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This paper reviews a substantial amount of research related to the Eschweiler–Clarke methylation reaction, summarizing its mechanism, development, and applications, to present the chemical essence and history of this reaction and its importance and application in modern synthetic chemistry. In particular, this review focuses on advances regarding the Eschweiler–Clarke methylation reaction since 2000. This work will provide researchers with a comprehensive and in-depth perspective of the Eschweiler–Clarke reaction, as well as guidance and inspiration for future research and application.

Tripterygium glycosides tablets (TGTs) are widely used in clinical practice to treat rheumatoid arthritis and other autoimmune diseases, with significant beneficial effects but also high toxicity, necessitating rigorous quality evaluation and control. In current study, a rapid resolution liquid chromatography tandem electrospray ionization triple quadrupole mass spectrometry (RRLC–ESI–MS/MS) method was developed and validated for the quantitative analysis of 14 components of ten batches of TGTs produced by different manufacturers, including four diterpenoids, three triterpenoids, and seven sesquiterpene alkaloids. Meanwhile, the NO inhibition effects of these TGTs were evaluated in LPS-induced RAW264.7 cells for their downstream anti-inflammatory activities, as well as their cytotoxicity. The results indicate that the TGTs from different manufacturers showed poor quality consistency, as evidenced by large variations in chemical profiles and biological effects, which may increase the risks associated with clinical use. To improve the quality status of TGTs, it is crucial to identify indicator components whose characterization can accurately reflect the efficacy and toxicity of TGTs from which they were derived. Our study reveals that triptolide, triptoquinone B, celastrol, and demethylzelaysteral considerably contributed to the anti-inflammatory activity and/or cytotoxicity of TGTs, implying that they should be further investigated as candidate indicator components for TGT quality control.

Tripterygium wilfordii Hook. f. is a well-known traditional Chinese medicine used to treat autoimmune diseases. Sesquiterpene pyridine alkaloids (SPAs) are a major class of components found in this herb that have piqued the interest of researchers due to their complex and diverse structures as well as significant biological activities. In this study, ten new SPAs, wilfordatine A–J (1–10), were isolated from the roots of T. wilfordii, along with ten known analogues (11–20). Their structures were primarily elucidated by extensive 1D and 2D NMR spectroscopic analysis. To search for more immunosuppressive ingredients related to the clinical efficacy of T. wilfordii, the total alkaloids (TA) and compounds 4, 5, and 9–16 were tested for their inhibitory effects on nuclear factor-kappa B (NF-κB) pathway in Lipopolysaccharide (LPS) induced HEK293/NF-κB-Luc cells. Among them, TA, compounds 5, 11, and 16 showed potent immunosuppressive activity, with IC50 values of 7.25 μg/mL, 8.75 μM, 0.74 μM, and 15.66 μM, respectively, and no influence on the cell viability at a concentration of 100 μg/mL (TA) or 100 μM (5, 11, and 16). Accordingly, TA, 5, 11, and 16, especially 11, were identified as promising candidates for further investigation into their potential use as immunosuppressive agents.

Luteolin is a natural flavonoid compound widely found in various plants, known for its antioxidant, anti-inflammatory, cardiovascular protective and anti-tumor activities. However, its low bioavailability due to rapid metabolism and low solubility hinders its clinical application. In recent years, with the development of nanotechnology, luteolin combined with nanomaterials to form nanocomposites has shown promising drug delivery performance and therapeutic effects in numerous diseases. This article reviews the latest research progress on luteolin nanocomposites in disease treatment, exploring their potential applications in cancer, diabetes, cardiovascular diseases, neurological disorders, and other conditions.

Objective: To systematically evaluate the potential of Saussurea involucrata cultures (SICs) against high-altitude illness under hypobaric hypoxia and establish a progressive experimental evidence chain covering acute hypoxia tolerance enhancement and acute/chronic hypoxic injury protection. Methods: A tiered experimental strategy was employed. Key findings were derived from primary rat models of acute (5500 m, 8 h) and chronic intermittent (5500 m, 8 h/d, 4–8 weeks) hypobaric hypoxia. A mouse acute tolerance model (10,000 m lethality, closed-system endurance) provided supplementary verification. Comprehensive analyses included survival, hemorheology, multi-organ function, and core mechanistic indicators of endothelial function and oxidative stress. Diamox, Rhodiola, and Compound Danshen Dripping Pills served as positive controls. Normoxic/hypoxic blank groups served as negative controls. Results: SICs significantly enhanced acute hypoxia tolerance in mice. In the rat models, SICs demonstrated dose-dependent and selective regulation of the endothelial–oxidative stress/hemorheology axis. Specifically, it downregulated endothelin-1, upregulated nitric oxide, enhanced total antioxidant capacity, and improved chronic hypoxia-induced blood hyperviscosity. Medium doses showed consistent optimal efficacy. SICs had limited effects on macroscopic organ remodeling. Conclusions: The core protective effect of SICs lies in enhancing hypoxic tolerance and selectively modulating the interconnected pathways of endothelial function, oxidative stress, and microcirculatory health. This mechanistic profile supports its potential as a preventive or early adjuvant intervention for high-altitude illness, providing a systematic preclinical foundation for translational development.

Background: Frostbite injury creates an ischemic, hypoxic, and acidic microenvironment that often triggers severe oxidative stress and inflammation. Current therapeutic approaches are limited by low drug delivery efficiency and an inability to adequately regulate multiple pathological pathways. Although oxyresveratrol (OR) exhibits excellent antioxidant and anti-inflammatory activities, its application is hampered by poor aqueous solubility and low stability. Methods: We constructed Oxyresveratrol@Zeolitic Imidazolate Framework-8 nanoparticles (OR@ZIF-8) and further embedded them in a sodium hyaluronate (HA) matrix to form an OR@ZIF-8@HA composite hydrogel. The physicochemical properties and pH-responsive drug release behavior of the system were characterized. Its antioxidant activity, ability to promote cell migration, and capacity to modulate macrophage polarization were evaluated in cellular assays. The therapeutic efficacy was further investigated using a mouse frostbite model, with wound repair analyzed via histological staining. Results: The OR@ZIF-8 nanoparticles achieved a cumulative release rate of 75.46 ± 3.68% under acidic conditions within 36 h. In vitro experiments demonstrated that the formulation significantly scavenged TNF-α and IL-6, by 161.85 ± 19.43% and 125.37 ± 12.65%, respectively, and increased the level of IL-10 by 44.97 ± 4.57%. In a scratch assay, it promoted wound healing, achieving a closure rate of 97.55 ± 2.77% after 36 h. In vivo studies revealed that the OR@ZIF-8@HA treatment group achieved a wound healing rate of 96.14 ± 4.12% on day 14. Conclusions: The OR@ZIF-8@HA composite hydrogel effectively overcomes the limitations of OR application via intelligent pH-responsive delivery. Through synergistic multi-mechanistic actions, it significantly accelerates frostbite wound healing, offering a novel and efficient therapeutic strategy for frostbite management.

The effectiveness of rabies vaccination in both humans and animals is determined by the presence of virus neutralizing antibodies (VNAs). The Rapid Fluorescent Focus Inhibition Test (RFFIT) is the method traditionally used for detection and quantification of VNAs. It is a functional in vitro test for assessing the ability of antibodies in serum to bind and prevent infection of cultured cells with rabies virus (RABV). The RFFIT is a labor intensive, low throughput and semi-quantitative assay performed by trained laboratorians. It requires staining of RABV-infected cells by rabies specific fluorescent antibodies and manual quantification of fluorescent fields for titer determination. Although the quantification of fluorescent fields observed in each sample is recorded, the corresponding images are not stored or captured to be used for future analysis. To circumvent several of these disadvantages, we have developed an alternative, automated high throughput neutralization test (HTNT) for determination of rabies VNAs based on green fluorescent protein (GFP) expression by a recombinant RABV and compared with the RFFIT. The HTNT assay utilizes the recombinant RABV ERA variant expressing GFP with a nuclear localization signal (NLS) for efficient quantification. The HTNT is a quantitative method where the number of RABV-infected cells are determined and the images are stored for future analysis. Both RFFIT and HTNT results correlated 100% for a panel of human and animal positive and negative rabies serum samples. Although, the VNA titer values are generally agreeable, HTNT titers tend to be lower than that of RFFIT, probably due to the differences in quantification methods. Our data demonstrates the potential for HTNT assays in determination of rabies VNA titers.

A major challenge for global rabies prevention and control is the lack of sufficient and affordable high quality vaccines. Such candidates should be pure, potent, safe, effective and economical to produce, with broad cross-reactivity against viral variants of public health and veterinary importance. The history of licensed human vaccines reviewed herein demonstrates clearly how the field has evolved to the current state of more passive development and postexposure management. Modern cell culture techniques provide adequate viral substrates for production of representative verified virus seeds. In contrast to outdated nervous tissue-based rabies vaccines, once a suitable substrate is identified, production of high titer virus results in a major qualitative and quantitative difference. Given the current scenario of only inactivated vaccines for humans, highly cell-adapted and stable, attenuated rabies viruses are ideal candidates for consideration to meet the need for seed viruses in the future.

While current rabies post-exposure prophylaxis (PEP) is highly effective, it is costly and the vaccination regimen is complicated, requiring both inactivated vaccines and immunoglobulins. A one-dose rabies vaccine for human PEP remains a long-term goal. Here, we describe development of a highly attenuated rabies virus ERAg3m, with a mutation in the glycoprotein (G) gene and a switch of the G gene with the matrix protein gene in the viral genome. After a one-dose intramuscular vaccination, the ERAg3m virus protected 100% of mice and hamsters from lethal challenge. In co-infections, using a lethal dose of street rabies virus mixed with ERAg3m, 100% of hamsters and 90% of mice survived and were protected against subsequent infection. A mock co-infection, using inactivated commercial human rabies vaccine and a lethal dose of street rabies virus, protected 100% and 40% of hamsters and mice, respectively. In co-infections, when vaccine was administrated in the left leg and challenge virus in the right leg, the ERAg3m virus protected 40% of mice, while the inactivated vaccine showed no protection. Therefore, live attenuated rabies virus when given pre-exposure or co-infected with street rabies virus, is capable of preventing rabies in two different animal models. Overall, this highly attenuated live rabies virus offered better protection than the inactivated vaccine.

We present an unconventional approach to antiviral drug discovery, which is used to identify potent small molecules against rabies virus. First, we conceptualized viral capsid assembly as occurring via a host-catalyzed biochemical pathway, in contrast to the classical view of capsid formation by self-assembly. This suggested opportunities for antiviral intervention by targeting previously unappreciated catalytic host proteins, which were pursued. Second, we hypothesized these host proteins to be components of heterogeneous, labile, and dynamic multi-subunit assembly machines, not easily isolated by specific target protein-focused methods. This suggested the need to identify active compounds before knowing the precise protein target. A cell-free translation-based small molecule screen was established to recreate the hypothesized interactions involving newly synthesized capsid proteins as host assembly machine substrates. Hits from the screen were validated by efficacy against infectious rabies virus in mammalian cell culture. Used as affinity ligands, advanced analogs were shown to bind a set of proteins that effectively reconstituted drug sensitivity in the cell-free screen and included a small but discrete subfraction of cellular ATP-binding cassette family E1 (ABCE1), a host protein previously found essential for HIV capsid formation. Taken together, these studies advance an alternate view of capsid formation (as a host-catalyzed biochemical pathway), a different paradigm for drug discovery (whole pathway screening without knowledge of the target), and suggest the existence of labile assembly machines that can be rendered accessible as next-generation drug targets by the means described.