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Clinical studies suggest that diets rich in ω-3 polyunsaturated fatty acids (PUFAs) provide beneficial anti-inflammatory effects, in part through their conversion to bioactive metabolites. Here we report on the endogenous production of a previously unknown class of ω-3 PUFA–derived lipid metabolites that originate from the crosstalk between endocannabinoid and cytochrome P450 (CYP) epoxygenase metabolic pathways. The ω-3 endocannabinoid epoxides are derived from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to form epoxyeicosatetraenoic acid-ethanolamide (EEQ-EA) and epoxydocosapentaenoic acid-ethanolamide (EDP-EA), respectively. Both EEQ-EAs and EDP-EAs are endogenously present in rat brain and peripheral organs as determined via targeted lipidomics methods. These metabolites were directly produced by direct epoxygenation of the ω-3 endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) by activated BV-2 microglial cells, and by human CYP2J2. Neuroinflammation studies revealed that the terminal epoxides 17,18-EEQ-EA and 19,20-EDP-EA dose-dependently abated proinflammatory IL-6 cytokines while increasing anti-inflammatory IL-10 cytokines, in part through cannabinoid receptor-2 activation. Furthermore the ω-3 endocannabinoid epoxides 17,18-EEQ-EA and 19,20-EDP-EA exerted antiangiogenic effects in human microvascular endothelial cells (HMVEC) and vasodilatory actions on bovine coronary arteries and reciprocally regulated platelet aggregation in washed human platelets. Taken together, the ω-3 endocannabinoid epoxides’ physiological effects are mediated through both endocannabinoid and epoxyeicosanoid signaling pathways. In summary, the ω-3 endocannabinoid epoxides are found at concentrations comparable to those of other endocannabinoids and are expected to play critical roles during inflammation in vivo; thus their identification may aid in the development of therapeutics for neuroinflammatory and cerebrovascular diseases.

A great hurdle in the production of synthetic polypeptides lies in the access of N -carboxyanhydrides (NCA) monomers, which requires dry solvents, Schlenk line/gloveboxe, and protection of side-chain functional groups. Here we report a robust method for preparing unprotected NCA monomers in air and under moisture. The method employs epoxy compounds as ultra-fast scavengers of hydrogen chloride to allow assisted ring-closure and prevent NCA from acid-catalyzed decomposition under moist conditions. The broad scope and functional group tolerance of the method are demonstrated by the facile synthesis of over 30 different α/β-amino acid NCAs, including many otherwise inaccessible compounds with reactive functional groups, at high yield, high purity, and up to decagram scales. The utility of the method and the unprotected NCAs is demonstrated by the facile synthesis of two water-soluble polypeptides that are promising candidates for drug delivery and protein modification. Overall, our strategy holds great potential for facilitating the synthesis of NCA and expanding the industrial application of synthetic polypeptides. Synthetic polypeptides are biomimetic materials that are commonly prepared by ring-opening polymerization of amino acid N -carboxyanhydrides (NCAs), but the methods for NCA synthesis usually require anhydrous and air-free conditions. Here, the authors report a method for the synthesis of NCAs under atmospheric conditions and room temperature, based on the use of epoxides as acid scavengers.

Natural musculoskeletal systems have been widely recognized as an advanced robotic model for designing robust yet flexible microbots. However, the development of artificial musculoskeletal systems at micro-nanoscale currently remains a big challenge, since it requires precise assembly of two or more materials of distinct properties into complex 3D micro/nanostructures. In this study, we report femtosecond laser programmed artificial musculoskeletal systems for prototyping 3D microbots, using relatively stiff SU-8 as the skeleton and pH-responsive protein (bovine serum albumin, BSA) as the smart muscle. To realize the programmable integration of the two materials into a 3D configuration, a successive on-chip two-photon polymerization (TPP) strategy that enables structuring two photosensitive materials sequentially within a predesigned configuration was proposed. As a proof-of-concept, we demonstrate a pH-responsive spider microbot and a 3D smart micro-gripper that enables controllable grabbing and releasing. Our strategy provides a universal protocol for directly printing 3D microbots composed of multiple materials. Musculoskeletal systems are recognized as a model for designing robust yet flexible microbots but the development of artificial musculoskeletal systems at nanoscale currently remains challenging. Here the authors report a laser programmed artificial musculoskeletal systems for prototyping 3D microbots, using relatively stiff SU-8 as the skeleton and pH-responsive proteins as the smart muscle.

The polarization of macrophages plays a critical role in the physiological and pathological progression of rheumatoid arthritis (RA). Activated M1 macrophages overexpress folate receptors in arthritic joints. Hence, we developed folic acid (FA)-modified liposomes (FA-Lips) to encapsulate triptolide (TP) (FA-Lips/TP) for the targeted therapy of RA. FA-Lips exhibited significantly higher internalization efficiency in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells than liposomes (Lips) in the absence of folate. Next, an adjuvant-induced arthritis (AIA) rat model was established to explore the biodistribution profiles of FA-Lips which showed markedly selective accumulation in inflammatory paws. Moreover, FA-Lips/TP exhibited greatly improved therapeutic efficacy and low toxicity in AIA rats by targeting M1 macrophages and repolarizing macrophages from M1 to M2 subtypes. Overall, a safe FA-modified liposomal delivery system encapsulating TP was shown to achieve inflammation-targeted therapy against RA via macrophage repolarization.

Triptolide (TP), derived from , exhibits anti-inflammatory, immunosuppressive, and antifibrotic properties with potential for treating renal diseases, but its clinical use is restricted by dose-dependent nephrotoxicity. The aim of this review is to comprehensively summarize the dual roles of TP, elucidate its therapeutic mechanisms and nephrotoxic pathways, and to explore strategies to mitigate its toxicity. A literature search was performed using the PubMed and Web of Science databases. The search covered publications from the earliest available date until November 2025. The key search terms included 'triptolide', 'renal', 'kidney' and their combinations. TP exerts dose-dependent dual effects in renal models. Therapeutic doses (typically ≤200 μg/kg ) demonstrate efficacy in modulating immune responses, protecting podocytes, promoting apoptosis in hyperproliferative cells and inhibiting renal fibrosis. Conversely, its nephrotoxicity manifests at supratherapeutic doses (often >400 μg/kg ) through oxidative stress, inflammation, metabolic dysregulation, and direct damage to renal tubular cells. The therapeutic efficacy and toxicity of TP are critically contingent on both dose and temporal parameters. TP holds significant but challenging potential for renal therapy. Future research should define its therapeutic window and advance strategies such as structural analogs, targeted delivery systems, and combination therapies to effectively separate efficacy from toxicity for clinical translation.

Modern pharmacological studies have demonstrated that although triptolide (TP) is effective against hepatocellular carcinoma, it has poor water solubility and more toxic side effects. In this study, we used triptolide (TP), a bioactive constituent in Hook F, as a model drug to develop a novel nano-liposome drug delivery system for the treatment of liver tumours. We constructed a functionally-modified triptolide liposome (FA+TPP-TP-Lips) using the film-dispersion method and investigated its physicochemical properties, mitochondrial targeting of hepatic tumour cells, in vitro and in vivo anti-hepatic tumour activity and its mechanism. The prepared FA+TPP-TP-Lips had a particle size of 99.28 ± 5.7 nm, a PDI of 0.20 ± 0.02, a zeta potential of 1.2 ± 0.08 mV, and an encapsulation rate of 74.37% ± 1.07%.FA+TPP-TP-Lips facilitates the cellular uptake of drug delivery systems and improves their targeted delivery to mitochondria. The results of cell efficacy showed that FA+TPP-TP-Lips significantly inhibited the growth of liver cancer cells, decreased mitochondrial membrane potential, and increased intracellular ROS, thus enhancing the highest apoptosis rate of liver cancer cells. The targeted liposomes (FA-TP-Lips, TPP-TP-Lips, and FA+TPP-TP-Lips) had some degree of inhibitory migration effect on Huh-7 cells relative to the unmodified TP-Lips. Studies on tumor-bearing mice demonstrated that FA+ TPP-TP-Lips effectively accumulated in tumor tissues and significantly inhibited the growth of subcutaneous tumors, achieving a tumor inhibition rate of 79.37%. FA+ TPP-TP-Lips demonstrated an enhanced anti-liver tumor effect and significantly mitigated the hepatotoxicity and systemic toxicity associated with TP. In summary, the results of this study can provide a feasible solution for improving the mitochondrial targeting of nano-liposomes, and lay a foundation for further developing a novel nano targeting preparation of triptolide for the treatment of hepatocellular carcinoma.

Epidemiological and preclinical evidence supports that omega-3 dietary fatty acids (fish oil) reduce the risks of macular degeneration and cancers, but the mechanisms by which these omega-3 lipids inhibit angiogenesis and tumorigenesis are poorly understood. Here we show that epoxydocosapentaenoic acids (EDPs), which are lipid mediators produced by cytochrome P450 epoxygenases from omega-3 fatty acid docosahexaenoic acid, inhibit VEGF- and fibroblast growth factor 2-induced angiogenesis in vivo, and suppress endothelial cell migration and protease production in vitro via a VEGF receptor 2-dependent mechanism. When EDPs (0.05 mg⋅kg ⁻¹⋅d ⁻¹) are coadministered with a low-dose soluble epoxide hydrolase inhibitor, EDPs are stabilized in circulation, causing ∼70% inhibition of primary tumor growth and metastasis. Contrary to the effects of EDPs, the corresponding metabolites derived from omega-6 arachidonic acid, epoxyeicosatrienoic acids, increase angiogenesis and tumor progression. These results designate epoxyeicosatrienoic acids and EDPs as unique endogenous mediators of an angiogenic switch to regulate tumorigenesis and implicate a unique mechanistic linkage between omega-3 and omega-6 fatty acids and cancers.

Background The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in tumor progression. Thus, CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy. Methods Amphiphilic SN38 prodrug polymeric micelles (PSN38) and encapsulated the hydrophobic esterase-responsive prodrug of Triptolide (TPL), triptolide-naphthalene sulfonamide (TPL-nsa), were synthesized to form PSN38@TPL-nsa nanoparticles. Then, CAFs were isolated from fresh GC tissues and immortalized. TPL at low dose concentration was used to investigate its effect on CAFs and CAFs-induced GC cells proliferation and migration. The synergistic mechanism and antitumor efficiency of SN38 and TPL co-delivery nanoparticle were investigated both in vitro and in vivo . Results Fibroblast activation protein (FAP), a marker of CAFs, was highly expressed in GC tissues and indicated poorer prognosis. TPL significantly reduced CAFs activity and inhibited CAFs-induced proliferation, migration and chemotherapy resistance of GC cells. In addition, TPL sensitized GC cells to SN38 treatment through attenuated NF-κB activation in both CAFs and GC cells. PSN38@TPL-nsa treatment reduced the expression of collagen, FAP, and α-smooth muscle actin (α-SMA) in tumors. Potent inhibition of primary tumor growth and vigorous anti-metastasis effect were observed after systemic administration of PSN38@TPL-nsa to CAFs-rich peritoneal disseminated tumor and patient-derived xenograft (PDX) model of GC. Conclusion TPL suppressed CAFs activity and CAFs-induced cell proliferation, migration and chemotherapy resistance to SN38 of GC. CAFs-targeted TPL and SN38 co-delivery nanoparticles exhibited potent efficacy of antitumor and reshaping TME, which was a promising strategy to treat advanced GC. Graphical Abstract

Background Pyroptosis is a lytic cell death form executed by gasdermins family proteins. Induction of tumor pyroptosis promotes anti-tumor immunity and is a potential cancer treatment strategy. Triptolide (TPL) is a natural product isolated from the traditional Chinese herb which possesses potent anti-tumor activity in human cancers. However, its role in pyroptosis remains to be elucidated. Methods Cell survival was measured by colony formation assay. Cell apoptosis was determined by Annexin V assay. Pyroptosis was evaluated by morphological features and release of interleukin 1β and lactate dehydrogenase A (LDHA). Immunofluorescence staining was employed to measure subcellular localization of proteins. Tumorigenicity was assessed by a xenograft tumor model. Expression levels of mRNAs or proteins were determined by qPCR or western blot assay, respectively. Results Triptolide eliminates head and neck cancer cells through inducing gasdermin E (GSDME) mediated pyroptosis. Silencing GSDME attenuates the cytotoxicity of TPL against cancer cells. TPL treatment suppresses expression of c-myc and mitochondrial hexokinase II (HK-II) in cancer cells, leading to activation of the BAD/BAX-caspase 3 cascade and cleavage of GSDME by active caspase 3. Silencing HK-II sensitizes cancer cells to TPL induced pyroptosis, whereas enforced expression of HK-II prevents TPL induced pyroptosis. Mechanistically, HK-II prevents mitochondrial translocation of BAD, BAX proteins and activation of caspase 3, thus attenuating cleavage of GSDME and pyroptosis upon TPL treatment. Furthermore, TPL treatment suppresses NRF2/SLC7A11 (also known as xCT) axis and induces reactive oxygen species (ROS) accumulation, regardless of the status of GSDME. Combination of TPL with erastin, an inhibitor of SLC7A11, exerts robust synergistic effect in suppression of tumor survival in vitro and in a nude mice model. Conclusions This study not only provides a new paradigm of TPL in cancer therapy, but also highlights a crucial role of mitochondrial HK-II in linking glucose metabolism with pyroptosis.

Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Cardiovascular disease is frequent and severe in patients with end-stage renal disease. Disorders of mineral metabolism may contribute by promoting cardiovascular calcification. We conducted a randomized clinical trial comparing sevelamer, a non-absorbed polymer, with calcium-based phosphate binders in 200 hemodialysis patients. Study outcomes included the targeted concentrations of serum phosphorus, calcium, and intact parathyroid hormone (PTH), and calcification of the coronary arteries and thoracic aorta using a calcification score derived from electron beam tomography. Sevelamer and calcium provided equivalent control of serum phosphorus (end-of-study values 5.1 ± 1.2 and 5.1 ± 1.4 mg/dL, respectively, P = 0.33). Serum calcium concentration was significantly higher in the calcium-treated group (P = 0.002), and hypercalcemia was more common (16% vs. 5% with sevelamer, P = 0.04). More subjects in the calcium group had end-of-study intact PTH below the target of 150 to 300 pg/mL (57% vs. 30%, P = 0.001). At study completion, the median absolute calcium score in the coronary arteries and aorta increased significantly in the calcium treated subjects but not in the sevelamer-treated subjects (coronary arteries 36.6 vs. 0, P = 0.03 and aorta 75.1 vs. 0, P = 0.01, respectively). The median percent change in coronary artery (25% vs. 6%, P = 0.02) and aortic (28% vs. 5%, P = 0.02) calcium score also was significantly greater with calcium than with sevelamer. Compared with calcium-based phosphate binders, sevelamer is less likely to cause hypercalcemia, low levels of PTH, and progressive coronary and aortic calcification in hemodialysis patients.