Search Results (134)

Ovarian cancer remains a top mortality contributor within gynecological cancers because patients receive diagnoses late in the disease course and conventional treatment resistance along with high recurrence rates cause poor outcomes. Aberrant regulation of autophagy and apoptosis has a critical role in the development, progression, chemoresistance, and immune escape from ovarian cancer. Recent evidence has demonstrated a complicated and dynamic crosstalk between autophagy and apoptosis, during which autophagy can act as a cytoprotective or cell death-promoting process depending on tumor stage and therapeutic context. In parallel, apoptosis functions as a tightly regulated form of programmed cell death that is essential for eliminating damaged or malignant cells and serves as a major tumor-suppressive mechanism in ovarian cancer. The PI3K/AKT/mTOR signaling pathway is the most active and clinically relevant pathway in the management of ovarian cancer as a master regulator of both autophagy and apoptosis, suppressing apoptotic cell death while promoting cytoprotective autophagy under chemotherapeutic stress. Bioactive natural products derived from plants, marine sources, and dietary intake have emerged as potential modulators of the autophagy-apoptosis crosstalk. Curcumin, resveratrol, quercetin, berberine, and epigallocatechin gallate are known to have the ability to restore apoptotic signaling, block pro-survival autophagy, and sensitize ovarian cancer cells to chemotherapy through the regulation of key pathways including PI3K/AKT/mTOR, AMPK, MAPK, p53, and Bcl-2 family proteins. In this review, we provide an updated understanding of the molecular mechanisms through which bioactive natural products modulate autophagy–apoptosis crosstalk in ovarian cancer. We also highlight the translational challenges, therapeutic potential, and future directions for the integration of natural product-based strategies in precision medicine for ovarian cancer. Full article

Berberine (BBR), a protoberberine alkaloid with a long history of medicinal use, has consistently demonstrated benefits in glucose–lipid metabolism and inflammatory balance across both preclinical and human studies. These diverse effects are not mediated by a single molecular target but by BBR’s capacity to restore network coordination among metabolic, immune, and microbial systems. At the core of this regulation is an AMP-activated Protein Kinase (AMPK)-centered mechanistic hub, integrating signals from insulin and nutrient sensing, Sirtuin 1/3 (SIRT1/3)-mediated mitochondrial adaptation, and inflammatory pathways such as nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-κB) and NOD-, LRR- and Pyrin Domain-containing Protein 3 (NLRP3). This hub is dynamically regulated by system-level inputs from the gut, mitochondria, and epigenome, which in turn strengthen intestinal barrier function, reshape microbial and bile-acid metabolites, improve redox balance, and potentially reverse the epigenetic imprint of metabolic stress. These interactions propagate through multi-organ axes, linking the gut, liver, adipose, and vascular systems, thus aligning local metabolic adjustments with systemic homeostasis. Within this framework, BBR functions as a negentropic modulator, reducing metabolic entropy by fostering a coordinated balance among these interconnected systems, thereby restoring physiological order. Combination strategies, such as pairing BBR with metformin, Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, and agents targeting the microbiome or inflammation, have shown enhanced efficacy and substantial translational potential. Berberine ursodeoxycholate (HTD1801), an ionic-salt derivative of BBR currently in Phase III trials and directly compared with dapagliflozin, exemplifies the therapeutic promise of such approaches. Within the hub–axis paradigm, BBR emerges as a systems-level modulator that recouples energy, immune, and microbial circuits to drive multi-organ remodeling. Full article

Mitochondrial dysfunction represents a central hallmark of aging and a broad spectrum of chronic diseases, ranging from metabolic to neurodegenerative and ocular disorders. Nicotinamide riboside (NR), a vitamin B₃ derivative and efficient precursor of NAD⁺ (nicotinamide adenine dinucleotide), and berberine (BBR), an isoquinoline alkaloid widely investigated in metabolic regulation, have independently emerged as promising mitochondrial modulators. NR enhances cellular NAD⁺ pools, thereby activating sirtuin-dependent pathways, stimulating PGC-1α–mediated mitochondrial biogenesis, and triggering the mitochondrial unfolded protein response (UPR^mt). BBR, by contrast, primarily activates AMPK (AMP-activated protein kinase) and interacts with respiratory complex I, improving bioenergetics, reducing mitochondrial reactive oxygen species, and promoting mitophagy and organelle quality control. Importantly, despite distinct upstream mechanisms, NR and BBR converge on shared signaling pathways that support mitochondrial health, including redox balance, metabolic flexibility, and immunometabolic regulation. Unlike previous reviews addressing these compounds separately, this article integrates current preclinical and clinical findings to provide a unified perspective on their converging actions. We critically discuss translational opportunities as well as limitations, including heterogeneous clinical outcomes and the need for robust biomarkers of mitochondrial function. By outlining overlapping and complementary mechanisms, we highlight NR and BBR as rational combinatorial strategies to restore mitochondrial resilience. This integrative perspective may guide the design of next-generation clinical trials and advance precision approaches in mitochondrial medicine. Full article

Major depressive disorder remains a leading cause of disability worldwide, with conventional antidepressants offering incomplete and often transient relief. Mounting evidence highlights disturbances in tryptophan (Trp) metabolism as a key biological axis linking inflammation, neuroplasticity, and mood regulation. Plant-derived compounds that modulate this pathway, including 5-hydroxytryptophan, isoflavones, berberine, and polyphenols, have emerged as promising candidates for integrative treatment strategies. Yet, despite encouraging preclinical and clinical findings, knowledge gaps persist regarding long-term efficacy, mechanistic specificity, and standardized therapeutic protocols. This narrative review explores how Trp modulators influence central and peripheral mechanisms relevant to depression, from serotonergic synthesis and kynurenine shunting to gut–brain–immune interactions. Evidence from animal models and randomized clinical trials is critically synthesized, with particular attention to outcomes on mood stabilization, anxiety reduction, cognitive function, and sleep regulation. Special emphasis is placed on translational potential, methodological limitations, and the need for harmonized research frameworks. Here we highlight that phytochemical interventions represent a mechanistically informed and biocompatible strategy for advancing depression management. By bridging neurobiology and clinical psychiatry, these insights may pave the way for next-generation therapeutics that integrate dietary, microbiota-targeted, and anti-inflammatory approaches. Broader application of this research could ultimately refine personalized psychiatry, expand therapeutic horizons, and contribute to global mental health resilience. Full article

Background/Objectives: Extracellular vesicles (EVs) are nanosized carriers with high biocompatibility, low immunogenicity, and the ability to cross biological barriers, making them attractive for drug delivery. Despite growing interest, the clinical translation of drug-loaded EVs remains limited. This systematic review aimed to summarize current evidence on EV sources, loading strategies, therapeutic applications, and translational challenges. Methods: Following PRISMA 2020 guidelines, a systematic search was conducted in Embase, PubMed, Reaxys, and Scopus for the period 2020–2025. Eligible studies included original articles on drug-loaded EVs from human, animal, plant, or other sources. Data on EV source, drug type, particle size, loading method, administration route, and therapeutic application were extracted. Clinical trials were identified through ClinicalTrials.gov. Results: A total of 65 studies were included after screening 5316 records, along with two clinical trials. Human mesenchymal stem cell (MSC)-derived EVs were the most frequent source in oncology, while plant-derived EVs predominated in non-oncology applications. Anti-cancer drugs such as doxorubicin, gemcitabine, and docetaxel were most frequently loaded, alongside curcumin, berberine, and atorvastatin. EV sizes generally ranged from 50 to 200 nm, with larger vesicles reported for plant-derived EVs. Intravenous administration predominated, with most studies demonstrating sustained release and enhanced therapeutic efficacy. Passive loading was most common, especially for hydrophobic drugs, whereas active methods such as electroporation and sonication were preferred for hydrophilic cargo. Two clinical trials showed preliminary therapeutic benefits with favorable safety. Conclusions: Drug-loaded EVs represent a promising and versatile drug delivery platform, yet their clinical translation is hindered by variability in isolation and loading methods, production scalability, and safety evaluation. Further standardization and large-scale studies are needed to advance EV-based therapeutics toward clinical use. Full article

Background: Berberine, a benzylisoquinoline alkaloid, has been traditionally used in Ayurvedic and Chinese medicine. We examined the resistance mechanisms to berberine in a panel of different cancer cells and focused on understanding its molecular mechanisms. Methods: Resazurin assay determined berberine’s cytotoxicity. Molecular docking unraveled the interaction of berberine with the BCRP transporter. Fluorescence microscopy evaluated its effect on microtubules. Further, proteomic profiling identified novel determinants of cellular response to berberine and its derivatives. Results: Cell lines overexpressing ABC transporters displayed cross-resistance to berberine compared to their counterparts. While cells over-expressing EGFR were 3.57-fold resistant, wild-type and p53 knockout cells showed similar sensitivity to berberine. P-glycoprotein/ABCB1, EGFR, and WT1 expression correlated with the log₁₀IC₅₀ values for berberine in the NCI cell line panel. Berberine was bound to the same pharmacophore of BCRP as BWQ, and live cell microscopy showed that BCRP-transfected cells did not uptake considerable amounts of berberine in contrast to wild-type cells. Berberine altered the microtubule cytoskeleton similarly to vincristine. The sensitivity of berberine and its derivatives could be predicted by 40 out of 3171 proteins. Of them, 29 proteins have been previously involved in drug resistance. Their relationship to berberine and its derivatives is novel. Conclusions: Berberine-type compounds may be new candidates against cancer; however, they may develop drug resistance. Full article

Disruption of the gut-microbiome-brain axis contributes to the development of chronic inflammation, impaired intestinal barrier integrity, and progressive tissue damage, ultimately reducing quality of life and increasing risk of comorbidities, including neurodegenerative diseases. Current therapies are often limited by adverse effects and insufficient long-term efficacy, highlighting the need for more comprehensive therapeutic approaches. Berberine (BRB), a plant-derived isoquinoline alkaloid, has attracted growing attention due to its pleiotropic immunomodulatory, neuroprotective, and gut-homeostasis-modulating properties, which involve reshaping the gut microbiota and underscore its therapeutic relevance within the gut–microbiome–brain axis. The aim of this review is to synthesize current scientific evidence regarding the anti-inflammatory mechanisms of BRB in inflammatory bowel disease (IBD). We compare its activity with first-line therapies and discuss its impact on microbial composition, including the bidirectional regulation of specific bacterial taxa relevant to intestinal and systemic disorders that originate in the gut. Furthermore, we emphasize that gut bacteria convert BRB into bioactive metabolites, contributing to its enhanced intraluminal activity despite its low systemic bioavailability. By integrating molecular and microbiological evidence, this review fills a critical knowledge gap regarding the comprehensive therapeutic potential of BRB as a promising candidate for future IBD interventions. The novelty of this work lies in unifying fragmented findings into a framework that explains how BRB acts simultaneously at the levels of host immunity, microbial ecology, and neuroimmune communication—thus offering a new conceptual model for its role within the gut–microbiome–brain axis. Full article

Berberine is a plant isoquinoline alkaloid widely used in traditional medicine for the therapy of diabetes, cardiovascular and other diseases. Ferroptosis, a regulated form of cell death driven by lipid peroxidation, is thought to contribute to the pathogenesis of various diseases associated with excessive oxidative stress. The therapeutic actions of berberine are mediated, at least in part, by its antioxidant effects. Here, we report that the lipophilic berberine derivative 13-decyl berberine (C10Berb) is a mitochondria-targeted antioxidant that exhibits superior ferroptosis inhibition compared to native berberine in H9c2 cardiomyocytes and human fibroblasts. C10Berb efficiently accumulates in mitochondria, suppressing both mitochondrial lipid peroxidation, reactive oxygen species formation, and lipofuscin accumulation at concentrations markedly lower than berberine. Mechanistic studies indicate that the anti-ferroptotic effect of C10Berb is independent of AMPK or Nrf2 activation and is primarily due to its direct antioxidant activity in mitochondria. In isolated cardiac mitochondria, C10Berb potently inhibited lipid peroxidation induced by either reactive oxygen species produced in the electron transport chain or artificial free radical initiators. These results support the hypothesis that mitochondrial lipid peroxidation is critical for ferroptosis and highlight the potential of mitochondria-targeted berberine derivatives as promising therapeutic agents for conditions associated with ferroptotic cell death. Full article

Dengue virus (DENV) and Zika virus (ZIKV) are flaviviruses transmitted by Aedes spp. mosquitoes, causing a spectrum of symptoms ranging from mild fevers and joint pain to severe damage to vital organs, including the kidneys, brain, and liver. Unfortunately, there are currently no specific treatments for these viruses. The NS2B/NS3 serine protease has been recognized as a crucial therapeutic target due to its pivotal role in viral replication. Herein, several molecular modeling techniques were employed to search for novel allosteric inhibitors against DENV and ZIKV NS2B/NS3 proteases from a set of 545 in-house compounds. Virtual screening based on molecular docking and MM/GBSA-based free energy calculations indicated that, among 545 derivatives, four compounds demonstrated high binding affinity against both targets, including two sulfonamide-vinyl sulfone hybrids (cpd48_e and cpd50_e), one sulfonamide-chalcone analog (cpd48), and one berberine-cinnamic acid derivative (DN071_f). Their molecular complexation was driven mainly by van der Waals forces rather than electrostatic attraction. Several residues at the enzyme allosteric site, particularly K74, L149, and N152 (DENV) and L76, I123, N152, and V155 (ZIKV), were identified as binding hotspots for the screened compounds. Drug-likeness predictions based on Lipinski’s rule of five further supported their potential as drug candidates. Overall, these findings provide valuable insights for the future design and development of novel antiviral drugs targeting the DENV and ZIKV NS2B/NS3 proteases. Full article

Berberine (BBR) has seen growing application in ophthalmology, yet the ocular toxicity of BBR and its metabolites remains poorly understood. This study aimed to evaluate the ocular toxicity of BBR and its major metabolite M1 and unravel their underlying mechanisms. Ocular toxicity was evaluated in human corneal epithelial cells and wild-type AB zebrafish. Mechanistic studies utilized fluorescence imaging, biochemical quantitative assays, and qPCR analyses in AB zebrafish and transgenic mitochondrial fluorescent zebrafish (strain Tg(Xla.Eef1a1:mlsEGFP)). Both BBR and M1 induced significant ocular toxicity across models, with BBR showing higher toxicity than M1. Mechanistic analyses revealed their toxicity stemmed from photoreceptor cell damage and Sirtuin 3 (SIRT3) inhibition, triggering a cascade of pathological events: mitochondrial dysfunction, oxidative stress, autophagic dysfunction, apoptosis, and inflammation. This study provides a reference for individualized risk assessment and clinical management of BBR-based therapies and paves the way for developing BBR derivatives with reduced ocular toxicity. Full article

Here we elucidated the effects of natural protoberberine alkaloids (rotundine, berberine, and nitidine) and cinnamic acid derivatives (ethyl-4-methoxycinnamate and osthole) found in Vietnamese medicinal plants, on the boundary potential of lipid bilayers and phase behavior of membrane lipids. Lipid bilayers were composed of neutral phosphatidylcholines (PC) and negatively charged phosphatidylserines (PS). Tested compounds did not produce any noticeable changes in the boundary potential with the exception of osthole, which caused a potential drop by about 30 mV independently of the membrane phospholipid composition. Protoberberine alkaloids did not demonstrate an ability to greatly influence phase transition of PC, while they dramatically disturbed PS melting by integrating two different lipid states by merging the low-melting component into the higher one. Ethyl-4-methoxycinnamate and osthole were able to decrease the temperature and sharpness of the PC and PS phase transition, although the effect on PS was higher. We also revealed that ethyl-4-methoxycinnamate and osthole diminished the melting point of both components of PS transition without the changes in their relative impacts. The observed membrane activity of the tested compounds may be related to their physiological and pharmacological potential. Full article

Background: Metabolically Associated Fatty Liver Disease (MAFLD) is a prevalent liver disorder closely tied to metabolic dysfunction, insulin resistance, and chronic low-grade inflammation. Vascular Endothelial Growth Factor (VEGF) may have a dual interesting role in MAFLD pathophysiology—supporting vascular repair in early stages, but potentially contributing to fibrosis in later stages. In this study, berberine (BBR), a plant-derived isoquinoline alkaloid, exhibits multiple beneficial properties, including anti-inflammatory, antioxidant, and endothelial-protective effects, on the study group, perhaps by influencing VEGF concentration. Objective: This study aimed to investigate the effectiveness of BBR in addressing vascular function parameters linked to MAFLD, particularly its impact on serum VEGF levels and arterial stiffness. Methods: This randomized, double-blind, placebo-controlled clinical trial enrolled seventy individuals with MAFLD who were overweight or obese. Participants were randomly assigned in a 1:1 ratio to receive either BBR (1500 mg/day) or a placebo orally for 12 weeks. The following parameters were assessed pre- and post-intervention: VEGF, brachial SBP (Systolic Blood Pressure)/DBP (Diastolic Blood Pressure), MAP (Mean Arterial Pressure), AIx (Augmentation Index), AP (Aortic Pressure), number of waveforms, Pulse Pressure (PP), PWV (Pulse Wave Velocity), and PWA-SP/PWA-DP (Pulse Wave Analysis Systolic/Diastolic Pressure). The results for the metabolic parameters—FLI (Fatty Liver Index)—and anthropometric parameters—BMI (Body Mass Index), fat mass corp—and laboratory parameters, among them, hsCRP (high-sensitivity C-reactive protein), were published by us earlier. Results: In the BBR-treated cohort, VEGF concentrations demonstrated a statistically significant increase following the intervention, rising from a baseline mean of 456.23 ± 307.61 pg/mL to 561.22 ± 389.77 pg/mL (p < 0.0001). In the BBR group, a significant reduction in PWA-SP was observed after 12 weeks of supplementation (134.85 ± 16.26 vs. 124.46 ± 13.47 mmHg, p < 0.0001). No statistically significant differences were observed in the parameters determining arterial stiffness in the BBR and placebo groups. In the BBR group, delta VEGF correlated negatively with delta FLI; no such associations were observed in the placebo group. Changes in PWV were consistent and significantly correlated with changes in brachial SBP/DBP, PWA-SP, PWA-DP, and MAP. No serious adverse events were reported, and BBR was well tolerated. Conclusions: BBR appears to be a safe and promising adjunct in MAFLD therapy, potentially exerting reparative effects through VEGF modulation and vascular support. Further research is warranted to confirm its long-term impact and elucidate underlying protective mechanisms. Full article

Wound healing is a tightly regulated biological process involving hemostasis, inflammation, proliferation, and tissue remodeling. When these phases are disrupted, wound repair can be delayed or become chronic. Key signaling pathways, including NF-κB, JAK/STAT, and MAPK, coordinate immune activation, cytokine expression, cell proliferation, and tissue repair. Medicinal plants and their bioactive compounds, such as flavonoids, alkaloids, tannins, and other phytoconstituents, have demonstrated significant anti-inflammatory, antioxidant, and immunomodulatory effects that modulate these pathways. Tannins contribute to repair through neutralization of reactive oxygen species (ROS), activation of antioxidant enzymes, and metal-chelating activity. Alkaloids, including tetrandrine, oxymatrine, and berberine, inhibit NF-κB signaling, thereby reducing pro-inflammatory cytokines such as IL-1β and TNF-α. Flavonoids regulate inflammatory mediators and enzymes, including COX and phospholipase A2, while also protecting against oxidative stress and stimulating fibroblast and keratinocyte proliferation—key steps in tissue regeneration. Collectively, these compounds accelerate wound closure by reducing oxidative stress and promoting cellular proliferation and migration. Thus, medicinal plants represent promising complementary approaches to wound management. Future research should focus on developing advanced drug delivery systems to enhance the stability, bioavailability, and targeted action of plant-derived compounds. Localized and biomaterial-based strategies show promise for sustained release at the wound site, and further preclinical and clinical studies are required to ensure their safety, reproducibility, and efficacy. Full article

Salmonella Typhimurium, a significant intracellular foodborne pathogen, regulates host cell autophagy to achieve its own survival by injecting effector proteins into host cells via its type III secretion system (T3SS). Berberine hydrochloride (BH), an isoquinoline alkaloid derived from medicinal plants such as Coptis chinensis, has demonstrated potential antibacterial and immunomodulatory properties. However, the mechanisms by which BH combats S. Typhimurium by enhancing host autophagic flux through the inhibition of the type III secretion system remain to be fully elucidated. Here, we found that BH disrupts biofilm formation of S. Typhimurium, significantly inhibits the expression of genes associated with T3SS, and robustly enhances autophagy activity in macrophages infected with the pathogen. In a mouse model (C57BL/6 female 20 ± 1 g/mouse), BH significantly improved survival rates, reduced bacterial loads in tissues, and alleviated pathological damage. Molecular docking studies revealed that BH binds to key T3SS proteins, including SipB, SseA, and SsrB. These findings indicate that BH holds promise as a potentially effective therapeutic strategy for combating S. Typhimurium infections. Full article

Phytotherapy is a growing field of modern medicine, offering natural alternatives with multidirectional pharmacological effects. Among plant-derived bioactive compounds, isoquinoline alkaloids exhibit antioxidant, anti-inflammatory, and antimicrobial properties. Our in vitro model of campylobacteriosis confirmed that berberine reduces pathological changes in colonocytes not only through its direct antibacterial (minimum inhibitory concentration for pure berberine against Campylobacter jejuni was 64 μg/mL) and anti-biofilm (fourfold reduction in C. jejuni biomass) effects, but also through its protective effect on the morphostructure and secretory profile of host cells exposed to bacterial components. Furthermore, berberine stabilized intercellular junction proteins, modulated bile acid and arachidonic acid metabolism, and supported host-protective signaling pathways. These findings indicate that berberine acts through a dual mechanism—directly reducing bacterial virulence while enhancing intestinal barrier integrity and metabolic homeostasis. In summary, berberine appears to be a multifunctional phytochemical in the development of new strategies for the prevention and treatment of C. jejuni-induced gastrointestinal infections and epithelial barrier dysfunctions. The protective effect we have demonstrated may contribute to alleviating the phenomenon of “leaky gut,” commonly associated with campylobacteriosis. Full article