Pharmaceuticals

21 pages, 5109 KiB

Open AccessArticle

Auricularia auricula’s Exopolysaccharide Mitigates DSS-Induced Colitis Through Dectin–1-Mediated Immunomodulation and Microbiota Remodeling

by Luísa Coutinho Coelho, Luísa Dan Favilla, Thais Bergmann de Castro, Maria Carolina B. Di Medeiros Leal, Christian Hoffmann and Anamélia Lorenzetti Bocca

Pharmaceuticals 2025, 18(8), 1085; https://doi.org/10.3390/ph18081085 - 22 Jul 2025

Abstract

Background/Objectives: Ulcerative colitis (UC) is characterized by the interplay between immune responses and dysbiosis in disease development. Aiming to provide additional insights into disease development and potential treatment strategies, the present study investigates the local effect of oral treatment with polysaccharides obtained from [...] Read more.

Background/Objectives: Ulcerative colitis (UC) is characterized by the interplay between immune responses and dysbiosis in disease development. Aiming to provide additional insights into disease development and potential treatment strategies, the present study investigates the local effect of oral treatment with polysaccharides obtained from Auricularia auricula’s submerged culture in an experimental model of DSS-induced colitis and its impact on lesion resolution. Methods: The structure and monosaccharide composition of Auricularia polysaccharides were characterized through Nuclear Magnetic Resonance (NMR). To evaluate the effect of this polysaccharide on the murine model, wild-type and Dectin-1 knockout mice were treated or not with the exopolysaccharide (EPS) while under DSS consumption. During the experimental period, feces samples were collected to evaluate microbial shifts during disease development, and, finally, the colonic tissue was analyzed to assess the inflammatory process and cytokine production. Results: The EPS composition showed a polymeric mixture of glucans and fucogalactomannans. The treatment of the wild-type DSS-induced colitis group improved the inflammatory response by increasing gut–homeostatic cytokines, such as interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-α). The Dectin-1 KO mice group did not show the same enhancement after EPS treatment. The microbiome analysis revealed a difference in the genotype, and the treatment modified the DSS microbiome modulation, with nine and four ASVs in WT and Dectin-1 KO mice, respectively. Conclusions: The EPS treatment demonstrated therapeutic potential in treating inflammatory intestinal diseases by modulating cytokine secretion and microbiota composition, which is dependent on the Dectin-1 receptor’s carbohydrate recognition. Full article

(This article belongs to the Special Issue Natural Products Derived from Fungi and Their Biological Activities)

12 pages, 1751 KiB

Open AccessArticle

Causal Inference of Adverse Drug Events in Pulmonary Arterial Hypertension: A Pharmacovigilance Study

by Hongmei Li, Xiaojun He, Cui Chen, Qiao Ni, Linghao Ni, Jiawei Zhou and Bin Peng

Pharmaceuticals 2025, 18(8), 1084; https://doi.org/10.3390/ph18081084 - 22 Jul 2025

Abstract

Objective: Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Adverse events (AEs) related to its drug treatment seriously damaged the patient’s health. This study aims to clarify the causal relationship between PAH drugs and these AEs by combining pharmacovigilance signal detection [...] Read more.

Objective: Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Adverse events (AEs) related to its drug treatment seriously damaged the patient’s health. This study aims to clarify the causal relationship between PAH drugs and these AEs by combining pharmacovigilance signal detection with the Bayesian causal network model. Methods: Patient data were obtained from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), covering reports from 2013 to 2023. In accordance with standard pharmacovigilance methodologies, disproportionality analysis was performed to detect signals. Target drugs were selected based on the following criteria: number of reports (a) ≥ 3, proportional reporting ratio (PRR) ≥ 2, and chi-square (χ²) ≥ 4. Bayesian causal network models were then constructed to estimate causal relationships. The do-calculus and adjustment formula were applied to calculate the causal effects between drugs and AEs. Results: Signal detection revealed that Ambrisentan, Bosentan, and Iloprost were associated with serious AEs, including death, dyspnea, pneumonia, and edema. For Ambrisentan, the top-ranked adverse drug events (ADEs) based on average causal effect (ACE) were peripheral swelling (ACE = 0.032) and anemia (ACE = 0.021). For Iloprost, the most prominent ADE was hyperthyroidism (ACE = 0.048). Conclusions: This study quantifies causal drug–event relationships in PAH using Bayesian causal networks. The findings offer valuable evidence regarding the clinical safety of PAH medications, thereby improving patient health outcomes. Full article

(This article belongs to the Section Pharmacology)

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26 pages, 1310 KiB

Open AccessReview

Combination Strategies with HSP90 Inhibitors in Cancer Therapy: Mechanisms, Challenges, and Future Perspectives

by Yeongbeom Kim, Su Yeon Lim, Hyun-Ouk Kim, Suk-Jin Ha, Jeong-Ann Park, Young-Wook Won, Sehyun Chae and Kwang Suk Lim

Pharmaceuticals 2025, 18(8), 1083; https://doi.org/10.3390/ph18081083 - 22 Jul 2025

Abstract

Heat shock protein 90 (HSP90) is a molecular chaperone that plays a pivotal role in the stabilization and functional activation of numerous oncoproteins and signaling molecules essential for cancer cell survival and proliferation. Despite the extensive development and clinical evaluation of HSP90 inhibitors, [...] Read more.

Heat shock protein 90 (HSP90) is a molecular chaperone that plays a pivotal role in the stabilization and functional activation of numerous oncoproteins and signaling molecules essential for cancer cell survival and proliferation. Despite the extensive development and clinical evaluation of HSP90 inhibitors, their therapeutic potential as monotherapies has been limited by suboptimal efficacy, dose-limiting toxicity, and the emergence of drug resistance. Recent studies have demonstrated that combination therapies involving HSP90 inhibitors and other anticancer agents such as chemotherapeutics, targeted therapies, and immune checkpoint inhibitors can enhance anticancer activity, overcome resistance mechanisms, and modulate the tumor microenvironment. These synergistic effects are mediated by the concurrent degradation of client proteins, the disruption of signaling pathways, and the enhancement of antitumor immunity. However, the successful clinical implementation of such combination strategies requires the careful optimization of dosage, administration schedules, toxicity management, and patient selection based on predictive biomarkers. In this review, we provide a comprehensive overview of the mechanistic rationale, preclinical and clinical evidence, and therapeutic challenges associated with HSP90 inhibitor-based combination therapies. We also discuss future directions leveraging emerging technologies including multi-omics profiling, artificial intelligence, and nanoparticle-mediated delivery for the development of personalized and effective combination regimens in oncology. Full article

(This article belongs to the Special Issue Hsp90 Inhibitors: Progress, Challenges, and Opportunities in Drug Discovery and Development)

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28 pages, 1104 KiB

Open AccessReview

Tumor Microenvironmental Dynamics in Shaping Resistance to Therapeutic Interventions in Melanoma: A Narrative Review

by Laci M. Turner, Hanna Terhaar, Victoria Jiminez, Bailey J. Anderson, Emily Grant and Nabiha Yusuf

Pharmaceuticals 2025, 18(8), 1082; https://doi.org/10.3390/ph18081082 - 22 Jul 2025

Abstract

Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, [...] Read more.

Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, and other signaling pathways. We explore the interplay between innate and adaptive immunity in the TME and tumor intrinsic resistance mechanisms, such as β-catenin, which has future implications for the usage of ICIs in patients with therapy-resistant tumors. Methods: A total of 1052 studies were extracted from the PubMed database searching for keywords and phrases that included [melanoma AND immune checkpoint inhibitor resistance]. After a title/abstract and full-text review, 101 studies were identified that fit the inclusion/exclusion criteria. Results: Cancer-associated fibroblasts (CAFs), M2 macrophages, and myeloid-derived suppressor cells (MDSCs) are significant in remodeling the TME to promote melanoma growth. Melanoma resistance to ICIs is complex and involves TME alterations, tumor intrinsic factors, and immune evasion. Key components of resistance include reduced CD8+ T cell infiltration, decreased host immune response, and immunosuppressive cytokines. Conclusions: Predictive biomarkers and specific models are the future of individualized melanoma management and show great promise in their approach to targeted therapy production. Tumor profiling can be utilized to help predict the efficacy of ICIs, and specific biomarkers predicting therapy responses are instrumental in moving towards personalized and more efficacious medicine. As more melanoma resistance emerges, alternative and combinatorial therapy based on knowledge of existing resistance mechanisms will be needed. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer)

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23 pages, 869 KiB

Open AccessArticle

Cognitive Behavioral Therapy for Muscle Dysmorphia and Anabolic Steroid-Related Psychopathology: A Randomized Controlled Trial

by Metin Çınaroğlu, Eda Yılmazer, Selami Varol Ülker and Gökben Hızlı Sayar

Pharmaceuticals 2025, 18(8), 1081; https://doi.org/10.3390/ph18081081 - 22 Jul 2025

Abstract

Background/Objectives: Muscle dysmorphia (MD), a subtype of body dysmorphic disorder, is prevalent among males who engage in the non-medical use of anabolic–androgenic steroids (AASs) and performance-enhancing drugs (PEDs). These individuals often experience severe psychopathology, including mood instability, compulsivity, and a distorted body [...] Read more.

Background/Objectives: Muscle dysmorphia (MD), a subtype of body dysmorphic disorder, is prevalent among males who engage in the non-medical use of anabolic–androgenic steroids (AASs) and performance-enhancing drugs (PEDs). These individuals often experience severe psychopathology, including mood instability, compulsivity, and a distorted body image. Despite its clinical severity, no randomized controlled trials (RCTs) have evaluated structured psychological treatments in this subgroup. This study aimed to assess the efficacy of a manualized cognitive behavioral therapy (CBT) protocol in reducing MD symptoms and associated psychological distress among male steroid users. Results: Participants in the CBT group showed significant reductions in MD symptoms from the baseline to post-treatment (MDDI: p < 0.001, d = 1.12), with gains sustained at follow-up. Large effect sizes were also observed in secondary outcomes including depressive symptoms (PHQ-9: d = 0.98), psychological distress (K10: d = 0.93), disordered eating (EDE-Q: d = 0.74), and exercise addiction (EAI: d = 1.07). No significant changes were observed in the control group. Significant group × time interactions were found for all outcomes (all p < 0.01), indicating CBT’s specific efficacy. Discussion: This study provides the first RCT evidence that CBT significantly reduces both core MD symptoms and steroid-related psychopathology in men engaged in AAS/PED misuse. Improvements extended to mood, body image perception, and compulsive exercise behaviors. These findings support CBT’s transdiagnostic applicability in addressing both the cognitive–behavioral and affective dimensions of MD. Materials and Methods: In this parallel-group, open-label RCT, 59 male gym-goers with DSM-5-TR diagnoses of MD and a history of AAS/PED use were randomized to either a 12-week CBT intervention (n = 30) or a waitlist control group (n = 29). CBT sessions were delivered weekly online and targeted distorted muscularity beliefs, compulsive behaviors, and emotional dysregulation. Primary and secondary outcomes—Muscle Dysmorphic Disorder Inventory (MDDI), PHQ-9, K10, EDE-Q, EAI, and BIG—were assessed at the baseline, post-treatment, and 3-month follow-up. A repeated-measures ANOVA and paired t-tests were used to analyze time × group interactions. Conclusions: CBT offers an effective, scalable intervention for individuals with muscle dysmorphia complicated by anabolic steroid use. It promotes broad psychological improvement and may serve as a first-line treatment option in high-risk male fitness populations. Future studies should examine long-term outcomes and investigate implementation in diverse clinical and cultural contexts. Full article

(This article belongs to the Special Issue Clinical Advances in the Neuropharmacological Treatment of Substance Use Disorders: 2nd Edition)

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16 pages, 7245 KiB

Open AccessArticle

α-Ketoglutarate Attenuates Oxidative Stress-Induced Neuronal Aging via Modulation of the mTOR Pathway

by Ruoqing Guan, Zhaoyun Xue, Kaikun Huang, Yanqing Zhao, Gongyun He, Yuxing Dai, Mo Liang, Yanzi Wen, Xueshi Ye, Peiqing Liu and Jianwen Chen

Pharmaceuticals 2025, 18(8), 1080; https://doi.org/10.3390/ph18081080 - 22 Jul 2025

Abstract

Background/Objectives: Oxidative stress constitutes a principal pathophysiological mechanism driving neurodegeneration and brain aging. α-Ketoglutarate (AKG), a key intermediate of the tricarboxylic acid (TCA) cycle, has shown potential in longevity and oxidative stress resistance. However, the role of AKG in oxidative stress-induced neuronal [...] Read more.

Background/Objectives: Oxidative stress constitutes a principal pathophysiological mechanism driving neurodegeneration and brain aging. α-Ketoglutarate (AKG), a key intermediate of the tricarboxylic acid (TCA) cycle, has shown potential in longevity and oxidative stress resistance. However, the role of AKG in oxidative stress-induced neuronal senescence and its interaction with the mTOR signaling pathway during neuronal aging remain poorly understood, posing a key challenge for developing senescence-targeted therapies. Methods: We investigated the neuroprotective effects of AKG using H₂O₂-induced senescence in HT22 cells and a D-galactose-induced brain aging mouse model. Assessments encompassed SA-β-gal staining, EdU incorporation, mitochondrial membrane potential (JC-1), and ROS measurement. Antioxidant markers, ATP levels, and the NAD⁺/NADH ratio were also analyzed. Proteomic profiling (DIA-MS) and KEGG/GSEA enrichment analyses were employed to identify AKG-responsive signaling pathways, and Western blotting validated changes in mTOR signaling and downstream effectors. Results: AKG significantly alleviated H₂O₂-induced senescence in HT22 cells, evidenced by enhanced cell viability, reduced ROS level, restored mitochondrial function, and downregulated p53/p21 expression. In vivo, AKG administration improved cognitive deficits and vestibulomotor dysfunction while ameliorating brain oxidative damage in aging mice. Proteomics revealed mTOR signaling pathways as key targets for AKG’s anti-aging activity. Mechanistically, AKG suppressed mTOR phosphorylation and activated ULK1, suggesting modulation of autophagy and metabolic homeostasis. These effects were accompanied by enhanced antioxidant enzyme activities and improved redox homeostasis. Conclusions: Our study demonstrates that AKG mitigates oxidative stress-induced neuronal senescence through suppression of the mTOR pathway and enhancement of mitochondrial and antioxidant function. These findings highlight AKG as a metabolic intervention candidate for age-related neurodegenerative diseases. Full article

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17 pages, 1681 KiB

Open AccessArticle

Pharmacokinetics, Safety, and Tolerability of (R)-Ketamine Hydrochloride Injection, a Novel Rapid-Acting Antidepressant, in Healthy Chinese Subjects

by Rui Wang, Yuqian Yang, Tong Zhou, Bingjie Zou and Li Ding

Pharmaceuticals 2025, 18(7), 1079; https://doi.org/10.3390/ph18071079 - 21 Jul 2025

Abstract

Objectives: (R)-ketamine hydrochloride injection is a novel, rapid-acting antidepressant for the treatment of treatment-resistant depression. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of (R)-ketamine hydrochloride injection in healthy Chinese subjects following ascending single intravenous doses ranging [...] Read more.

Objectives: (R)-ketamine hydrochloride injection is a novel, rapid-acting antidepressant for the treatment of treatment-resistant depression. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of (R)-ketamine hydrochloride injection in healthy Chinese subjects following ascending single intravenous doses ranging from 10.0 mg to 180 mg. Methods: This randomized, double-blind, placebo-controlled study was conducted in 50 healthy male and female Chinese subjects after single ascending doses of (R)-ketamine hydrochloride injection (10.0, 30.0, 60.0, 120, and 180 mg). Ten subjects (including two subjects treated with a placebo) were included in each dose cohort. Pharmacokinetic characteristics, safety, and tolerability profiles of the study drug were evaluated. Results: After the intravenous doses administered from 10.0 mg to 180 mg of (R)-ketamine hydrochloride injection to the subjects, the C_max and AUC values for both (R)-ketamine and its metabolite (R)-norketamine in the subjects increased approximately proportionally to the doses. The average peak plasma concentration levels at the five dose cohorts ranged from 56.0 to 1424 ng/mL and 27.7 to 491 ng/mL for (R)-ketamine and (R)-norketamine, respectively. The adverse events of (R)-ketamine hydrochloride injection were temporary and recovered spontaneously without treatment. Conclusions: In summary, (R)-ketamine hydrochloride injection was safe and well tolerated in healthy Chinese subjects. The clinical study results laid a foundation for the further clinical studies of (R)-ketamine hydrochloride injection in patients. Full article

(This article belongs to the Section Pharmacology)

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19 pages, 5443 KiB

Open AccessArticle

Toosendanin Induces Hepatotoxicity by Facilitating ALOX5-Mediated Lipid Peroxidation and Sensitizing Cells to Ferroptosis

by Jiajie Ni, Liru Huang, Yifan Tian, Changxin Zhao, Ziyi Zhou, Feihai Shen and Zhiying Huang

Pharmaceuticals 2025, 18(7), 1078; https://doi.org/10.3390/ph18071078 - 21 Jul 2025

Abstract

Background: Fructus Meliae Toosendan (FMT) is a traditional Chinese medicine used to treat ascariasis; however, its reported hepatotoxicity limits its application. Toosendanin (TSN), as a principal active component, is recognized as the primary toxic ingredient responsible for FMT-induced hepatotoxicity, but the underlying [...] Read more.

Background: Fructus Meliae Toosendan (FMT) is a traditional Chinese medicine used to treat ascariasis; however, its reported hepatotoxicity limits its application. Toosendanin (TSN), as a principal active component, is recognized as the primary toxic ingredient responsible for FMT-induced hepatotoxicity, but the underlying mechanisms remain elusive. Methods: HepG2 cells were treated with TSN and analyzed using Western blotting and qPCR assays for related gene transcription and protein expression. Lipid peroxidation and ferroptosis markers were measured. Balb/c and C57BL/6 mice received various doses of TSN administration, and their liver function was assessed with serum biochemistry and histopathology. Network pharmacology and oxidative lipidomics were performed to identify key targets and metabolites. Results: TSN triggered ferroptosis both in vitro and in vivo, accompanied by the elevated expression of 5-lipoxygenase (ALOX5) and its downstream metabolites. The ALOX5 level modulated hepatocyte sensitivity to TSN-induced ferroptotic damage. An ALOX5 knockdown alleviated TSN-induced liver injury and ferroptosis in vivo. Conclusions: Our study demonstrated that TSN induces hepatotoxicity by facilitating ALOX5-mediated lipid peroxidation, thereby sensitizing cells to ferroptosis. Full article

(This article belongs to the Section Pharmacology)

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21 pages, 3781 KiB

Open AccessArticle

Ginsenoside Rg3 Adjunctively Increases the Efficacy of Gefitinib Against NSCLC by Regulating EGFR Copy Number

by Xinyi Lv, Yuehan Song, Tianhua Liu, Dingdan Zhang, Xinpeng Ye, Qingqing Wang, Rongrong Li, Jiayi Chen, Shujing Zhang, Xue Yu and Chunying Hou

Pharmaceuticals 2025, 18(7), 1077; https://doi.org/10.3390/ph18071077 - 21 Jul 2025

Abstract

Background: Lung cancer has the highest morbidity and mortality of all tumors, and the development of TKI drugs targeting EGFR activating mutations has brought lung cancer treatment into the targeted era. In view of their low efficacy and susceptibility to drug resistance, [...] Read more.

Background: Lung cancer has the highest morbidity and mortality of all tumors, and the development of TKI drugs targeting EGFR activating mutations has brought lung cancer treatment into the targeted era. In view of their low efficacy and susceptibility to drug resistance, there is an urgent need to find strategies to increase their efficacy and reduce the incidence of drug resistance. Methods: In this study, we examined the distribution and probability of EGFR mutations in non-small cell lung cancer patients in the cBioPortal database and compared the survival prognosis of patients with normal and abnormal EGFR, NSCLC patients treated with and without TKI, and NSCLC patients with different EGFR gene copy numbers. We established a mouse lung cancer model and examined the histomorphological characteristics of lung tissues via hematoxylin and eosin staining. Additionally, changes in the copy number of the EGFR gene and its protein expression levels were detected using RT-qPCR and Western blotting. Furthermore, we quantified the concentration of the EGFR protein using ELISA. Results: We found no significant advantage of EGFR-TKI therapy over first-line chemotherapeutic agents in patients with EGFR-abnormal NSCLC. The reason for this may be related to the abnormal EGFR gene copy number; the higher the copy number increases, the worse the survival prognosis of the patients. In molecular biology experiments, we demonstrated that ginsenoside Rg3 down-regulated the copy number of 18, 19, 20, and 21 exons and protein expression of EGFR in lung adenocarcinoma cells. The results of in vivo pharmacodynamic assays confirmed that sequential administration of ginsenoside Rg3 with TKI drugs could achieve a gainful complementary effect. Conclusions: Ginsenoside Rg3 down-regulates the copy number of EGFR important exons in EGFR-mutant cells of lung adenocarcinoma and reduces EGFR protein expression, thus providing a high gainful complementary effect in combination with EGFR-TKI. Full article

(This article belongs to the Topic Advances in Anti-Cancer Drugs: 2nd Edition)

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22 pages, 973 KiB

Open AccessReview

Zebrafish Models of Induced Lymphangiogenesis: Current Advancements and Therapeutic Discovery

by Srdjan Boskovic and Kazuhide Shaun Okuda

Pharmaceuticals 2025, 18(7), 1076; https://doi.org/10.3390/ph18071076 - 21 Jul 2025

Abstract

Lymphangiogenesis, the formation of new lymphatic vessels, is essential for embryonic development and the maintenance of tissue fluid balance, as well as for responding to physiological challenges such as injury, inflammation, and oedema. This process is also aberrantly activated in pathological conditions including [...] Read more.

Lymphangiogenesis, the formation of new lymphatic vessels, is essential for embryonic development and the maintenance of tissue fluid balance, as well as for responding to physiological challenges such as injury, inflammation, and oedema. This process is also aberrantly activated in pathological conditions including lymphatic anomalies and cancer. Understanding the molecular and cellular mechanisms regulating induced lymphangiogenesis in various conditions is critical for the development of novel anti- or pro-lymphangiogenic therapeutic strategies. In recent years, the zebrafish has emerged as an important model organism for studying both physiological and pathological lymphangiogenesis. Its optical transparency, conserved lymphatic architecture and signalling pathways, and amenability to genetic manipulation and drug screening make it an especially well-suited model. In this review, we highlight zebrafish models used to investigate induced lymphangiogenesis in the context of regeneration, inflammation, fluid imbalance, and congenital lymphatic anomalies. We will also demonstrate how zebrafish are used to discover new drugs targeting lymphatic vessels under various conditions. Finally, we will discuss the current limitations of using zebrafish to model induced lymphangiogenesis and highlight potential future directions. The findings presented in this review underscore the undeniable value the zebrafish model brings to lymphatic research and therapeutic discovery. Full article

(This article belongs to the Section Medicinal Chemistry)

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20 pages, 1648 KiB

Open AccessArticle

Semaglutide in MASLD Patients: Improved Survival and Liver Outcomes

by Mohamad Suki, Johnny Amer, Yael Milgrom, Muhammad Massarwa, Wadi Hazou, Yariv Tiram, Ofer Perzon, Yousra Sharif, Joseph Sackran, Revital Alon, Nachum Emil Eliezer Lourie, Itamar Raz, Ashraf Imam, Abed Khalaileh and Rifaat Safadi

Pharmaceuticals 2025, 18(7), 1075; https://doi.org/10.3390/ph18071075 - 21 Jul 2025

Abstract

Introduction: Semaglutide (SEMA) has shown potential benefits in metabolic dysfunction-associated steatotic liver disease (MASLD). This large real-world study aimed to evaluate the effects of SEMA on MASLD patients’ clinical outcomes and liver-related complications. Results: Following propensity score matching based on 34 [...] Read more.

Introduction: Semaglutide (SEMA) has shown potential benefits in metabolic dysfunction-associated steatotic liver disease (MASLD). This large real-world study aimed to evaluate the effects of SEMA on MASLD patients’ clinical outcomes and liver-related complications. Results: Following propensity score matching based on 34 variables (demographics, comorbidities, laboratory tests, and medication history), SEMA-treated (n = 19,112) patients were compared with non-SEMA (n = 19,112) cases. Both cohorts were well-balanced, except for higher BMI in the SEMA group (36.60 ± 6.25 vs. 34.89 ± 6.84 kg/m²). After one year, the SEMA group demonstrated ~one BMI point reduction but maintained significantly higher BMI (35.51 ± 6.34 vs. 34.11 ± 6.64, p < 0.001). LDL, triglycerides, and HbA1c levels significantly improved with SEMA, as evidenced by decreased rates of poor metabolic markers (31.13% vs. 34.32%, p < 0.001). The SEMA-treated patients demonstrated significantly higher survival, lower cardiovascular risk, and reduced progression to advanced liver disease compared to controls. Discussion: In this large real-world cohort, SEMA use in MASLD patients was associated with significantly improved 1-year survival, cardiovascular, and liver-related outcomes. These benefits appear to result primarily from metabolic improvements and anti-inflammatory effects. Materials and Methods: Data were sourced from TriNetX, a global health research platform with de-identified electronic medical records spanning 135 million patients across 112 healthcare organizations worldwide. We included MASLD adults diagnosed according to ICD9 criteria. Assessed outcomes included survival, biochemical, hematologic, AFP, metabolic and cardiovascular parameters, advanced liver disease (ALD), synthetic function, and metabolic markers. Conclusions: Semaglutide may serve as an effective therapeutic strategy to improve outcomes in MASLD. Full article

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25 pages, 4050 KiB

Open AccessReview

Network Pharmacology-Driven Sustainability: AI and Multi-Omics Synergy for Drug Discovery in Traditional Chinese Medicine

by Lifang Yang, Hanye Wang, Zhiyao Zhu, Ye Yang, Yin Xiong, Xiuming Cui and Yuan Liu

Pharmaceuticals 2025, 18(7), 1074; https://doi.org/10.3390/ph18071074 - 21 Jul 2025

Abstract

Traditional Chinese medicine (TCM), a holistic medical system rooted in dialectical theories and natural product-based therapies, has served as a cornerstone of healthcare systems for millennia. While its empirical efficacy is widely recognized, the polypharmacological mechanisms stemming from its multi-component nature remain poorly [...] Read more.

Traditional Chinese medicine (TCM), a holistic medical system rooted in dialectical theories and natural product-based therapies, has served as a cornerstone of healthcare systems for millennia. While its empirical efficacy is widely recognized, the polypharmacological mechanisms stemming from its multi-component nature remain poorly characterized. The conventional trial-and-error approaches for bioactive compound screening from herbs raise sustainability concerns, including excessive resource consumption and suboptimal temporal efficiency. The integration of artificial intelligence (AI) and multi-omics technologies with network pharmacology (NP) has emerged as a transformative methodology aligned with TCM’s inherent “multi-component, multi-target, multi-pathway” therapeutic characteristics. This convergent review provides a computational framework to decode complex bioactive compound–target–pathway networks through two synergistic strategies, (i) NP-driven dynamics interaction network modeling and (ii) AI-enhanced multi-omics data mining, thereby accelerating drug discovery and reducing experimental costs. Our analysis of 7288 publications systematically maps NP-AI–omics integration workflows for natural product screening. The proposed framework enables sustainable drug discovery through data-driven compound prioritization, systematic repurposing of herbal formulations via mechanism-based validation, and the development of evidence-based novel TCM prescriptions. This paradigm bridges empirical TCM knowledge with mechanism-driven precision medicine, offering a theoretical basis for reconciling traditional medicine with modern pharmaceutical innovation. Full article

(This article belongs to the Special Issue Sustainable Approaches and Strategies for Bioactive Natural Compounds)

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10 pages, 721 KiB

Open AccessArticle

Pharmacokinetic Analysis of the Bioavailability of AQUATURM^®, a Water-Soluble Curcumin Formulation, in Comparison to a Conventional Curcumin Tablet, in Human Subjects

by Lillian Jabur, Rishi Pandey, Meena Mikhael, Garry Niedermayer, Erika Gyengesi, David Mahns and Gerald Münch

Pharmaceuticals 2025, 18(7), 1073; https://doi.org/10.3390/ph18071073 - 21 Jul 2025

Abstract

Background/Objectives: Curcumin, the principal bioactive component of Curcuma longa, is known for its anti-inflammatory, antioxidant, and neuroprotective properties. Despite its therapeutic potential, curcumin exhibits poor oral bioavailability due to low solubility, rapid metabolism, and limited gastrointestinal absorption. Various delivery systems have been developed [...] Read more.

Background/Objectives: Curcumin, the principal bioactive component of Curcuma longa, is known for its anti-inflammatory, antioxidant, and neuroprotective properties. Despite its therapeutic potential, curcumin exhibits poor oral bioavailability due to low solubility, rapid metabolism, and limited gastrointestinal absorption. Various delivery systems have been developed to overcome these limitations. This study aimed to evaluate and compare the pharmacokinetic profile of AQUATURM®, a novel, water-soluble curcumin formulation, with that of a widely available commercial curcumin supplement. Methods: A randomized, double-blind, two-period crossover study was conducted in 12 healthy adult participants (6 male, 6 female; aged 20–45 years). Each participant received a single oral dose of either AQUATURM® or the comparator product, followed by a 7-day washout period before receiving the alternate treatment. Blood samples were collected at multiple time points over a 12-h period post-dosing. Plasma curcumin concentrations were quantified using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). Results: AQUATURM® achieved a significantly higher systemic exposure compared to the comparator, with a more than 7-fold increase in area under the curve (AUC_0–12h) and higher peak plasma concentrations (Cmax). AQUATURM® also maintained detectable curcumin levels for the full 12-h observation period, whereas levels from the comparator fell below quantification limits in most participants after 4 h. Conclusions: AQUATURM® significantly enhances curcumin bioavailability in humans compared to a standard curcumin formulation. These pharmacokinetic improvements support its potential for greater clinical efficacy and warrant further evaluation in therapeutic setting Full article

(This article belongs to the Special Issue Phytochemicals and Analogues as Sources of Bioactive Substances of Pharmacological and Industrial Interest)

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35 pages, 8014 KiB

Open AccessArticle

Chitosan Nanoparticles for Topical Drug Delivery in Chemotherapy-Induced Alopecia: A Comparative Study of Five Repurposed Pharmacological Agents

by Salma A. Fereig, John Youshia, Ghada M. El-Zaafarany, Mona G. Arafa and Mona M. A. Abdel-Mottaleb

Pharmaceuticals 2025, 18(7), 1071; https://doi.org/10.3390/ph18071071 - 21 Jul 2025

Abstract

Background/Objectives: Chemotherapy-induced alopecia is a common and distressing side effect of cancer treatment, significantly impacting patients’ psychological well-being. Nanocarriers offer a promising strategy for targeted drug delivery to hair follicles, while chitosan nanoparticles have demonstrated hair-growth-promoting properties. This study explores the potential [...] Read more.

Background/Objectives: Chemotherapy-induced alopecia is a common and distressing side effect of cancer treatment, significantly impacting patients’ psychological well-being. Nanocarriers offer a promising strategy for targeted drug delivery to hair follicles, while chitosan nanoparticles have demonstrated hair-growth-promoting properties. This study explores the potential of chitosan nanoparticles as a topical delivery system for five pharmacological agents—phenobarbital, pioglitazone, rifampicin, N-acetylcysteine, and tacrolimus—to prevent chemotherapy-induced alopecia. Methods: Drug-loaded chitosan nanoparticles were prepared using the ionic gelation technique and characterized by particle size, zeta potential, entrapment efficiency, FT-IR spectroscopy, and TEM imaging. Their efficacy was assessed in a cyclophosphamide-induced alopecia model in C57BL/6 mice through macroscopic observation, histopathological examination, and scanning electron microscopy of regrown hair. Results: The prepared particles were spherical, cationic, and between 205 and 536 nm in size. The entrapment efficiencies ranged from 8% to 63%. All five drugs mitigated follicular dystrophy, shifting the hair follicle response from dystrophic catagen to dystrophic anagen. Phenobarbital demonstrated the most significant hair regrowth and quality improvements, followed by N-acetyl cysteine and pioglitazone. Tacrolimus showed moderate efficacy, while rifampicin was the least effective. Conclusions: These findings suggest that phenobarbital-loaded chitosan nanoparticles represent a promising approach for the prevention and treatment of chemotherapy-induced alopecia, warranting further investigation for clinical applications. Full article

(This article belongs to the Special Issue Advances in Topical and Mucosal Drug Delivery Systems)

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30 pages, 11312 KiB

Open AccessArticle

Study on the Mechanism and Dose–Effect Relationship of Flavonoids in Different Extracts of Radix Hedysari Against Gastrointestinal Injury Induced by Chemotherapy

by Shasha Zhao, Miaomiao Yang, Zimu Yang, Hai He, Ziyang Wang, Xinyu Zhu, Zhijia Cui and Jing Shao

Pharmaceuticals 2025, 18(7), 1072; https://doi.org/10.3390/ph18071072 - 20 Jul 2025

Abstract

Background: Previous studies have shown Radix Hedysari (RH)’s gastroprotective potential, but its active components and mechanisms remain uncharacterized. This study aimed to identify RH’s bioactive fractions, elucidate protection mechanisms, establish flavonoid dose-effect relationships, and determine the pharmacodynamic basis. Methods: Chemical profiling quantified [...] Read more.

Background: Previous studies have shown Radix Hedysari (RH)’s gastroprotective potential, but its active components and mechanisms remain uncharacterized. This study aimed to identify RH’s bioactive fractions, elucidate protection mechanisms, establish flavonoid dose-effect relationships, and determine the pharmacodynamic basis. Methods: Chemical profiling quantified eight flavonoids via HPLC. Network pharmacology screened targets/pathways using TCMSP, GeneCards databases. In vivo validation employed cisplatin–induced injury models in Wistar rats (n = 10/group). Assessments included: behavioral monitoring; organ indices; ELISA (MTL, VIP, IFN–γ, IgG, IL–6, TNF–α etc.); H&E; and Western blot:(SCF, c–Kit, p65). Dose–effect correlations were analyzed by PLS–DA. Results: Content determination indicated that Calycosin–7–glucoside and Ononin were notably enriched on both the n–BuOH part and the EtOAc part. Network pharmacology identified 5 core flavonoids and 8 targets enriched in IL–17/TNF signaling pathways. n–BuOH treatment minimized weight loss vs. MCG, increased spleen/thymus indices. n–BuOH and HPS normalized gastrointestinal, immune, inflammatory biomarkers (p < 0.01 vs. MCG). Histopathology confirmed superior mucosal protection in n–BuOH group vs. MCG. Western blot revealed n–BuOH significantly downregulated SCF, c–kit, and p65 expressions in both gastric and intestinal tissues (p < 0.001 vs. MCG). PLS–DA demonstrated Calycosin–7–glucoside had the strongest dose–effect correlation (VIP > 1) with protective outcomes. Conclusions: The n–BuOH fraction of RH is the primary bioactive component against chemotherapy–induced gastrointestinal injury, with Calycosin–7–glucoside as its key effector. Protection is mediated through SCF/c–Kit/NF–κB pathway inhibition, demonstrating significant dose–dependent efficacy. These findings support RH’s potential as a complementary therapy during chemotherapy. Full article

(This article belongs to the Special Issue Exploring the Anticancer and Immunomodulatory Mechanisms of Phytochemicals and Natural Bioactive Compounds)

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15 pages, 1365 KiB

Open AccessArticle

SUMOylation Regulates Neutrophil Phagocytosis and Migration

by Ran Zhang, Wanying Miao, Jin Zhang, Xinyuan Yu, Lihong Dang, Ata Ur Rehman, Feng Xu, Huaxin Sheng, G. Chad Hughes, Joseph P. Mathew, Jörn Karhausen and Wei Yang

Pharmaceuticals 2025, 18(7), 1070; https://doi.org/10.3390/ph18071070 - 20 Jul 2025

Abstract

Introduction: Accumulating evidence indicates that neutrophils undergo reprogramming of their effector functions as they migrate from the bloodstream into an inflamed tissue. Here, we examined the role of the small ubiquitin-like modifier (SUMO) conjugation in modulating neutrophil functional changes in the inflammatory [...] Read more.

Introduction: Accumulating evidence indicates that neutrophils undergo reprogramming of their effector functions as they migrate from the bloodstream into an inflamed tissue. Here, we examined the role of the small ubiquitin-like modifier (SUMO) conjugation in modulating neutrophil functional changes in the inflammatory microenvironment. Methods: Primary human and murine neutrophils were used to assess SUMOylation levels in vitro by Western blotting and results were validated in clinical samples from patients undergoing surgery involving hypothermic circulatory arrest. SUMOylation was inhibited with TAK-981, and its impact on neutrophil migration, NETosis, and phagocytosis was assessed in vitro. The in vivo effect of TAK-981 on neutrophil tissue infiltration was further evaluated using a sterile sponge assay in mice. Results: Our results demonstrated that neutrophil SUMOylation was induced by factors of the inflammatory microenvironment (temperature and oxidative stress) and inflammatory stimulants in vitro, and under conditions of general inflammatory activation in patients. Further, we found that blocking SUMOylation with TAK-981 in vitro blunted neutrophil migration and phagocytosis but did not affect NETosis. Notably, TAK-981 treatment reduced neutrophil accumulation in sterile sponges in mice. Conclusions: Our work identifies SUMOylation as a novel mechanism of neutrophil tissue reprogramming. Blocking SUMOylation may provide a therapeutic option to limit the contribution of neutrophils to inflammation-associated tissue damage. Full article

(This article belongs to the Section Pharmacology)

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25 pages, 912 KiB

Open AccessArticle

Association of SLCO1B3 and SLCO1B1 Polymorphisms with Methotrexate Efficacy and Toxicity in Saudi Rheumatoid Arthritis Patients

by Rania Magadmi, Ahlam M. Alharthi, Lina A. Alqurashi, Ibtisam M. Jali, Zeina W. Sharawi, Maha H. Jamal, Yasser Bawazir, Mohammad Mustafa, Sami M. Bahlas, Basma T. Jamal, Hassan Daghasi, Abdulrahman S. Altowairqi and Dalal Sameer Al Shaer

Pharmaceuticals 2025, 18(7), 1069; https://doi.org/10.3390/ph18071069 - 20 Jul 2025

Abstract

Background: Methotrexate (MTX) remains the most commonly prescribed drug used to treat rheumatoid arthritis (RA). Polymorphisms in solute carrier organic anion transporter family member 1B3 (SLCO1B3) and SLCO1B1 may play a critical role in MTX pharmacokinetics and patient outcomes. However, research [...] Read more.

Background: Methotrexate (MTX) remains the most commonly prescribed drug used to treat rheumatoid arthritis (RA). Polymorphisms in solute carrier organic anion transporter family member 1B3 (SLCO1B3) and SLCO1B1 may play a critical role in MTX pharmacokinetics and patient outcomes. However, research on these polymorphisms in Saudi Arabia remains limited. We evaluated the association of SLCO1B3 (rs4149117, rs7311358) and SLCO1B1 (rs2306283, rs4149056) polymorphisms with MTX efficacy and safety in Saudi patients with RA. Methods: This multicenter, case-control study included patients diagnosed with RA in Jeddah and Taif. Demographic and clinical data were collected and analyzed. Genotyping of SLCO1B3 (rs4149117, rs7311358) and SLCO1B1 (rs2306283, rs4149056) polymorphisms was performed using Sanger sequencing. Statistical analyses, including logistic regression and haplotype analysis, were conducted to evaluate associations between these polymorphisms, MTX efficacy, and toxicity. Results: The study cohort comprised 100 patients with RA, with 46 showing a good response to MTX and 54 showing a poor response. Clinical predictors of MTX response were significantly higher in patients with poor response. Both SLCO1B3 polymorphisms (rs4149117, rs7311358) were significantly associated with anemia. Significant associations were found between SLCO1B1 (rs2306283) and gastrointestinal disturbances and anemia. The GAAT haplotype was significantly more prevalent among good responders, while the TGGT haplotype was significantly associated with poor responders. Conclusions: These results highlight the importance of genetic testing in predicting MTX treatment outcomes and tailoring personalized treatment plans for patients with RA to improve efficacy and minimize adverse effects. Full article

(This article belongs to the Special Issue The Application of Pharmacogenetics in Toxicity Prevention and Drug Effect Improvement)

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12 pages, 1336 KiB

Open AccessReview

Bisphosphonates in the Management of Patients with Postmenopausal Osteoporosis; Back to the Future

by Socrates E. Papapoulos and Polyzois Makras

Pharmaceuticals 2025, 18(7), 1068; https://doi.org/10.3390/ph18071068 - 20 Jul 2025

Abstract

Osteoporosis is a chronic disease associated with significant morbidity and mortality and requires long-term therapy. Efficacious and well-tolerated treatments are available, but their effect is either short-lived or lost following their discontinuation. The exception is bisphosphonates that reduce bone resorption and turnover, can [...] Read more.

Osteoporosis is a chronic disease associated with significant morbidity and mortality and requires long-term therapy. Efficacious and well-tolerated treatments are available, but their effect is either short-lived or lost following their discontinuation. The exception is bisphosphonates that reduce bone resorption and turnover, can be administered in regimens ranging from once-daily to once-yearly, and have been shown in randomized clinical trials to reduce the incidence of all osteoporotic fractures, but their effect persists following their discontinuation. This is due to their property of being taken-up selectively by the skeleton and being slowly released following treatment arrest. This property allows the discontinuation of bisphosphonate treatment for different periods of time, the so-called drug holiday, which reduces the risk of rare adverse events while maintaining the effect; an action particularly important for patients at very high risk of fractures for whom sequential therapy with different agents is currently advised. Thus, bisphosphonates, apart from being the treatment of choice for certain groups of patients, are also indispensable for the consolidation and maintenance of the gains of all other treatments, providing, in addition, the opportunity of temporary treatment arrest. Most patients with postmenopausal osteoporosis will, therefore, receive bisphosphonate at some stage during therapy of their disease, regardless of their initial fracture risk. Full article

(This article belongs to the Special Issue The Pharmacology of Bisphosphonates: New Advances)

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21 pages, 3324 KiB

Open AccessArticle

Curcumin and Papain-Loaded Liposomal Natural Latex Dressings with Phototherapy: A Synergistic Approach to Diabetic Wound Healing

by Franciéle M. Silva, Jaqueline R. Silva, Wellington Rodrigues, Breno A. S. M. Sousa, Thamis F. S. Gomes, Mario F. F. Rosa, Suélia S. R. F. Rosa and Marcella L. B. Carneiro

Pharmaceuticals 2025, 18(7), 1067; https://doi.org/10.3390/ph18071067 - 20 Jul 2025

Abstract

Background: Wound healing in diabetic individuals is a prolonged process, often complicated by infections and impaired tissue regeneration. Innovative strategies combining natural bioactive compounds are needed to enhance repair. Methods: This study reports the development and characterization of natural latex-based biomembranes (NLBs) incorporated [...] Read more.

Background: Wound healing in diabetic individuals is a prolonged process, often complicated by infections and impaired tissue regeneration. Innovative strategies combining natural bioactive compounds are needed to enhance repair. Methods: This study reports the development and characterization of natural latex-based biomembranes (NLBs) incorporated with liposome-encapsulated curcumin and papain. The therapeutic efficacy of these composite dressings, in combination with red light-emitting diode (LED) phototherapy, was evaluated in a diabetic rat model. NLBs were produced by blending natural latex with multilamellar liposomes containing either curcumin, papain, or both. In vivo wound healing was assessed by applying the biomembranes to the dorsal lesions and administering red LED irradiation (650 ± 20 nm, 10 min every 48 h) over 11 days. Results: Fourier transform infrared spectroscopy (FTIR) confirmed that the integration of liposomes did not induce significant chemical alterations to the latex matrix. The treated diabetic rats exhibited enhanced wound contraction, with the curcumin and papain groups demonstrating up to 99% and 95% healing, respectively. Plasma fructosamine levels were significantly reduced (p < 0.05), indicating improved glycemic control. Conclusions: Combining NLBs with bioactive-loaded liposomes and phototherapy accelerated wound healing in diabetic rats. This multifunctional platform shows promise for the treatment of chronic wounds in diabetic patients. Full article

(This article belongs to the Section Pharmacology)

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