Mesenchymal stem cells (MSCs) are pluripotent stem cells isolated from human tissues. Due to their strong self-renewal capacity, pluripotency, and immunomodulatory properties, MSCs have garnered significant attention in cell therapy and tissue regeneration. However, cellular senescence induced by replication or external stimuli can impair MSC proliferation and differentiation, making it crucial to develop interventions that delay or reverse the senescence process. From a traditional Chinese medicine perspective, senescence stems from spleen and stomach deficiency, kidney deficiency, and related factors; thus, medicines that tonify the kidney and promote Qi and blood circulation play vital roles in anti-senescence therapy. Chinese medicine, characterized by low toxicity and multi-target, multi-functional properties, has become prominent in anti-senescence research. This paper examines the MSC senescence process by discussing its causes, characteristics, and mechanisms, then summarizes how active ingredients in herbal medicines and natural compounds reverse MSC senescence, facilitating the discovery of additional anti-senescence Chinese medicines and their effective components.
Ischemic stroke (IS) presents a major threat to human life and health due to its high disability and mortality rates. 3-n-Butylphthalide (NBP), derived from celery seeds of the Apiaceae family native to the Mediterranean region, was first introduced in China for acute IS treatment in 2004. NBP demonstrates multiple therapeutic actions, including reconstruction of microcirculation in the cerebral ischemia area, inhibition of platelet aggregation, reduction of cerebral infarction volume, maintenance of blood-brain barrier (BBB) integrity, and enhancement of cerebral blood perfusion. However, its overall efficacy remains moderate, limited by poor water solubility and low bioavailability, which constrains its clinical application. To address these limitations, researchers have actively pursued the development of NBP derivatives and analogs, achieving notable progress. These efforts, including substituent introduction, ring opening derivatization, esterification, and atom substitution, have generated diverse NBP derivatives. Several of these derivatives have advanced to clinical studies. Specifically, potassium 2-(1-hydroxypentyl)-benzoate (PHPB), brozopentyl sodium (BZP), and XY-03-EA (ZONK1103) have reached phase II clinical trials, while (S)-2-(1-acetoxypentyl)benzoic acid L-arginine salt (AAPB) has received clinical trial approval for 2024. This review examines the structural modification and optimization of NBP over the past two decades from a medicinal chemistry perspective, aiming to facilitate the development of superior derivatives and advance cerebral ischemia treatment.
Pulmonary fibrosis (PF) is a progressive, fatal fibrotic disease caused by respiratory conditions. The condition can ultimately lead to severe organ failure and mortality, and is associated with multiple risk factors. Growing evidence highlights the immune system’s role in PF, with various immune components participating in inflammatory and fibrotic processes. Different immune cells, including neutrophils, lymphocytes, and macrophages, demonstrate distinct effects on PF progression and development. Furthermore, key immune system cytokines, including the interleukin (IL) family, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-β, and connective tissue growth factor (CTGF), contribute to PF initiation and progression through independent mechanisms and mutual regulation. Currently, limited effective treatments exist for PF, with several treatments causing severe adverse reactions. Natural products, characterized by multi-target effects, holistic regulation, and low toxicity, have emerged as a research focus. This review compiles the mechanisms, therapeutic potential, and active components of various natural products. These compounds can ameliorate pulmonary inflammation, epithelial-mesenchymal transition, and collagen deposition through diverse immune mechanisms, acting at specific stages or throughout the fibrotic process, thereby supporting PF management. This review examines current scientific understanding of natural products’ immunological effects in PF, which is crucial for developing future anti-PF therapeutics.
Cardiovascular diseases (CVDs) are driven by intricate and multifactorial pathophysiological mechanisms, presenting substantial challenges for the development of effective therapeutic strategies. Recent studies have highlighted the therapeutic potential of various traditional Chinese medicines (TCMs), which exert vasodilatory, anti-inflammatory, and antioxidant effects that may alleviate clinical symptoms and slow CVD progression. Ziziphora clinopodioides, a traditional herbal medicine, contains primarily flavonoids, phenolic acids, and essential oils. These compounds contribute to its pharmacological activities, including inhibition of apoptosis inhibition, inflammation reduction, oxidative stress mitigation, mitochondrial function improvement, and vasodilation promotion, all of which are relevant to CVD treatment. This review comprehensively examines the pathophysiological basis of CVDs, elucidates the molecular mechanisms and signaling pathways involved in the cardioprotective actions of Ziziphora clinopodioides, and summarizes its emerging clinical applications in cardiovascular therapy. The findings aim to inform future research and promote the rational development of this medicinal plant as a complementary or adjunctive treatment for CVDs.
Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition affecting the gastrointestinal tract. The global incidence and prevalence of IBD continue to increase. While multiple clinical treatments exist, conventional therapies frequently present limitations and adverse effects. Natural polysaccharides (PSs) have emerged as a significant focus of research interest due to their therapeutic potential and applications in functional foods and health products. This review synthesizes current understanding of IBD pathophysiology and the mechanisms by which natural PSs counter IBD, including their capacity to restore immune homeostasis and intestinal barrier function, modulate gut microbiota and metabolites, reduce oxidative stress, and address irregularities in autophagy and endoplasmic reticulum stress (ERS). The review examines the structure-activity relationships of PSs demonstrating anti-IBD effects and identifies promising therapeutic products. The discussion encompasses pharmacokinetics, safety evaluations, and clinical applications of these compounds. This comprehensive review establishes a theoretical foundation for developing natural PS-based therapeutic approaches for IBD management.
Diabetes mellitus (DM) is a chronic disease influenced by gut microbiome disturbances. Honokiol (HON), a low oral bioavailability compound from Magnolia officinalis bark, has demonstrated potential as a treatment for DM. This research investigates the effects of HON on gut microbiota and host metabolism to elucidate its mechanism of action in DM. After 8 weeks of intervention through fecal microbiota transplantation (FMT) or antibiotic treatment, HON improved glucose tolerance and lipid metabolism in a gut microbiota-dependent manner. Specifically, HON administration significantly increased Akkermansia muciniphila (AKK) abundance and modulated tryptophan (TRP) metabolism, as evidenced by 16S ribosomal ribonucleic acid (rRNA) gene sequencing and untargeted/targeted metabolomics analysis. Notably, research revealed that AKK metabolized TRP into tryptamine (TA) and other metabolites in vitro. Both AKK and TA activated the aryl hydrocarbon receptor (AHR) pathway, increasing circulating glucagon-like peptide-1 (GLP-1) levels and ameliorating diabetes-related symptoms in DM mice. These findings indicate that HON’s hypoglycemic effect primarily stems from AHR-GLP-1 pathway activation through targeted modulation of AKK and microbial TRP metabolite TA, potentially enhancing HON’s clinical applications.
;Chronic heart failure (CHF) impairs cognitive function. Xijiaqi Formula (XJQ), a traditional Chinese medicine (TCM) used clinically to treat CHF, demonstrates potential for improving cognition in CHF patients. However, its precise mechanism in treating post-CHF cognitive dysfunction remains unclear. This study systematically investigates XJQ’s effects on post-CHF cognitive dysfunction and the underlying mechanisms. The components of XJQ were identified through liquid chromatography-mass spectrometry. CHF was induced in rats via ligation of the left anterior descending coronary artery, followed by six weeks of XJQ treatment. Cardiac function was evaluated through echocardiography and hemodynamic parameters, while cognitive function was assessed using Morris water maze (MWM) and open field tests (OFT). XJQ treatment enhanced both cardiac and cognitive functions in CHF rats. Network pharmacology identified 12 core active components of XJQ and indicated its effect on cognitive dysfunction involved regulating synapses, inflammation, and phosphodiesterase 4 (PDE4)-dependent cyclic adenosine monophosphate (cAMP) signaling. XJQ inhibited microglial and astrocyte activation, decreased proinflammatory cytokines, and mitigated neuronal damage. Notably, XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP, protein kinase A (PKA), cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), PSD95, and synapsin I levels. Molecular docking and Bio-layer interferometry assays confirmed direct binding of quercetin, kaempferol, isorhamnetin, and darutoside to PDE4. In conclusion, XJQ alleviates neuroinflammation and enhances synaptic plasticity to improve cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling pathway. These findings provide valuable insight into the heart-brain axis.
The activation of pancreatic stellate cells (PSCs) and the secretion of inflammatory factors play critical roles in the development of pancreatic fibrosis. While gambogic acid (GA), a flavonoid with anti-tumor properties, has been studied, its role in this process remains unclear. This study demonstrated that GA promoted YAP1 degradation and reduced its nuclear localization, thereby inhibiting PSC activation and the progression of pancreatic fibrosis. GA inhibited PSC proliferation, decreased α-smooth muscle actin (α-SMA) expression, and reduced lipid droplets in LTC14 and primary mouse PSCs (mPSCs). Additionally, GA suppressed the expression of inflammatory factors [nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), nuclear factor erythroid 2-related factor 2 (NRF2), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and nuclear factor κB (NF-κB)] in PSCs and counteracted the transforming growth factor (TGF)-β-induced increase in these proteins. GA also reduced collagen Ι and tissue inhibitor of metalloproteinase-1 (TΙMP1) expression, thereby attenuating fibrosis. Mechanistically, GA decreased YAP1 expression and nuclear translocation and reversed TGF-β-induced YAP1 upregulation. YAP1 overexpression abrogated GA’s inhibitory effects on PSC activation and inflammation. Furthermore, GA activated the Hippo pathway, increased phosphorylated (p)-LATS1 and p-YAP levels, and promoted ubiquitin-mediated YAP1 degradation. In vivo studies confirmed that GA inhibited dibutyltin dichloride (DBTC)-induced pancreatic fibrosis via suppressing YAP1 and NF-κB in BALB/c mice. In conclusion, GA activates the Hippo pathway and promotes YAP1 translocation to the cytoplasm, leading to its degradation and subsequent inhibition of PSC activation and fibrosis. These findings highlight the critical role of ubiquitin-mediated YAP1 degradation in regulating PSC activity and offer novel insights into the therapeutic potential of GA for treating pancreatic fibrosis.
Insects represent emerging sources of bioactive peptides and functional materials. Mantidis Oötheca (Sang-Piao-Xiao in Chinese, SPX) serves as an insect-derived medicine for treating kidney disease. This study demonstrated that supernatant (SPX) improved kidney function in adriamycin (ADR)-induced nephropathy mice model. Transcriptomic analysis revealed that SPX inhibited complement activation by targeting the MASP1-C3/C3a receptor (C3aR) pathway. Peptidomic analysis identified 304 peptides from SPX, with 49 peptides selected for evaluation using prediction tools and molecular docking with complement core protein C3. Three peptides (PMGFPFDR, FNDPK, AAQFFNR) exhibiting docking scores below −8.0 were synthesized to verify complement inhibition and anti-fibrotic activities. The synthetic peptide AAQFFNR demonstrated complement inhibitory activity, with an inhibitory complement hemolytic 50% (ICH50) value of 24.54 μmol·L−1, and exhibited superior protective effects in ADR-induced HK-2 cells. Surface plasmon resonance (SPR) assay revealed direct interaction between AAQFFNR and complement C3 with Kd value of 16.8 μmol·L−1. The reno-protective effect of AAQFFNR was subsequently verified in ADR-induced mice. This research provides initial evidence that complement C3-inhibiting peptides from insects demonstrate potential in preventing nephropathy through in silico and in vivo validation approaches.
Penicine A (1), a meroterpenoid featuring a novel 3/5/6/6/11/6/6 polycyclic backbone, together with two new metabolites, penicines B (2) and C (4), and six known compounds, were isolated from the mangrove rhizosphere soil-derived fungus Penicillium brefeldianum SMU03. The structures of these metabolites were elucidated through extensive spectroscopic analysis combined with quantum chemical calculations. Notably, 1 exhibits a highly unusual molecular architecture, incorporating a dioxaspiro[4.5]decane motif and a rare bridgehead double bond (anti-Bredt system). A plausible biosynthetic pathway, involving sequential intermolecular [4 + 2] cycloaddition reactions, is proposed. Additionally, meroterpenoids 1 and 3 demonstrate significant antifibrotic activity in transforming growth factor β1 (TGF-β1)-induced human renal proximal tubular epithelial cells.
Atractylodes macrocephala Koidz. (A. macrocephala) is a medicinal and edible plant species belonging to the Compositae family. Its rhizome serves both therapeutic and nutritional purposes in China. This investigation led to the isolation of thirteen novel rearranged 9(8→7)-abeo-eudesmane-type sesquiterpenoid dimers (SDs), atramacronins A−M (1−13), three eudesmane-type SDs, atramacronins N−P (14−16), and two previously identified meroterpenoids, atrachinenin G (17) and atrachinenin Ι (18), from Atractylodes macrocephala. Structure elucidation was accomplished through comprehensive spectroscopic analysis and single-crystal X-ray diffraction. Compounds 1, 4−7, 9, and 10 exhibited notable cytotoxicity against Hep3B, HepG2, and Huh7 cell lines, with half maximal inhibitory concentration (IC50) values ranging from 3.71 to 13.99 μmol·L−1.