Biomedicines

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28 pages, 16544 KB

Open AccessArticle

Ferulic Acid Alleviates Chemotherapy-Induced POI by Targeting the Grp78 and Perk-eIF2α-ATF4-CHOP Pathway to Attenuate Endoplasmic Reticulum Stress

by Fan Li, Yanjing Huang, Zhuo Liu, Yuli Geng, Runan Hu, Yufan Song, Lijun Xu and Mingmin Zhang

Biomedicines 2026, 14(3), 714; https://doi.org/10.3390/biomedicines14030714 - 19 Mar 2026

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Abstract

Backgrounds: Premature ovarian insufficiency (POI) is a clinical syndrome characterized by premature ovarian dysfunction, amenorrhea, and infertility. Ferulic acid (FA) is a prominent bioactive phenolic compound derived from traditional Chinese herbs Angelica sinensis (Oliv.) Diels and Ligusticum chuanxiong Hort. These herbs are [...] Read more.

Backgrounds: Premature ovarian insufficiency (POI) is a clinical syndrome characterized by premature ovarian dysfunction, amenorrhea, and infertility. Ferulic acid (FA) is a prominent bioactive phenolic compound derived from traditional Chinese herbs Angelica sinensis (Oliv.) Diels and Ligusticum chuanxiong Hort. These herbs are commonly used to treat gynecological disorders including menstrual irregularities and infertility, and are known to modulate endoplasmic reticulum (ER) stress. However, the therapeutic potential and molecular mechanisms of FA in the context of POI remain largely unexplored. This study aimed to investigate the protective effects of FA against POI and to elucidate the underlying pharmacological mechanisms. Methods: In vivo, a mouse model of POI was established via a single intraperitoneal injection of cyclophosphamide (CTX; 120 mg/kg), and using FA for 28 days of continuous gavage to observe its therapeutic effect. Ovarian function and pathological changes were assessed by hormone levels, follicle development and oxidative stress (OS) level. In vitro, the effects of FA were examined using 4-hydroperoxy cyclophosphamide (4-OHCP)-treated KGN granulosa cells. Transcriptome sequencing, molecular docking, and molecular dynamics simulations were employed to identify potential targets of FA. Results: Our findings demonstrated that FA administration helped preserve regular estrous cycles, promoted follicle development and hormone secretion, and attenuated OS in both ovarian tissue and granulosa cells (GCs). Transcriptomic profiling combined with molecular docking and molecular dynamics simulations suggested that FA potentially targets key ER stress proteins, specifically Grp78 and Perk. Further in vivo and in vitro experiments confirmed that FA alleviates ER stress by inhibiting the overactivation of the Perk/eIF2α/ATF4/CHOP signaling pathway. Notably, the protective effects of FA were comparable to those of the ER stress inhibitor 4-Phenylbutyric acid (4-PBA) and were reversed by the ER stress activator tunicamycin (TM). Additionally, FA downregulates ERO1α expression, further blocking secondary oxidative damage triggered by ER stress. In KGN cells, FA significantly inhibits 4-OHCP-induced apoptosis and upregulates the anti-apoptotic proteins BCL-2 and BCL-xL, exhibiting efficacy similar to 4-PBA. Conclusions: FA improves ovarian function in CTX-induced POI by coordinately regulating OS and ER stress, inhibiting the Perk/eIF2α/ATF4/CHOP pathway, and suppressing GC apoptosis. These findings provide experimental evidence supporting FA as a potential therapeutic candidate for POI. Full article

(This article belongs to the Special Issue Natural Product for the Interventions of Chronic Diseases: From Source to Therapy)

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15 pages, 1720 KB

Open AccessArticle

Antiproliferative Activity of α-Tocopherol, γ-Tocopherol and Tocotrienols and Their Drug Interactions Evaluated Using Loewe and Chou–Talalay Models in HeLa and MCF-7 Cancer Cell Lines

by Jazmín Cristina Stevens Barron, Laura A. de la Rosa, Emilio Alvarez-Parrilla, Abraham Wall-Medrano and Christian Chapa González

Biomedicines 2026, 14(2), 458; https://doi.org/10.3390/biomedicines14020458 - 18 Feb 2026

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Abstract

Background: Food rich in tocopherols (T) and tocotrienols (T3) are considered functional due to their ability to reduce oxidative stress and modulate anti-viability and pro-apoptotic pathways with anticancer potential; however, their efficacy differs between T and T3 and among isoforms (α and γ) [...] Read more.

Background: Food rich in tocopherols (T) and tocotrienols (T3) are considered functional due to their ability to reduce oxidative stress and modulate anti-viability and pro-apoptotic pathways with anticancer potential; however, their efficacy differs between T and T3 and among isoforms (α and γ) likely due to differences in intracellular uptake and, consequently, in the activation of anticancer signaling pathways. To address these isoform-dependent differences, HeLa and MCF7 cancer cell lines were used to assess the antiproliferative activity of α-tocopherol (αT), γ-tocopherol (γT) and tocotrienols (Tocomin) as well as their pharmacological interactions according to Loewe and Chou–Talalay models. Methods: The tocol profile of the commercial mixture of T3 (Tocomin) was quantified by normal-phase HPLC. HeLa, MCF7, and ARPE-19 cells were cultured in DMEM supplemented with 10% FBS and exposed to αT, γT, or Tocomin (50–800 µg/mL; DMSO vehicle) for 48 h; viability was measured by the MTT assay and EC50 values were obtained from log(dose)–response fits (n = 3). Fixed-ratio (1:1) combinations were evaluated in HeLa and MCF7, and interactions were quantified using Loewe additivity and Chou–Talalay combination indices, supported by isobologram analysis. Results: Tocomin showed greater potency with αT and γT, and synergy with αT/γT; however, the combination of αT + γT showed antagonism in both cell lines. Conclusions: The higher potency of Tocomin and its synergistic interactions with αT or γT suggest that tocotrienol-rich mixtures may enhance the antiproliferative response, whereas combining αT and γT together may reduce efficacy under the tested conditions. Full article

(This article belongs to the Special Issue Natural Product for the Interventions of Chronic Diseases: From Source to Therapy)

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21 pages, 8960 KB

Open AccessArticle

Kaempferol Alleviates Glucocorticoid-Induced Osteonecrosis of the Femoral Head by Modulating Macrophage M1/M2 Polarization Through RhoA/ROCK-Mediated Mitophagy Activation

by Yuankai Zhang, Yan Zhao, Shangqing Zhang, Tian Lei, Bocheng Xiang, Xin Zhang, Kai Nan and Lihong Fan

Biomedicines 2026, 14(2), 400; https://doi.org/10.3390/biomedicines14020400 - 9 Feb 2026

Cited by 1 | Viewed by 797

Abstract

Background/Objectives: Dysregulated macrophage M1/M2 polarization is implicated in glucocorticoid-induced osteonecrosis of the femoral head (GONFH). Reprogramming M1 to M2 macrophages represents a potential therapeutic strategy. Kaempferol (KPF), a natural flavonoid with anti-inflammatory properties, may offer benefits, but its mechanism in GONFH is [...] Read more.

Background/Objectives: Dysregulated macrophage M1/M2 polarization is implicated in glucocorticoid-induced osteonecrosis of the femoral head (GONFH). Reprogramming M1 to M2 macrophages represents a potential therapeutic strategy. Kaempferol (KPF), a natural flavonoid with anti-inflammatory properties, may offer benefits, but its mechanism in GONFH is unknown. Purpose: This study aims to explore the therapeutic impact of KPF on GONFH and the mechanisms involved. Methods: In vitro, macrophage viability (CCK-8 assay) and polarization (RT-qPCR, flow cytometry) were assessed. Conditioned medium from KPF-treated macrophages was co-cultured with BMSCs and HUVECs to evaluate osteogenic and angiogenic effects. Mechanisms were analyzed using Western blot, immunofluorescence, and flow cytometry. A rat GONFH model validated in vivo effects. Results: In vitro experiments revealed that KPF significantly augmented the ratio of M2 macrophages while concurrently diminishing the proportion of M1 macrophages. The conditioned medium derived from macrophages treated with KPF markedly improved the osteogenic and angiogenic capabilities of BMSCs and HUVECs. Immunofluorescence staining and Western blot revealed that KPF regulated macrophage polarization by enhancing mitophagy, which was reversed by the addition of a mitophagy inhibitor. Further experiments confirmed that KPF activated mitophagy by inhibiting the RhoA/ROCK signaling pathway. In vivo, KPF increased the proportion of M2 macrophages and promoted the expression of osteogenic and angiogenic markers. Conclusions: In conclusion, our study demonstrates that KPF alleviates GONFH by modulating macrophage M1/M2 polarization through RhoA/ROCK-mediated mitophagy activation. These findings provide novel insights into the treatment of GONFH. Full article

(This article belongs to the Special Issue Natural Product for the Interventions of Chronic Diseases: From Source to Therapy)

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21 pages, 3421 KB

Open AccessArticle

Bioactive-Rich Piper sarmentosum Aqueous Extract Mitigates Osteoarthritic Pathology by Enhancing Anabolic Activity and Attenuating NO-Driven Catabolism in Human Chondrocytes

by Yi Ting Lee, Mohd Heikal Mohd Yunus, Rizal Abdul Rani, Chiew Yong Ng, Muhammad Dain Yazid, Azizah Ugusman and Jia Xian Law

Biomedicines 2026, 14(1), 128; https://doi.org/10.3390/biomedicines14010128 - 8 Jan 2026

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Abstract

Background: Osteoarthritis (OA) is a prevalent degenerative joint disease often causing functional disability. Current therapies provide only temporary relief and can cause adverse effects that frequently result in pain and disability. Current pharmacological options offer only temporary symptom relief and may cause adverse [...] Read more.

Background: Osteoarthritis (OA) is a prevalent degenerative joint disease often causing functional disability. Current therapies provide only temporary relief and can cause adverse effects that frequently result in pain and disability. Current pharmacological options offer only temporary symptom relief and may cause adverse effects. Piper sarmentosum (PS), a plant traditionally used for its medicinal properties, has demonstrated antioxidant and anti-inflammatory activities that may counteract OA-related degeneration. This study provides preliminary insight into the therapeutic potential of PS aqueous extract in human OA chondrocytes. Methods: Compounds in the PS aqueous extract were profiled using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Primary human OA chondrocytes (HOCs) were treated with 0.5, 2, and 4 µg/mL of PS aqueous extract for 72 h. Key OA-related parameters were assessed, including anabolic markers (sulfated glycosaminoglycan (sGAG), collagen type II (COL II), aggrecan core protein (ACP), SRY-box transcription factor 9 (SOX9)), catabolic markers (matrix metalloproteinase (MMP) 1, MMP13, cyclooxygenase 2 (COX2)), oxidative stress (nitric oxide (NO) production, inducible NO synthase (iNOS) expression), and inflammatory responses (interleukin (IL) 6). Gene expression was quantified using qPCR, and protein levels were evaluated using the colorimetric method, immunocytochemistry, and Western blot. Results: A total of 101 compounds were identified in the extract, including vitexin, pterostilbene, and glutathione—bioactives known for antioxidant, anti-inflammatory, and chondroprotective functions. PS-treated chondrocytes maintain healthy polygonal morphology. PS aqueous extract significantly enhanced anabolic gene expression (COL2A1, ACP, SOX9) and sGAG production, while concurrently suppressing COX2 expression and NO synthesis. Additionally, PS aqueous extract reduced COX2 and iNOS protein levels, indicating inhibition of the NO signaling pathway. Catabolic activity was attenuated, and inflammatory responses were partially reduced. Conclusions: PS aqueous extract exhibits promising chondroprotective, antioxidant, and anti-inflammatory effects in human OA chondrocytes, largely through the suppression of NO-mediated catabolic signaling. The presence of multiple bioactive compounds supports its mechanistic potential. These findings highlight PS aqueous extract as a potential therapeutic candidate for OA management. Further ex vivo and in vivo studies are warranted to validate its efficacy and clarify its mechanism in joint-tissue environments. Full article

(This article belongs to the Special Issue Natural Product for the Interventions of Chronic Diseases: From Source to Therapy)

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15 pages, 1439 KB

Open AccessArticle

Sweet Relief? Short-Term Post-Traumatic High-Sucrose Intake Attenuates Acute but Not Long-Term Fear Responses in Mice

by Prabhat Kumar, Pedro Correia, Imola Plangár and Dóra Zelena

Biomedicines 2025, 13(9), 2233; https://doi.org/10.3390/biomedicines13092233 - 11 Sep 2025

Cited by 1 | Viewed by 1932

Abstract

People often turn to sweet foods for comfort during times of stress, as energy imbalance is implicated in several neuropsychiatric disorders including post-traumatic stress disorder (PTSD). Although acute sucrose consumption may improve cognitive capabilities, its long-term effectiveness has been debated. Objectives: In [...] Read more.

People often turn to sweet foods for comfort during times of stress, as energy imbalance is implicated in several neuropsychiatric disorders including post-traumatic stress disorder (PTSD). Although acute sucrose consumption may improve cognitive capabilities, its long-term effectiveness has been debated. Objectives: In a widely used mouse model, we examined the effect of sucrose drinking on conditioned fear-induced freezing (as a model of PTSD), with emphasis on the concentrations and timing of the intervention as well as sex differences. We aimed to develop a low-cost, widely accessible therapeutic option. Methods: A short electric foot shock was used for trauma, and freezing was detected 24 h (mimicking acute stress disorder, ASD) or 14 days (PTSD-like symptoms) later in the trauma context and with trauma cues. Results: First, we confirmed that our trauma increased freezing, independent of previous habituation to sucrose drinking. Next, we confirmed that 16% and 32%, but not 2% sucrose drinking for 24 h (but not 3 h) immediately after trauma, diminished freezing behavior the next day. However, the same intervention did not influence behavior 14 days later. Moreover, we could not find any curative effect of 24 h of 16% sucrose consumption before testing remote fear memory 14 days after trauma. Conclusions: Consuming a high-calorie solution immediately following trauma for 24 h may influence ASD but does not necessarily alter the development of PTSD symptoms. Here, we offer a new perspective on energy regulation in neuropsychiatric disorders. Full article

(This article belongs to the Special Issue Natural Product for the Interventions of Chronic Diseases: From Source to Therapy)

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Review

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17 pages, 734 KB

Open AccessReview

Pterostilbene in Cardiovascular Diseases: From Molecular Mechanisms to Therapeutic Potential

by Xin-Fang Leong

Biomedicines 2026, 14(4), 858; https://doi.org/10.3390/biomedicines14040858 - 9 Apr 2026

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Abstract

Cardiovascular disease continues to impose a substantial global health burden and arises from interconnected pathological processes, including oxidative injury, inflammatory signaling, endothelial dysfunction, metabolic imbalance, and progressive cardiac and vascular structural remodeling. Growing interest has therefore emerged in naturally derived compounds capable of [...] Read more.

Cardiovascular disease continues to impose a substantial global health burden and arises from interconnected pathological processes, including oxidative injury, inflammatory signaling, endothelial dysfunction, metabolic imbalance, and progressive cardiac and vascular structural remodeling. Growing interest has therefore emerged in naturally derived compounds capable of influencing multiple disease pathways simultaneously. Pterostilbene, a dimethoxylated stilbene structurally related to resveratrol, has gained attention due to its enhanced lipophilicity and improved bioavailability. Recent experimental studies have investigated the cardiovascular effects of pterostilbene in both cellular systems and animal models. Evidence from in vitro studies indicates that this compound modulates key regulatory networks involved in cellular energy metabolism, redox homeostasis, endothelial signaling, and stress-associated cardiomyocyte injury. These actions involve pathways linked to 5′ adenosine monophosphate-activated protein kinase and sirtuin-1 signaling, nitric oxide regulation, antioxidant responses, and ferroptosis-related mechanisms. Findings from in vivo investigations further demonstrate protective effects across multiple cardiovascular disease models, including pulmonary hypertension, pressure overload-associated cardiac remodeling, ischemic myocardial injury, toxin-induced cardiotoxicity, and metabolic or atherosclerotic vascular dysfunction. Improvements in functional, structural, and biochemical parameters have been reported in these experimental settings. Overall, current preclinical evidence suggests that pterostilbene may act as a multifunctional modulator of key processes involved in cardiovascular pathology. Although clinical evidence remains limited, the convergence of mechanistic and experimental findings highlights its potential as a multi-target cardiometabolic therapeutic candidate and provides a foundation for future translational and clinical investigation. Full article

(This article belongs to the Special Issue Natural Product for the Interventions of Chronic Diseases: From Source to Therapy)

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40 pages, 2982 KB

Open AccessReview

Beyond PAD Inhibition: Emerging Avenues and Natural Products for Targeting Citrullination in Immune Diseases

by Qilei Chen, Yuhang Ma, Yingyi Liu, Xiaojie Wang, Guanhua Huang, Yizhao Yang, Joshua Ka-Shun Ko and Hubiao Chen

Biomedicines 2026, 14(4), 850; https://doi.org/10.3390/biomedicines14040850 - 8 Apr 2026

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Abstract

Immune-mediated inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, impose a severe and growing global health burden, where current therapies are limited by poor specificity and significant side effects. The peptidylarginine deiminase (PAD)/citrullination axis, in which protein citrullination catalyzed [...] Read more.

Immune-mediated inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, impose a severe and growing global health burden, where current therapies are limited by poor specificity and significant side effects. The peptidylarginine deiminase (PAD)/citrullination axis, in which protein citrullination catalyzed by PADs drives autoantigen generation and sustains inflammation, has emerged as a critical therapeutic target. This review outlines a comprehensive strategy for targeting this axis using natural products. We first detail the established role of natural compounds as direct PAD inhibitors, covering their chemical diversity, inhibitory mechanisms, and therapeutic applications in disease models. Subsequently, the discussion extends to their broader, indirect modulatory functions, highlighting how these compounds can suppress pathogenic citrullination by regulating upstream processes like NETosis and inflammatory signaling. Furthermore, the review introduces the innovative substrate-centric intervention strategy, which represents a paradigm shift toward shielding key arginine residues on autoantigens, thereby preventing the formation of immunogenic neoepitopes. The translational challenges and future directions for each of these avenues are outlined, addressing persistent obstacles including achieving isoform selectivity and biomarker validation. By integrating these multifaceted strategies, from direct inhibition and indirect modulation to substrate protection, this work provides a strategic roadmap for advancing the next generation of more precise, effective, and safe anti-citrullination therapies, ultimately moving beyond conventional enzyme inhibition toward targeted immunomodulation in immune-mediated inflammatory diseases. Full article

(This article belongs to the Special Issue Natural Product for the Interventions of Chronic Diseases: From Source to Therapy)

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22 pages, 1228 KB

Open AccessReview

Therapeutic Potential of Gentianaceae Family Plants in the Treatment of Diabetes and Its Complications

by Svetlana Dinić, Melita Vidaković, Jelena Arambašić Jovanović, Aleksandra Uskoković, Nevena Grdović, Marija Đorđević, Jovana Rajić and Mirjana Mihailović

Biomedicines 2025, 13(11), 2822; https://doi.org/10.3390/biomedicines13112822 - 19 Nov 2025

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Diabetes, a metabolic disorder characterized by hyperglycemia resulting from insulin insufficiency or impaired insulin sensitivity, is one of the major global health challenges. Persistent hyperglycemia in diabetes affects microcirculation, eyes, kidneys, liver, pancreas, muscle, and adipose tissue, which consequently leads to irreversible health [...] Read more.

Diabetes, a metabolic disorder characterized by hyperglycemia resulting from insulin insufficiency or impaired insulin sensitivity, is one of the major global health challenges. Persistent hyperglycemia in diabetes affects microcirculation, eyes, kidneys, liver, pancreas, muscle, and adipose tissue, which consequently leads to irreversible health issues such as retinopathy, nephropathy, neuropathy, cardiovascular complications, abnormalities of lipoprotein metabolism, and gastrointestinal dysfunction. Although available therapies are effective to some extent, they remain limited in efficacy and are often associated with side effects, underscoring the urgent need for novel treatment options. Traditionally, plant extracts and natural compounds have been used for centuries to treat diabetes and its complications. Plant extracts from the Gentianaceae family have emerged as a particularly promising source of bioactive compounds proven to be useful for the treatment of various diseases, including diabetes. This review provides a comprehensive overview of the most studied plant extracts and isolated compounds from the Gentianaceae family, with a focus on their use in diabetes treatment as well as their action in managing hyperglycemia, antioxidant activity, protection of pancreatic beta cells and associated complications. Numerous in vitro and in vivo studies have demonstrated their great potential to regulate blood glucose levels, reduce oxidative stress, alleviate tissue and organ damage—primarily in the liver and kidney—and improve lipid metabolism. To fully achieve this potential, future research should prioritize well-designed clinical trials to verify safety and efficacy in humans, conduct detailed molecular and cellular studies, standardize extraction and characterization methods to ensure reproducibility, and incorporate conservation biology principles into pharmacognostic investigations. Full article

(This article belongs to the Special Issue Natural Product for the Interventions of Chronic Diseases: From Source to Therapy)

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46 pages, 3165 KB

Open AccessReview

Unveiling the Miracle Tree: Therapeutic Potential of Moringa oleifera in Chronic Disease Management and Beyond

by Edgar Yebran Villegas-Vazquez, Rocio Gómez-Cansino, Gabriel Marcelino-Pérez, Domingo Jiménez-López and Laura Itzel Quintas-Granados

Biomedicines 2025, 13(3), 634; https://doi.org/10.3390/biomedicines13030634 - 5 Mar 2025

Cited by 19 | Viewed by 21850

Abstract

Moringa oleifera (MO) has gained recognition as a potent natural intervention for preventing and managing chronic diseases (CDs) due to its diverse phytochemical composition and pharmacological properties. Rich in antioxidants, polyphenols, flavonoids, and glucosinolates, MO exerts anti-inflammatory, anti-hyperglycemic, cardioprotective, and anti-obesity effects. These [...] Read more.

Moringa oleifera (MO) has gained recognition as a potent natural intervention for preventing and managing chronic diseases (CDs) due to its diverse phytochemical composition and pharmacological properties. Rich in antioxidants, polyphenols, flavonoids, and glucosinolates, MO exerts anti-inflammatory, anti-hyperglycemic, cardioprotective, and anti-obesity effects. These properties make it a valuable therapeutic agent for CDs, including diabetes, cardiovascular diseases, obesity, neurodegenerative disorders, and cancer. MO’s ability to modulate oxidative stress and inflammation—key drivers of CDs—highlights its significant role in disease prevention and treatment. MO enhances insulin sensitivity, regulates lipid profiles and blood pressure, reduces inflammation, and protects against oxidative damage. MO also modulates key signaling pathways involved in cancer and liver disease prevention. Studies suggest that MO extracts possess anticancer activity by modulating apoptosis, inhibiting tumor cell proliferation, and interacting with key signaling pathways, including YAP/TAZ, Nrf2-Keap1, TLR4/NF-κB, and Wnt/β-catenin. However, challenges such as variability in bioactive compounds, taste acceptability, and inconsistent clinical outcomes limit their widespread application. While preclinical studies support its efficacy, large-scale clinical trials, standardized formulations, and advanced delivery methods are needed to optimize its therapeutic potential. MO’s multifunctional applications make it a promising and sustainable solution for combating chronic diseases, especially in resource-limited settings. Full article

(This article belongs to the Special Issue Natural Product for the Interventions of Chronic Diseases: From Source to Therapy)

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Other

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18 pages, 3294 KB

Open AccessSystematic Review

Targeting the AMPK Pathway with Natural Products for Heart Failure: A Systematic Review of Preclinical Evidence

by Xiaoxiao Huang and Haitong Wan

Biomedicines 2026, 14(4), 765; https://doi.org/10.3390/biomedicines14040765 - 27 Mar 2026

Viewed by 999

Abstract

Background: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, and its dysregulation is implicated in HF pathophysiology. Traditional Chinese Medicine (TCM) has been investigated in HF management, [...] Read more.

Background: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, and its dysregulation is implicated in HF pathophysiology. Traditional Chinese Medicine (TCM) has been investigated in HF management, but a systematic synthesis of preclinical evidence on TCM-mediated AMPK modulation is lacking. Methods: PubMed and Web of Science were searched from January 2020 to December 2025 using a comprehensive strategy combining terms for AMPK, HF, and TCM. Studies were included if they were original research investigating TCM-derived compounds or formulas in HF models and reporting AMPK modulation. Study quality and evidence levels were assessed using predefined criteria. The review was conducted in accordance with PRISMA 2020 guidelines. Results: Of 243 records identified, 56 studies met the inclusion criteria (7 from database search and 49 from manual screening). Direct evidence for AMPK-dependent cardioprotection was limited. Cinnamaldehyde and paeoniflorin showed the most rigorous validation with confirmed target engagement and loss-of-function rescue. Berberine, crocin, ginsenoside Rb1, and honokiol demonstrated pathway-specific effects validated by pharmacological or genetic approaches. Most complex herbal formulas provided correlative evidence only, with Fuyu Decoction being a notable exception where AMPK agonist EX229 confirmed pathway involvement. Conclusions: Current evidence for TCM-mediated AMPK modulation in HF remains predominantly preliminary and correlative. Future research should prioritize causality validation using genetic models and human-relevant systems. Full article

(This article belongs to the Special Issue Natural Product for the Interventions of Chronic Diseases: From Source to Therapy)

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19 pages, 808 KB

Open AccessSystematic Review

Percutaneous Drug Delivery to the Masticatory System: A Systematic Review and Analysis of Randomized Clinical Trials

by Kacper Galant, Kalina Romańczyk, Maciej Chęciński, Kamila Chęcińska, Natalia Turosz, Iwona Rąpalska, Amelia Hoppe, Alicja Jakubowska, Dariusz Chlubek and Maciej Sikora

Biomedicines 2025, 13(12), 3110; https://doi.org/10.3390/biomedicines13123110 - 17 Dec 2025

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Abstract

Background: Due to the high frequency of pain associated with the masticatory system, in addition to the use of physiotherapy, it is sometimes beneficial to introduce percutaneous pharmacology. This is an example of a non-invasive alternative to the traditional route of administration, which [...] Read more.

Background: Due to the high frequency of pain associated with the masticatory system, in addition to the use of physiotherapy, it is sometimes beneficial to introduce percutaneous pharmacology. This is an example of a non-invasive alternative to the traditional route of administration, which can be highly effective and limit the risk of many side effects. The aim of this study is to evaluate the efficacy and safety of transdermal drug application by patients with temporomandibular disorders (TMD). Methods: A review of randomized controlled trials retrieved from PubMed, ACM, BASE, Scopus, Cochrane, and Google Scholar on 23 October 2025 was performed using the PRISMA Checklist. Studies that evaluated transdermal drug administration for masticatory system-related conditions were included. Trials involving interventions such as muscle punctures or any systemic treatments were excluded. The revised Cochrane tool (RoB 2) was used to assess the risk of bias. A statistical analysis of the effect of such therapy on pain and its influence on changes in mandibular abduction was performed. Results: A total of nine articles meeting the inclusion criteria were included, with a total of 390 participants. The risk of bias assessment indicated that most articles were of low risk of bias (6/8), while two were assessed as “some concerns”. The review found a significant reduction in pain on the visual analog scale (VAS) for selected active substances (p < 0.05). The greatest pain reduction occurred when 1.46% cannabidiol was used. There are few results regarding the effect of this method on jaw opening, and the results obtained are comparable for the placebo group, which was related to the application method. Conclusions: The results of this systematic review are promising and indicate the probable effectiveness of this method, but due to some limitations, this topic requires further investigation. Full article

(This article belongs to the Special Issue Natural Product for the Interventions of Chronic Diseases: From Source to Therapy)

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