Knee osteoarthritis (KOA) is a prevalent chronic degenerative joint disorder characterized by an imbalance between articular cartilage degradation and synthesis, a central mechanism in KOA pathogenesis. Given the absence of disease-modifying therapies, there is a critical need to elucidate the underlying pathological processes, establish reliable biomarkers for early detection and prognosis, and identify safer, more effective therapeutic agents. In recent years, natural products have attracted considerable interest due to their low toxicity, cost-effectiveness, and distinct biological activities, demonstrating significant potential in KOA management. These compounds can impede KOA progression through multiple mechanisms, including promoting cartilage matrix synthesis, mitigating inflammation, reducing oxidative stress, suppressing chondrocyte apoptosis, and modulating autophagy, thereby supporting their translational application. This review summarizes biomarkers relevant to early diagnosis and phenotypic stratification in KOA, with a focus on elucidating the pharmacological actions and molecular mechanisms of natural products, such as flavonoids, alkaloids, saponins, terpenes, and traditional Chinese medicine (TCM) formulas, in KOA intervention, aiming to provide evidence-based strategies for improved disease management.

Guggulsterone (GS) is a bioactive compound primarily extracted from the oleo-gum resin of plants in the Commiphora and Boswellia genera. Modern pharmacological studies have demonstrated that GS possesses a broad spectrum of biological activities, with notable therapeutic potential in inflammatory disorders, neurodegenerative conditions, diabetes mellitus, and various cancers. In this review, we systematically analyzed relevant literature published up to 2024 from the CNKI, Web of Science, ScienceDirect, and PubMed databases to summarize the current understanding of GS’s pharmacological effects, toxicity profile, and pharmacokinetic properties. The findings indicate that GS exerts potent antioxidant, anti-inflammatory, anticancer, antiviral, antidepressant, lipid-lowering, and cardiovascular protective effects, primarily through modulation of key signaling pathways such as the Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3), nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1), Nrf2/Keap1, nuclear factor kappa-B (NF-κB), AMPK, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), and mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1). Additionally, GS may help overcome limitations associated with conventional chemotherapy by modulating drug resistance via regulation of p-glycoprotein activity. Following hepatic metabolism mediated by cytochrome P450 enzymes, GS does not appear to cause significant adverse effects. This review provides a comprehensive synthesis of the sources, pharmacological actions, safety, pharmacokinetics, and potential applications of GS. Future research should focus on structural modification of GS, development of novel formulations, and exploration of synergistic combinations with other therapeutic agents to broaden its clinical utility.

Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass, compromised bone microstructure, and an increased risk of fractures, primarily due to excessive osteoclast-mediated bone resorption relative to osteoblast-mediated bone formation. While current anti-osteoporosis drugs, such as bisphosphonates and denosumab, predominantly focus on reducing bone resorption, osteoanabolic approaches are essential for restoring bone microarchitecture and ultimately reducing fracture risk. Traditional Chinese medicines (TCMs) and their active ingredients have long been used in China for osteoporosis prevention and treatment. This review provides a comprehensive evaluation of the effects and molecular mechanisms of 65 natural products across 24 categories on osteoblast-mediated bone formation. These compounds promote bone formation by regulating key transcription factors (RUNX2 and Osterix) and signaling pathways, including WNT/β-catenin, bone morphogenic protein (BMP), mitogen-activated protein kinase (MAPK), phosphoinositide 3‐kinase/protein kinase B (PI3K/AKT), oxidative stress, autophagy, and epigenetic regulation. Notably, certain natural products [e.g., icariin (ICA)] exert their effects through multiple targets and pathways. Many of these natural products have demonstrated significant therapeutic efficacy in animal models, such as ovariectomized (OVX) mice. Our findings suggest that natural products with kidney-tonifying, anti-inflammatory, and antioxidant properties, as well as those inhibiting adipocyte differentiation, may hold promise for osteoporosis treatment. Additionally, we highlight current research gaps and propose future directions, including high-throughput screening and validation in diverse animal models, development of novel bone-targeting delivery systems, and identification of natural compounds targeting osteocytes.

Cyclocarya paliurus (Batalin) Iljinsk., a medicinal and edible plant widely utilized in China, is a rich source of triterpenoids and flavonoids, which are recognized for their hypoglycemic, hypolipidemic, antioxidant, and antitumor properties. However, recent comprehensive summaries of its bioactive constituents and associated biosynthetic mechanisms remain limited. In this review, we systematically categorized the principal bioactive compounds isolated from C. paliurus, classifying triterpenoids into seven structural groups and flavonoids into four, based on their core skeletal frameworks. Notably, C-11 glycosylation was identified as a distinctive structural feature specific to C. paliurus triterpenoids. Furthermore, we summarized the key enzymes involved in the biosynthesis of these triterpenoids and flavonoids and, for the first time, proposed putative biosynthetic pathways by integrating current biochemical and genomic evidence. This review provides a comprehensive overview of the bioactive constituents and their associated biosynthetic enzymes in C. paliurus, offering valuable insights into the molecular basis of these natural products and establishing a foundation for future in vitro biosynthesis efforts.

Despite effective antiretroviral therapy (ART), many individuals with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) achieve viral suppression but fail to fully restore cluster of differentiation 4 (CD4)⁺ T lymphocyte (CD4 cell) counts—a condition known as immunological non-response (INRs). INRs are associated with elevated health risks, including increased susceptibility to AIDS-related and non-AIDS-related complications. The pathogenesis of INRs remains incompletely understood, and no established therapeutic interventions exist, posing a major challenge in contemporary HIV/AIDS management. Emerging evidence indicates that INRs exhibit significant alterations in gut microbiota composition. Dysbiosis of the gut microbiota may contribute to persistent immune activation, cytokine imbalance, and cellular pyroptosis, all of which could impair immune reconstitution in people living with HIV/AIDS. Traditional Chinese medicine (TCM) has demonstrated potential immunomodulatory effects and is increasingly utilized in the management of INRs. Targeting the gut microbiota and elucidating the mechanisms by which TCM modulates this microbial ecosystem may offer new avenues for preventing and treating INRs. This review explores the interplay between gut microbiota and TCM, examines the association between gut dysbiosis and INRs, discusses the mechanistic pathways through which microbiota imbalance contributes to INRs development, and highlights how TCM interventions regulate gut microbiota to promote immune recovery. By focusing on the gut microbiota as a therapeutic interface, this article provides novel insights into TCM-based strategies for improving outcomes in INRs and supports the development of innovative treatment approaches.

Traditional Chinese medicine (TCM) has garnered increasing attention globally, with its modernization becoming a prominent research focus both within China and internationally. However, the lack of a precise definition for TCM modernization has hindered clear guidance for its development. Additionally, cancer remains a significant global public health challenge, largely untreatable with current methods. Therefore, a comprehensive understanding of TCM modernization is crucial for its evolution, revolution, drug discovery, and cancer therapy. This study provides an overview of the history, theory, characteristics, and evolution of TCM, highlighting its potential in cancer prevention and treatment. We propose a definition for TCM modernization, innovative Chinese medicine (ICM), and elucidate strategies to elevate TCM from a supporting role to a leading one. Electronic databases such as PubMed, Web of Science, ScienceDirect, and Clinical Trials were utilized to retrieve relevant literature spanning from 1979 to 2024, with most publications being from the last five years, using keywords like “Traditional Chinese medicine”, “Cancer”, “Mechanism”, and “Clinical trial”. In this study, we introduce the theory of TCM modernization following target identification and initial compound screening: ICM, defined by “3 D” elements: definite active ingredient composition and content, determined functional mechanism, and detection through evidence-based medicine. Overall, the “3 D” definition of ICM will establish a standard for ICM, accelerate TCM modernization, enhance drug discovery targeting cancer and various human diseases, and benefit patients worldwide.

Hair loss, a multifactorial disorder characterized by follicular miniaturization and excessive shedding, significantly impairs psychological well-being and quality of life. Cyperus rotundus rhizome (CR), a traditional Chinese medicine used for various ailments, has not been evaluated for efficacy in treating hair loss. This study presents the first comprehensive assessment of the hair growth-promoting effects of ethanol extract from CR on mouse primary dermal papilla cells (MDPCs) and human immortalized hair DPCs (IHHDPCs), employing cell counting kit-8 (CCK-8), scratch assay, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and Western blot (WB). CR treatment activated the Wnt/β-Catenin signaling pathway by upregulating Wnt10b, increasing β-Catenin protein levels and promoting its nuclear translocation, while simultaneously downregulating transforming growth factor-beta 1 (TGF-β1), BMP4, and dickkopf-related protein 1 (DKK1) in MDPCs. These molecular changes enhanced cell proliferation and increased secretion of key growth factors—insulin-like growth factor 1 (IGF1), keratinocyte growth factor (KGF), and vascular endothelial growth factor (VEGF)—thereby stimulating hair growth and prolonging the anagen phase, which was confirmed in an ex vivo hair follicle (HF) organ culture model. Chromatographic analysis identified the petroleum ether fraction (CRP), enriched in sesquiterpenes, as the primary bioactive component. Both CR and CRP promoted IHHDPC proliferation, migration, and growth factor expression through activation of the Wnt/β-Catenin pathway, with CRP exhibiting superior bioactivity. Furthermore, both treatments stimulated HF cycling, increased follicular density, and upregulated Ki67 and β-Catenin expression in the dorsal skin of C57BL/6 mice. Collectively, these findings demonstrate that CR and CRP promote hair growth and modulate the hair cycle via enhancement of Wnt/β-Catenin signaling, providing a scientific basis for the potential clinical application of C. rotundus rhizomes in hair loss therapy and the development of related pharmaceuticals or cosmetics.

Colitis-associated colorectal cancer (CAC) is a major contributor to cancer-related mortality worldwide. Titanium dioxide (TiO₂, E171), a widely used food additive, has been insufficiently studied regarding its effects on macrophages within colon tumors during CAC development. In this study, CAC mouse models were used to investigate the biological impact of dietary E171 on macrophages in vivo, while lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cell lines were employed to elucidate the underlying mechanisms in vitro. We found that dietary E171 intake accelerated CAC development, exacerbated inflammatory responses and oxidative stress, and upregulated CAC-associated genes, including S100a8, S100a9, Lcn2, S100a11, Cxcl2, and interleukin-1α (Il-1α). E171 also increased the expression of S100A8, S100A9, NOD-like receptor family pyrin domain-containing 3 (NLRP3), and gasdermin-D N-terminal (GSDMD-N) in macrophages within colon tumors. In inflammatory macrophages, E171 exposure enhanced cell viability, increased reactive oxygen species (ROS) levels, and elevated the expression and secretion of S100A8 and S100A9, consistent with in vivo histological observations. Furthermore, E171-induced secretion of S100A8 and S100A9 in macrophages was suppressed by specific inhibitors, including N-acetylcysteine (NAC, ROS inhibitor), MCC950 (NLRP3 inhibitor), Z-YVAD-FMK (caspase 1 inhibitor), disulfiram (GSDMD inhibitor), and transfection of NLRP3 small interfering ribonucleic acid (siRNA). These results indicate that dietary E171 promotes CAC development by activating macrophages, with S100A8 and S100A9 serving as key mediators, and the NLRP3/caspase 1/GSDMD pathway acting as a critical mechanism.

Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), ranks among the most prevalent malignancies and is a leading cause of cancer-related mortality worldwide. Therefore, there is an urgent need to identify novel anti-pancreatic cancer agents. This study reports a newly identified homogeneous polysaccharide, designated ESPPW, isolated from Arthrospira platensis (A. platensis). The molecular weight of ESPPW is estimated at 356 kDa, and it consists predominantly of glucose and rhamnose, with minor amounts of mannose, glucuronic acid, galacturonic acid, galactose, xylose, arabinose, and fucose. ESPPW inhibits the proliferation and migration of PDAC cells both in vitro and in vivo. Mechanistic investigations reveal that ESPPW induces apoptosis through activation of caspase-3 and is associated with upregulation of the tumor-suppressor protein p53. Notably, treatment with 2.8 nmol·L⁻¹ of ESPPW leads to significant time-dependent downregulation of galectin-3 (Gal-3) and glypican-6 (GPC-6). These findings are corroborated by immunohistochemical analysis of tumor xenograft tissues. Furthermore, overexpression of Gal-3 and GPC-6 reverses the pro-apoptotic effect of ESPPW, as indicated by restored cycle regulatory proteins (CDK2) expression. In conclusion, these data demonstrate that ESPPW suppresses PDAC cell growth by promoting apoptosis and disrupting the functional activity of Gal-3 and GPC-6.

TMPRSS2 plays a crucial role in facilitating the entry of both the influenza virus and the SARS-CoV-2 coronavirus into host cells. Recent studies have identified a guanine-rich sequence in the proximal promoter region of the TMPRSS2 gene, which can form G-quadruplex structures (TMPRSS2-G4s) that are potential targets for small molecules to inhibit TMPRSS2 expression. However, the structural details of the major TMPRSS2-G4 and its complex with small molecules remain unknown, hindering the development of antiviral drugs targeting TMPRSS2-G-quadruplexes (G4s). This study reports the first high-resolution nuclear magnetic resonance (NMR) solution structure of the major TMPRSS2-G4, which consists of a three-tetrad core parallel-stranded G4. Both 3′ and 5′ flanking regions form well-defined capping structures stabilized by multiple hydrogen bonds. Importantly, we found that berberine, an antiviral alkaloid, strongly binds to the major TMPRSS2-G4 and determined its binding complex structure with TMPRSS2-G4 at a 2∶1 binding stoichiometry. Each berberine molecule recruits an adjacent flanking residue, forming a coplanar structure superimposed on two outer G-tetrads. Moreover, we demonstrated that the major TMPRSS2-G4 can stably form within a longer deoxyribonucleic acid (DNA) context and be targeted by small molecules to inhibit DNA polymerase activity. Overall, this study provides structural insights into the recognition mechanism of small molecules by the major TMPRSS2-G4 and may facilitate the development of novel antiviral therapeutics targeting TMPRSS2-G4.

Twelve new diterpenoids, euphorwallnoids A−L (1−12), comprising five rhamnofolanes (1−5), five tiglianes (6−10), and two daphnanes (11 and 12), along with six known analogues (13−18), were isolated from the whole plants of Euphorbia wallichii (E. wallichii). Their structures were determined using spectroscopic analysis, computational methods, chemical derivatization, and single-crystal X-ray diffraction. Euphorwallnoid A (1) features an unusual 5/7/6/5-tetracyclic scaffold, whereas 2−5 represent a rare subclass of 4-deoxygenated rhamnofolanes and 6−8 constitute 13-deoxygenated tiglianes. Notably, compound 1 demonstrated promising anti-liver fibrosis activity by significantly inhibiting the expression of fibronectin (FN), α-smooth muscle actin (α-SMA), and collagen I in transforming growth factor β1 (TGF-β1)-stimulated LX-2 cells at micromolar concentrations.