Rui Wang

Introduction: The administration of drugs at specific acupoints is a traditional practice in Chinese medicine, yet scientific evidence supporting its pharmacokinetic and pharmacodynamic (PK/PD) advantages remains limited. This study aimed to evaluate the transdermal absorption and therapeutic effects of miRNA55 when delivered via microneedles at different acupoints in a rabbit model of rheumatoid arthritis (RA). Methods: An RA model was established in New Zealand rabbits using ovalbumin-Freund’s complete adjuvant emulsion. miRNA55 was encapsulated in cationic liposomes and combined with hyaluronic acid for microneedle preparation. Microneedles were applied at classical acupoint (ST36), atypical acupoints (GB34), and non-acupoint areas above the knee joint of the rabbits (avoiding ST35). Drug concentrations in the joint cavity fluid were assessed by microdialysis and enzyme-linked immunosorbent assay (ELISA). The encapsulation rate and in vitro release of miRNA55 were analyzed by UV spectrophotometry. PK/PD modeling was conducted using WinNonlin 8.1, with IL-1β, TNF- α , and IL-6 as pharmacodynamic markers. The protein expression of TNF-α, MMP-1, and MMP-3 was assessed using western blotting (WB), and histopathological changes in the synovial tissue were observed by hematoxylin–eosin (H&E) staining. Results: miRNA55 concentrations in the joint cavity were the highest in the ST36 group, followed by the GB34 and non-acupoint groups. This observation indicated that the degree of drug absorption. PK/PD modeling showed higher efficacy value for ST36 across all three cytokines. For IL-1β, Emax model for ST36 was E = 81.09 C e 169.56 + C e ; for TNF- α , E = 70.35 C e 136.15 + C e ; and for IL-6, E = 69.93 C e 167.88 + C e , all higher than those observed in the GB34 and non-acupoint groups. WB analysis confirmed lower expression level of inflammatory proteins in the ST36 group. H&E staining showed reduced synovial erosion and lymphokine infiltration in the ST36 group compared to those in the other two groups. Discussion: This study demonstrates that transdermal administration of miRNA55 via microneedle at specific acupoints enhances drug absorption and improves therapeutic outcomes in a rabbit model of RA. These findings support the traditional concept of acupoint specificity and offer a scientific basis for integrating acupoint-based drug delivery in modern RA treatment strategies.

With the aggravation of population aging, frailty has become a major public health issue. However, the association between indoor air pollution from solid fuels and frailty is unclear. We analyzed data collected from 13,233 middle-aged and older adults (> 45 years) who were non-frail at baseline survey (2011, 2013, 2015, and 2018) from the China Health and Retirement Longitudinal Study to investigate the association between the use of solid fuels for cooking and frailty. After excluding 1853 participants with missing data on heating fuel, 11,380 individuals surveyed in 2011, 2013, and 2015 were retained for the heating-fuel analyses. We constructed the frailty index (FI) based on 40 health deficit items. Frailty was defined as FI > 0.25. The seven fuel types surveyed were categorized as clean and solid fuels. Time-dependent Cox proportional hazards models were used to analyze the association of solid fuel use for cooking or heating, alone or in combination, with frailty. Cox models were also used to explore the association of fuel type switching. Covariates included individual characteristics, health behaviors, socioeconomic factors, and household dwelling characteristics. Sensitivity analyses were performed to test the robustness of the main results, and interaction and subgroup analyses were performed to explore the influence of potential confounding factors on the results. Compared with participants using clean fuels, those using solid fuels had a higher risk of frailty (cooking: HR 1.46, 95% CI 1.28–1.67, p < 0.001; heating: HR 1.58, 95% CI 1.29–1.94, p < 0.001). Participants who switched from solid to clean fuel showed a reduction in the risk of frailty (HR 0.61, 95% CI 0.51–0.73, p < 0.001). Indoor air pollution caused by solid fuels is associated with an increased risk of frailty among middle-aged and older adults in China. Our findings provide evidence supporting the restriction of solid fuel use and improvement of indoor air quality to protect this population from frailty risk.

The development of RNA-based drugs for MAFLD-related fibrosis is severely hampered by the poor oral bioavailability of nucleic acids. This study employed a novel, patent-protected LNP formulation to orally deliver plant-derived miR-55 and investigate its therapeutic potential, focusing on its novel mechanism of action via the CK2α/SMO interaction. In a rat model established with a methionine-choline-deficient diet, orally administered miR-55 markedly improved liver injury, lipid dysregulation, oxidative stress, and pathological collagen deposition. The anti-fibrotic efficacy was quantitatively confirmed by a significant reduction in hepatic hydroxyproline content and downregulation of key fibrogenic genes (Col1a1, Col3a1, TIMP-1, TGF-β1, CTGF) and pro-inflammatory cytokines (TNF-α, IL-6), achieving effects comparable to the full Ge Xia Zhu Yu Decoction. Mechanistically, both bioinformatic prediction and in vivo validation indicated that miR-55 is predicted to target CK2α. This targeting suppressed CK2α expression and disrupted the endogenous CK2α-SMO complex, thereby promoting the ubiquitin-mediated degradation of SMO—a previously unreported mechanism. This cascade inhibited the downstream Gli1 pathway and downregulated pro-fibrotic and pro-angiogenic factors (VEGF, PDGF), thereby providing a comprehensive mechanistic basis for the therapeutic effects. This study is the first to provide evidence that orally delivered, plant-derived miR-55 may act as a natural modulator that potentially through disrupting the CK2α/SMO interaction via a unique complex disruption-promoted degradation mechanism, attenuating Hedgehog signaling and alleviating liver fibrosis. These findings offer important insights into cross-kingdom regulation and highlight miR-55 as a potential targeted therapeutic candidate.

Purpose: Bone morphogenetic protein 7 (BMP7) plays a crucial role in the pathogenesis of hepatocellular carcinoma (HCC). Traditional therapies have severe side effects and cannot achieve the desired therapeutic effect. Delivery of small interfering RNA targeting BMP7 (siBMP7) can specifically down-regulate the expression of BMP7 and induce apoptosis of cancer cells, thereby achieving the effect of gene therapy. We aimed to use cationic safflower polysaccharide (SPS) as the basic carrier, and encapsulate it with synthetic hyaluronic acid (HA) and folic acid (FA) polymer to form a dual-targeting nano-carrier. After encapsulating siBMP7, we obtain dual-targeted self-assembled nanoparticles (NPs). This not only improves the delivery efficiency, maintains stability in the blood circulation, and enhances accumulation in the tumor site, but also achieves the effect of gene therapy for HCC. Methods: We identified SPS, and then prepared and characterized the self-assembled NPs modified with polyethyleneimine (PEI), which can target the HA receptors and FA receptors on the surface of SMMC-7721 cells and deliver siBMP7 to hepatoma cells and induce cell apoptosis. The temperature stability, serum stability, cytotoxicity, buffering capacity, hemolytic properties, release behavior, uptake ability, and gene silencing effect of the NPs were evaluated in vitro. Further evaluation of their in vivo distribution, therapeutic effect, and safety was conducted in a nude rats model. Results: The HA-FA polymer is light yellow and has strong water solubility. The blank NPs and self-assembled NPs have uniform particle size, physical stability, and stable release ability. HFSPNPs showed strong uptake ability and apoptotic effect in SMMC-7721 cells and LO2 cells. HFSPNPs could relatively effectively accumulate in the liver of rats and down-regulate the expression of BMP7 to induce apoptosis of hepatoma cells. Pathological analysis showed that the safety of HFSPNPs is better. Conclusion: HFSPNPs have better tumor targeting properties, enabling siBMP7 to accumulate more in the tumor tissue and be released, thereby promoting apoptosis of hepatoma cells. This indicates that their potential for treating HCC is equivalent to that of gene therapy. This study highlights the potential of cationic SPS as a drug delivery material.

Background: Carthamus tinctorius L. has a long history of ethnomedicinal use for various ailments. This review focuses on the botany, ethnopharmacology, phytochemistry, pharmacological effects, and clinical applications of safflower, aiming to enhance current research in this field.Methods: The study incorporated relevant scientific literature up to April 2025. It involved the collection of both Chinese and English studies on safflower from various databases, including PubMed, Elsevier, Web of Science, Springer, ScienceDirect, Wiley, ACS, and CNKI (China National Knowledge Infrastructure). Additionally, doctoral and master’s dissertations were included in the analysis.Results: From 1978 to April 2025, various active metabolites were identified, primarily comprising flavonoids, polyacetylenes, and alkaloids, with flavonoids being the predominant group. Extracts and metabolites derived from safflower have demonstrated a range of bioactivities, including antioxidant, hepatoprotective, anti-inflammatory, and anticancer effects. In clinical practice, the effective components of safflower have been utilized in the treatment of cardiovascular and cerebrovascular diseases, diabetes, hepatobiliary conditions, poor blood circulation, sudden deafness, and other ailments.Conclusion: This review elucidates the research surrounding safflower in the domains of ethnopharmacology, phytochemistry, pharmacological activity, and clinical applications. Safflower is known to contain a diverse array of compounds, with flavonoids in particular demonstrating significant pharmacological activity. These compounds are extensively utilized in the pharmaceutical, food, and cosmetic industries, positioning safflower as a promising candidate for development and application in the treatment of various diseases. Nonetheless, research on safflower remains limited, and many active metabolites have yet to be thoroughly investigated in terms of their phytochemical and pharmacological properties. To date, only a handful of active metabolites have been isolated and assessed for their biological activity, and there is a notable deficiency in research regarding their mechanisms of action. Therefore, comprehensive studies are imperative to enhance our understanding of safflower and to substantiate its therapeutic potential.

Purpose: Macrophages play a pivotal role in rheumatoid arthritis (RA) pathogenesis. Paeoniflorin, a traditional Chinese medication, reduces inflammation by suppressing immune cell activation and inducing synovial fibroblast apoptosis, attenuating RA disease progression. Despite the potential therapeutic benefits, free paeoniflorin has limitations, including low drug utilization, poor selectivity, and short half-life during administration. We aimed to develop and evaluate dextran sulfate-modified paeoniflorin pH-responsive lipid–polymer hybrid nanoparticles (Pae–PPNPs–DS) for targeted macrophage delivery and improved treatment efficacy in RA. The pH sensitivity is attributed to the incorporation of poly(cyclohexane-1,4-dimethylene ketal), which undergoes hydrolysis-triggered degradation under acidic conditions enabling passive targeting to inflammatory sites through pH-dependent drug release. Simultaneously, dextran sulfate serves as a ligand to actively target Scavenger receptor class A type I overexpressed on activated macrophages in RA synovium, achieving dual-targeted delivery via environmental responsiveness and ligand-receptor interaction. Methods: We developed dextran sulfate-modified Pae–PPNPs–DS, which exhibits dual capabilities of active macrophage targeting and pH-triggered drug release, to deliver paeoniflorin to macrophages and improve drug delivery at the joint inflammation site. Nanoparticle characterization, in vitro release behavior, stability, macrophage uptake, macrophage polarization pathway, phenotypic polarization, and therapeutic efficacy were evaluated in a rat model of RA. Results: Pae–PPNPs–DS had smooth surfaces, uniform particle sizes, physical stability, and pH-responsive characteristics. RAW264.7 macrophages showed enhanced Pae–PPNPs–DS uptake. Pae–PPNPs–DS effectively modulated the STAT signaling pathway and modulated macrophage polarization. Pae–PPNPs–DS inhibited the expression of TNF-α/IL-1β/iNOS/IL-6 (pro-inflammatory and M1 markers), while promoting IL-10/Arg-1/TGF-β (anti-inflammatory and M2 markers) secretion. Pathological analysis revealed that Pae–PPNPs–DS prevented synovial tissue proliferation, inhibited inflammatory cell infiltration, and exhibited therapeutic efficacy. Conclusion: Pae–PPNPs–DS actively target macrophages, regulate polarization through STAT pathway, and inhibit joint inflammation, suggesting its potential in treating RA. The study highlights the potential of pH-responsive nanocarriers as an innovative approach to treating autoimmune diseases. Plain Language Summary: Rheumatoid arthritis (RA) is a chronic condition that causes painful swelling and damage to the joints and is driven in part by overactive immune cells called macrophages, which produce harmful inflammation. Current treatments for RA can be expensive and have significant side effects, highlighting the need for new, safer therapies. Our study focused on improving how a natural compound called paeoniflorin is delivered to the inflamed joints of people with RA. Paeoniflorin has anti-inflammatory properties, but it does not last long in the body and is not very effective on its own. To address this, we developed tiny, specially designed carriers called nanoparticles to deliver paeoniflorin directly to the inflamed areas of the joints. These nanoparticles are coated with a material that helps them target macrophages and release the drug when they reach the acidic environment of the inflamed tissue. We tested our nanoparticles in vitro and in vivo with RA-like symptoms. The results were promising: the nanoparticles were endocytosed by macrophages, reduced harmful inflammation, and promoted healing. In rats, these nanoparticles reduced joint swelling and tissue damage more effectively than the drug on its own. They also showed good safety and stability. These findings suggest that this new delivery system could be a more effective and targeted way to treat RA, reducing the inflammation and pain caused by the disease while avoiding some of the side effects of current treatments. This approach could lead to better outcomes for people living with RA.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death with chemotherapy and traditional surgery showing limited effectiveness. The present work aimed to study the feasibility of safflower polysaccharide (SPS) as an instinctive liver-targeting drug delivery carrier with applications in HCC. SPS-polyethyleneimine (SPS-PEI), hyaluronic acid-SPS-polyethyleneimine (HA-SPS-PEI), and hyaluronic acid-folic acid-SPS-polyethyleneimine (HA-FA-SPS-PEI) conjugates were synthesized by an esterification reaction and characterized by conventional methods. SPS-PEI, HA-SPS-PEI, and HA-FA-SPS-PEI self-assembled nanoparticles (SPNPs, HSPNPs, and HFSPNPs, respectively) and siRNA-loaded SPNPs, HSPNPs, and HASPNPs (siRNA^FAM/SPNPs, siRNA^FAM/HSPNPs and siRNA/HASPNPs, respectively) were fabricated with a roughly spherical shape, with sizes were ranging 100 ~ 200 nm in aqueous solution. Compared with free siRNA^FAM, siRNA^FAM/HASPNPs displayed enhanced serum stability, hypo toxicity, and a sustained release of siRNA^FAM over 64 h. In the in vivo cellular uptake behavior study, the HASPNPs showed excellent HCC tumor-targeting capability because of the specific recognition by the folic acid and hyaluronan receptors (CD44) overexpressed on the HCC tumor membrane. The tissue staining of siRNA^FAM/HASPNPs in mice further demonstrated that HASPNPs could distinctly enhance the distribution of siRNA^FAM into the HCC tumor. Our results indicate that HASPNPs may serve as a promising HCC tumor-targeting drug delivery carrier for HCC prevention.

Epigenetic and metabolic reprogramming alterations are two important features of tumors, and their reversible, spatial, and temporal regulation is a distinctive hallmark of carcinogenesis. Epigenetics, which focuses on gene regulatory mechanisms beyond the DNA sequence, is a new entry point for tumor therapy. Moreover, metabolic reprogramming drives hepatocellular carcinoma (HCC) initiation and progression, highlighting the significance of metabolism in this disease. Exploring the inter-regulatory relationship between tumor metabolic reprogramming and epigenetic modification has become one of the hot directions in current tumor metabolism research. As viral etiologies have given way to metabolic dysfunction-associated steatotic liver disease (MASLD)-induced HCC, it is urgent that complex molecular pathways linking them and hepatocarcinogenesis be explored. However, how aberrant crosstalk between epigenetic modifications and metabolic reprogramming affects MASLD-induced HCC lacks comprehensive understanding. A better understanding of their linkages is necessary and urgent to improve HCC treatment strategies. For this reason, this review examines the interwoven landscape of molecular carcinogenesis in the context of MASLD-induced HCC, focusing on mechanisms regulating aberrant epigenetic alterations and metabolic reprogramming in the development of MASLD-induced HCC and interactions between them while also updating the current advances in metabolism and epigenetic modification-based therapeutic drugs in HCC.

Senile plaques composed of β-amyloid protein (Aβ) and neurofibrillary tangles (NFTs) composed of intracellular hyper-phosphorylated tau are major causes of cognitive impairment and neuronal damage in Alzheimer disease (AD). Astragalin (AST), a naturally-occurring flavonoid compound, was reported to have neuroprotective effects in the brain, but its effects in AD remain unknown. Herein, the learning and memory deficits were alleviated and neuronal damage in the hippocampus were inhibited after the senescence-accelerated mouse prone 8 (SAMP8) mouse were given AST (5 mg/kg or 10 mg/kg) daily by gavage for 2 months. Furthermore, AST reduced Aβ₁₋₄₀ and Aβ₁₋₄₂ deposition, decreased β-carboxyl-terminal fragment (β-CTF) protein level and tau hyper-phosphorylation, but increased α-CTF protein level and glycogen synthase kinase-3beta (GSK-3β) phosphorylation in hippocampus of SAMP8 mice. Meanwhile, the effects of AST on AD were also explored in vitro by treating primary neurons with amyloid-β1–42 oligomers (Aβ₁₋₄₂O). Consistently, AST also alleviated amyloid-β1–42 oligomers (Aβ₁₋₄₂O)-induced neuronal damage, amyloid plaques, and tau phosphorylation in vitro model. Of note, estrogen receptor (ER)α and ERβ expression in the hippocampus of SAMP8 mice and Aβ₁₋₄₂O-treated neurons was significantly decreased but their levels were increased by AST. Moreover, in vivo and in vitro experiments revealed that ER antagonist, Fulvestrant, reversed the effects caused by AST. Altogether, our investigation indicates that AST may ameliorate cognitive deficits and AD-type pathologies in SAMP8 mice and Aβ₁₋₄₂O-treated neurons through upregulating ERα and ERβ expression. Our findings indicate the value of AST as a potential reagent for AD treatment.