Pharmaceuticals

22 pages, 948 KiB

Open AccessReview

New Approaches to the Treatment of Alzheimer’s Disease

by Marta Kruk-Słomka, Dominika Kuceł, Maria Małysz, Adrianna Machnikowska, Jolanta Orzelska-Górka and Grażyna Biała

Pharmaceuticals 2025, 18(8), 1117; https://doi.org/10.3390/ph18081117 (registering DOI) - 26 Jul 2025

Abstract

Alzheimer’s disease (AD) is one of the most common chronic neurodegenerative disorders worldwide. It is characterized by progressive memory loss and cognitive decline, leading to dementia. The pathogenesis of the disease is primarily attributed to two pathological protein structures: amyloid-beta (Aβ) plaques and [...] Read more.

Alzheimer’s disease (AD) is one of the most common chronic neurodegenerative disorders worldwide. It is characterized by progressive memory loss and cognitive decline, leading to dementia. The pathogenesis of the disease is primarily attributed to two pathological protein structures: amyloid-beta (Aβ) plaques and tau protein neurofibrils. The current treatment strategies for AD are mainly symptomatic, highlighting the urgent need for the development of new, more effective therapies for the disease. The purpose of this paper is to provide a comprehensive and scientific review of the latest research regarding novel therapeutic options in the treatment of AD. In recent years, research has focused on more advanced and diversified strategies, including immunotherapy, gene therapy, tyrosine kinase inhibitors, therapies targeting mitochondrial function, and neurogenesis-related process modulation. One of the most promising treatment strategies for AD is immunotherapy. Intensive research is currently underway on both passive immunization, which involves the administration of monoclonal antibodies, and active immunization through vaccinations that stimulate the body to produce specific antibodies. Further research into novel therapeutic directions is essential, particularly concerning the role of the immune system in the pathogenesis of AD. Immunization appears to be a highly promising approach to developing effective methods for preventing AD or delaying the progression of this disease. Full article

(This article belongs to the Special Issue NeuroImmunoEndocrinology)

18 pages, 1256 KiB

Open AccessArticle

Analysis of the Recurrence of Adverse Drug Reactions in Pediatric Patients with Epilepsy

by Ernestina Hernández García, Brenda Lambert Lamazares, Gisela Gómez-Lira, Julieta Griselda Mendoza-Torreblanca, Pamela Duke Lomeli, Yessica López Flores, Laura Elena Rangel Escobar, Eréndira Mejía Aranguré, Silvia Ruiz-Velasco Acosta and Lizbeth Naranjo Albarrán

Pharmaceuticals 2025, 18(8), 1116; https://doi.org/10.3390/ph18081116 (registering DOI) - 26 Jul 2025

Abstract

Epilepsy is a chronic neurological disease with a relatively high incidence in the pediatric population. Anti-seizure medication (ASM) may cause adverse drug reactions (ADRs), which may occur repeatedly. Objective: This study aimed to analyze the recurrence of ADRs caused by ASMs over a [...] Read more.

Epilepsy is a chronic neurological disease with a relatively high incidence in the pediatric population. Anti-seizure medication (ASM) may cause adverse drug reactions (ADRs), which may occur repeatedly. Objective: This study aimed to analyze the recurrence of ADRs caused by ASMs over a period of 122 months in hospitalized Mexican pediatric epilepsy patients. The patients were under monotherapy or polytherapy treatment, with valproic acid (VPA), phenytoin (PHT), and levetiracetam (LEV), among others. A total of 313 patients met the inclusion criteria: 211 experienced ADRs, whereas 102 did not. Patient sex, age, seizure type, nutritional status and related drugs were considered explanatory variables. Methods: Four statistical models were used to analyze recurrent events that were defined as “one or more ADRs occurred on a single day”, considering both the classification of ADR seriousness and the ASM causing the ADR. Results: A total of 499 recurrence events were identified. The recurrence risk was significantly greater among younger patients for both nonsevere and severe ADRs and among those with focal seizures for nonsevere ADRs. Interestingly, malnutrition was negatively associated with the risk of nonsevere ADRs, and obesity was positively associated with the risk of severe ADRs. Finally, LEV was associated with a significantly greater risk of causing nonsevere ADRs than VPA. However, LEV significantly reduced the risk of severe ADRs compared with VPA, and PHT increased the risk in comparison with VPA. In conclusion, this study offers a robust clinical tool to predict risk factors for the presence and recurrence of ASM-ADRs in pediatric patients with epilepsy. Full article

(This article belongs to the Special Issue Pharmacoepidemiology and Pharmacovigilance in Drug Therapy: New Issues, Challenges, and Applications)

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45 pages, 969 KiB

Open AccessReview

Bacteriophage Therapy: Discovery, Development, and FDA Approval Pathways

by Sarfaraz K. Niazi

Pharmaceuticals 2025, 18(8), 1115; https://doi.org/10.3390/ph18081115 (registering DOI) - 26 Jul 2025

Abstract

The escalating global crisis of antimicrobial resistance, responsible for approximately 1.27 million deaths in 2019, has catalyzed renewed interest in bacteriophage therapy as a viable therapeutic alternative. With projections indicating that drug-resistant bacteria could cause over 39 million deaths worldwide by 2050, developing [...] Read more.

The escalating global crisis of antimicrobial resistance, responsible for approximately 1.27 million deaths in 2019, has catalyzed renewed interest in bacteriophage therapy as a viable therapeutic alternative. With projections indicating that drug-resistant bacteria could cause over 39 million deaths worldwide by 2050, developing alternative antimicrobial strategies has become critically urgent. This comprehensive review examines the scientific foundation of bacteriophage therapy, traces its historical development from early Soviet applications through contemporary regulatory frameworks, and provides strategic guidance for developers seeking FDA approval for bacteriophage-based therapeutics. We analyze the current regulatory landscape across major jurisdictions, including manufacturing requirements and clinical development pathways essential for successful market authorization. Approximately 90 clinical trials involving bacteriophages are ongoing worldwide, with 41 studies in the United States demonstrating significant momentum in this field Full article

(This article belongs to the Section Biopharmaceuticals)

14 pages, 555 KiB

Open AccessArticle

Tailoring Treatment in Complex Regional Pain Syndrome: A Comparative Study of Therapeutic Approaches in Complex Rehabilitation

by Iana Andreieva, Beata Tarnacka, Adam Zalewski and Justyna Wiśniowska

Pharmaceuticals 2025, 18(8), 1114; https://doi.org/10.3390/ph18081114 - 25 Jul 2025

Abstract

Complex regional pain syndrome (CRPS) is a disabling pain condition, which is distinct from other pain syndromes by the presence of autonomic dysfunction and regional inflammatory changes. Objectives: To explore the impact of pharmacological treatment strategies, specifically scheduled, on-demand dosing regimens versus lack [...] Read more.

Complex regional pain syndrome (CRPS) is a disabling pain condition, which is distinct from other pain syndromes by the presence of autonomic dysfunction and regional inflammatory changes. Objectives: To explore the impact of pharmacological treatment strategies, specifically scheduled, on-demand dosing regimens versus lack of medical treatment, on pain-related and functional outcomes in rehabilitation for individuals with CRPS. Methods: A total of 32 participants with CRPS were assigned to three treatment groups depending on analgesic treatment during the course of complex rehabilitation. Pre- and post-rehabilitation assessments were conducted using validated measures, including the Numerical Rating Scale (NRS) for pain, the Short-Form McGill Pain Questionnaire (SF-MPQ), PainDETECT, the Disabilities of the Arm, Shoulder, and Hand (DASH), and the Lower Extremity Functional Scale (LEFS). Results: Significant improvements in pain and upper limb function (DASH scores) were observed across all groups (p < 0.05). No statistically significant changes were found in lower limb function (LEFS). Between-group comparisons revealed significant differences in post-treatment pain scores (SFMPQ-B), particularly between groups with a constant treatment regimen and those without treatment. Conclusions: There were no statistically significant changes compared to different treatment regimen groups. The constant treatment group showed slightly better average improvements in pain and disability compared to other groups. Statistically significant improvements in all CRPS patients were observed in pain-related and functional measures. Full article

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

39 pages, 3767 KiB

Open AccessReview

Therapeutic Potential of Bioactive Compounds from Traditional Chinese Medicine in Modulating Macrophage Cholesterol Metabolism for Atherosclerosis Treatment

by Lijiao Yan, Jiageng Guo, Dan Huang, Fan Zhang, Zhengcai Du, Xiaotao Hou, Jiagang Deng, Yan Xie and Erwei Hao

Pharmaceuticals 2025, 18(8), 1113; https://doi.org/10.3390/ph18081113 - 25 Jul 2025

Abstract

Atherosclerosis (AS) is a complex pathological process characterized by the pivotal involvement of foam cells in its pathogenesis. As the primary cellular components of arterial plaques, foam cells critically determine plaque stability. Foam cells derive mainly from macrophages, and their formation is driven [...] Read more.

Atherosclerosis (AS) is a complex pathological process characterized by the pivotal involvement of foam cells in its pathogenesis. As the primary cellular components of arterial plaques, foam cells critically determine plaque stability. Foam cells derive mainly from macrophages, and their formation is driven by dysregulated lipid metabolism within these immune cells. Macrophage cholesterol metabolism is a highly regulated process comprising four key phases: uptake, esterification, hydrolysis, and efflux. Under physiological conditions, these four phases maintain a delicate balance. However, disruption of cholesterol homeostasis results in the excessive accumulation of intracellular lipid, promoting the formation of foam cell and inflammasome activation, thereby accelerating the atherosclerotic progression. Therefore, targeting macrophage cholesterol metabolism has emerged as a promising therapeutic approach for AS. This review summarizes the mechanisms underlying macrophage cholesterol metabolism and highlights recent progress in identifying bioactive components of traditional Chinese medicines (TCMs) that mitigate AS through the modulation of macrophage cholesterol homeostasis. These findings may offer novel insights into the development of clinically effective therapies for the prevention of AS. Full article

26 pages, 5270 KiB

Open AccessArticle

Gallic Acid and Taurine Attenuate Thiamethoxam-Induced Hepatotoxicity in Rats by Modulating SIRT-1/PGC-1α, NF-κB/iNOS, and p53/Bax/Caspase-3 Pathways

by Sara T. Elazab, Fatmah A. Safhi, Rasha K. Al-Akeel, Raghda H. Deraz, Souvarish Sarkar and Rania Essam Ali Gamal Eldin

Pharmaceuticals 2025, 18(8), 1112; https://doi.org/10.3390/ph18081112 - 25 Jul 2025

Abstract

Background/Objectives: Thiamethoxam (TMX) is one of the most extensively utilized insecticides of the neonicotinoid family; however, its application is associated with notable toxic effects on multiple organs of mammals. Our purpose was to explore the potential hepatoprotective effect of taurine (TAU) and/or [...] Read more.

Background/Objectives: Thiamethoxam (TMX) is one of the most extensively utilized insecticides of the neonicotinoid family; however, its application is associated with notable toxic effects on multiple organs of mammals. Our purpose was to explore the potential hepatoprotective effect of taurine (TAU) and/or gallic acid (GA) against TMX-induced liver damage, with an emphasis on their role in regulating SIRT-1/PGC-1α, NF-κB/iNOS, and p53/Bax/caspase-3 pathways. Methods: Rats were assigned to seven groups (n = 6) and gavaged daily for 28 days with saline (control group), TAU at 50 mg/kg, GA at 20 mg/kg, TMX at 78.15 mg/kg, TMX + TAU, TMX + GA, and TMX + TAU + GA. Results: The findings revealed that TAU and/or GA attenuated TMX-induced liver injury, as demonstrated by the restoration of hepatic performance hallmarks and histological structure. TAU and GA mitigated TMX-mediated oxidative stress and boosted the antioxidant defense mechanism by upregulating the transcription levels of SIRT-1, PGC-1α, Nrf2, and HO-1. Moreover, TAU and GA suppressed TMX-associated inflammatory response by increasing IL-10 concentration and lowering the levels of NF-κB, IL-1β, and iNOS; the mRNA levels of NLRP3; and TNF-α immunoexpression. Both compounds, individually or concurrently, exerted an anti-apoptotic effect in TMX-treated rats, evidenced by increased Bcl-2 expression and reduced p53 mRNA level, Bax expression, and caspase-3 concentration. Conclusions: TAU and/or GA may be regarded as promising remedies that can alleviate TMX-induced hepatotoxicity by activating SIRT-1/PGC-1α signaling and abolishing inflammation and apoptosis. Full article

(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology—2nd Edition)

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34 pages, 10401 KiB

Open AccessArticle

UPLC-MS/MS Metabolomics Reveals Babao Dan’s Mechanisms in MASH Treatment with Integrating Network Pharmacology and Molecular Docking

by Shijiao Zhang, Yanding Su, Ao Han, He Qi, Jiade Zhao and Xiangjun Qiu

Pharmaceuticals 2025, 18(8), 1111; https://doi.org/10.3390/ph18081111 - 25 Jul 2025

Abstract

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive disease that easily develops into cirrhosis and hepatocellular carcinoma, but its pathogenesis is not clear, and most therapeutic drugs have obvious limitations. However, Babao Dan (BBD) has a good therapeutic effect on liver disease, [...] Read more.

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive disease that easily develops into cirrhosis and hepatocellular carcinoma, but its pathogenesis is not clear, and most therapeutic drugs have obvious limitations. However, Babao Dan (BBD) has a good therapeutic effect on liver disease, but its treatment mechanism is still to be studied. Therefore, we further investigated the mechanism of BBD in treating MASH. Methods: We predicted BBD-related targets through network pharmacology and further verified the binding ability of BBD-related targets through molecular docking. We also detected relevant indicators before and after model treatment, as well as metabolomics analysis and identification of the mechanism of action of BBD on MASH. Results: Through network pharmacology methods, 158 key cross targets and the top 10 core targets were identified, and it was determined that the PI3K-AKT signaling pathway plays an important regulatory role in the treatment of MASH with BBD. The molecular docking results indicate that the representative compounds quercetin and 17 Beta Estradiol have good binding activity with five core targets. Metabolomics has identified four metabolic biomarkers, such as Piceid, and it is determined that the key pathway for BBD treatment of MASH is the bile secretion pathway. Conclusions: BBD effectively treats MASH by modulating Piceid and other biomarkers, targeting ESR1 and other core proteins via quercetin and 17-beta-estradiol, and regulating the PI3K-AKT and bile secretion pathways to alleviate liver injury. Full article

(This article belongs to the Section Pharmacology)

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20 pages, 4049 KiB

Open AccessArticle

ADMET-Guided Docking and GROMACS Molecular Dynamics of Ziziphus lotus Phytochemicals Uncover Mutation-Agnostic Allosteric Stabilisers of the KRAS Switch-I/II Groove

by Abdessadek Rahimi, Oussama Khibech, Abdessamad Benabbou, Mohammed Merzouki, Mohamed Bouhrim, Mohammed Al-Zharani, Fahd A. Nasr, Ashraf Ahmed Qurtam, Said Abadi, Allal Challioui, Mostafa Mimouni and Maarouf Elbekay

Pharmaceuticals 2025, 18(8), 1110; https://doi.org/10.3390/ph18081110 - 25 Jul 2025

Abstract

Background/Objectives: Oncogenic KRAS drives ~30% of solid tumours, yet the only approved G12C-specific drugs benefit ≈ 13% of KRAS-mutant patients, leaving a major clinical gap. We sought mutation-agnostic natural ligands from Ziziphus lotus, whose stereochemically rich phenolics may overcome this limitation by occupying [...] Read more.

Background/Objectives: Oncogenic KRAS drives ~30% of solid tumours, yet the only approved G12C-specific drugs benefit ≈ 13% of KRAS-mutant patients, leaving a major clinical gap. We sought mutation-agnostic natural ligands from Ziziphus lotus, whose stereochemically rich phenolics may overcome this limitation by occupying the SI/II (Switch I/Switch II) groove and locking KRAS in its inactive state. Methods: Phytochemical mining yielded five recurrent phenolics, such as (+)-catechin, hyperin, astragalin, eriodictyol, and the prenylated benzoate amorfrutin A, benchmarked against the covalent inhibitor sotorasib. An in silico cascade combined SI/II docking, multi-parameter ADME/T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) filtering, and 100 ns explicit solvent molecular dynamics simulations. Pharmacokinetic modelling predicted oral absorption, Lipinski compliance, mutagenicity, and acute-toxicity class. Results: Hyperin and astragalin showed the strongest non-covalent affinities (−8.6 kcal mol⁻¹) by forging quadridentate hydrogen-bond networks that bridge the P-loop (Asp30/Glu31) to the α3-loop cleft (Asp119/Ala146). Catechin (−8.5 kcal mol⁻¹) balanced polar anchoring with entropic economy. ADME ranked amorfrutin A the highest for predicted oral absorption (93%) but highlighted lipophilic solubility limits; glycosylated flavonols breached Lipinski rules yet remained non-mutagenic with class-5 acute-toxicity liability. Molecular dynamics trajectories confirmed that hyperin clamps the SI/II groove, suppressing loop RMSF below 0.20 nm and maintaining backbone RMSD stability, whereas astragalin retains pocket residence with transient re-orientation. Conclusions: Hyperin emerges as a low-toxicity, mutation-agnostic scaffold that rigidifies inactive KRAS. Deglycosylation, nano-encapsulation, or soft fluorination could reconcile permeability with durable target engagement, advancing Z. lotus phenolics toward broad-spectrum KRAS therapeutics. Full article

(This article belongs to the Section Natural Products)

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25 pages, 10636 KiB

Open AccessArticle

Qifu Decoction Alleviates Lipopolysaccharide-Induced Myocardial Dysfunction by Inhibiting TLR4/NF-κB/NLRP3 Inflammatory Pathway and Activating PPARα/CPT Pathway

by Lingxin Zhuo, Mingxuan Ma, Jiayi Zhang, Jiayu Zhou, Yuqi Zheng, Aiyin Liang, Qingqing Sun, Jia Liu and Wenting Liao

Pharmaceuticals 2025, 18(8), 1109; https://doi.org/10.3390/ph18081109 - 25 Jul 2025

Abstract

Background/Objectives: Sepsis-induced cardiomyopathy (SIC) is a serious clinical disorder with a high death rate. Qifu decoction (QFD) is a renowned traditional Chinese medicine with documented pharmacological actions, such as anti-inflammatory, anti-oxidant and anti-apoptosis activities, and it has good therapeutic effects on cardiovascular [...] Read more.

Background/Objectives: Sepsis-induced cardiomyopathy (SIC) is a serious clinical disorder with a high death rate. Qifu decoction (QFD) is a renowned traditional Chinese medicine with documented pharmacological actions, such as anti-inflammatory, anti-oxidant and anti-apoptosis activities, and it has good therapeutic effects on cardiovascular diseases. This study aimed to reveal the cardioprotective effects and underlying mechanisms of QFD against SIC. Methods: Electrocardiography, histopathological examination, and biochemical indicator determination were carried out to investigate the cardioprotective effects of QFD in the treatment of LPS-induced SIC mice. Metabolomics and network pharmacology strategies were employed to preliminarily analyze and predict the mechanisms of QFD against SIC. Molecular docking and Western blot were further applied to validate the core targets and potential pathways for the treatment of SIC in in vitro and in vivo models. Results: It was found that QFD considerably enhanced cardiac function; attenuated myocardial injury; and reduced the serum levels of LDH, CK-MB, IL-1β, and TNF-α by 28.7%, 32.3%, 38.6%, and 36.7%, respectively. Metabolomic analysis showed that QFD could regulate seven metabolic pathways, namely, glutathione metabolism; alanine, aspartate, and glutamate metabolism; arachidonic acid metabolism; glycerophospholipid metabolism; purine metabolism; sphingolipid metabolism; and fatty acid metabolism. Network pharmacology suggested that the anti-SIC effect of QFD may be mediated through the TNF, toll-like receptor, NOD-like receptor, NF-κB, and PPAR signaling pathways. Additionally, 26 core targets were obtained. Molecular docking revealed that active ingredients such as formononetin, kaempferol, quercetin, and (R)-norcoclaurine in QFD had a high affinity for binding to PPARα and TLR4. Further Western blot validation indicated that QFD could regulate the protein levels of NLRP3, TLR4, NF-κB, IL-6, TNF-α, COX2, sPLA2, PPARα, CPT1B, and CPT2. Conclusions: This study demonstrates that QFD can alleviate SIC by suppressing the TLR4/NF-κB/NLRP3 inflammatory pathway and modulating impaired FAO through the activation of the PPARα/CPT pathway, highlighting QFD as a promising candidate drug for SIC treatment. Full article

(This article belongs to the Section Natural Products)

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24 pages, 5895 KiB

Open AccessArticle

Comparative Immunomodulatory Efficacy of Secukinumab and Honokiol in Experimental Asthma and Acute Lung Injury

by Andrei Gheorghe Vicovan, Diana Cezarina Petrescu, Lacramioara Ochiuz, Petru Cianga, Daniela Constantinescu, Elena Iftimi, Mariana Pavel-Tanasa, Codrina Mihaela Ancuta, Cezar-Cătălin Caratașu, Mihai Glod, Carmen Solcan and Cristina Mihaela Ghiciuc

Pharmaceuticals 2025, 18(8), 1108; https://doi.org/10.3390/ph18081108 - 25 Jul 2025

Abstract

Background: The study evaluates the immunomodulatory potential of secukinumab (SECU) and honokiol (HONK) in a murine model of allergic asthma complicated by acute lung injury (ALI), with an emphasis on modulating key inflammatory pathways. The rationale is driven by the necessity to [...] Read more.

Background: The study evaluates the immunomodulatory potential of secukinumab (SECU) and honokiol (HONK) in a murine model of allergic asthma complicated by acute lung injury (ALI), with an emphasis on modulating key inflammatory pathways. The rationale is driven by the necessity to attenuate Th17-mediated cytokine cascades, wherein IL-17 plays a critical role, as well as to explore the adjunctive anti-inflammatory effects of HONK on Th1 cytokine production, including IL-6, TNF-α, and Th2 cytokines. Methods: Mice were sensitized and challenged with ovalbumin (OVA) and lipopolysaccharide (LPS) was administrated to exacerbate pulmonary pathology, followed by administration of SECU, HONK (98% purity, C₁₈H₁₈O₂), or their combination. Quantitative analyses incorporated OVA-specific IgE measurements, differential cell counts in bronchoalveolar lavage fluid (BALF), and extensive cytokine profiling in both BALF and lung tissue homogenates, utilizing precise immunoassays and histopathological scoring systems. Results: Both SECU and HONK, when used alone or in combination, display significant immunomodulatory effects in a murine model of allergic asthma concomitant with ALI. The combined therapy synergistically reduced pro-inflammatory mediators, notably Th1 cytokines, such as TNF-α and IL-6, as measured in both BALF and lung tissue homogenates. Conclusions: The combined therapy showed a synergistic attenuation of pro-inflammatory mediators, a reduction in goblet cell hyperplasia, and an overall improvement in lung histoarchitecture. While the data robustly support the merit of a combinatorial approach targeting multiple inflammatory mediators, the study acknowledges limitations in cytokine diffusion and the murine model’s translational fidelity, thereby underscoring the need for further research to optimize clinical protocols for severe respiratory inflammatory disorders. Full article

(This article belongs to the Section Pharmacology)

13 pages, 1388 KiB

Open AccessArticle

Indazole Derivatives Against Murine Cutaneous Leishmaniasis

by Niurka Mollineda-Diogo, Yunierkis Pérez-Castillo, Sergio Sifontes-Rodríguez, Osmani Marrero-Chang, Alfredo Meneses-Marcel, Alma Reyna Escalona-Montaño, María Magdalena Aguirre-García, Teresa Espinosa-Buitrago, Yeny Morales-Moreno and Vicente Arán-Redó

Pharmaceuticals 2025, 18(8), 1107; https://doi.org/10.3390/ph18081107 - 25 Jul 2025

Abstract

Background/Objectives: Leishmaniasis is a zoonotic and anthropozoonotic disease with significant public health impact worldwide and is classified as a neglected tropical disease. The search for new affordable treatments, particularly oral and/or topical ones that are easy to administer and have fewer side [...] Read more.

Background/Objectives: Leishmaniasis is a zoonotic and anthropozoonotic disease with significant public health impact worldwide and is classified as a neglected tropical disease. The search for new affordable treatments, particularly oral and/or topical ones that are easy to administer and have fewer side effects, remains a priority for the scientific community in this field of research. In previous investigations, 3-alkoxy-1-benzyl-5-nitroindazole derivatives showed remarkable in vitro results against Leishmania species, and predictions of absorption, distribution, metabolism, excretion, and toxicity properties, as well as pharmacological scores, of the compounds classified as active were superior to those of amphotericin B, indicating their potential as candidates for in vivo studies. Therefore, the aim of the present study was to evaluate the in vivo antileishmanial activity of the indazole derivatives NV6 and NV16. Methods: The compounds were administered intralesionally at concentrations of 10 and 5 mg/kg in a BALB/c mouse model of cutaneous leishmaniasis caused by Leishmania amazonensis. To evaluate the efficacy of the compounds, indicators such as lesion size, ulcer area, lesion weight, and parasitic load were determined. Amphotericin B was used as a positive control. Results: The compound NV6 showed leishmanicidal activity comparable to that observed with amphotericin B, with a significant reduction in lesion development and parasite load, while NV16 caused a reduction in ulcer area. Conclusions: These results provide strong evidence for the antileishmanial activity of NV6 and support future studies to improve its pharmacokinetic profile, as well as the investigation of combination therapies with other chemotherapeutic agents currently in use. Full article

(This article belongs to the Special Issue Novel Drug Targets and Drug Candidates for Neglected Tropical Diseases)

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16 pages, 1786 KiB

Open AccessArticle

Repurposing Analysis of Nitroxoline (8-Hydroxy-5-nitroquinoline) as an Antichagasic Compound

by Carlos J. Bethencourt-Estrella, Atteneri López-Arencibia, Isabel M. Calero-Docina, Frieder Fuchs, Patrick Scheid, Jacob Lorenzo-Morales and José E. Piñero

Pharmaceuticals 2025, 18(8), 1106; https://doi.org/10.3390/ph18081106 - 25 Jul 2025

Abstract

Background/Objectives: Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains a major neglected tropical disease, with over six million cases concentrated, primarily in Latin America. Despite decades of research, treatment continues to rely on two outdated drugs—benznidazole and nifurtimox—both of which [...] Read more.

Background/Objectives: Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains a major neglected tropical disease, with over six million cases concentrated, primarily in Latin America. Despite decades of research, treatment continues to rely on two outdated drugs—benznidazole and nifurtimox—both of which exhibit limited efficacy and are associated with severe side effects. In this context, drug repurposing presents a promising strategy to accelerate the development of safer and more effective therapies. Nitroxoline, a hydroxyquinoline compound widely used in Europe to treat bacterial urinary tract infections, has recently garnered attention for its broad-spectrum antimicrobial and anticancer activities. This study evaluated the antitrypanosomal potential of nitroxoline against both epimastigote and intracellular amastigote forms of T. cruzi, demonstrating significantly greater efficacy than benznidazole. Methods: In addition to its antiparasitic activity, we investigated the mechanism of parasite death and found that nitroxoline induces hallmarks of programmed cell death, including chromatin condensation, mitochondrial membrane depolarization, ATP depletion, reactive oxygen species accumulation, and increased membrane permeability. These cellular events are critical for minimizing host tissue inflammation and suggest a safer therapeutic profile. Results: The nitroxoline was shown to induce greater activity than the reference treatment, benznidazole, in addition to triggering events related to apoptotic or silent cell death. Conclusions: Given its established clinical use and favorable safety data, nitroxoline emerges as a strong candidate for further investigation as a repurposed treatment for Chagas disease. Future work should focus on in vivo efficacy, pharmacokinetics, and drug delivery strategies to enhance systemic bioavailability. Full article

(This article belongs to the Special Issue Recent Advancements in the Development of Antiprotozoal Agents)

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18 pages, 7108 KiB

Open AccessArticle

SMYD5-BRD4 Interaction Drives Hepatocellular Carcinoma Progression: A Combined in Silico and Experimental Analysis

by Mingye Hu, Shiji Chen, Yumiao Zhen, Xin Wang, Yiwen Zhong, Xiaoxu Liang, Cheong-Meng Chong and Hai-Jing Zhong

Pharmaceuticals 2025, 18(8), 1105; https://doi.org/10.3390/ph18081105 - 25 Jul 2025

Abstract

Background/Objectives: Hepatocellular carcinoma (LIHC) poses significant challenges due to limited targeted therapeutic options. This study investigates SMYD5, an oncogene implicated in the pathogenesis of LIHC, and its interaction with the BRD4 protein. Methods: We employed bioinformatics analyses alongside experimental validations to assess [...] Read more.

Background/Objectives: Hepatocellular carcinoma (LIHC) poses significant challenges due to limited targeted therapeutic options. This study investigates SMYD5, an oncogene implicated in the pathogenesis of LIHC, and its interaction with the BRD4 protein. Methods: We employed bioinformatics analyses alongside experimental validations to assess SMYD5 expression across various cancers, particularly LIHC. This included survival analysis, protein expression studies, and functional assays to understand the role of SMYD5 in LIHC progression. Results: Our findings demonstrate that SMYD5 expression is markedly elevated in LIHC tumor tissues compared to normal liver tissues. Moreover, high levels of SMYD5 correlate with poor overall survival and disease-free survival rates in LIHC patients. Functional assays indicate that the knockdown of SMYD5 significantly inhibits cell proliferation and increases apoptosis in LIHC cell lines. Additionally, a notable interaction between SMYD5 and BRD4 was identified, suggesting a potential therapeutic target in the SMYD5-BRD4 axis. Conclusions: These findings collectively establish SMYD5 as a molecular driver in LIHC pathology and identify the SMYD5-BRD4 interaction axis as a promising therapeutic target for future drug development. Full article

(This article belongs to the Special Issue Selective Histone Deacetylase Isoforms as Potential Therapeutic Targets)

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47 pages, 1514 KiB

Open AccessReview

Iron Deficiency and Iron Deficiency Anemia: A Comprehensive Overview of Established and Emerging Concepts

by Bela Kolarš, Vesna Mijatović Jovin, Nemanja Živanović, Ivana Minaković, Nemanja Gvozdenović, Isidora Dickov Kokeza and Marija Lesjak

Pharmaceuticals 2025, 18(8), 1104; https://doi.org/10.3390/ph18081104 - 25 Jul 2025

Abstract

Iron deficiency (ID) is the most prevalent micronutrient deficiency globally, affecting approximately one in four individuals, with a particularly high burden among children, women of reproductive age, and populations in low- and middle-income countries. It contributes significantly to the global burden of disease, [...] Read more.

Iron deficiency (ID) is the most prevalent micronutrient deficiency globally, affecting approximately one in four individuals, with a particularly high burden among children, women of reproductive age, and populations in low- and middle-income countries. It contributes significantly to the global burden of disease, with consequences ranging from impaired cognitive and motor development in children to increased risks during pregnancy, including low birth weight, preterm delivery, and maternal mortality, as well as reduced physical performance and quality of life in adults. ID often precedes iron deficiency anemia (IDA), though clinical and functional impairments—such as cognitive deficits, immune dysfunction, and fatigue—can occur even in the absence of anemia. Despite its widespread nature, challenges remain in precisely defining, diagnosing, and treating ID effectively. Advances in diagnostic tools allow for earlier detection, while novel therapeutic strategies, including updated oral dosing regimens and modern intravenous iron formulations, offer improved efficacy and tolerability. These approaches are particularly valuable in minimizing gastrointestinal side effects and enhancing patient adherence. This review is based on a comprehensive literature search conducted primarily through PubMed and Scopus, emphasizing studies published within the past 10–15 years. It is thematically structured to explore the epidemiology, health consequences, diagnostic complexities, and therapeutic developments related to ID. It highlights the multifactorial nature of ID and underscores the urgent need for early identification, targeted interventions, and updated clinical guidelines to reduce the long-term health and societal impacts of this preventable and treatable condition. Full article

(This article belongs to the Section Pharmacology)

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38 pages, 12524 KiB

Open AccessArticle

Therapeutic Efficacy of Plant-Derived Exosomes for Advanced Scar Treatment: Quantitative Analysis Using Standardized Assessment Scales

by Lidia Majewska, Agnieszka Kondraciuk, Iwona Paciepnik, Agnieszka Budzyńska and Karolina Dorosz

Pharmaceuticals 2025, 18(8), 1103; https://doi.org/10.3390/ph18081103 - 25 Jul 2025

Abstract

Background: Wound healing and scar management remain significant challenges in dermatology and aesthetic medicine. Recent advances in regenerative medicine have introduced plant-derived exosome-like nanoparticles (PDENs) as potential therapeutic agents due to their bioactive properties. This study examines the clinical application of rose [...] Read more.

Background: Wound healing and scar management remain significant challenges in dermatology and aesthetic medicine. Recent advances in regenerative medicine have introduced plant-derived exosome-like nanoparticles (PDENs) as potential therapeutic agents due to their bioactive properties. This study examines the clinical application of rose stem cell exosomes (RSCEs) in combination with established treatments for managing different types of scars. Methods: A case series of four patients with different scar etiologies (dog bite, hot oil burn, forehead trauma, and facial laser treatment complications) was treated with RSCEs in combination with microneedling (Dermapen 4.0, 0.2–0.4 mm depth) and/or thulium laser therapy (Lutronic Ultra MD, 8–14 J), or as a standalone topical treatment. All cases underwent sequential treatments over periods ranging from two to four months, with comprehensive photographic documentation of the progression. The efficacy was assessed through clinical photography and objective evaluation using the modified Vancouver Scar Scale (mVSS) and the Patient and Observer Scar Assessment Scale (POSAS), along with assessment of scar appearance, texture, and coloration. Results: All cases demonstrated progressive improvement throughout the treatment course. The dog bite scar showed significant objective improvement, with a 71% reduction in modified Vancouver Scar Scale score (from 7/13 to 2/13) and a 61% improvement in Patient and Observer Scar Assessment Scale scores after four combined treatments. The forehead trauma case exhibited similar outcomes, with a 71% improvement in mVSS score and 55–57% improvement in POSAS scores. The hot oil burn case displayed the most dramatic improvement, with a 78% reduction in mVSS score and over 70% improvement in POSAS scores, resulting in near-complete resolution without visible scarring. The facial laser complication case showed a 75% reduction in mVSS score and ~70% improvement in POSAS scores using only topical exosome application without device-based treatments. Clinical improvements across all cases included reduction in elevation, improved texture, decreased erythema, and better integration with surrounding skin. No adverse effects were reported in any of the cases. Conclusions: This preliminary case series suggests that plant-derived exosome-like nanoparticles, specifically rose stem cell exosomes (RSCEs), may enhance scar treatment outcomes when combined with microneedling and laser therapy, or even as a standalone topical treatment. The documented objective improvements, measured by standardized scar assessment scales, along with clinical enhancements in scar appearance, texture, and coloration across different scar etiologies—dog bite, burn, traumatic injury, and iatrogenic laser damage—suggest that this approach may offer a valuable addition to the current armamentarium of scar management strategies. Notably, the successful treatment of laser-induced complications using only topical exosome application demonstrates the versatility and potential of this therapeutic modality. Full article

(This article belongs to the Special Issue Exosome and Biotherapeutic Strategies for Dermatological and Oncological Skin Complications)

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16 pages, 1248 KiB

Open AccessArticle

Coronary Artery Calcium Score as a Predictor of Anthracycline-Induced Cardiotoxicity: The ANTEC Study

by Anna Borowiec, Patrycja Ozdowska, Magdalena Rosinska, Agnieszka Maria Zebrowska, Sławomir Jasek, Beata Kotowicz, Joanna Waniewska, Hanna Kosela-Paterczyk, Elzbieta Lampka, Katarzyna Pogoda, Zbigniew Nowecki and Jan Walewski

Pharmaceuticals 2025, 18(8), 1102; https://doi.org/10.3390/ph18081102 - 25 Jul 2025

Abstract

Background: Many risk factors for cancer therapy-related cardiovascular toxicity overlap with risk factors for atherosclerosis. According to the ESC 2022 Cardio-Oncology Guidelines, coronary computed tomography angiography and coronary artery calcium score are not recommended as part of routine risk assessment prior to oncological [...] Read more.

Background: Many risk factors for cancer therapy-related cardiovascular toxicity overlap with risk factors for atherosclerosis. According to the ESC 2022 Cardio-Oncology Guidelines, coronary computed tomography angiography and coronary artery calcium score are not recommended as part of routine risk assessment prior to oncological treatment. The aim of this study was to prospectively assess the influence of coronary artery calcium score (CAC score) on cancer therapy-related cardiac dysfunction in patients with moderate and high risk of cardiovascular toxicity, qualified for anthracycline treatment. Methods: In all patients, risk factors were collected, laboratory tests, echocardiography with global longitudinal strain (GLS) assessment and coronary artery tomography with coronary artery calcium score were performed. A total of 80 patients were included in the study, of which 77 (96.25%) were followed for an average of 11.5 months. The mean age at baseline was 60.5 years and 72 (93.51%) were women. Results: During observation, five patients (6.49%) died, including two due to heart failure and three due to cancer progression. The majority of patients (59, 76.6%) had breast cancer, 11 (14.3%) were diagnosed with sarcoma and seven (9.1%) with lymphoma. According to the HFA-ICOS risk score, 40 patients (51.9%) were classified as moderate risk (MR), and 37 patients (48.1%) as high risk (HR) for cancer therapy-related cardiovascular toxicity. A CAC score greater than 100 was calculated in 17 (22.1%) patients and greater than 400 in three (3.9%) patients. The CAC score above zero was more common in older patients and in patients classified as high risk (p < 0.001). There was also a significant association between CAC score and hypertension, hyperlipidemia, chronic kidney disease, and the level of NT-proBNP. During 12-month follow-up, mild CTRCD occurred in 38 (49.4%) patients, moderate CTRCD was diagnosed in seven (9.1%), and severe in three (3.9%) patients. In the univariable analysis, CTRCD was more common in the high-risk group (p = 0.005) and in patients with a CAC score greater than zero (p = 0.036). In multivariable analysis, the incidence of CTRCD remains higher in the CAC score > 0 group, even after adjusting for age, hypertension, and hyperlipidemia. In this study group, the CTRCD rates increased with the HFA-ICOS risk score. Conclusions: In moderate and high-risk patients, a coronary artery calcium score greater than zero was identified as a significant risk factor for the development of cancer therapy-related cardiac dysfunction during anthracycline-based treatment. Furthermore, the HFA-ICOS risk score demonstrated good correlation with the incidence of CTRCD in this study, supporting its validity as a predictive tool in patients receiving anthracycline therapy. Full article

(This article belongs to the Special Issue Advancing Cardio-Oncology: Mechanisms of Cardiotoxicity and Therapeutic Options for Old and New Anticancer Drugs)

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39 pages, 2934 KiB

Open AccessReview

Phytocannabinoids as Novel SGLT2 Modulators for Renal Glucose Reabsorption in Type 2 Diabetes Management

by Raymond Rubianto Tjandrawinata, Dante Saksono Harbuwono, Sidartawan Soegondo, Nurpudji Astuti Taslim and Fahrul Nurkolis

Pharmaceuticals 2025, 18(8), 1101; https://doi.org/10.3390/ph18081101 - 24 Jul 2025

Abstract

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have transformed type 2 diabetes mellitus (T2DM) management by promoting glucosuria, lowering glycated hemoglobin (HbA1c), blood pressure, and weight; however, their use is limited by genitourinary infections and ketoacidosis. Phytocannabinoids—bioactive compounds from Cannabis sativa—exhibit multi-target [...] Read more.

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have transformed type 2 diabetes mellitus (T2DM) management by promoting glucosuria, lowering glycated hemoglobin (HbA1c), blood pressure, and weight; however, their use is limited by genitourinary infections and ketoacidosis. Phytocannabinoids—bioactive compounds from Cannabis sativa—exhibit multi-target pharmacology, including interactions with cannabinoid receptors, Peroxisome Proliferator-Activated Receptors (PPARs), Transient Receptor Potential (TRP) channels, and potentially SGLT2. Objective: To evaluate the potential of phytocannabinoids as novel modulators of renal glucose reabsorption via SGLT2 and to compare their efficacy, safety, and pharmacological profiles with synthetic SGLT2 inhibitors. Methods: We performed a narrative review encompassing the following: (1) the molecular and physiological roles of SGLT2; (2) chemical classification, natural sources, and pharmacokinetics/pharmacodynamics of major phytocannabinoids (Δ⁹-Tetrahydrocannabinol or Δ⁹-THC, Cannabidiol or CBD, Cannabigerol or CBG, Cannabichromene or CBC, Tetrahydrocannabivarin or THCV, and β-caryophyllene); (3) in silico docking and drug-likeness assessments; (4) in vitro assays of receptor binding, TRP channel modulation, and glucose transport; (5) in vivo rodent models evaluating glycemic control, weight change, and organ protection; (6) pilot clinical studies of THCV and case reports of CBD/BCP; (7) comparative analysis with established synthetic inhibitors. Results: In silico studies identify high-affinity binding of several phytocannabinoids within the SGLT2 substrate pocket. In vitro, CBG and THCV modulate SGLT2-related pathways indirectly via TRP channels and CB receptors; direct IC₅₀ values for SGLT2 remain to be determined. In vivo, THCV and CBD demonstrate glucose-lowering, insulin-sensitizing, weight-reducing, anti-inflammatory, and organ-protective effects. Pilot clinical data (n = 62) show that THCV decreases fasting glucose, enhances β-cell function, and lacks psychoactive side effects. Compared to synthetic inhibitors, phytocannabinoids offer pleiotropic benefits but face challenges of low oral bioavailability, polypharmacology, inter-individual variability, and limited large-scale trials. Discussion: While preclinical and early clinical data highlight phytocannabinoids’ potential in SGLT2 modulation and broader metabolic improvement, their translation is impeded by significant challenges. These include low oral bioavailability, inconsistent pharmacokinetic profiles, and the absence of standardized formulations, necessitating advanced delivery system development. Furthermore, the inherent polypharmacology of these compounds, while beneficial, demands comprehensive safety assessments for potential off-target effects and drug interactions. The scarcity of large-scale, well-controlled clinical trials and the need for clear regulatory frameworks remain critical hurdles. Addressing these aspects is paramount to fully realize the therapeutic utility of phytocannabinoids as a comprehensive approach to T2DM management. Conclusion: Phytocannabinoids represent promising multi-target agents for T2DM through potential SGLT2 modulation and complementary metabolic effects. Future work should focus on pharmacokinetic optimization, precise quantification of SGLT2 inhibition, and robust clinical trials to establish efficacy and safety profiles relative to synthetic inhibitors. Full article

(This article belongs to the Special Issue Advancements in Cardiovascular and Antidiabetic Drug Therapy, 2nd Edition)

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Graphical abstract

29 pages, 1550 KiB

Open AccessReview

Phytochemical Modulators of Nociception: A Review of Cannabis Terpenes in Chronic Pain Syndromes

by Aniello Alfieri, Sveva Di Franco, Vincenzo Maffei, Pasquale Sansone, Maria Caterina Pace, Maria Beatrice Passavanti and Marco Fiore

Pharmaceuticals 2025, 18(8), 1100; https://doi.org/10.3390/ph18081100 - 24 Jul 2025

Abstract

Cannabis sativa L. is a phytochemically rich plant with therapeutic potential across various clinical domains, including pain, inflammation, and neurological disorders. Among its constituents, terpenes are gaining recognition for their capacity to modulate the pathophysiological processes underlying chronic pain syndromes. Traditionally valued for [...] Read more.

Cannabis sativa L. is a phytochemically rich plant with therapeutic potential across various clinical domains, including pain, inflammation, and neurological disorders. Among its constituents, terpenes are gaining recognition for their capacity to modulate the pathophysiological processes underlying chronic pain syndromes. Traditionally valued for their aromatic qualities, terpenes such as myrcene, β-caryophyllene (BCP), limonene, pinene, linalool, and humulene have demonstrated a broad spectrum of biological activities. Beyond their observable analgesic, anti-inflammatory, and anxiolytic outcomes, these compounds exert their actions through distinct molecular mechanisms. These include the activation of cannabinoid receptor type 2 (CB₂), the modulation of transient receptor potential (TRP) and adenosine receptors, and the inhibition of pro-inflammatory signalling pathways such as Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Cyclooxygenase-2 (COX-2). This narrative review synthesizes the current preclinical and emerging clinical data on terpene-mediated analgesia, highlighting both monoterpenes and sesquiterpenes, and discusses their potential for synergistic interaction with cannabinoids, the so-called entourage effect. Although preclinical findings are promising, clinical translation is limited by methodological variability, the lack of standardized formulations, and insufficient pharmacokinetic characterization. Further human studies are essential to clarify their therapeutic potential. Full article

(This article belongs to the Section Pharmacology)

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16 pages, 2379 KiB

Open AccessArticle

Atractylodes lancea (Thunb.) DC. [Asteraceae] Rhizome-Derived Exosome-like Nanoparticles Suppress Lipopolysaccharide-Induced Inflammation by Reducing Toll-like Receptor 4 Expression in BV-2 Murine Microglial Cells

by Mizusa Hyodo, Kei Kawada, Tomoaki Ishida, Yuki Izawa-Ishizawa, Ryoko Matoba, Rina Okamoto, Kohei Jobu, Io Horikawa, Fuka Aizawa, Kenta Yagi, Takahiro Niimura, Yayoi Kawano, Shinji Abe, Yukihiro Hamada, Mitsuhiro Goda and Keisuke Ishizawa

Pharmaceuticals 2025, 18(8), 1099; https://doi.org/10.3390/ph18081099 - 24 Jul 2025

Abstract

Background/Objectives: Atractylodes lancea (Thunb.) DC. [Asteraceae] (ALR)-derived exosome-like nanoparticles (ALR-ELNs) exhibit anti-neuroinflammatory effects in microglial cells. However, the associated mechanisms and pathways are unknown. We aimed to characterize the effects of ALR-ELNs on inflammatory responses of BV-2 microglial cells to lipopolysaccharide (LPS) [...] Read more.

Background/Objectives: Atractylodes lancea (Thunb.) DC. [Asteraceae] (ALR)-derived exosome-like nanoparticles (ALR-ELNs) exhibit anti-neuroinflammatory effects in microglial cells. However, the associated mechanisms and pathways are unknown. We aimed to characterize the effects of ALR-ELNs on inflammatory responses of BV-2 microglial cells to lipopolysaccharide (LPS) using RNA sequencing. Methods: ALR-ELNs were fractionated from ALR. BV-2 microglial murine cells were stimulated with LPS after treatment with ALR-ELNs. RNA sequencing was performed to analyze variations in mRNA levels. Ingenuity pathway analysis (IPA) was performed to investigate the mechanism of action of ALR-ELNs. mRNA expression was assessed using real-time quantitative polymerase chain reaction (qPCR). Results: The expression of 651 genes was downregulated, whereas that of 1204 genes was upregulated in LPS-stimulated BV2 cells pretreated with ALR-ELNs. The IPA showed that the effects of ALR-ELNs on inflammation took place through pathogen-influenced signaling. Network analysis via IPA showed that the Toll-like receptor (TLR) is involved in the suppression of inflammation by ALR-ELNs. The qPCR analysis showed that pretreatment with ALR-ELNs significantly reduced TLR4 mRNA expression. Conclusions: ALR-ELNs suppress the release of inflammatory mediators by downregulating TLR4 expression, which is a novel mechanism by which ALR-ELNs act on microglia. Identifying active ingredients in ALR-ELNs that downregulate TLR4 expression can advance the development of therapeutic drugs for neuroinflammatory diseases. Full article

(This article belongs to the Section Natural Products)

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