Intramuscular fat (IMF) is a key meat quality determinant. While coated methionine (CM), 2-hydroxy-4-(methylthio)-butanoic acid (HMBA) and its isopropyl ester (HMBi) enhance milk fat in dairy cows, their effects on IMF in meat ruminants remain unclear. A total of 30 goats (n = 10 per treatment) were assigned to basal diet, or basal diet plus 0.12% CM or 0.22% HMBi for a 4.5-month feeding trial. Carcass traits, meat quality and serum lipid profiles were determined. Results showed HMBi increased live and carcass weights, while both CM and HMBi reduced GR value, shear force and moisture content. HMBi increased IMF, total, saturated and monounsaturated fatty acids, while CM increased most amino acids in Longissimus thoracis et lumborum (LTL) muscle. Furthermore, HMBi upregulated adipogenic genes and downregulated lipolytic genes, whereas CM downregulated both in LTL muscle. Both CM and HMBi significantly increased serum APOA1 and decreased TG/HDL-C, while HMBi alone also increased HDL-C and decreased LDL-C. In vitro experiments showed HMBA had a quadratic relationship with intramuscular preadipocyte proliferation and differentiation (max at 200 μM). Transcriptomics revealed it altered immune/inflammatory/apoptotic pathways and promoted fat deposition via APOH inhibition. Collectively, HMBi outperformed CM in growth promotion. HMBi enhanced IMF deposition via APOH downregulation, while CM promoted amino acid accumulation, laying a foundation for methionine use in meat quality improvement in meat ruminant.

ETHNOPHARMACOLOGICAL RELEVANCE:Tiebangchui (TBC) is a commonly used Tibetan medicine. However, its narrow therapeutic safety window necessitates strategies to reduce toxicity while preserving therapeutic efficacy. At present, tsamba-stir-fried TBC (TS-TBC) has become a characteristic pretreatment approach for TBC. AIM OF THE STUDY:This study aimed to preliminary explore the material basis and mechanism underlying toxicity reduction and efficacy retention in tsamba-stir-fried TBC. MATERIALS AND METHODS:First, UV, UPLC-Q-Exactive-Orbitrap-MS and HPLC were employed to characterize chemical compounds of raw TBC and TS-TBC. Subsequently, we conducted comprehensive evaluation in analgesia efficacy, basic toxicity, overall toxicity, neurotoxicity and cardiotoxic-like toxicity of using C. elegans N2. Further, network pharmacology and molecular docking approaches were adopted to screen for the potential targets of TS-TBC. To clarify the molecular mechanism of TS-TBC, we performed assays using C. elegans N2 and five mutant strains, combined with qRT-PCR detection. Finally, a compounds-phenotype-gene network was constructed via correlation analysis. RESULTS:We preliminarily identified 77 alkaloids in raw TBC and 80 alkaloids in TS-TBC. The contents of aconitine, 3-deoxyaconitine and 3-acetylaconitine decreased after processing, while the level of benzoylaconine increased. TS-TBC treatment showed to reduce toxicity of raw TBC in C. elegans N2 without compromising its analgesic efficacy. According to the result of network pharmacology and molecular docking, TRPV channel proteins were identified as potential targets of TS-TBC. In C. elegans mutant strains, deficiency in ocr-1, ocr-2, ocr-3, ocr-4, or osm-9 genes led to the loss of TS-TBC efficacy. Similarly, deletion of ocr-2 or osm-9 genes enhanced TS-TBC-induced apoptosis, while ablation of ocr-4 or osm-9 abolished its antioxidant effect. qRT-PCR validation showed that TS-TBC could downregulate the expression of ocr-2, ocr-3, and ocr-4 genes, while it exerted no significant effect on osm-9 gene. CONCLUSIONS:Our findings revealed that changes in the contents of characteristic alkaloids, rather than total alkaloids, constitute the material basis for the toxicity reduction and efficacy retention of TS-TBC, and TRPV channel proteins serve as its potential targets. These findings provide a scientific basis for the rational clinical application of processed TBC.

To promote the transition of traditional Chinese medicine(TCM) preparation production towards intelligent and controllable manufacturing, this study addressed the challenges in practical production, such as the lack of quantitative evaluation system for physical quality attributes and the difficulty in determining batch-to-batch variability in mixing units. Based on samples from actual production batches of Tongren Niuhuang Qingxin Pills, a digital characterization strategy for the physical quality attributes of the mixing unit was established, followed by critical quality attribute(CQA) identification and batch-to-batch consistency evaluation. Sixteen physical quality attributes, including particle size, specific surface area, density, and color, were digitally quantified from 30 batches of mixed raw medicinal powder. The results showed that the particle-size-related indicators and specific surface area exhibited relative standard deviations(RSDs) greater than 10%, indicating pronounced batch-to-batch variability in the mixing unit. Subsequently, Euclidean distance was employed to evaluate sample consistency and identify discrepant batches. Combined with orthogonal partial least squares discriminant analysis(OPLS-DA) and a variable importance in projection(VIP) threshold greater than 1, the contribution of physical quality attributes was assessed. Ultimately, twelve attributes with substantial impact on batch-to-batch variability were identified, including relative homogeneity index(Iθ), particle size range(Width), particle size corresponding to 90% cumulative particle size distribution(D_(90)), and percentage of particle size<50 μm(%Pf). These can serve as critical physical quality attributes for quality control of the mixing unit. In summary, this study established a digital characterization and consistency evaluation approach for the physical quality attributes of TCM mixing units. It identified critical physical quality attributes and batch-to-batch variations, providing a basis for consistency analysis and variation elucidation. Furthermore, these findings support process optimization and quality stability of subsequent processing units, thereby facilitating the transition of TCM mixing units toward a digital and intelligent process control paradigm.

Apparent amylose content is a key determinant of rice flavor quality, yet traditional detection methods are often costly and time-consuming. To address this, we developed Ce-UiO66 nanozyme-based microfluidic paper-based analytical devices (μPADs) for rapid apparent amylose quantification. The sensing mechanism relies on the formation of a blue-purple apparent amylose -iodine complex via in situ catalytic oxidation, which is quantified through smartphone-based grayscale analysis. Mechanistic studies reveal that the catalytic activity of Ce-UiO66 is driven by O2- and H2O2 intermediates. The μPAD’s tri-zonal design (droplet, reaction, and detection zones) effectively minimizes in situ reaction interference. Under optimized conditions, the method achieved a linear range of 0–40% within 15 minutes, showing excellent agreement with flow injection analysis. This Ce-UiO66@μPADs platform demonstrates significant potential as a low-cost, portable tool for rapid apparent amylose monitoring in rice.

Two new compounds, (1S,5S,7R,10S)-10-hydroxyl-deoxysecoatractylo-δ-lactone-11-O-β-D-glucopyranoside (1) and (3 R,5S,10S)-Atracty-lenolide I-3-O-β-D-apiopyranosyl(1→6)-β-D-glucopyranoside (2), were isolated from the CH2Cl2 extract of Atractylodes japonica Koidz. ex Kitam., along with fifteen known compounds (3-17). Their structures were elucidated by 1D NMR spectroscopy (1H-NMR,1³C-NMR), 2D NMR experiments (HMBC, HMQC, 1H-1H COSY, NOESY), together with high-resolution mass spectrometry. The two compounds exhibited cytotoxicity against the HepG-2 cancer cell line, with IC50 values of 44.34 ± 1.79 and 46.27 ± 1.46 μM, respectively. In addition, compound 1 was evaluated for its cytotoxic activity against the A549 and HeLa cell lines, with IC50 values of 30.54 ± 1.58 and 36.73 ± 1.19 μM, respectively; compound 2 showed strong effects against the BGC-823 and HT-29 cell lines, with IC50 values of 32.53 ± 1.13 and 35.16 ± 1.78 μM, respectively.

Two new furostanol saponins, (25S)-22-O-methoxy-5β-furostan-1β,2β,3β,4β,5β,6β,22ξ, 26-octaol-26-O-β-d-glucopyranoside (1) and (25S)-22-O-methoxy-26-O-β-d-glucopyranosyl-5β-furostan-1β,2β,3β,22ξ, 26-pentol-1-O-β-d-xylopyranoside (2) were isolated from the whole plant of Reineckia carnea (Andr.) Kunth along with seven known compounds (3-9). The structures of the new saponins were elucidated by detailed analysis of their NMR spectra, chemical evidence and comparison with spectral data of known compounds. Based on the chemical structural characteristics, functional group substitution rules, sugar chain connection methods of the two new furostanol saponins, as well as the natural biogenic synthesis and evolution rules of steroid saponins, an in-depth analysis of the possible biogenetic relationship were conducted. Compound 4, 6, and 9 were obtained for the first time from the Reineckia genus. In addition, the cytotoxic activities in U87-MG and MCF-7 tumor cells of the isolated compounds (1-9) were determined by the MTT method. The results showed that Compound 4 had inhibitory effects on U87-MG cells and MCF-7 cells, with IC50 values of 35.21 μM and 28.26 μM, respectively.

A supramolecular system of active pharmaceutical ingredients (APIs) can modify the physicochemical properties and enhance the synergistic efficacy of their components; however, the relevant underlying mechanisms in vivo remain unclear. This study employed a metabolomics-driven approach, combined with biological validation, to investigate the synergistic mechanisms of API-based supramolecular systems. Metabolic dysfunction exacerbates insulin resistance and obesity, contributing to hepatic steatosis and cardiac hypertrophy. A novel sodium-dependent glucose transporter 2 (SGLT-2)/peroxisome proliferator-activated receptor-γ (PPAR-γ) dual receptor (dapagliflozin-pioglitazone (DAP-PIO)) supramolecular system was selected as the model to explore the synergistic mechanism involved in the treatment of metabolic dysfunctions, diabetes and obesity. First, metabolomics analyses were performed to compare the effects of a simple physical mixture (PM) of DAP and PIO with the DAP-PIO supramolecular system after absorption into the bloodstream. The results demonstrated significant differences, with the supramolecular system activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways. Ceramide (Cer), a key metabolite in sphingolipid metabolism, emerged as a critical mediator. Subsequently, the mechanisms underlying the DAP-PIO supramolecular system’s hypoglycemic effects and its ability to ameliorate hepatic steatosis and myocardial hypertrophy by reducing insulin resistance were evaluated and confirmed. These findings provide an innovative strategy for developing SGLT-2/PPAR-γ dual-receptor supramolecular systems to enhance the therapeutic outcomes for diabetes and obesity.

Bisphenol S (BPS) has become extensively used in the manufacturing of consumer products. BPS mainly enters the body through food and water, with oral exposure targeting the gastrointestinal tract. However, its safety profile remains contentious and warrants further investigation. In this study, we aimed to assess whether BPS exerts harmful effects on the body in the absence of overt pathological damage. Our results revealed that although BPS did not lead to significant histopathological damage, it induced intestinal barrier dysfunction. Additionally, in vitro investigations utilizing NCM460 cells and human-derived colorectal organoids demonstrated that BPS exposure induced mitochondrial reactive oxygen species (ROS) levels in intestinal endocrine cells (EECs), upregulating the expression of inflammatory mediators TNF-α and CXCL10. Using a DSS-induced colitis mouse model, it was found that BPS exposure exacerbates the progression of intestinal inflammatory diseases. Analysis of single-cell databases demonstrated a significant reduction in the expression of CHGA, a functional protein of enteroendocrine cells (EECs), in patients with inflammatory bowel disease (IBD). The expression of CHGA showed a significant negative correlation with the expression of IL17. Notably, supplementation with 3-Indoleglyoxylic acid effectively mitigates the intestinal damage induced by BPS. These findings highlight the role of mitochondrial oxidative stress and IL-17/CXCL10/TNF-α signaling in BPS-induced intestinal damage and demonstrate the therapeutic potential of 3-Indoleglyoxylic acid in mitigating these effects.

The increasing incidence and associated metabolic complications pose major challenges in the treatment of hyperlipidaemia. Cinnamon is a food and medicinal resource associated with lipid metabolism, but the mechanism by which its active components, cinnamic acid (CA) and cinnamaldehyde (CM), alleviate hyperlipidaemia remains unclear. Biochemical, pathological, gut microbiota, and metabolomic analyses were performed to investigate the effects of CA and CM on HFD-fed mice and the underlying mechanisms involved. Supplementation with CA and CM reduced body weight, liver, and adipose tissue accumulation in HFD-induced mice; improved glucose and lipid metabolism; and decreased inflammation and oxidative stress levels, with CM showing superior efficacy. Faecal microbiota transplantation confirmed that the therapeutic effect was closely related to core gut bacteria and metabolites. Specifically, CA and CM inhibited the growth of lipid metabolism-related genera (e.g., Turicibacter and Romboutsia) and metabolites (e.g., PC, LysoPCs, prostaglandin E2, and arachidonic acid) while promoting the growth of beneficial genera (e.g., Oscillospiraceae and Colidextribacter) and metabolites (e.g., linoleic acid, phytosphingosine, and stercobilin). Additionally, Spearman's correlation analysis revealed that serum and hepatic lipids, as well as inflammatory factors, were positively correlated with Erysipelatoclostridium, Turicibacter, Eubacterium fissicatena, Enterorhabdus, cervonoyl ethanolamide, and acetoxystachybotrydial acetate, whereas they were negatively correlated with Lachnospiraceae NK4A136, stercobilin, LysoPE (15:0/0:0), and phytosphingosine. In contrast, hepatic oxidative stress markers exhibited the opposite correlation pattern. In conclusion, CA and CM have the potential to regulate the core gut microbiota and metabolites to improve lipid metabolism and decrease related inflammation and oxidative stress levels.

Hypothesis: Chemotherapy is effective against oral squamous cell carcinoma (OSCC), but its utility is hindered by significant side effects and drug resistance. Photodynamic therapy (PDT) offers a less invasive alternative, but challenges remain due to the hydrophobic nature of most photosensitizers (PS), limiting their effectiveness. A novel nano-composite, combining hyaluronic acid-carbon dots (HA-CDs) with cisplatin (DDP), may overcome these limitations by improving drug hydrophobicity and enabling dual-function therapy. Experiments: Hyaluronic acid-carbon dots (HA-CDs) were synthesized via a hydrothermal method using hyaluronic acid as the primary precursor. The resulting HA-CDs were then combined with cisplatin (DDP) to form the HA-CDs-DDP composite, designed to enhance DDP hydrophobicity and serve as both a chemotherapy agent and a PS. Findings: The HA-CDs-DDP composite facilitates self-targeting chemotherapy while acting as an intrinsic photosensitizer, eliminating the need for additional PS. The composite generated reactive oxygen species (ROS), effectively inhibiting tumor growth in vivo. This study demonstrates the potential of HA-CDs-DDP to induce cell death in OSCC via a combined chemotherapy/photodynamic therapy pathway, providing a promising new approach for clinical OSCC treatment.

Background Previous studies have shown that obesity is associated with an increased risk of various cardiovascular diseases. The Body Roundness Index (BRI) is a novel indicator for assessing body fat and visceral fat. However, the relationship between BRI and all-cause and cardiovascular mortality in individuals with hypertension remains unclear. This study aims to investigate the association between BRI and all-cause and cardiovascular mortality among US adults with hypertension. Methods This study utilized data from the National Health and Nutrition Examination Survey (NHANES) (1999–2018). The study population consisted of 20,532 hypertensive adults. Cox proportional hazards models were used to assess the association between BRI and all-cause and cardiovascular mortality. A generalized additive model were employed to evaluate potential nonlinear relationships between BRI and mortality. Results Among the 20,532 hypertensive adults (mean age: 59.5 ± 15.9 years), a total of 5,044 (25.4%) participants died during follow-up. BRI exhibited a U-shaped association with all-cause mortality, with an inflection point at 5.09. Below the inflection point, each unit increase in BRI was associated with a decreased risk of all-cause mortality (HR = 0.82, 95% CI: 0.79–0.86, P < 0.0001); above the inflection point, each unit increase in BRI was associated with an increased risk (HR = 1.05, 95% CI: 1.04–1.07, P < 0.0001). A similar U-shaped relationship was observed for cardiovascular mortality, with an inflection point at 4.97 (HR = 0.87 [0.80, 0.94], P = 0.0006 below the inflection point; HR = 1.23 [1.12, 1.36], P < 0.0001 above the inflection point). After adjusting for age, sex, race, and education level, both the lowest and highest BRI tertiles were associated with higher all-cause mortality. Conclusion Among US adults with hypertension, BRI demonstrates a U-shaped relationship with all-cause and cardiovascular mortality. Further research is needed to validate these findings.

The development of multitargeted drugs is urgent for ischemic stroke. TRPV1 and TRPM8 are important targets of ischemic stroke. Previous drug candidate screening has identified that muscone, l-borneol, and ferulic acid may target TRPV1 and TRPM8 for ischemic stroke. However, the mechanisms of these drug candidates on targets were ill-informed. Therefore, firstly, a tongue-tissue biosensor was constructed. It explored the activation or inhibition mechanisms of drug candidates targeting TRPV1 and TRPM8 in a near-physiological environment. It was found that muscone could specifically inhibit TRPM8 and selectively activate TRPV1, while l-borneol exhibited the opposite effect. It suggested a synergistic network between these two drug candidates. Furthermore, more selective protein biosensors were developed to delve deeper into the synergistic mechanisms. A strong synergistic effect of muscone and l-borneol was proved. Molecular docking revealed that the synergistic effect was caused by different action sites, respectively. Subsequently, the synergistic effect of muscone and l-borneol was further confirmed by hypoxic nerve injury models of Caenorhabditis elegans (C. elegans) and antithrombus and anti-ischemic models of zebrafish. Ultimately, through nontargeted metabolomics, it was found that muscone and l-borneol mainly regulated Ca2+ concentration and energy metabolism by pathways such as purine and amino acid metabolisms. In conclusion, this research identified critical targets and synergistic drug candidates for multitarget neuroprotection of ischemic stroke. In addition, it has systemically demonstrated the feasibility of the integration of tissue/protein biosensors and metabolomics for the research and development of multitarget drugs. Compared to other screening and validation methods for drugs and targets, the biosensors we developed not only achieved higher sensitivity and specificity in complex physiological environments, ensuring a wider detection range, but also greatly saved biological samples. Simultaneously, they could be extended to other complex systems, such as biomarker screening in clinical samples and exosomes isolated from stem cells.

Cardiovascular diseases (CVDs) are a leading cause of death worldwide, and new therapeutic strategies are urgently needed. In recent years, enhancer RNAs (eRNAs) have gradually attracted attention because they offer new directions for the treatment of CVDs. Super-enhancer RNAs (seRNAs) are a subset of non-coding RNAs that are transcribed from regions of the genome known as super enhancers, which are large clusters of enhancers with a high density of transcription factors and cofactors. These regions play a pivotal role in regulating genes involved in cell identity and disease progression. This article reviews the characteristics of seRNAs, their expression patterns, and regulatory mechanisms in the cardiovascular system. We also explore their role in the occurrence and development of CVDs, as well as their potential as diagnostic biomarkers and therapeutic targets. Currently, therapies targeting seRNAs are a research hotspot. The development of specific inhibitors or activators is expected to facilitate precise interventions for CVDs. In addition, the use of gene editing techniques to modify relevant eRNA introduces new possibilities for disease treatment. This review aims to provide a comprehensive overview of seRNAs in CVDs and discusses their potential as a novel class of therapeutic targets.

[This corrects the article DOI: 10.3389/fpubh.2025.1562186.].

Ethnopharmacological relevance Corydalis decumbens (Thunb.) (CD) is a traditional Chinese medicine and as a single herb or formula has been used to treat RA for decades. Rheumatoid arthritis (RA) is a persistent, systemic autoimmune inflammatory disease. However, the anti-inflammatory target, effective constituents and mechanism was unclear. Aim of the study The purpose of this study was to identify anti-RA and anti-inflammatory targets of CD, elucidate effective constituents and molecular pharmacological mechanism. Materials and methods Anti-RA and anti-inflammatory effect of CD were evaluated on CIA-rats and in LPS-induced RAW264.7 cells respectively. The anti-inflammatory target of CD was identified using thermal proteome profiling (TPP). The recombinant Fosl2 protein was expressed and purified and the target-based effective constituents was screened with bio-layer interferometry (BLI) analysis. Combining photoaffinity probe, LC-MS/MS analysis, docking and point mutation, the binding site was confirmed between Fosl2 and THP. Furtherly, immunofluorescence (IF), co-immunoprecipitation (co-IP) were used to research the pharmacological mechanism of THP and the THP-influenced downstream pathways were elucidated by transcriptomics analysis. Results CD had therapeutic effect on CIA-rats and a significant anti-inflammation on macrophages. Fosl2 was identified as a target of CD and we elucidated the target-based effective constituents was protoberberine-type alkaloids. THP can inhibit inflammation and transcription of AP-1 via targeting Fosl2 on LPS-induced RAW264.7 cells. For mechanism, THP promoted Fosl2 nuclear translocating and interacting with c-Jun. Conclusions These findings firstly elucidated the target and effective constituents of CD treating RA, and found that “undruggable target” Fosl2 can be used as therapeutic targets for RA. Meanwhile, our research suggested that THP has a significant potential for the treatment of RA.

The quality of traditional Chinese medicine(TCM) is a critical foundation for ensuring the stability of its efficacy, as well as the safety and effectiveness of its clinical use. The identification of critical quality attributes(CQAs) is one of the core components of TCM preparation quality control. This study focuses on Jianwei Xiaoshi Tablets and explores their CQAs related to property and flavor from the perspective of taste receptor proteins. Three taste receptor proteins, T1R2, T1R3, and TRPV1, were selected, and a biosensor based on high-electron-mobility transistor(HEMT) was constructed to detect the interactions between Jianwei Xiaoshi Tablets and taste receptor proteins. Simultaneously, liquid chromatography-mass spectrometry(LC-MS) technology was used to analyze the chemical composition of Jianwei Xiaoshi Tablets. In examining the interaction strength, the results indicated that the interaction between Jianwei Xiaoshi Tablets and TRPV1 protein was the strongest, followed by T1R3, with the interaction with T1R2 being relatively weaker. By combining biosensing technology with LC-MS, 16 chemical components were identified from Jianwei Xiaoshi Tablets, among which six were selected as CQAs for sweetness and seven for pungency. Further validation experiments demonstrated that CQAs such as hesperidin and hesperetin had strong interactions with their corresponding taste receptor proteins. Through the combined use of multiple technological approaches, this study successfully determined the property and flavor-related CQAs of Jianwei Xiaoshi Tablets. It provides novel ideas and approach for the identification of CQAs in TCM preparations and offers comprehensive theoretical support for TCM quality control, contributing to the improvement and development of TCM preparation quality control systems.

Epigallocatechin-3-gallate (EGCG), the predominant bioactive compound in green tea, has shown promise in lung cancer treatment; however, its molecular targets and antitumor mechanisms remain unclear. In this study, the therapeutic potential of EGCG against non-small cell lung (NSCLC) was evaluated, core targets were prioritized via network pharmacology, and molecular docking were employed to decipher the potential mechanism of action. Using bioinformatics, molecular docking, and functional enrichment analyses, 224 NSCLC-related targets were identified, with TP53, STAT3, AKT1, IL6, HSP90AA1, and JUN emerging as central hubs. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses revealed oxidative stress regulation and the PI3K/Akt pathway as critical mechanisms. Molecular docking confirmed strong binding affinities between EGCG and hub targets. These findings highlight EGCG as a multi-target agent against NSCLC via PI3K/Akt modulation, redox homeostasis restoration, and inflammation suppression, offering novel insights for phytochemical-based NSCLC therapy.

BackgroudCaowu (CW, Aconitum kusnezoffii Reichb.) is a well-known Mongolian medicine with the effects of dispelling cold and relieving pain. In China, it is widely used in the prevention and treatment of rheumatoid arthritis (RA). However, its cardiotoxicity and neurotoxicity seriously restrict its clinical application. Different from the use of CW as a decoction after being boiled in water in TCM, in Mongolian medicine, CW is processed using Hezi (HZ, dry ripe fruit of Terminalia chebula Retz. and T. chebula Retz. var. tomentella Kurt.) decoction or combined with HZ to prepare pills or powders, and administered at a small dosage, thereby ensuring medication safety. This way of medication is a useful experience of the minority. Thus, multi-dimensional research (quantitation of alkaloid + in vitro + in vivo + mechanism) is critical to elucidate the characteristics of the Mongolian ethnic group’s detoxification experience. We investigated the content of alkaloids, the anti-inflammatory and analgesic effects, the cardiorenal-hepatic toxicities, and the oxidative stress levels in both powder and decoction of raw CW (SCW) and HZ-processed CW (HCW), with a focus on the toxicity mechanisms in H9c2 cells (specifically for the powder dosage).MethodsHPLC was used to quantify the content of main metabolites in SCW and HCW (in powder or decoction form). The pharmacological effects were evaluated using in vivo animal models (xylene-induced inflammation and formalin-induced pain). The toxicity of SCW and HCW was assessed via electrocardiographic analysis, histological analysis, and biochemical analysis. Subsequently, in vitro toxicity mechanism studies were conducted on H9c2 cells using techniques such as MTT, fluorescent probes, ELISA, and Western blotting. Additionally, the involvement of the p38/JNK signaling pathway in their cardiotoxicity was verified by treating cells with p38/JNK pathway inhibitors.ResultsUsing HPLC, we found that both the use of HZ as an excipient for processing CW and decocting CW with water affect the content of alkaloids in CW. In the xylene-induced ear edema model, SCW powder, SCW decoction, and HCW powder showed significant anti-inflammatory effects by regulating inflammation-related factors (IL-1β, IL-6, and IL-10); in contrast, HCW decoction did not show significant anti-inflammatory effects compared with the model group. In the formalin-induced pain model, both SCW and HCW exerted analgesic effects to varying degrees by regulating pain-related factors (5-HT and PGE2). In the toxicity study, SCW powder exhibited the strongest toxicity to the heart; in contrast, SCW decoction had the weakest toxicity, while HCW powder and HCW decoction fell in between. Furthermore, the types of arrhythmia induced by SCW powder were most complex. In addition, the cardiotoxicity of SCW was closely related to oxidative stress. Cell experiments showed that SCW induced H9c2 cell damage, which HCW partially mitigated by regulating the p38/JNK pathway.ConclusionIn conclusion, compared with SCW, HCW reduces toxicity while exerting pharmacological effects in powder dosage form. This attenuation is linked to a reduction in oxidative stress, inhibition of p38/JNK phosphorylation, and regulation of mitochondrial apoptosis-related protein expression. This finding advances our understanding of the coexistence of toxicity and efficacy in clinical application of CW.

Tumor drug resistance emerges from the interaction of two critical factors: tumor cellular heterogeneity and the immunosuppressive nature of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) constitute essential components of the TME. M2-like TAMs are essential in facilitating tumor metastasis as well as augmenting the drug resistance of tumors. This review encapsulates the mechanisms that M2-like TAMs use to promote tumor drug resistance. We also describe the emerging therapeutic strategies that are currently targeting M2-like TAMs in combination with other antitumor drugs, with some still undergoing clinical trial evaluation. Furthermore, we summarize and analyze various existing approaches for developing novel drugs that target M2-like TAMs to overcome tumor resistance, highlighting how targeting M2-like TAMs can effectively stop tumor growth, metastasis, and overcome tumor drug resistance.