Ethnopharmacological relevance Sarcandra glabra (S. glabra) has been traditionally used to promote diuresis and reduce swelling, which is employed to treat facial and lower limb edema, one of the earliest and most visible external signs of chronic kidney disease (CKD). The alleviating effect of S. glabra on CKD and its mechanism remains unclear. Aim of the study This study aims to determine the therapeutic effect of trishizukaol A (TSA), a lindenane sesquiterpenoid isolated from S. glabra, on CKD and investigate its underlying mechanism. Methods First, the biolayer interferometry (BLI) method was used to screen compounds from S. glabra targeting P2X7. Next, the effects of TSA on different stages of CKD were examined. The protein differences between P2X7 KO and WT mice were assessed using proteomic methods. Then, a series of biochemical methods was employed to explore the mechanism by which TSA alleviates CKD through P2X7. Results In mouse models of CKD, TSA significantly reduced urinary albumin excretion and decreased KIM-1 and NGAL, supporting that TSA has a notable ameliorative effect on CKD. Target screening results showed that TSA bound to and inhibited the P2X7 protein. Furthermore, we found that P2X7 was highly expressed in the tubular epithelial cells (TECs) of CKD mice, and blocking this receptor attenuated renal injury. In vivo, proteomic analysis comparing shP2X7 and shCTRL mice identified significant differential protein expression. P2X7 knockdown was predominantly associated with proteasome pathways. In vitro, siP2X7 and siPSME3 inhibited 20s proteasome activation, activated autophagy, and reduced TEC injury. At the same time, activation of autophagy can inhibit the proteasome. These results supported that P2X7 can regulate the crosstalk between proteasome and autophagy and promote TEC injury. In conclusion, TSA alleviates CKD in mice and regulates the P2X7/PSME3 axis, leading to the inactivation of the 20S proteasome hyper-activation and promoting autophagy in TECs. Conclusions This study reveals that TSA alleviates CKD by inhibiting P2X7/PSME3-driven hyperactivation of the 20S proteasome. TSA serves as a mechanistic probe and lead scaffold for dissecting the P2X7-proteasome axis in CKD.

Chemical investigation of the soil-derived actinomycete Streptomyces sp. CPU-W6 led to the discovery of three novel aminated benzoic dimers, cpumycins A-C (1-3). Their structures, featuring a distinctive C-N-C-linked heterodimeric skeleton, were determined through extensive spectroscopic techniques and X-ray diffraction. Bioinformatic analysis and targeted gene deletions identified a shikimate-derived biosynthetic gene cluster (CPU BGC) responsible for the assembly of these metabolites. Further investigations revealed that the formation of cpumycins 1 and 2 follows a hybrid "enzymatic-plus-spontaneous" biosynthetic paradigm, in which the enzymatic production of shikimate-derived aromatic precursors is coupled with a pH-dependent, spontaneous dimerization. In biological assays, cpumycins B (2) and C (3) exhibited cytoprotective effects against CoCl2-induced injury in undifferentiated H9c2 cells at nanomolar concentrations, while exhibiting negligible cytotoxicity (IC50 > 620 μM). These findings significantly expand the chemical diversity of shikimate-derived microbial metabolites and provide promising lead scaffolds for the development of therapeutics with potential cardioprotective benefits.

Background and Purpose Heatstroke is a life-threatening condition characterised by severe inflammation and often linked to necroptosis, a form of programmed cell death mediated by receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL). Annexin A1 (AnxA1) is known to play a role in resolving inflammation, but its effects on heatstroke remain unclear. This study investigates the role of AnxA1 in heatstroke and its potential mechanisms.Experimental Approach The levels of AnxA1 were measured in patients with heatstroke and in a mouse model of heatstroke. The severity of heatstroke symptoms was compared between wild-type (WT) male C57BL/6 mice and those lacking AnxA1 or its receptor FPR2 on a C57BL/6 background. Additionally, recombinant AnxA1 was administered in vivo and in vitro to assess its therapeutic potential and to investigate underlying mechanisms.Key Results The expression of AnxA1 increased significantly in response to heat stress in both heatstroke patients and mice. The absence of AnxA1 or FPR2 exacerbated heatstroke severity, while administering AnxA1 alleviated the symptoms in heat-stressed mice and cell models. These protective effects were mediated through the FPR2 receptor. Further analysis of the mechanism revealed that AnxA1 treatment inhibited the phosphorylation of key necroptosis proteins, RIPK3 and MLKL.Conclusion and Implications This study highlights the activation of the endogenous AnxA1-FPR2 signalling pathway following heat exposure and demonstrates that AnxA1 can mitigate heatstroke by inhibiting RIPK3/MLKL-mediated necroptosis. These findings suggest that enhancing endogenous AnxA1 levels or administering recombinant AnxA1 may be promising therapeutic strategies for managing heatstroke.

Mufolinoids W and X (1 and 2), two new trinortriterpenoids, along with their biosynthetic precursor triterpenoids (3 and 4), were isolated and identified from the medicinal plant Munronia unifoliolata Oliv.—a species used in Traditional Chinese Medicine for treating rheumatic arthritis pain and traumatic injuries. Their structures were identified by high-resolution mass spectrometry (HR-MS), one-dimensional/two-dimensional nuclear magnetic resonance (1D/2D NMR), and experimental and calculated electronic circular dichroism (ECD) methods. Structurally, 1 and 2 were the second example of 3/4-seco trinortriterpenoids from the plant kingdom. Biologically, the inhibitory effects of 1 and 2 on nitric oxide (NO) production and their multidrug resistance reversal activity were evaluated and screened.

(+/-)-Grifdosaether A (1a and 1b), a pair of bisdecarbonized phenanthrone derivatives possessing unprecedented benzospirocyclic skeleton, were discovered and elucidated from the fruiting bodies of edible-medicinal Grifola frondosa. Their structures including absolute configuration were thoroughly elucidated by using chiral separation, HR-MS, NMR, chemical transformation, ECD exciton chirality and calculation. Structurally, the unprecedented 6/5/5-tricyclic benzospirocyclic skeleton of 1a and 1b are originated from 6/6/6-tricyclic phenanthrone through Baeyer-Villiger oxidation, decarboxylation and dyotropic rearrangement. In bioassays, 1a and 1b were evaluated for inhibitory effects on IL-1(1.

Phytochemical investigation of the seeds of Khaya senegalensis (Desr.) A. Juss. led to the isolation of three new mexicanolide-type limonoids (1, 2, 5) and two new gedunin-type limonoids (3, 4), along with five known compounds (6-10). The structures of all new compounds including absolute configuration were unequivocally established by comprehensive spectroscopic analysis, including HRESIMS, 1D/2D NMR and ECD, and those of 1-3 were further confirmed by single-crystal X-ray diffraction analysis. Notably, limonoids 1-4 were identified as rare lactonization derivatives arising from the furan ring, and compounds 6-10 are first reported from this species. Assessment of anti-inflammatory activity using two complementary in vitro models (IL-1β production in LPS-stimulated THP-1 macrophages and NO production in LPS-stimulated RAW264.7 macrophages) indicated that the isolated limonoids (1-10) did not exhibit significant inhibitory activity at 40 μM.

Surgical resection remains the primary treatment for most solid tumours, yet metastatic tumour cells remaining after surgery substantially contribute to cancer-related mortality and recurrence. Here we identify syntaxin 11 as a key regulator that enhances the expression of MHC I and co-stimulatory molecules CD80/CD86 on tumour cell membranes, enabling cancer cells to acquire dendritic-cell-like features. By overexpressing syntaxin 11 in autologous tumour cells obtained from surgical resections, we generated MHC Ihigh/CD80high/CD86high dendritic-cell-like cells. Utilizing the cell membranes of these modified cells, we engineered artificial dendritic-cell-like cell-derived vesicles as a personalized autologous nanovaccine for the immunotherapy of postoperative metastatic cancer. This nanovaccine substantially improves antigen delivery to lymphoid organs and enhances antigen presentation efficiency through tumour self-presentation, thereby disrupting traditional vaccine development paradigms. Our work provides a promising avenue for developing effective metastatic cancer immunotherapies and offers hope for personalized postoperative immunotherapy.

Tetrasargltones A and B (1 and 2, respectively), representing the first examples of lindenane sesquiterpenoid (LS) tetramers, were isolated from Sarcandra glabra. Their structures were fully elucidated via HR-MS and NMR, with their authenticity further confirmed by X-ray diffraction. Structurally, 1 and 2 possess two unprecedented fully helically polymerized carbon skeletons, which are formed through plausible sequential Diels-Alder cycloadditions at different sites of the triene LS precursor. Biologically, 1 and 2 exhibit cytotoxic activity against five cancer cell lines, with 2 showing the best activity in HCT116 cells (IC50 = 2.51 ± 0.13 μM) and exerting its cytotoxic effects through NF-κB pathway inhibition.

This study presents the first phytochemical investigation of Helianthus annuus L. tubular flowers, leading to the isolation of three undescribed polyamine-conjugated hydroxycinnamic acid amides. These were characterised as N1,N5,N10,N14-tetra-p-coumaroylspermine analogues with distinct Z/E configurations (1-3). Their structures were elucidated through comprehensive spectroscopic analysis, including 1D/2D NMR and HR-ESIMS. All isolated compounds were evaluated for their antioxidant activity using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, which demonstrated that each compound possessed significant radical scavenging properties with IC50 values ranging from 4.34 to 9.35 mM.

Fifteen sesquiterpenoids, including five previously undescribed monomers with oxidative rearranged skeletons (sarglabenoids A-E, 1-5) and three previously unreported lindenane [2 + 2] dimers (sarglabenoids F-H, 6-8), alongside seven related precursors (9-15), were isolated from the root of Sarcandra glabra. The structures of these compounds were elucidated using a combination of high-resolution electrospray ionization mass spectrometry, one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy, the circular dichroism exciton chirality method, electronic circular dichroism, and nuclear magnetic resonance calculations integrated with DP4+ analysis. Compounds 1 and 2 feature an unique 5/5 spiro ring system, which is likely derived from a pinacol rearrangement of precursor 14. Compounds 3 and 4 are seco-C8/9 derivatives formed via Baeyer-Villiger oxidation of precursors 14 and 15, while compounds 6-8 represent the [2 + 2] dimers of various lindenane monomers (9-13). Notably, compounds 4 and 5 exhibited moderate inhibition of Interleukin-1 beta production in non-cytotoxic concentration in lipopolysaccharide-induced Tohoku Hospital Pediatrics-1 cells, with IC50 values of 16.28 +/- 0.76 mu M and 11.32 +/- 0.77 mu M respectively.

Ten non-limonoids type ingredients with four structural skeletons, including two cyclic peptide (1/3), a 5-hydroxymethylfurfural derivative (2), two monoterpenoid glycosides (4/5), and five coumarins (6-10), were discovered from Citrus medica var. Sarcodactylis fruits guided by single-node based CMN and feature-based molecular networking (FBMN) strategy. Among of them, the new cyclic heptapeptide 1 is with rare asparagine unit, and the new skeleton of 2 is formed between 5-hydroxymethylfurfural and malonic acid through aldol condensation, which were elucidated undoubtedly through NMR and single crystal diffraction. The cyclic dipeptide and monoterpenoid glycosides were also isolated from this plant for the first time. Bioactivities evaluation indicated that the cyclic heptapeptide 1 can significantly inhibit the production of IL-1β (IC50: 7.65 ± 0.04 μM) in THP-1 Cells and possess potential anti-inflammatory activity. This research provided further basis for clarification of its chemical constituents and development as natural medicine and food.

Sarcglabtenes A-G (1-7), seven lindenane-based sesquiterpenoid hetero-oligomers with six unprecedented skeletons, along with five new biosynthetic analogues sarcglabtenes H-L (8-12), were isolated from Sarcandra glabra. Their structures including absolute configurations were comprehensively elucidated using HR-MS, NMR, ECD, and single crystal X-ray diffraction. Structurally, sarcglabtenes A-G are lindenane hetero-oligomers including a geranyl homogentisic acid (1/2), geranylgeranyl p-toluquinone (3/4), germarane (5), campholenal (6/7) derivatives, for which plausible biosynthesis pathways are also proposed. In bioassays, 1-4 exhibited cytotoxic activity against five cancer cell lines, and in particular, 4 acted as extracellular-regulated protein kinase (Erk) inhibitor of the MAPK signaling pathway involved in apoptosis.

A Pd-II-catalyzed ortho-C(sp(2))-H hydroxylation of benzyl alcohols using an oxime ether as a monodentate directing group was developed. An N-acetylglycine ligand, in facilitating the cleavage of a C-H bond, is crucial to the reaction. The reaction might involve the formation of hydroxyl radicals generated from Oxone, and a six-membered exo-palladacycle intermediate is proposed. Various substituents on the phenyl ring were tolerated in the reaction. A gram-scale reaction and directing-group removal were also performed, demonstrating the applicability of the reaction in syntheses of salicyl alcohols.

Agledulines L-N (1 - 3), three previously undescribed limonoids with the A/D-ring-seco structural characteristics and high degree oxidation, along with the three reported compounds (4 - 6), were isolated from the fruits of Aglaia edulis. The structures of 1 - 3 were elucidated by NMR data, HRESIMS, ECD spectra, and circular dichroism exciton chirality method. The furan rings in 1 and 2 were oxidized to γ-hydroxy-butene lactone moiety, and the tautomerism of hemiacetal C-21 contributed to the disappearance of NMR signals in the segments. The biological evaluation showed that 1 - 3 had no anti-inflammatory activity by inhibiting NO release in LPS-activated RAW264.7 macrophages.

Twenty-seven dimeric lindenane sesquiterpenoid (LS) derivatives, including thirteen new hetero- or homo-dimers (1-13), were discovered from rare Chloranthaceae plant Chloranthus holostegius var. shimianensis. Their structures were elucidated by a combination of HRMS, spectroscopic analysis, single-crystal X-ray diffraction and CD exciton chirality method. Fortunoids D-G (1-4) and chlorfortunones C-F (5-8) are rare hetero-dimers of lindenane with eudesmane or acrane sesquiterpenoid through classical [4 + 2] cycloaddition respectively, and 9-13 are homo-LS dimers with low oxidation at C4'/13'/15'. Anti-inflammatory potential of these new isolates was evaluated by screening the IL-1β inhibition in THP-1 cells. Compounds 2-4 exhibited moderate anti-inflammatory effect (IC50 ≈ 10 μM) at non-cytotoxic concentrations (cell viability >80 %), and subsequent investigation on 2 demonstrated that it inhibited IL-1β production by inhibiting NLRP3 inflammasome activation but not the assembly. Based on the structural features of these LS dimers, the abundance of hetero-LS dimers and the low oxidation level at C4'/13'/15' of homo-LS dimers might be the chemotaxonomic characteristics distinguished from other Chloranthus species.

Hypertension is a major risk factor for cardiovascular diseases and needs effective blood pressure reduction. Current antihypertensive drugs, such as captopril, face challenges, including the enzymatic degradation and the liver first-pass effect. Here, we developed a dissolving microneedle (MN) loaded with a peptide-based enzyme-responsive prodrug peptide-captopril (PC) to enhance the stability of captopril and enable efficient transdermal delivery. Kinetic studies revealed that PC exhibited a lower Km value (1.1 × 10-5 M) for esterase-mediated hydrolysis compared to free captopril (2.1 × 10-5 M), indicating improved enzymatic stability. Meanwhile, PC was encapsulated stably in microneedle tips to form the PC MN, achieving approximately 90% transdermal drug delivery. In spontaneously hypertensive rat models, PC MN elicited a rapid and potent blood-pressure-lowering effect, outperforming oral captopril administration. This study presents a promising self-administering strategy to enhance hypertension treatment through efficient transdermal drug delivery.

Dysoxydenins A-M (1-13), thirteen new and rare prenyleudesmane diterpenoids were isolated and elucidated from the fruits of Dysoxylum densiflorum. Their structures, especially the absolute configurations of bridged C-5/C-7 in double ring skeleton and C-11 or C-14 in the flexible side chain, were elucidated through a comprehensive approach involving nuclear magnetic resonance (NMR) spectroscopy, electronic circular dichroism (ECD), Mosher, quantum chemical calculations, and single-crystal X-ray crystallography with Cu Kα radiation. Compounds 1, 3-7, 9, 10 shown significant reversing effects on multidrug resistance in MCF-7/doxorubicin (DOX) cells, which of 3 was higher than that of positive drug Verapamil. These rare but abundant prenyleudesmane diterpenoids also have the potential to serve as the chemotaxonomic marker of Dysoxylum plant differing from other Meliaceae plant.

Sarcglabates A-F (1-6), six lindenane sesquiterpenoid dimers possessing two unprecedented skeletons, were isolated from Sarcandra glabra. Their structures were thoroughly determined using HR-MS, NMR, and ECD and verified by single crystal X-ray diffraction. Structurally, compounds 1-2 represent the first examples of aromatized pentanor lindenane dimers featuring a critical 6/5/6 skeleton with a rare benzene ring, which formed via a plausible intramolecular nucleophilic reaction and aromatization assisted departure of a penta-carbon fragment. Lindenanes 3-5 were fused through rare tetrahydrofuran by nucleophilic addition. Compounds 1-6 were assessed through screening the inhibitory effect on the inflammatory factor IL-1β, with 6 further inhibiting the progression of inflammation by suppressing the activation of P65.

The presence of the blood–brain barrier limits the drug concentration in the brain, while low concentrations of antibiotics make it difficult to kill infecting bacteria and tends to induce drug resistance, making the clinical treatment of bacterial meningitis challenging. Herein, a nose-to-brain delivery strategy of small-sized nanozyme has been fabricated for combating bacterial meningitis, to overcome the low drug concentration and drug resistance. This strategy was achieved by a protein-supported Au nanozyme (ANZ). With a particle size of less than 10 nm, it possesses both glucose oxidase-like and peroxidase-like activities and can generate large amounts of reactive oxygen species through a cascade effect without the addition of external H2O2. Benefiting from the cascade catalytic amplification effect generated by its dual enzyme-like activities, ANZ shows significant broad-spectrum antibacterial activity without inducing bacterial resistance in vitro. Notably, small-sized ANZ exhibits higher brain entry efficiency and greater accumulation after intranasal administration compared to oral or intravenous administration. In a mouse model of bacterial meningitis, the mice treated with ANZ had lower bacterial loads in the brain and higher survival and clinical behavior scores compared to the classical antibiotic ceftriaxone. Additionally, the meningitis mice exhibited undamaged cognitive and behavioral abilities, indicating the excellent biocompatibility of ANZ. The above results demonstrate that nose-to-brain delivery of ANZ exhibits high intracerebral accumulation, strong antibacterial efficacy and does not lead to bacterial resistance. It holds broad prospects for the treatment of bacterial meningitis.

Background Septic acute kidney injury (S-AKI) is associated with high morbidity and mortality, and dysregulation of oxidative stress and remodeling of the inflammatory microenvironment are emerging as central pathogenic mechanisms. Alleviating inflammation and oxidative stress are the primary effects of limonoids found in nature, and our previously discovered walrobsin A (WA) from Walsura robusta has exhibited significant anti-inflammatory properties. Moreover, bioactive natural products with novel skeletons are ideal molecular probes for identifying potential novel molecular targets for diseases using chemical biology methods. Purpose To explore the therapeutic effect and mechanism of WA for treating S-AKI and to identify previously unrecognized targets in S-AKI. Methods The effect of WA was detected by establishing LPS-induced mouse S-AKI in vivo. Functional and pathological changes in murine kidneys were evaluated by measuring serum creatinine (CRE), cystatin C (Cys C), blood urea nitrogen (BUN), NGAL levels, and HE pathology. A RAW264.7/mTEC coculture system was established to elucidate the target and mechanism of WA by techniques such as RNA-seq, gene interference, DARTS, LC-MS/MS, molecular docking, BLI, and SPR. Results The screening results revealed that WA, a limonoid, significantly alleviated LPS-induced mouse S-AKI, and a RAW264.7/mTEC coculture experiment revealed that WA directly acted on macrophages. Transcriptomic analysis and further research revealed that WA promoted the expression of the antioxidant proteins HMOX1 and SOD2 and inhibited IL-1β, IL-6, and TNF-α secretion. G protein-coupled receptor 75 (GPR75), which was highly expressed in the renal macrophages of S-AKI mice, was subsequently identified as the direct target of WA. In the RAW264.7/mTEC coculture system, siGPR75 inhibited macrophage oxidative stress and restrained IL-1β, IL-6, and TNF-α secretion, thereby reducing mTEC injury, and overexpression of GPR75 resulted in the opposite effects. Moreover, siGPR75 reversed the WA-mediated remission of macrophage oxidative stress and the inflammatory microenvironment in vitro, and coadministration of WA failed to increase the therapeutic efficacy of 20-SOLA (a GPR75 inhibitor) in S-AKI in vivo. These results indicate that the WA-GPR75 axis mitigates S-AKI by regulating oxidative stress in macrophages and the inflammatory microenvironment. Conclusion In this study, we elucidated the novel role of GPR75 as a potential target for S-AKI using a bioactive limonoid-type natural product and identified a natural GPR75 inhibitor (WA) as a potential candidate for S-AKI treatment. This study firstly identifies GPR75 in pathological renal conditions and demonstrates its direct role in driving renal injury, thus establishing it as a novel therapeutic target for kidney diseases.