Gentiana straminea Maxim. (GSM), a cornerstone medicinal plant in Tibetan ethnopharmacology, has been utilized for over two millennia. This species exhibits a wide distribution across China, predominantly in the northwest. Its roots and flowers characterized by bitter, pungent taste and neutral properties are used medicinally. Traditional applications include treating rheumatoid arthritis, icteric hepatitis, leprosy, and “toxic heat” syndromes. Recent research has identified critical bioactive constituents: secoiridoids (gentiopicroside, swertiamarin, sweroside), loganic acid, flavonoids (vitexin, isovitexin), volatile compounds, and saccharides. GSM demonstrates significant pharmacological activities, including anti-inflammatory, analgesic, antioxidant, hepatoprotective, cardioprotective, anti-hypoxic, anti-bacterial, and insecticidal effects. By systematically reviewing domestic and international literature from the past two decades, this study summarizes the morphological characteristics, resource distribution, breeding practices, cultivation methods, chemical composition, and pharmacological actions of GSM. The aim is to provide a scientific basis for its cultivation, identification, rational clinical application, and to promote its development and utilization. Botany, pharmacological effects, and chemical composition of Gentiana straminea Maxim.

ETHNOPHARMACOLOGICAL RELEVANCE:Rhodiola crenulata (Hook. f. & Thomson) H. Ohba, a perennial herbaceous plant of the Rhodiola genus in the Crassulaceae family, is a commonly used Tibetan medicinal material grown in high-altitude areas ranging from 2800 to 5600 m. It is primarily distributed in China, Nepal, Bhutan, and so on. The roots of R. crenulata are its medicinal part, which possesses significant medicinal and health-care functions, and is commonly used to treat conditions such as hemoptysis, pneumonia, cough, and gynecological disorders like leucorrhea. With the development and utilization of R. crenulata resources, wild resources have been blindly excavated, putting them in an endangered state, and have been listed as a national second-class key protected wild plant. AIM OF THE REVIEW:This review systematically summarized the research progress and achievements in traditional use, artificial cultivation, chemical composition, pharmacological activity, clinical application, and quality standard of R. crenulata, aiming to provide theoretical support for its further research and clinical application. MATERIALS AND METHODS:A literature search on R. crenulata was performed using published scientific databases including SciFinder, Elsevier ScienceDirect, Web of Science, Taylor & Francis, ACS, Springer, PubMed, CNKI, and so on. Information was also collected from Classical books on Chinese and Tibetan medicines, Ph.D. and M.Sc. Dissertations, Baidu Scholar, and so on. Structures of chemical compounds were drawn by ChemDraw software. RESULTS:Through literature review, 134 natural compounds have been reported from R. crenulata, which include flavonoids, phenylpropanoids, phenylethanes, terpenoids, and other compounds. R. crenulata exhibited extensive pharmacological activities, such as anti-aging, anti-hypoxia, anti-fatigue, anti-radiation, antitumor, cardiovascular system improvement, and anti-aging effects. With the development and utilization of R. crenulata resources, wild resources are gradually decreasing, and artificial breeding and in-depth research on its active compounds are becoming increasingly important, and a series of progress has been made. Due to the similar origins of species within the Rhodiola genus, current quality standards struggle to distinguish between them. This paper reviews HPLC fingerprint methods, thin layer chromatography, and 1H NMR fingerprint technology, providing a reference for improving the quality standards of R. crenulata. CONCLUSIONS:Extensive research has been conducted on the chemical composition and pharmacological activity of R. crenulata, yielding significant results. New compounds and activities are continuously being reported, yet research on its mechanism of action still needs to be strengthened. Various artificial cultivation techniques has been conducted, but current techniques cannot meet the actual demand for this plant. It is believed that with in-depth research, the resource issue of R. crenulata will be resolved. Continuous research is also being conducted to improve the quality standards of R. crenulata. This review provides a useful reference for in-depth research on R. crenulata and the development of new functional products.

This study aims to meet the therapeutic needs of rheumatoid arthritis(RA)by focusing on the traditional anti-arthritic medicinal plant Gentiana straminea.An integrated strategy combining characterization of absorbed components,network pharmacology,molecular docking,and molecular interaction verification was employed to systematically investigate the pharmacodynamic material basis and mechanism of this herb against RA.Ultra-high performance liquid chromatography-quadrupole-time of flight-tandem mass spectrometry(UHPLC-Q-TOF-MS/MS)was performed,which identified gentiopicroside,swertiamarin,and loganic acid as the core components absorbed into blood.Network pharmacology prediction and target mapping revealed that these components were primarily involved in RA-related biological processes such as inflammatory response and immune cell activation.Molecular docking suggested that the core components exhibited favorable binding potential with key targets including STAT3,EGFR,and MMP9.Further quantitative validation with bio-layer interferometry demonstrated that gentiopicroside(KD=50.1 nmol·L-1)and swertiamarin(KD=87.7 nmol·L-1)specifically bound to STAT3 with high affinity.The results indicate that G.straminea exert anti-RA effects through its iridoids by targeting STAT3 and modulating related inflammatory pathways,providing a scientific basis for the clinical application of G.straminea and the development of natural anti-RA drugs.

Casbanes and the related diterpenoids (e.g., lathyranes, tiglianes, and ingenanes) are yielded from oxidation and oxidation-mediated cyclization of casbene, in which cytochrome P450 enzymes (CYPs) play vital roles. Herein, we characterized four CYPs involved in casbene oxidation from Euphorbia fischeriana Staud. The discovery of these CYPs enables oxidation of C-16, C-17, and C-19 of casbene, which has not been achieved by the previously characterized CYPs. And we found that casbene-5-oxidases can catalyze both 5S- and 5R-hydroxylation of casbene, but not only 5S-hydroxylation as previously reported. Moreover, the CYP orthologues (e.g., casbene-5,6-oxidases EfCYP726A47 and ElCYP726A27) involved in casbene oxidation in Euphorbiaceae may possess different substrate specificity. Overall, this study expands the enzymatic tools for casbene oxidation and exhibits the complexity of casbene-related diterpenoid biosynthesis.

Many labdane-related diterpenoids (LRDs) exhibit high values in drug development. Their diversity in structure and bioactivity, to a large extent, arise from oxidative modifications which are mainly catalyzed by cytochrome P450s (CYPs). The medicinal plant Euphorbia fischeriana Steud. is rich in LRDs with distinct scaffolds. Herein, we characterized three cytochrome P450s involved in LRD biosynthesis from this plant. Notably, CYP71D450 and CYP701A148 are two substrate-promiscuity CYPs. The former is the first example of CYPs which can oxidize C-3 of ent-atisane skeleton and ent-isopimara-7(8),15-diene, and the latter is the first example of CYPs which can oxidize C-19 of ent-abietane and ent-pimarane skeletons. This study expands the toolkit for bioproduction of diverse LRDs.

Gymnadenia orchidis Lindl. - a traditional Orchidaceae Gymnadenia medicinal plant-exhibits validated pharmacological activities, including potent anti-inflammatory and antioxidant capacities. Nonetheless, current research on its resource development, utilization, and underlying pharmacological mechanisms remains limited. Its polysaccharides' potential in periodontitis management aligns with market demands for high-quality natural oral healthcare products. This study aimed to characterize Gymnadenia orchidis polysaccharides (GOP), assess anti-inflammatory/anti-osteoclastogenic potencies on Lipopolysaccharide (LPS)-induced RAW264.7 macrophage, and clarify the mechanisms. GOP was purified via ultrasonic-assisted aqueous extract isolation and refined via DEAE Sepharose Fast Flow chromatography. structural features were analyzed by Methylation analysis, Fourier-transform infrared (FT-IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and microscopic morphological analysis In an LPS-elicited inflammatory model established in RAW264.7 macrophage, cell viability, inflammatory cytokine production, and the underlying mechanisms were evaluated using the Reverse Transcription-quantitative PCR (RT-qPCR), Enzyme-Linked Immunosorbent Assay (ELISA), Cell Counting Kit-8 (CCK-8), and Western blot. Two fractions (GOP-N: 2.52 kDa; GOP-A: 27.56 kDa), mainly composed of alpha-1,4-D-Glcp (GOP-A additionally containing alpha-1,4,6-D-Glcp), exhibited lamellar morphologies. In vitro anti-inflammatory bioassessments demonstrated that in an LPS-elicited RAW264.7 cell inflammation models, GOP-N and GOP-A exert dual regulatory potencies by impeding the TLR4/RANKL/NF-kappa B pathway: they inhibit osteoclast differentiation, downregulate proinflammatory mediator secretion, and upregulate IL-10 expression, exerting potent anti-inflammatory activity. Collectively, GOP possess significant immunomodulatory activity and are potential periodontitis agents, providing a theoretical foundation for polysaccharide-based oral products and supporting rational G. orchidis resource development.

Three new ent-atisane diterpenoids (1-3) and five known ones (4-8) were obtained from the bioactive fraction of E. micractina. Their structures and absolute configurations were elucidated by a comprehensive analysis of the spectroscopic data, including high-resolution electrospray ionization mass spectrometry, infrared, nuclear magnetic resonance, X-ray crystallography, and electronic circular dichroism data. Among them, compound 1 was the first example of an ent-atisane diterpenoid with an α-oriented hydroxyl group at C-7. In addition, the cytotoxicity of all the isolated ent-atisane diterpenoids was evaluated against human cervical carcinoma, human acute promyelocytic leukemia, and human hepatoma cell lines. Compound 3 demonstrated significant cytotoxic activity against the selected cell lines with an IC50 value from 7.5 to 10.1 µM.

Aneuploidy is pervasive in cancers and contributes to chemoresistance; however, how aneuploidy-inducing stresses, such as infection and hypoxia, promote chemoresistance remains unclear. Here, we identify a prolyl hydroxylase domain protein 1 (PHD1)-E3 ubiquitin ligase TRIM21-cell division cycle protein 20 (CDC20) signaling axis that integrates infection- and PHD1-inhibitory signals to drive aneuploidy and chemoresistance. Analysis of clinical specimens revealed that HPV-positive cervical cancers exhibited reduced CDC20 expression and increased aneuploidy compared with HPV-negative tumors. Through proteomic screening, we found that CDC20 is targeted for degradation by TRIM21, which preferentially recognizes CDC20 when prolines 337 and 340 are non-hydroxylated. Hypoxia and α-ketoglutarate (α-KG) limitation impair the activity of the dioxygenase PHD1, thereby increasing the fraction of non-hydroxylated CDC20. In parallel, infection activates TRIM21. Thus, PHD1 inactivation and infection converge on CDC20 to reduce its abundance, leading to the accumulation of CDC20 substrates, including the separase inhibitor securin and the anti-apoptotic protein MCL1. Infection- and PHD1 inhibition-induced securin accumulation promotes aneuploidy, whereas MCL1 accumulation enhances chemoresistance. In cultured cancer cells and mouse xenograft models, stabilization of CDC20, either through TRIM21 inhibition or PHD1 activation, attenuates aneuploidy and restores chemosensitivity. Together, our study reveals a PHD1-TRIM21-CDC20 signaling axis that integrates hypoxic and infection-associated cues to regulate aneuploidy and chemoresistance, highlighting this pathway as a potential therapeutic target for overcoming chemoresistance.

The functional difference between the two catalytic subunits, α1 and α2, of AMP-activated protein kinase (AMPK) complexes remains elusive. Herein, we report that AMPKα2 specifically transduces amino acid insufficiency signals to protein synthesis. Low amino acid levels, high protein levels, and reduced phosphorylation of AMPKα threonine 172 (p-T172) are observed in blood samples in patients with Alzheimer's disease (AD) from a cohort of 1,000,000 Chinese individuals. Loss of α2, but not α1, recaptures these observations and induces AD-like cognitive dysfunction in mice. Mechanistically, low amino acid-activated general control nonderepressible 2 (GCN2) specifically phosphorylates α2 at T172 independent of AMP and fructose 1,6-bisphosphate to inhibit protein synthesis. α2-p-T172 loss renders protein over-synthesis and AD-pathologic protein aggregation in cells and in mouse brain. AMPK activators metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), as well as branched-chain amino acid (BCAA) or protein restriction, α2-p-T172-dependently prevent AD-like symptoms in mice. We identify AMPKα2 as a specific amino acid abundance detector for protein synthesis.

Magnesium is an essential metallic element in living organisms, but its excessive release into the environment and overaccumulation within organisms can severely impact ecosystems and human health.

Przewalskia tangutica is an endangered alpine plant,found in the Qinghai-Tibet Plateau,contains tropane alkaloids as its main active ingredients.The roots,seeds and whole herb of P.tangutica are used in medicine and have significant medicinal value.The study was conducted to analyze the changes in the root exudates of P.tangutica induced by methyl jasmonate.The plants were treated with 0,150 μmol·L-1 methyl jasmonate for 3 d and 7 d,and the root exudates were analyzed using the non-targeted metabolomics technique of LC-MS/MS.The results were as follows:(1)There was a significant difference in the content of root exudates from P.tangutica after 3 d and 7 d treatments with 0,150 µmol·L-1 methyl jasmonate.(2)The amount of root exudate increased significantly with the 150 µmol·L-1 methyl jasmonate treatment compared to the control.(3)The KEGG pathways mainly involved in the root exudates of P.tangutica were α-linolenic acid metabolism pathway,plant hormone signal transduction pathway and lysine biosynthesis pathway.In summary,it was concluded that the induction of methyl jasmonate affected the metabolism and changed the content and quantity of induced exudates in the root system of P.tangutica.Through non-targeted metabolomics analysis,the study preliminarily reveals the key metabolites involved in the root exudate response to methyl jasmonate of P.tangutica,which provides a theoretical reference for further understanding of the changes in root exudate and metabolism mechanism of this alpine plant under methyl jasmonate.In addition,the results also offer a new way of thinking on the continuation of the resources.

Cell proliferation requires anabolic supports. How the cell cycle integrates anabolism remains poorly understood. Herein, it is identified that G1-phase regulator cell division cycle 20-like protein 1 (CDH1) coordinates anabolic events to ensure cell cycle initiation. CDH1 degrades Von Hippel-Lindau (VHL), concomitantly activates hypoxia-inducible factor 1α (HIF1α), which enhances angiogenesis and glucose metabolism, and activates mitochondrial lactyltransferase alanyl tRNA synthetase (AARS2), which lactylates and inactivates pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), thereby conserving anabolites. Among the CDH1-accumulated anabolites, ribose-5-phosphate (R5P) binds to transketolase-like-1 (TKTL1) to bridge CDH1 to cyclin-dependent kinase 2 (CDK2) and Skp1-Cullin-F-box and β-transducin repeat-containing protein (SCFβ -TRCP) complex, thereby facilitating CDH1 phosphorylation and degradation to promote cell cycle initiation. This CDH1-VHL-HIF1α/AARS2-R5P/TKTL1 circuit is supported by the observation that low R5P levels and high CDH1 expression correlate with proliferating cancer cells and tissues. Moreover, it is demonstrated that an artificial R5P signal, generated by ribose-5-sulfate (R5S), sensitizes cancer cells to apoptosis by initiating the cell cycle in the absence of sufficient anabolite supply. These suggest that cancer signatures, including the Warburg effect and angiogenesis, are intrinsically driven by CDH1.

Magnesium is an essential metallic element in living organisms, but its excessive release into the environment and overaccumulation within organisms can severely impact ecosystems and human health. Therefore, developing detection methods that precisely identify Mg2+ is crucial for environmental monitoring and biomedical applications. In this study, we designed and synthesized an AIEE-based peptide fluorescent probe, Rb-SWHEFQ-NH2, for Mg2+ detection. By flexibly incorporating hydrophobic amino acids into the probe system, we prevented self-assembly into nanostructures in solution, thereby achieving excellent selectivity and stable morphological characteristics. Furthermore, this probe exhibits a low detection limit for Mg2+ (15.4 nM) and strong resistance to interference. Notably, Rb-SWHEFQ-NH2 demonstrates excellent cellular permeability and low cytotoxicity, enabling its successful application in fluorescence imaging of intracellular Mg2+ in CT26 cells.

Panax japonicus (T.Nees) C. A. Mey var. major (Burkill) C. Y. Wu & K. M. Feng is a plant of the Panax L. genus in the Araliaceae family. The medicinal part is the rhizome of P. japonicus, which is a traditional medicine used by ethnic minorities such as the Naxi, Yi, Tibetan etc. It has the effects of tonifying the lungs, nourishing yin, stopping bleeding, and activating collaterals, and is widely used in medicine, pharmaceuticals, and health products. The main chemical components of P. japonicus are triterpenoid saponins, as well as phenolic acids, polysaccharides, etc. It has various pharmacological activities such as anti-tumor, cardiovascular and cerebrovascular protection, antioxidant, and liver protection. To better develop and utilise the plant resources of P. japonicus and clarify its pharmacological substance basis, this article reviews the chemical composition, pharmacological activity, clinical application, and quality control of P. japonicus, in order to provide theoretical basis for in-depth research of P. japonicus.

Copper is central to many enzymes in living organisms, and imbalances in copper levels are linked to various diseases. Therefore, developing probes to detect copper ions is essential. Histidine, especially in the polypeptide sequences at the first three N-terminal positions (His1, His2, and His3), uniquely binds to copper ions. This study introduces three groups of tripeptide probes designed to monitor copper ion levels in living cells and organisms. The results show that tripeptides with histidine at the -2 position, specifically HDQL-2 (Asp-His-Gln-Dansyl), HMFM-2 (Met-His-Phe-Dansyl), and HDMB-2 (Asp-His-Met-Dansyl), exhibit a higher affinity for copper ions. These probes responded quickly to copper ions, demonstrating excellent fluorescence turn-off performance and stable detection within a pH range of 6.0-11.0. The detection limits for fluorescence titration, calculated using the 3σ/k equation, were 17.65 nM (HDQL-2), 18.04 nM (HMFM-2), and 15.50 nM (HDMB-2). Peptide probes are ideal for detecting copper ions in living cells via fluorescence imaging because of their low toxicity and good biocompatibility. The fluorescence intensity decreases as copper ion content changes.

In this work, a blue-green NPCl-CDs was synthesized by one-step hydrothermal method using glucose, ethylenediamine, concentrated hydrochloric acid and concentrated phosphoric acid as reaction precursors. Then NPCl-CDs/Fe (3+) fluorescent probe was constructed for the quantitative detection of L-Cys in actual samples. The fluorescence intensity of NPCl-CDs could be quenched after addition of Fe (3+). The fluorescence intensity of the NPCl-CDs/Fe (3+)system was restored when L-Cys was introduced into the system. Therefore, a novel "on-off-on" NPCl-CDs/Fe (3+)- L-Cys fluorescence sensing system for L-Cys quantitative detection was constructed. This experiment showed a wide linear region in the concentration range of 5.8-60.0 mu mol/L with a detection limit of 0.052 mu mol/L. The results indicated that the fluorescence sensing system had good selectivity, sensitivity and potential application value for the detection of L-Cys in real samples.

Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced β-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 ( GAD1 ). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.

Plants of genus Paeonia have both medicinal and edible value for a long history. Albiflorin (AF), one of the characteristic monoterpenoid glycosides of Paeonia L. plants, has extensive protective effects in nervous system, cardiovascular and cerebrovascular system, digestive system, endocrine system, skeletal system, and other diseases. AF has demonstrated favorable outcomes in the treatment of depression, neurodegenerative diseases inflammation, oxidative stress, and other related disorders. The aforementioned effects of AF are primarily mediated by the antioxidant activity, modulation of mitochondrial autophagy, regulation of the gut microbiota, and involvement in cell signaling pathways including NF-u03BAB, AMPK, PI3K/Akt, Wnt/u03B2-catenin, and so on. Based on studies over the past several decades, this review systematically summarizes the pharmacological effects of AF to provide an overall understanding of the pharmacological functions of AF and propose valuable insights for future research of AF on food and medicine applications.

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. Inadequate understanding of the ovulation drivers hinders PCOS intervention. Herein, we report that follicle stimulating hormone (FSH) controls follicular fluid (FF) glutamine levels to determine ovulation. Murine ovulation starts from FF-exposing granulosa cell (GC) apoptosis. FF glutamine, which decreases in pre-ovulation porcine FF, elevates in PCOS patients FF. High-glutamine chow to elevate FF glutamine inhibits mouse GC apoptosis and induces hormonal, metabolic, and morphologic PCOS traits. Mechanistically, follicle-development-driving FSH promotes GC glutamine synthesis to elevate FF glutamine, which maintain follicle wall integrity by inhibiting GC apoptosis through inactivating ASK1-JNK apoptotic pathway. FSH and glutamine inhibit the rapture of cultured murine follicles. Glutamine removal or ASK1-JNK pathway activation with metformin or AT-101 reversed PCOS traits in PCOS models that are induced with either glutamine or EsR1-KO. These suggest that glutamine, FSH, and ASK1-JNK pathway are targetable to alleviate PCOS.