuticals 2025, 18(5), 660; https://doi.org/10.3390/ph18050660 (registering DOI) - 30 Apr 2025

Abstract

Background/Objectives: Fructose-1,6-bisphosphate (FBP) is an intermediate product of the glycolytic pathway with analgesic effect in acute inflammatory pain model via the production of adenosine. However, whether FBP is active in neuropathic pain is unknown. Therefore, we reason that it would be suitable to [...] Read more.

Background/Objectives: Fructose-1,6-bisphosphate (FBP) is an intermediate product of the glycolytic pathway with analgesic effect in acute inflammatory pain model via the production of adenosine. However, whether FBP is active in neuropathic pain is unknown. Therefore, we reason that it would be suitable to investigate the analgesic effect and mechanism of action of FBP in a model of chronic constriction injury (CCI) of sciatic nerve-induced neuropathic pain in mice. Methods: After CCI induction, mice received FBP, adenosine, A1 and/or A2A receptor antagonists, and/or inhibitors of the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)/ATP sensitive K channels (KATP) signaling pathway. Results: FBP (up to 85%) and adenosine (up to 84%) inhibited the mechanical hyperalgesia (electronic aesthesiometer) induced by CCI with similar profiles. FBP analgesia was dependent on adenosine because adenosine A1 and A2A receptors antagonists diminished FPB activity (100% and 79%, respectively). FBP analgesia was also dependent on activating the NO/cGMP/PKG/KATP signaling pathway. Furthermore, FBP treatment increased the production of NO in cultured dorsal root ganglia (DRG) neurons (100% increase), whereas neuronal nitric oxide synthase (nNOS) inhibition decreased (up to 70%) the analgesic effect of FBP. We also observed that FBP reduced the calcium levels of transient receptor potential ankyrin 1 (TRPA1)⁺ DRG neurons (85%) and paw-flinching triggered by TRPA1 activation (38%). Conclusions: FBP reduced neuropathic pain by reducing DRG neuron activation. The mechanisms involved the activation of adenosine A1 and A2A receptors to trigger the analgesic NO/cGMP/PKG/KATP signaling pathway and reducing TRPA1⁺ DRG neuron activity. Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

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12 pages, 1044 KiB

Open AccessReview

A Review of the Clinical Progress of CT1812, a Novel Sigma-2 Receptor Antagonist for the Treatment of Alzheimer’s Disease

by Sara R. Steinfield, Daniel F. Stenn, Helen Chen and Bettina E. Kalisch

Pharmaceuticals 2025, 18(5), 659; https://doi.org/10.3390/ph18050659 (registering DOI) - 30 Apr 2025

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease marked by the accumulation of toxic amyloid-beta (Aβ) oligomers. These oligomers are thought to cause synaptic dysfunction and contribute to neurodegeneration. CT1812 is a small-molecule sigma-2 receptor antagonist that is currently being investigated and tested as [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disease marked by the accumulation of toxic amyloid-beta (Aβ) oligomers. These oligomers are thought to cause synaptic dysfunction and contribute to neurodegeneration. CT1812 is a small-molecule sigma-2 receptor antagonist that is currently being investigated and tested as a potential disease-modifying treatment for AD. CT1812 acts by displacing Aβ oligomers into the cerebrospinal fluid and preventing their interaction with receptors on neurons. Preclinical studies and early clinical trials of CT1812 show promising results and provide evidence for its potential to slow AD progression. This review outlines the role of Aβ oligomers in AD, CT1812’s mechanism of action, and the effectiveness and limitations of CT1812 based on preclinical and clinical studies. Full article

(This article belongs to the Special Issue Pharmacotherapy for Alzheimer’s Disease)

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20 pages, 10156 KiB

Open AccessArticle

Molecular Imaging of Fibroblast Activation Protein in Response to Cardiac Injury Using [⁶⁸Ga]Ga-DATA^5m.SA.FAPi

by Victoria Weissenböck, Lukas Weber, Michaela Schlederer, Laura Silva Sousa, Anna Stampfer, Simge Baydar, Thomas Nakuz, Raffaella Calabretta, Ana Isabel Antunes Goncalves, Xiang Li, Frank Rösch, Bruno K. Podesser, Lukas Kenner, Marcus Hacker, Attila Kiss and Cecile Philippe

Pharmaceuticals 2025, 18(5), 658; https://doi.org/10.3390/ph18050658 (registering DOI) - 29 Apr 2025

Abstract

Background/Objectives: Fibroblast activation protein (FAP) has gained tremendous traction as a target for tumor imaging and cancer treatment, while also playing a key role in fibrosis. Our study aimed to evaluate [⁶⁸Ga]Ga-DATA^5m.SA.FAPi for PET imaging of replacement fibrosis [...] Read more.

Background/Objectives: Fibroblast activation protein (FAP) has gained tremendous traction as a target for tumor imaging and cancer treatment, while also playing a key role in fibrosis. Our study aimed to evaluate [⁶⁸Ga]Ga-DATA^5m.SA.FAPi for PET imaging of replacement fibrosis following myocardial infarction (MI) or interstitial fibrosis associated with hypertrophy. Methods: MI or transverse aortic constriction (TAC)-induced hypertrophy was induced in C57BL/6 mice, with sham-operated animals serving as controls. At multiple time points during disease progression (1, 2, and 6 weeks post-surgery), [⁶⁸Ga]Ga-DATA^5m.SA.FAPi PET/CT scans were performed, followed by ex vivo investigations. Additionally, in vitro cell uptake experiments simulating hypertrophy were conducted. Results: Cardiac uptake of [⁶⁸Ga]Ga-DATA5m.SA.FAPi significantly increased two weeks after MI induction (MI: 2.1 ± 0.2%ID/g, n = 7 vs. SHAM: 1.1 ± 0.2%ID/g, n = 5; p = 0.002), confirmed by ex vivo autoradiography. No significant difference was observed at six weeks post-MI (MI: 1.1 ± 0.1%ID/g, n = 4 vs. SHAM: 0.8 ± 0.0%ID/g, n = 3), indicating infarct healing completion. In contrast, TAC mice showed increased uptake after six weeks (TAC: 1.8 ± 0.2%ID/g, n = 6; p = 0.007), related to interstitial fibrosis progression. Consistently, high-stretched cardiac fibroblasts demonstrated a higher uptake compared to low-stretched conditioned ones, suggesting the stretch mediates regulation of FAP. Conclusions: This study demonstrated the efficacy of [⁶⁸Ga]Ga-DATA^5m.SA.FAPi for longitudinal imaging of cardiac fibrosis in response to different cardiac injuries. In vivo FAP imaging during cardiac remodeling may serve as a valuable tool for diagnosing and predicting disease progression, ultimately aiding in the clinical management of patients. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

19 pages, 3230 KiB

Open AccessArticle

Unlocking the Neuroprotective Effect of Quercetin Against Cadmium-Induced Hippocampal Damage in Rats: PPARγ Activation as a Key Mechanism

by Doha M. Al-Nouri

Pharmaceuticals 2025, 18(5), 657; https://doi.org/10.3390/ph18050657 (registering DOI) - 29 Apr 2025

Abstract

Background: This study investigates the effects of cadmium chloride (CdCl₂) on hippocampal peroxisome proliferator-activated receptor gamma (PPARγ) expression and examines whether PPARγ activation mediates the neuroprotective effects of quercetin (QUR). Methods: Sixty adult male rats were included in this study, separated [...] Read more.

Background: This study investigates the effects of cadmium chloride (CdCl₂) on hippocampal peroxisome proliferator-activated receptor gamma (PPARγ) expression and examines whether PPARγ activation mediates the neuroprotective effects of quercetin (QUR). Methods: Sixty adult male rats were included in this study, separated into 12 rats per group as follows: control, CdCl₂ (0.5 mg/kg), CdCl₂ + PPARγ agonist (Pioglitazone, 10 mg/kg), CdCl₂ + QUR (25 mg/kg), and CdCl₂ + QUR + PPARγ antagonist (GW9662, 1 mg/kg). Treatments were administered orally for 30 days. At the end of the experiment, behavioral memory tests, hippocampal histology, markers of cholinergic function, neuroplasticity, oxidative stress, inflammation, and apoptosis, as well as transcription levels of some genes were carried out. Results: CdCl₂ exposure significantly reduced hippocampal PPARγ mRNA and DNA binding potential and nuclear levels. Additionally, CdCl₂ impaired spatial, short-term, and recognition memory, decreased granular cell density in the dentate gyrus (DG), and reduced levels of neuroprotective factors, including Nrf2, brain-derived neurotrophic factor (BDNF), acetylcholine (ACh), and several antioxidant enzymes including heme-oxygenase-1 (HO-1) and superoxide dismutase (SOD), as well as reduced glutathione (GSH). Conversely, CdCl₂ elevated levels of oxidative stress, inflammation, and apoptosis markers such as interleukin-6 (IL-6), malondialdehyde (MDA), Bax, tumor necrosis factor-α (TNF-α), and cleaved caspase-3. QUR and Pioglitazone reversed these effects, restoring expression and PPARγ activation, improving memory, and modulating antioxidant and anti-inflammatory pathways. In contrast, blocking PPARγ with GW9662 negated the neuroprotective effects of QUR, exacerbating oxidative stress and inflammation by reversing all their beneficial effects. Conclusions: Activation of PPARγ by QUR or Pioglitazone offers a promising therapeutic strategy for mitigating CdCl₂-induced neurotoxicity. Full article

(This article belongs to the Section Natural Products)

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23 pages, 4228 KiB

Open AccessArticle

Diosmin Potentiates the Antidiabetic Effects of Linagliptin in Nicotinamide/Streptozotocin-Induced Diabetic Wistar Rats

by Eman B. Abbas, Asmaa M. El-Kalaawy, Noha A. Ahmed, Anwar Shams, Amal K. Khaliefa and Osama M. Ahmed

Pharmaceuticals 2025, 18(5), 656; https://doi.org/10.3390/ph18050656 (registering DOI) - 29 Apr 2025

Abstract

Background/Objectives: Natural therapeutics for the treatment of diabetes mellitus represent a common challenge for many researchers. Thus, the aim of this study was to evaluate the antihyperglycemic and anti-inflammatory effects and the hepatic antioxidant activities of both diosmin and linagliptin on nicotinamide/streptozotocin-induced diabetes [...] Read more.

Background/Objectives: Natural therapeutics for the treatment of diabetes mellitus represent a common challenge for many researchers. Thus, the aim of this study was to evaluate the antihyperglycemic and anti-inflammatory effects and the hepatic antioxidant activities of both diosmin and linagliptin on nicotinamide/streptozotocin-induced diabetes mellitus in rats. Methods: Induction of diabetes mellitus was produced by injecting an intraperitoneal dose of nicotinamide (60 mg/kg) to 16-hour-fasted rats, then after 15 min, an intraperitoneal dose of streptozotocin (60 mg/kg) was injected. The rats with diabetes were orally treated with linagliptin (1 mg/kg), diosmin (10 mg/kg), and both of them every other day for 4 weeks. Results: The elevated hepatic glucose-6-phosphatase and glycogen phosphorylase activities, the lowered concentrations of serum insulin, C-peptide, and hepatic glycogen, and the diminished hepatic antioxidant defense system of nicotinamide/streptozotocin-induced diabetic rats were all potentially improved by the therapies. The treatments also improved the deteriorated adiponectin and resistin mRNA expression in visceral adipose tissue of nicotinamide/streptozotocin-induced diabetic rats. In addition, the treatments induced a recovery of damaged islets of Langerhans and a regeneration of islet cells in association with the enhancement of the formation of insulin granules in β-cells and the improvement of kidney function; the combined effect was the most potent. Conclusions: Diosmin alone or in combination with linagliptin has potent antidiabetic effects, which were managed through their insulinotropic and insulin-improving actions. The diosmin in combination with linagliptin has the most potent antihyperglycemic effects. Full article

(This article belongs to the Special Issue Natural Products in Diabetes Mellitus: 2nd Edition)

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