Search Results (895)

Physical integration between endosymbiotic algae and host mitochondria is a recurring feature across photosynthetic symbioses, yet the structural nature of this association has remained unresolved. In the ciliate Paramecium bursaria, each endosymbiotic Chlorella cell is enclosed by a perialgal vacuole (PV) membrane consistently surrounded by host mitochondria, suggesting a conserved architecture for metabolic interaction. Although transmission electron microscopy has shown close membrane apposition, it has remained unclear whether this reflects incidental proximity or a reinforced adhesion. Here, we provide direct evidence that the PV membrane and host mitochondrial membrane form a stable physical association. Using discontinuous Percoll centrifugation, we isolated intact units in which Chlorella and mitochondria co-sedimented, indicating that their association withstands mechanical disruption. By fluorescently labeling the PV and mitochondrial membranes with BODIPY FL C₅-ceramide (BC₅C), together with a mitochondria-specific monoclonal antibody and DAPI, we visualized the PV membrane under light microscopy and demonstrated that the mitochondrial–PV membrane complex persists after homogenization and centrifugation. As expected from the membrane-insertion behavior of BC₅C, this fluorescent labeling revealed that the PV–mitochondrial membrane association is structurally reinforced rather than incidental, providing a mechanistic framework for understanding how Chlorella cells are stably positioned beneath the host cortex. Full article

Scorpion neurotoxins are small peptides that target ion channels and offer opportunities for novel therapeutic discovery. This study analyzed the functional effects of the venom and toxins from the Costa Rican endemic scorpion, Tityus championi. Initially, crude venom was tested on different isoforms of voltage-gated sodium channels. Our findings revealed that the venom contains toxins that affect mammalian Na_V1.6 and Na_V1.7, as well as the cockroach BgNa_V1 channel. Increased currents through Na_V1.6 and BgNa_V1 channels were associated with bigger window currents and inhibition of inactivation. Decreased Na_V1.7 currents were associated with smaller conductance. Crude venom and TCh3 toxin inhibited action potential generation in invertebrate neurons expressing Na_V1.7-like channels. In these neurons, Tch2 and Tch4 toxins shifted voltage sensitivity to more negative potentials, ultimately widening the window current but decreasing channel availability. Conversely, Tch3 behaved as an inhibitory toxin, closing window currents and decreasing channel availability. Structural modeling showed that Tch3 adopts an αββ fold and binds the S3–S4 loop of Domain II in human Na_V1.7. These data show the diverse effects of scorpion venoms on channels and neurons, characterize its principal toxins, and show that Tch3 has therapeutic potential for pain relief. Full article

Propolis produced by honeybees, Apis mellifera, has been valued since ancient times as a remedy for different ailments for its broad medicinal properties. This wide range of biological activities may arise from the production of distinct propolis types within the hive, each serving specific functions and containing unique molecular compositions. In this study, we investigated the effects of four propolis types—masonry, sealing, brood-protection, and intruder-neutralizing—on hydrogen peroxide (H₂O₂)-induced oxidative injury in human skeletal muscle cells. Among these, only brood-protection propolis significantly prevented the H₂O₂-induced loss of cell viability. Bio-guided fractionation of this active propolis identified five major compounds: benzyl caffeate (BC), caffeic acid phenethyl ester (CAPE), cinnamyl caffeate (CC), prenyl caffeate (PC), and (E)-3-methyl-3-butenyl caffeate (MBC), all displaying stronger cytoprotective effects than their ferulate equivalents. We finally demonstrated that propolis extract and its active compounds reduced lipid peroxidation in post-mortem minced mouse skeletal muscle and compared their efficacy to other natural compounds. Chemical analysis of resins from neighboring flora suggested that black poplar (Populus nigra) buds are the primary botanical source of these caffeate derivatives. Collectively, these results highlight the functional diversity of hive propolis and its potential applications in food preservation as well as in complementary and preventive medicine. Full article

Aging is a multifactorial process characterized by progressive physiological changes, including cellular senescence, cellular loss, and organ decline, which collectively accelerate the development of metabolic syndrome (MetS) in older adults. MetS, in turn, not only significantly increases the risk of cardiovascular disease (CVD) but also contributes to decreased functional and cognitive capacity, partly due to diminished ability to adapt to metabolic stress. While genetic predisposition has a substantial influence on the risk of developing MetS, other intrinsic factors, including chronic inflammation, insulin resistance (InsR), and altered neurohormonal activation, also play crucial roles. Targeted therapies, lifestyle interventions, and pharmacotherapy can decelerate the progression of CVD, improving the likelihood of survival with favorable neurological and functional outcomes in older individuals with MetS. However, adverse drug reactions and the lack of adequate interventions for cognitive decline have led to the emergence of self-medication with nonprescription products. The anti-inflammatory, antioxidant, anti-channelopathy, antiaging, and neuroprotective properties of flavonoids, alkaloids, polysaccharides, and polyphenols found in key traditional medicines have shown promising potential in the treatment of MetS-induced cognitive decline. This narrative review summarizes current evidence on bioactive compounds and herbal medicines that may offer cognitive benefits in elderly patients with MetS. Full article

The ocular surface system, essential for maintaining visual function, is highly susceptible to a range of ocular surface diseases (OSDs) that significantly impair patients’ quality of life. Current treatments for OSDs often face limitations including low bioavailability, A lack of targeted delivery, and an inadequate capacity to fully address the complex pathophysiology involving inflammation, oxidative stress, and impaired tissue repair. In recent years, exosomes have emerged as promising cell-free therapeutic platforms for OSDs. This review evaluates their therapeutic potential across the OSD spectrum, focusing on three key aspects: mechanisms—modulation of inflammation, oxidative stress, and tissue repair via bioactive cargo; applications—preclinical therapeutic effects in dry eye disease, corneal injury, keratitis, and transplant rejection; and optimization strategies—engineering approaches and biomaterial integration to enhance stability, targeting, and ocular retention. We also discuss critical challenges in standardization, scalable production, and clinical translation, highlighting future directions for exosome-based OSD therapies. Full article

The growing interest in harnessing natural compounds for health and medical applications underscores the necessity for innovative approaches to decipher their mechanisms of action. Among diverse strategies, non-probe-based methods for identifying the molecular targets of compounds represent one of the frontiers in drug discovery. This review focuses on an array of non-probe techniques for unveiling interactions between natural molecules and biological targets. The advantages and limitations of label-free protein target identification schemes suitable for lysed cells and living cells are analyzed. High-throughput target screening methods and their role in facilitating a holistic understanding of compound–target interactions are summarized. Based on comprehensive evaluation and comparison, this review aims to provide guidelines for selecting appropriate non-probe strategies to accelerate the characterization of the therapeutic potential of natural compounds. Full article

Bovine viral diarrhea virus (BVDV), a globally persistent pathogen, causes bovine viral diarrhea-mucosal disease (BVD-MD), a contagious bovine disease posing significant pressures on both public health and economic development. Baicalin (BA), a flavonoid derived from Scutellaria baicalensis, exhibits broad antiviral activities but suffers from poor aqueous solubility and low bioavailability, limiting its therapeutic potential against BVDV. To address this limitation, we developed BA-loaded poly (ethylene gly-col)-poly (lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (BA-PEG-PLGA NPs). While autophagy and NLRP3 inflammasome activation have been individually implicated in viral pathogenesis, their functional crosstalk during BVDV infection remains uncharacterized. Herein, we evaluated the antiviral efficacy of BA-PEG-PLGA NPs through integrated in vitro and in vivo experiments. We employed quantitative polymerase chain reaction (qPCR), transcriptome sequencing, Western blot analysis, immunofluorescence microscopy, flow cytometry, and enzyme-linked immunosorbent assay (ELISA) to investigate the mechanisms by which BA and BA-PEG-PLGA NPs combat bovine viral diarrhea virus (BVDV) infection. We found that both free BA and BA-PEG-PLGA NPs effectively attenuated BVDV replication in vitro and in vivo; notably, the nano-formulation exhibited superior efficacy. Mechanistically, BA and its nano-formulation restored autophagy homeostasis, suppressed ROS overproduction, and blocked NLRP3 inflammasome activation and pyroptotic cell death effects comparable to the specific NLRP3 inhibitor MCC950. These findings establish the autophagy–NLRP3/pyroptosis axis as a critical pathogenic mechanism in BVDV infection and reveal that nano-formulated baicalin represents an antiviral strategy by coordinately targeting this axis. This work not only provides a translatable nanomedicine approach for BVDV control but also expands the mechanistic understanding of flavonoid-based interventions in viral inflammatory diseases. Full article

Immunosuppression is associated with impaired immune responses and increased susceptibility to disease, highlighting the need for safe and effective immunomodulatory strategies. Oligosaccharides derived from natural sources have attracted growing interest due to their bioactivity and regulatory effects on host immunity. The present study was designed to evaluate the immune-enhancing potential of Periplaneta americana oligosaccharides (PAOSs) and to explore their association with SCFA-producing gut microbiota and metabolic regulation in an immunosuppressed mouse model. PAOS administration significantly increased serum immunoglobulin levels (IgG and IgM), promoted the secretion of immunoregulatory cytokines (IFN-γ, IL-2, TNF-α, IL-10, and IL-4), and elevated the proportion of CD4⁺ T cells in the spleen. In addition, PAOSs alleviated oxidative stress by reducing malondialdehyde accumulation while promoting the activity of key antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase. Metabolomic analysis revealed that PAOSs altered host metabolic profiles, particularly enhancing pyrimidine metabolism. Furthermore, PAOSs markedly enriched short-chain fatty acid (SCFA)-producing bacteria, and elevated colonic short-chain fatty acid levels. These changes were closely associated with the observed improvement in immune function. Collectively, this study demonstrated that PAOSs exerted immunomodulatory effects through coordinated regulation of SCFA-producing gut microbiota and host metabolism, elucidating the mechanisms underlying the bioactivity of insect-derived oligosaccharides. Full article

Ginkgetin (GK) is a naturally occurring biflavonoid predominantly isolated from Ginkgo biloba and has attracted increasing attention because of its broad pharmacological activities. Structurally, GK belongs to the 3′-8″-linked biflavone subclass, which distinguishes it from other biflavonoids like amentoflavone (the parent compound of this subclass) and its monomeric counterparts such as apigenin. This unique C-C linked dimeric architecture confers distinct molecular planarity and lipophilicity, contributing to its enhanced membrane permeability and multitarget engagement capabilities. GK has been shown to exert pleiotropic biological effects in preclinical studies, including anti-inflammatory, antioxidant, antifibrotic, anticancer, neuroprotective, cardioprotective, metabolic regulatory and antibacterial activities. Mechanistically, preclinical evidence indicates that GK functions as a multitarget modulator of key signaling pathways involved in oxidative stress, inflammation, cell death and tissue remodeling, such as nuclear factor erythroid 2–related factor 2/heme oxygenase-1 (Nrf2/HO-1), nuclear factor kappa-B(NF-κB), Janus kinase/signal transducer and activator of transcription(JAK/STAT), mitogen-activated protein kinases(MAPKs), AMP-activated protein kinase/mechanistic target of rapamycin(AMPK/mTOR), phosphoinositide 3-kinase/protein kinase B(PI3K/Akt) and cyclic GMP-AMP synthase–stimulator of interferon genes(cGAS–STING). Notably, GK has been observed to display context-dependent regulation of cell fate decisions, including apoptosis, autophagy and ferroptosis, thereby enabling the selective elimination of pathological cells while preserving normal tissue function. Preclinical studies further demonstrate that GK exhibits therapeutic potential across diverse disease systems, including cancer, metabolic disorders, cardiovascular diseases, neurological disorders and musculoskeletal diseases. In addition, emerging evidence highlights its antibacterial and antivirulence properties through the inhibition of biofilm formation and quorum sensing. It is crucial to note, however, that this promising profile is predominantly derived from preclinical studies, and clinical evidence in humans remains to be established. Despite these promising findings, the clinical translation of GK remains limited by challenges related to pharmacokinetics, bioavailability and druggability. This review systematically summarizes the chemical characteristics, pharmacological activities and molecular mechanisms of GK, with an emphasis on its multitarget actions and therapeutic potential across disease systems, and discusses current limitations and future perspectives to facilitate the rational development of GK-based interventions. Full article

Breast cancer is the most commonly diagnosed cancer among women, with approximately one in eight women developing the disease during their lifetime. Despite advancements in current treatment options, breast cancer was responsible for an estimated 670,000 deaths worldwide in 2022. This highlights the urgent need for the development of novel therapeutic strategies. Historically, plant-derived compounds have played a significant role in cancer therapy, exemplified by widely used chemotherapeutic agents such as paclitaxel and docetaxel. In recent years, increasing attention has been directed toward novel plant-derived compounds as potential anti-cancer agents. Among these, Naringenin, a flavonoid predominantly found in citrus fruits, has shown promising antioxidant, anti-inflammatory, and anti-cancer properties. This review highlights recent studies investigating the effects of Naringenin and its derivatives on breast cancer. Evidence from both in vitro and in vivo animal models suggests that Naringenin may exert anti-tumor activity by inhibiting cell proliferation, promoting apoptosis, modulating key cell signaling pathways, and enhancing radio-sensitivity in breast cancer cells. Although preclinical evidence strongly supports the anticancer potential of Naringenin in breast cancer, comprehensive clinical studies are urgently needed to validate its efficacy and safety in humans. Full article

Ganglioside GM3, a fundamental glycosphingolipid on the mammalian cell surface, is a key regulator of transmembrane signaling and cellular recognition. In oncology, GM3 acts as a tumor suppressor by modulating the activity of various receptor tyrosine kinases (RTKs) and their downstream pathways. Recent studies highlight its function in the tumor microenvironment (TME), specifically its ability to impede pathological angiogenesis. This review summarizes the molecular mechanisms by which GM3 interferes with pro-angiogenic signaling, such as the VEGF/VEGFR axis, and discusses how this inhibition can be used for therapy. We explore the clinical potential of GM3-based strategies, including monoclonal antibodies and cancer vaccines, discussing the potential of targeting GM3 to reshape the TME and suppress tumor-associated vascularization. Full article

The escalating global burden of Ulcerative Colitis (UC) underscores the urgent need for novel therapeutic strategies. Although dietary modulation is known to influence UC progression, the specific molecular mediators remain largely undefined. Recently, the G protein coupled receptor 35 (GPR35) has emerged as a promising target for maintaining gut homeostasis and promoting intestinal epithelium repair. Yet, whether the therapeutic benefits of dietary polyphenols are mediated through the direct activation of GPR35 remains unexplored. Here, the NanoLuc Binary Technology (NanoBiT) assay was first used to identify the potential GPR35 agonist from a library of 30 natural polyphenolic compounds. We discovered Ellagic acid (EA), a natural polyphenol abundant in fruits and nuts, as the potent GPR35 agonist owing to its most potent agonistic effect. The dose-dependent effect was further confirmed by both NanoBiT and Bret assay. Then, the binding site of the ligand-receptor complex was predicted via molecular docking, and key interactions were validated by site-directed mutagenesis. The results indicated the key binding site of the complex was Gln93, Arg100, Arg151, Phe163 and Ser262. And the conformation of the complex was verified stable by the molecular dynamics simulation. The bioactivity of EA was then evaluated in vivo. And the in vivo experiment indicated that EA alleviated the symptoms of UC. In addition, complementary in vitro assays, including a wound healing (scratch) assay and an SRB proliferation assay, were employed to investigate its effect on intestinal epithelial repair. The in vitro experiment demonstrated that EA enhanced the migration and proliferation of human colonic epithelial cells, an effect that was specifically abolished by the GPR35 antagonist CID2745687, indicating the key role GPR35 played in the intestinal repair. Collectively, our study demonstrates that the natural polyphenolic compound EA promotes epithelial healing and ameliorates colitis by acting as a GPR35 agonist. Full article

Gastric cancer (GC) is a highly prevalent and rapidly progressing cancer with a poor prognosis, primarily due to chemoresistance and treatment-related toxicity. Moracin D (MD), a benzofuran extracted from Morus alba L., has shown potential antitumor effects in various malignancies, although its impact on GC remains limited. The aim of this study was to assess the anticancer potential of MD in human gastric cancer cell lines and subcutaneous xenograft models. We examined cell proliferation, clonogenic ability, cell cycle progression, and apoptosis using MTT, BrdU, colony formation assays, flow cytometry, Western blotting, and immunohistochemistry. Our findings suggest that MD selectively inhibited GC cell proliferation and reduced DNA synthesis in vitro. It also inhibited colony formation and tumor growth in vivo, affecting GC cell clonogenicity without affecting body weight or vital organs, and without overt toxicity under the experimental conditions tested. Mechanistically, MD was found to induce G₂/M cell-cycle arrest, potentially through modulation of cyclin B1 and CDK1, and to trigger apoptosis in GC cells, which may involve the mitochondrial pathway as suggested by changes in Bcl-2 and pro-apoptotic protein levels. While Bcl-2 overexpression partially reversed MD-induced inhibition of proliferation and apoptosis, further studies are required to confirm its role as a mediator. Additionally, MD enhances the anticancer effects of 5-fluorouracil (5-FU) through synergistic mechanism. This study highlights the observed antiproliferative and proapoptotic effects of MD in preclinical models and suggests its potential as monotherapy or in combination with 5-FU as a promising therapeutic approach in the treatment of gastric cancer. Full article

Toxoplasmosis is a zoonotic disease with limited therapeutic options, which are further hampered by significant toxicity and suboptimal efficacy. Effective interventions for chronic infection remain insufficient, and thus, natural product-derived drug screening remains a key focus in anti-Toxoplasma research. Licochalcone A (Lico A), a major bioactive compound isolated from Glycyrrhiza uralensis, exhibits potent activity against Toxoplasma tachyzoites. However, systematic studies of its targets, pharmacokinetics, and efficacy are lacking, hindering its development as an anti-Toxoplasma candidate drug. In this study, we used SPR-MS to identify 33 high-affinity target proteins (affinity score > 1000). Furthermore, an AI-driven multidimensional analysis identified a cluster of five proteins (TgMORN1, D3XD37, ABCB2, MIC15, and IDH), with TgMORN1 yielding the highest composite score. RNAi experiments confirmed TgMORN1 as a key target, as its silencing attenuated the anti-proliferative effect of Lico A. Western blotting, NanoDSF, and SPR supported direct binding between Lico A and TgMORN1, suggesting that Lico A modulates TgMORN1 thermal stability through residues S168 and D203, with high species specificity. Pharmacokinetic evaluation revealed that Lico A had favorable absorption and blood–brain barrier permeability, supporting its potential utility in treating brain disease. In vitro assays showed that Lico A effectively inhibited Toxoplasma gondii brain cyst formation. Collectively, these findings support Lico A as a promising candidate for the treatment of toxoplasmosis. Full article

Current wound healing strategies must confront numerous challenges. Helminth-induced immunomodulation offers a promising therapeutic avenue for inflammatory diseases and injury repair. However, research on the role of helminths in damage recovery remains limited. We utilized glycogen—a naturally occurring biomaterial—to encapsulate SJMHE1, a bioactive peptide derived from Schistosoma japonicum, and successfully developed a facilely prepared hydrogel formulation denoted as SJMHE1-gel. The properties of SJMHE1-gel, its effect on cell activity, and its performance in a murine full-thickness skin defect model were evaluated. The glycogen-based hydrogel exhibited a uniform pore size, excellent biocompatibility, and sustained release of SJMHE1. Topical application of SJMHE1-gel enhanced collagen deposition, promoted angiogenesis, facilitated the regeneration of hair follicles and sebaceous glands, and accelerated full-thickness wound healing. SJMHE1-gel also promoted M2 macrophage polarisation and suppressed inflammatory cytokine expression both in vivo and in vitro. Mechanistically, SJMHE1-treated macrophages upregulate TGF-β, which in turn promotes the migration of L929 fibroblasts and human umbilical vein endothelial cells (HUVECs) via the Smad3 pathway. Neutralization of TGF-β attenuates phosphorylated Smad3 (p-Smad3) levels and impairs the migratory capacity of both fibroblasts and HUVECs. Additionally, SJMHE1-treated macrophages upregulate VEGFA, thereby enhancing angiogenic tube formation in HUVECs. This easy-to-prepare hydrogel can regulate macrophage polarization, inhibit inflammation, promote angiogenesis, and accelerate collagen deposition, acting across wound healing stages to provide a novel therapeutic strategy. Full article