[Metabolomics of quality formation of different cultivars of Peucedanum praeruptorum].

This study aims to reveal the quality formation of different cultivars of Peucedanum praeruptorum based on the metabolic differences and provide a theoretical basis for the development and utilization of this medicinal herb. The non-target metabonomics analysis based on ultra-high performance liquid chromatography tandem mass spectrometry(UHPLC-MS/MS) was conducted for six cultivars(YS, H, LZ, LY, LX, and Z) of P. praeruptorum of the same origin and at the same development stage. The principal component analysis, orthogonal partial least squares discriminant analysis, and univariate statistical analysis were carried out to screen the differential metabolites of different cultivars. The potential biomarkers associated with quality formation were predicted based on the mass-to-charge ratio, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, information of relevant literature, and correlation analysis. The results showed that metabolites differed significantly among the six cultivars, and 571 and 465 differential metabolites were obtained in the positive and negative ion modes, respectively. From the differential metabolites, 22 potential biomarkers related to quality formation were predicted, which involved 9 metabolic pathways, including phenylalanine, tyrosine and tryptophan biosynthesis, biosynthesis of phenylpropanoids, and biosynthesis of plant hormones. Compared with the YS cultivar, other cultivars showed decreased concentrations of psoralen, imperatorin, and luvangetin and increased concentrations of 7-hydroxycoumarine, esculetin, columbianetin, and jasmonic acid, which were involved in the biosynthesis of phenylpropanoids. The concentrations of 2-succinylbenzoate, heraclenol, and L-tyrosine involved in other metabolic pathways decreased, especially in the Z and H cultivars. Therefore, regulating the biosynthesis of phenylpropanoids is one of the key mechanisms for improving the cultivar quality of P. praeruptorum. The Z and H cultivars have better quality and metabolic processes than other cultivars and thus can be used for the screening and breeding of high-quality germplasm.

Longistylin A from Cajanus cajan (L.) Millsp. disturbs glycerophospholipid metabolism and cytokinin biosynthesis of Nocardia seriolae.

ETHNOPHARMACOLOGICAL RELEVANCE: Nocardiosis is an uncommon infectious disease that bears certain similarities to tuberculosis, with a continuous increase in its incidence and a poor prognosis. In traditional Chinese medicine, the leaves of Cajanus cajan (L.) Millsp. are employed to treat wounds, malaria, coughs, and abdominal pain. AIM OF THE STUDY: In this study, we investigated the effects and mechanisms of longistylin A (LGA), a natural stilbene isolated from C. cajan, as a potential antibiotic against nocardiosis. MATERIALS AND METHODS: LGA was isolated from the leaves of C. cajan and assessed using a minimum bactericidal concentration (MBC) determination against Nocardia seriolae. Multi-omics analysis encompassing genes, proteins, and metabolites was conducted to investigate the impact of LGA treatment on N. seriolae. Additionally, quantitative analysis of 40 cytokinins in N. seriolae mycelium was performed to assess the specific effects of LGA treatment on cytokinin levels. Cryo-scanning electron microscopy was utilized to examine morphological changes induced by LGA treatment, particularly in the presence of exogenous trans-zeatin-O-glucoside (tZOG). The therapeutic effect of LGA was investigated by feeding N. seriolae-infected largemouth bass. RESULTS: LGA exhibited significant efficacy against N. seriolae, with MBC value of 2.56 µg/mL. Multi-omics analysis revealed that LGA disrupted glycerophospholipid metabolism and hormone biosynthesis by notably reducing the expression of glycerol-3-phosphate dehydrogenase and calmodulin-like protein. Treatment with LGA markedly disrupted 12 distinct cytokinins in N. seriolae mycelium. Additionally, the addition of exogenous tZOG counteracted the inhibitory effects of LGA on filamentous growth, resulting in mycelial elongation and branching. Furthermore, LGA treatment improved the survival rate of largemouth bass infected with N. seriolae. CONCLUSIONS: We found for the first time that LGA from C. cajan exhibited significant efficacy against N. seriolae by interfering with glycerophospholipid metabolism and cytokinin biosynthesis.

AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation.

Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.

Telocinobufagin, a PLK1 suppressor that inhibits tumor growth and metastasis by modulating CDC25c and CTCF in HNSCC cells.

BACKGROUND: The high metastasis and mortality rates of head and neck squamous cell carcinoma (HNSCC) urgently require new treatment targets and drugs. A steroidal component of ChanSu, telocinobufagin (TBG), was verified to have anti-cancer effects in various tumors, but its activity and mechanism in anti-HNSCC were still unknown. PURPOSE: This study tried to demonstrate the anti-tumor effect of TBG on HNSCC and verify its potential mechanism. METHODS: The effect of TBG on cell proliferation and metastasis were performed and the TBG changed genes were detected by RNA-seq analysis in HNSCC cells. The GSEA and PPI analysis were used to identify the pathways targeted for TBG-regulated genes. Meanwhile, the mechanism of TBG on anti-proliferative and anti-metastasis were investigated in vitro and in vivo. RESULTS: The in vitro and in vivo experiments confirmed that TBG has favorable anti-tumor effects by induced G2/M phase arrest and suppressed metastasis in HNSCC cells. Further RNA-seq analysis demonstrated the genes regulated by TBG were enriched at the G2/M checkpoint and PLK1 signaling pathway. Then, the bioinformatic analysis of clinical data found that high expressed PLK1 were closely associated with poor overall survival in HNSCC patients. Furthermore, PLK1 directly and indirectly modulated G2/M phase and metastasis (by regulated CTCF) in HNSCC cells, simultaneously. TBG significantly inhibited the protein levels of PLK1 in both phosphorylated and non-phosphorylated forms and then, in one way, inactivated PLK1 failed to activate G2/M phase-related proteins (including CDK1, CDC25c, and cyclin B1). In another way, be inhibited PLK1 unable promote the nuclear translocation of CTCF and thus suppressed HNSC cell metastasis. In contrast, the anti-proliferative and anti-metastasis effects of TBG on HNSCC cell were vanished when cells high-expressed PLK1. CONCLUSION: The present study verified that PLK1 mediated TBG induced anti-tumor effect by modulated G2/M phase and metastasis in HNSCC cells.

Metabolomic analysis reveals biogenic selenium nanoparticles improve the meat quality of thigh muscle in heat-stressed broilers is related to the regulation of ferroptosis pathway.

Heat stress (HS) causes oxidative damage and abnormal metabolism of muscle, thus impairing the meat quality in broilers. Selenium is an indispensable element for enhancing antioxidant systems. In our previous study, we synthesized a novel type of biogenic selenium nanoparticles synthesized with alginate oligosaccharides (SeNPs-AOS), and found that the particle size of Se is 80 nm and the Se content is 8% in the SeNPs-AOS; and dietary 5 mg/kg SeNPs-AOS has been shown to be effective against HS in broilers. However, whether SeNPs-AOS can mitigate HS-induced the impairment of thigh muscle quality in broilers is still unclear. Therefore, the purpose of this study was to investigate the protective effects of dietary SeNPs-AOS on meat quality, antioxidant capacity, and metabolomics of thigh muscle in broilers under HS. A total of 192 twenty-one-day-old Arbor Acres broilers were randomly divided into 4 groups with 6 replicates per group (8 broilers per replicate) according to a 2 × 2 experimental design: thermoneutral group (TN, broilers raised under 23±1.5°C); TN+SeNPs-AOS group (TN group supplemented 5 mg/kg SeNPS-AOS); HS group (broilers raised under 33 ± 2°C for 10 h/d); and HS + SeNPs-AOS group (HS group supplemented 5 mg/kg SeNPS-AOS). The results showed that HS increased the freezing loss, cooking loss, and malondialdehyde (MDA) content of thigh muscle, whereas decreased the total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities, as well as downregulated the mRNA expression of SOD2, CAT, GPX3, nuclear factor erythroid 2-related factor 2 (Nrf2), selenoprotein S (SELENOS), solute carrier family 7 member 11 (SLC7A11), GPX4, and ferroportin 1 (Fpn1) of thigh muscle (P < 0.05). Dietary SeNPS-AOS reduced the b* value, elevated the pH0min value and the activities of T-SOD, GSH-Px, glutathione S-transferase (GST) and the mRNA expression levels of GSTT1, GSTA3, GPX1, GPX3, ferritin heavy polypeptide-1 (FTH1), and Fpn1 of thigh muscle in broilers under HS (P < 0.05). Nontargeted metabolomics analysis identified a total of 79 metabolites with significant differences among the four groups, and the differential metabolites were mainly enriched in 8 metabolic pathways including glutathione metabolism and ferroptosis (P < 0.05). In summary, dietary 5 mg/kg SeNPs-AOS (Se content of 8%) could alleviate HS-induced impairment of meat quality by improving the oxidative damage, metabolic disorders and ferroptosis of thigh muscle in broilers challenged with HS. Suggesting that the SeNPs-AOS may be used as a novel nano-modifier for meat quality in broilers raised in thermal environment.

Loureirin A Promotes Cell Differentiation and Suppresses Migration and Invasion of Melanoma Cells via WNT and AKT/mTOR Signaling Pathways.

Resina Draconis is a traditional Chinese medicine, with the in-depth research, its medicinal value in anti-tumor has been revealed. Loureirin A is extracted from Resina Draconis, however, research on the anti-tumor efficacy of Loureirin A is rare. Herein, we investigated the function of Loureirin A in melanoma. Our research demonstrated that Loureirin A inhibited the proliferation of and caused G0/G1 cell cycle arrest in melanoma cells in a concentration-dependent manner. Further study showed that the melanin content and tyrosinase activity was enhanced after Loureirin A treatment, demonstrated that Loureirin A promoted melanoma cell differentiation, which was accompanied with the reduce of WNT signaling pathway. Meanwhile, we found that Loureirin A suppressed the migration and invasion of melanoma cells through the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Taken together, this study demonstrated for the first time the anti-tumor effects of Loureirin A in melanoma cells, which provided a novel therapeutic strategy against melanoma.

Biogenic Selenium Nanoparticles Synthesized with Alginate Oligosaccharides Alleviate Heat Stress-Induced Oxidative Damage to Organs in Broilers through Activating Nrf2-Mediated Anti-Oxidation and Anti-Ferroptosis Pathways.

Selenium (Se) is an essential trace element for maintaining health due to its ideal antioxidant properties. We previously prepared a new type of biogenic selenium nanoparticles based on alginate oligosaccharides (SeNPs-AOS), and this study aimed to investigate the protective effects of SeNPs-AOS (Se particle size = 80 nm, Se content = 8%) on organ health in broilers challenged with HS. A total of 192 21-day-old Arbor Acres broilers were randomly divided into four groups according to a 2 × 2 experimental design, including a thermoneutral zone group (TN, raised under 23 ± 1.5 °C); TN + SeNPs-AOS group (TN group supplemented 5 mg/kg SeNPS-AOS); HS group (HS, raised under 33 ± 2 °C for 10 h/day); and HS + SeNPs-AOS group (HS group supplemented 5 mg/kg SeNPS-AOS). There were six replicates in each group (eight broilers per replicate). The results showed that SeNPs-AOS improved the splenic histomorphology, enhanced the activity of catalase (CAT) and glutathione peroxidase (GSH-Px) of the spleen, as well as upregulating the splenic mRNA expression of antioxidant-related genes in broilers under HS. In addition, SeNPs-AOS reversed the pathological changes in bursa caused by HS increased the activity of GST, GSH-Px, and CAT and upregulated the mRNA expression of Nrf2 and antioxidant-related genes in the bursa of heat-stressed broilers. In addition, dietary SeNPs-AOS improved the hepatic damage, increased the activity of GSH-Px in the liver, and upregulated the mRNA expression of antioxidant-related genes while downregulating the Keap1 gene expression of the liver in broilers during HS. Moreover, dietary SeNPs-AOS upregulated the anti-ferroptosis-related genes expression of liver in broilers under HS. In conclusion, dietary SeNPs-AOS could relieve HS-induced oxidative damage to the spleen, bursa of Fabricius and liver in broilers by upregulating the Nrf2-mediated antioxidant gene expression and SeNPs-AOS could also upregulate the expression of hepatic Nrf2-related anti-ferroptosis genes in heat-stressed broilers. These findings are beneficial for the development of new nano-antioxidants in broilers.

Pharmacological Effects of Botanical Drugs on Myocardial Metabolism in Chronic Heart Failure.

Although there have been significant advances in the treatment of heart failure in recent years, chronic heart failure remains a leading cause of cardiovascular disease-related death. Many studies have found that targeted cardiac metabolic remodeling has good potential for the treatment of heart failure. However, most of the drugs that increase cardiac energy are still in the theoretical or testing stage. Some research has found that botanical drugs not only increase myocardial energy metabolism through multiple targets but also have the potential to restore the balance of myocardial substrate metabolism. In this review, we summarized the mechanisms by which botanical drugs (the active ingredients/formulas/Chinese patent medicines) improve substrate utilization and promote myocardial energy metabolism by activating AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptors (PPARs) and other related targets. At the same time, some potential protective effects of botanical drugs on myocardium, such as alleviating oxidative stress and dysbiosis signaling, caused by metabolic disorders, were briefly discussed.

Danhong Injection Up-regulates miR-125b in Endothelial Exosomes and Attenuates Apoptosis in Post-Infarction Myocardium.

OBJECTIVE: To investigate the involvement of endothelial cells (ECs)-derived exosomes in the anti-apoptotic effect of Danhong Injection (DHI) and the mechanism of DHI-induced exosomal protection against postinfarction myocardial apoptosis. METHODS: A mouse permanent myocardial infarction (MI) model was established, followed by a 14-day daily treatment with DHI, DHI plus GW4869 (an exosomal inhibitor), or saline. Phosphate-buffered saline (PBS)-induced ECs-derived exosomes were isolated, analyzed by miRNA microarray and validated by droplet digital polymerase chain reaction (ddPCR). The exosomes induced by DHI (DHI-exo), PBS (PBS-exo), or DHI+GW4869 (GW-exo) were isolated and injected into the peri-infarct zone following MI. The protective effects of DHI and DHI-exo on MI hearts were measured by echocardiography, Masson's trichrome staining, and TUNEL apoptosis assay. The Western blotting and quantitative reverse transcription PCR (qRT-PCR) were used to evaluate the expression levels of miR-125b/p53-mediated pathway components, including miR-125b, p53, Bak, Bax, and caspase-3 activities. RESULTS: DHI significantly improved cardiac function and reduced infarct size in MI mice (P<0.01), which was abolished by the GW4869 intervention. DHI promoted the exosomal secretion in ECs (P<0.01). According to the results of exosomal miRNA microarray assay, 30 differentially expressed miRNAs in the DHI-exo were identified (28 up-regulated miRNAs and 2 down-regulated miRNAs). Among them, DHI significantly elevated miR-125b level in DHI-exo and DHI-treated ECs, a recognized apoptotic inhibitor impeding p53 signaling (P<0.05). Remarkably, treatment with DHI and DHI-exo attenuated apoptosis, elevated miR-125b expression level, inhibited capsase-3 activity, and down-regulated the expression levels of proapoptotic effectors (p53, Bak, and Bax) in post-MI hearts, whereas these effects were blocked by GW4869 (P<0.05 or P<0.01). CONCLUSION: DHI and DHI-induced exosomes inhibited apoptosis, promoted the miR-125b expression level, and regulated the p53 apoptotic pathway in post-infarction myocardium.

Tubson-2 decoction ameliorates rheumatoid arthritis complicated with osteoporosis in CIA rats involving isochlorogenic acid A regulating IL-17/MAPK pathway.

BACKGROUND: Osteoporosis (OP) is considered as one of the major comorbidities of rheumatoid arthritis (RA), and is responsible for fragility fracture. However, there is currently no effective treatment for RA complicated with OP. Tubson-2 decoction (TBD), a Mongolian medicine also known as Erwei Duzhong Decoction, has been shown to exert a preventive effect on post-menopausal osteoporosis (PMOP). The preventive effects of TBD on RA-induced OP, as well as the bioactive compound responsible and the underlying mechanisms, remain to be elucidated. OBJECTIVE: To explore the effects of TBD on RA-induced OP in vivo, and to elucidate the mechanism of isochlorogenic acid A (ICA), the effective component of TBD, in vitro. METHODS: To evaluate the anti-arthritic and anti-osteoporotic effects of TBD, we conducted H&E straining and safranine O/fast green, TEM, immunohistochemistry (IHC), bone histomorphometry, micro-CT imaging, and biomechanical testing in collagen induced arthritis (CIA) rats. The active ingredient in TBD was identified using network pharmacology and molecular docking. The identification was supported by in vivo IHC assay, and further confirmed using qRT-PCR, Western blot, and SEM analysis in TNF-α-treated MH7A cells and/or in LPS-exposed RAW264.7 cells. RESULTS: Oral administration of TBD attenuated the severity of arthritis and osteopenia as well as poor bone quality, in CIA rats. Additionally, TBD and the positive control, tripterygium glycosides (TG), exhibited similar effects in reducing inflammation in both the synovium and ankle joint. They also were both effective in improving bone loss, microarchitecture, and overall bone quality. TBD reduced the expression of MMP13, IL-17, and p-JNK protein in the synovium of CIA rats. ICA, which was screened, suppressed TNF-α or LPS-triggered inflammatory responses via down-regulating IL-17 signaling, involving in MMP13, IL-1ß, IL-23, and IL-17, and the MAPK pathway including p-ERK, p-JNK, and p-P38, both in MH7A cells and in RAW264.7 cells. Furthermore, ICA prevented osteoclasts from differentiating and bone resoprtion in a dose-dependent manner in vitro. CONCLUSION: This study provides the first evidence that TBD exerts intervening effects on RA-induced OP, possibly through the downregulation of the IL-17/MAPK signaling pathway by ICA. The findings of our study provides valuable insights for further research in this area.

Pinostrobin from plants and propolis against human coronavirus HCoV-OC43 by modulating host AHR/CYP1A1 pathway and lipid metabolism.

Coronaviruses, as enveloped positive-strand RNA viruses, manipulate host lipid compositions to enable robust viral replication. Temporal modulation of the host lipid metabolism is a potential novel strategy against coronaviruses. Here, the dihydroxyflavone pinostrobin (PSB) was identified through bioassay that inhibited the increment of human coronavirus OC43 (HCoV-OC43) in human ileocecal colorectal adenocarcinoma cells. Lipid metabolomic studies showed that PSB interfered with linoleic acid and arachidonic acid metabolism pathways. PSB significantly decreased the level of 12, 13- epoxyoctadecenoic (12, 13-EpOME) and increased the level of prostaglandin E2. Interestingly, exogenous supplement of 12, 13-EpOME in HCoV-OC43-infected cells significantly stimulated HCoV-OC43 virus replication. Transcriptomic analyses showed that PSB is a negative modulator of aryl hydrocarbon receptor (AHR)/cytochrome P450 (CYP) 1A1signaling pathway and its antiviral effects can be counteracted by supplement of FICZ, a well-known AHR agonist. Integrative analyses of metabolomic and transcriptomic indicated that PSB could affect linoleic acid and arachidonic acid metabolism axis through AHR/CYP1A1 pathway. These results highlight the importance of the AHR/CYP1A1 pathway and lipid metabolism in the anti-coronavirus activity of the bioflavonoid PSB.

Molecular and physiological mechanisms of tea (Camellia sinensis (L.) O. Kuntze) leaf and root in response to nitrogen deficiency.

BACKGROUND: As an economically important crop, tea is strongly nitrogen (N)-dependent. However, the physiological and molecular mechanisms underlying the response of N deficiency in tea are not fully understood. Tea cultivar "Chunlv2" [Camellia sinensis (L.) O. Kuntze] were cultured with a nutrient solution with 0 mM [N-deficiency] or 3 mM (Control) NH4NO3 in 6 L pottery pots containing clean river sands. RESULTS: N deficiency significantly decreased N content, dry weight, chlorophyll (Chl) content, L-theanine and the activities of N metabolism-related enzymes, but increased the content of total flavonoids and polyphenols in tea leaves. N deficiency delayed the sprouting time of tea buds. By using the RNA-seq technique and subsequent bioinformatics analysis, 3050 up-regulated and 2688 down-regulated differentially expressed genes (DEGs) were isolated in tea leaves in response to N deficiency. However, only 1025 genes were up-regulated and 744 down-regulated in roots. Gene ontology (GO) term enrichment analysis showed that 205 DEGs in tea leaves were enriched in seven GO terms and 152 DEGs in tea roots were enriched in 11 GO items based on P < 0.05. In tea leaves, most GO-enriched DEGs were involved in chlorophyll a/b binding activities, photosynthetic performance, and transport activities. But most of the DEGs in tea roots were involved in the metabolism of carbohydrates and plant hormones with regard to the GO terms of biological processes. N deficiency significantly increased the expression level of phosphate transporter genes, which indicated that N deficiency might impair phosphorus metabolism in tea leaves. Furthermore, some DEGs, such as probable anion transporter 3 and high-affinity nitrate transporter 2.7, might be of great potential in improving the tolerance of N deficiency in tea plants and further study could work on this area in the future. CONCLUSIONS: Our results indicated N deficiency inhibited the growth of tea plant, which might be due to altered N metabolism and expression levels of DEGs involved in the photosynthetic performance, transport activity and oxidation-reduction processes.

Shen-Qi-Jiang-Tang granule ameliorates diabetic nephropathy via modulating tumor necrosis factor signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Shen-Qi-Jiang-Tang granule (SQJTG), a classic traditional Chinese medicine (TCM) prescription, has been widely used in clinical for diabetes, especially type Ⅱ diabetes. Previous anti-diabetic studies stumbled across that SQJTG has a potential kidney protective effect on diabetic nephropathy (DN). However, the protective mechanism of SQJTG on DN still needs to be explored. AIM OF THE STUDY: The purpose of the present study was to explore the therapeutic effect of SQJTG on DN through both bioinformatics analysis and in vivo experiments. METHODS AND MATERIALS: The TCMIP database was used for screening potential compounds and targets of SQJTG, and the GeneCards, OMIM, DrugBank, and TTD databases were used for collecting DN-related genes. Then protein-protein interaction analysis for the common targets of SQJTG and DN was performed by the STRING database. Meanwhile, KEGG and GO were carried out using the Metascape and DAVID databases. In vivo experiments, to testify the potential kidney protective effects of SQJTG, STZ-induced DN mice with different dosages of SQJTG treatment were collected and the renal tissues were detected by H&E, PAS, Masson and TUNEL staining. Immunohistochemistry and immunoblotting were used to assess the proteins' expressions. Flow cytometry and ELISA assay were used to detect the levels of pro-inflammatory cytokines. RESULTS: Among the 338 compounds ascertained by SQJTG, there were 789 related targets as well. Moreover, 1,221 DN-related targets were predicted and 20 core targets were screened by the PPI analyses. According to GO and KEGG pathway analysis, SQJTG may affect DN via the TNF pathway. For the in vivo experiments, renal histomorphological examinations demonstrated that SQJTG treatment significantly ameliorated STZ-induced kidney damage and had a dosage dependence. Meanwhile, mice with DN were found to have dramatic increases in IL-1, TNF-α, IL-6, and IL-12, but markedly decreased after administration of SQJTG. In addition, the protein levels of TNF signaling molecules, like p-P65, p-JNK, and p-p38, showed significantly elevated in kidney tissues of DN mice and attenuated after SQJTG treatment. CONCLUSIONS: SQJTG exerts a kidney protective effect in DN mice via modulating TNF signaling pathways, and it has promising applications for the treatment of DN.

Active components of Solanum nigrum and their antitumor effects: a literature review.

Cancer poses a serious threat to human health and overall well-being. Conventional cancer treatments predominantly encompass surgical procedures and radiotherapy. Nevertheless, the substantial side effects and the emergence of drug resistance in patients significantly diminish their quality of life and overall prognosis. There is an acute need for innovative, efficient therapeutic agents to address these challenges. Plant-based herbal medicines and their derived compounds offer promising potential for cancer research and treatment due to their numerous advantages. Solanum nigrum (S. nigrum), a traditional Chinese medicine, finds extensive use in clinical settings. The steroidal compounds within S. nigrum, particularly steroidal alkaloids, exhibit robust antitumor properties either independently or when combined with other drugs. Many researchers have delved into unraveling the antitumor mechanisms of the active components present in S. nigrum, yielding notable progress. This literature review provides a comprehensive analysis of the research advancements concerning the active constituents of S. nigrum. Furthermore, it outlines the action mechanisms of select monomeric anticancer ingredients. Overall, the insights derived from this review offer a new perspective on the development of clinical anticancer drugs.

Sanggenon C Suppresses Tumorigenesis of Gastric Cancer by Blocking ERK-Drp1-Mediated Mitochondrial Fission.

Sanggenon C is a flavonoid extracted from the root bark of white mulberry, which is a traditional Chinese medicine with anti-inflammatory, antioxidative, and antitumor pharmacological effects. In this study, sanggenon C was found to inhibit human gastric cancer (GC) cell proliferation and colony formation, induce GC cell cycle arrest in the G0-G1 phase, and promote GC cell apoptosis. Moreover, sanggenon C was found to decrease the level of mitochondrial membrane potential in GC cells and inhibit mitochondrial fission. Mechanistically, RNA sequencing, bioinformatics analysis, and a series of functional analyses confirmed that sanggenon C inhibited mitochondrial fission to induce apoptosis by blocking the extracellular regulated protein kinases (ERK) signaling pathway, and constitutive activation of ERK significantly abrogated these effects. Finally, sanggenon C was found to suppress the growth of tumor xenografts in nude mice without obvious side effects to the vital organs of animals. This study reveals that sanggenon C could be a novel therapeutic strategy for GC treatment.

Multi-target mechanisms against coronaviruses of constituents from Chinese Dagang Tea revealed by experimental and docking studies.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Eurya chinensis（Chinese Dagang Tea）have been consumed as herbal tea for centuries in Guangdong, China, and have also been used to prevent influenza and treat colds and fevers in traditional Chinese medicine. However, there are no reports on the chemical profile and efficacy of its leaves for the treatment of fever and viral infections. MATERIALS AND METHODS: The chemical constituents of Eurya chinensis leaves were isolated and identified by phytochemical study and spectroscopic data, E. chinensis extracts and compounds were evaluated for their antiviral activities by cytopathic effect (CPE) reduction and antibody-based EC50 assay. The antiviral effect of the main component was confirmed by immunofluorescence and transmission electron microscopy. Virtual screening and docking enzyme inhibition experiments were performed to analyze the anti-coronavirus mechanisms of the compounds from E. chinensis leaves. RESULTS: In this study, we found for the first time that E. chinensis leaf extract exhibited inhibitory effects against coronaviruses HCoV-OC43 in vitro. Among 23 monomer compounds isolated from E. chinensis leaf extract, the triterpenoids (betulinic acid, α-amyrin) and the flavonoids (naringenin, eriodictyol and quercetin) showed marked antiviral activity. Microscopic optical analyses further demonstrated that betulinic acid can remove virus particles from HCoV-OC43 infected cells. Virtual screening and docking analysis towards the coronavirus in vogue revealed that betulinic acid was able to bind well to PLpro and Nsp14N7-MTase, and that the flavonoids prefer to bind with PLpro, Nsp3MES, NspP14N7-MTase, Nsp16GTA, and Nsp16SAM. The enzyme inhibition experiments demonstrated that betulinic acid (1) exhibited significant inhibition of PLpro and N7-MTase activity of SARS-CoV-2. CONCLUSION: This study proposes E. chinensis and its triterpenoids and flavonoids as promising potential treatments for coronaviruses.

Icariin attenuates excessive alcohol consumption-induced susceptibility to atrial fibrillation through SIRT3 signaling.

Excessive alcohol consumption has long been identified as a risk factor for adverse atrial remodeling and atrial fibrillation (AF). Icariin is a principal active component from traditional Chinese medicine Herba Epimedii and has been demonstrated to exert potential antiarrhythmic effect. The present study was designed to evaluate the effect of icariin against alcohol-induced atrial remodeling and disruption of mitochondrial dynamics and furthermore, to elucidate the underlying mechanisms. Excessive alcohol-treated C57BL/6 J mice were infected with serotype 9 adeno-associated virus (AAV9) carrying mouse SIRT3 gene or negative control virus. Meanwhile, icariin (50 mg/kg/d) was administered to the animals in the presence or absence of AAV9 carrying SIRT3 shRNA. We noted that 8 weeks of icariin treatment effectively attenuated alcohol consumption-induced atrial structural and electrical remodeling as evidenced by reduced AF inducibility and reversed atrial electrical conduction pattern as well as atrial enlargement. Furthermore, icariin-treated group exhibited significantly enhanced atrial SIRT3-AMPK signaling, decreased atrial mitoSOX fluorescence and mitochondrial fission markers, elevated mitochondrial fusion markers (MFN1, MFN2) as well as NRF-1-Tfam-mediated mitochondrial biogenesis. Importantly, these beneficial effects were mimicked by SIRT3 overexpression while abolished by SIRT3 knockdown. These data revealed that targeting atrial SIRT3-AMPK signaling and preserving mitochondrial dynamics might serve as the novel therapeutic strategy against alcohol-induced AF genesis. Additionally, icariin ameliorated atrial remodeling and mitochondrial dysfunction by activating SIRT3-AMPK signaling, highlighting the use of icariin as a promising antiarrhythmic agent in this circumstance.

Paeoniflorin Regulates NEDD4L/STAT3 Pathway to Induce Ferroptosis in Human Glioma Cells.

Background: Paeoniflorin is an active component of a widely used traditional Chinese medicine with antitumor activity through ferroptosis induction. It has been reported recently that ferroptosis is emerging in certain types of cancer; however, its relevance in glioma is still not well studied. Methods: CCK8 assay was performed for cell proliferation. Expression of mRNA and protein was tested by qPCR and western blot, respectively. Clinical section samples were detected by IHC. The relationship between NEDD4L and STAT3 was validated by a coimmunoprecipitation assay. Apoptosis was identified by TUNEL assay. A xenograft mouse model was utilized to validate the potential of paeoniflorin toward glioma cancer cells. Results: The data suggested that paeoniflorin could increase NEDD4L expression in glioma cells. The NEDD4L expression level was lower in glioma cancer tissues compared to adjacent normal tissues, and it correlates with poor prognosis. Meanwhile, NEDD4L mediates the ubiquitination of STAT3. Furthermore, increased NEDD4L significantly inhibited cell viability and induced accumulation of intracellular ROS levels, accompanied by decreased expression of key ferroptosis factors Nrl2 and GPX4, while NEDD4L knockdown had a reverse effect, suggesting that ferroptosis could be involved. NEDD4L-induced ferroptosis could be rescued by forced expression of STAT3. A xenograft nude mouse model showed that paeoniflorin inhibits tumor growth and further sensitizes glioma cells to RSL3, another well-known ferroptosis inducer. Conclusions: In summary, this study demonstrated that paeoniflorin might function as an effective drug for glioma by inducing ferroptosis via upregulation of NEDD4L and repression of Nrl2, GPX4, and STAT3.

Activation of PKG-CREB-KLF15 by melatonin attenuates Angiotensin II-induced vulnerability to atrial fibrillation via enhancing branched-chain amino acids catabolism.

Mitochondrial reactive oxygen species (ROS) damage and atrial remodeling serve as the crucial substrates for the genesis of atrial fibrillation (AF). Branched-chain amino acids (BCAAs) catabolic defect plays critical roles in multiple cardiovascular diseases. However, the alteration of atrial BCAA catabolism and its role in AF remain largely unknown. This study aimed to explore the role of BCAA catabolism in the pathogenesis of AF and to further evaluate the therapeutic effect of melatonin with a focus on protein kinase G (PKG)-cAMP response element binding protein (CREB)-Krüppel-like factor 15 (KLF15) signaling. We found that angiotensin II-treated atria exhibited significantly elevated BCAA level, reduced BCAA catabolic enzyme activity, increased AF vulnerability, aggravated atrial electrical and structural remodeling, and enhanced mitochondrial ROS damage. These deleterious effects were attenuated by melatonin co-administration while exacerbated by BCAA oral supplementation. Melatonin treatment ameliorated BCAA-induced atrial damage and reversed BCAA-induced down-regulation of atrial PKGIα expression, CREB phosphorylation as well as KLF15 expression. However, inhibition of PKG partly abolished melatonin-induced beneficial actions. In summary, these data demonstrated that atrial BCAA catabolic defect contributed to the pathogenesis of AF by aggravating tissue fibrosis and mitochondrial ROS damage. Melatonin treatment ameliorated Ang II-induced atrial structural as well as electrical remodeling by activating PKG-CREB-KLF15. The present study reveals additional mechanisms contributing to AF genesis and highlights the opportunity of a novel therapy for AF by targeting BCAA catabolism. Melatonin may serve as a potential therapeutic agent for AF intervention.

The GC-TOF/MS-based Metabolomic analysis reveals altered metabolic profiles in nitrogen-deficient leaves and roots of tea plants (Camellia sinensis).

BACKGROUND: Nitrogen (N) fertilizer is commonly considered as one of the most important limiting factors in the agricultural production. As a result, a large amount of N fertilizer is used to improve the yield in modern tea production. Unfortunately, the large amount of N fertilizer input has led to increased plant nitrogen-tolerance and decreased amplitude of yield improvement, which results in significant N loss, energy waste and environment pollution. However, the effects of N-deficiency on the metabolic profiles of tea leaves and roots are not well understood. RESULTS: In this study, seedlings of Camellia sinensis (L.) O. Kuntze Chunlv 2 were treated with 3 mM NH4NO3 (Control) or without NH4NO3 (N-deficiency) for 4 months by sandy culture. The results suggested that N-deficiency induced tea leaf chlorosis, impaired biomass accumulation, decreased the leaf chlorophyll content and N absorption when they were compared to the Control samples. The untargeted metabolomics based on GC-TOF/MS approach revealed a discrimination of the metabolic profiles between N-deficient tea leaves and roots. The identification and classification of the altered metabolites indicated that N deficiency upregulated the relative abundances of most phenylpropanoids and organic acids, while downregulated the relative abundances of most amino acids in tea leaves. Differentially, N-deficiency induced the accumulation of most carbohydrates, organic acids and amino acids in tea roots. The potential biomarkers screened in N-deficient leaves compared to Control implied that N deficiency might reduce the tea quality. Unlike the N-deficient leaves, the potential biomarkers in N-deficient roots indicated an improved stress response might occur in tea roots. CONCLUSIONS: The results demonstrated N deficiency had different effects on the primary and secondary metabolism in tea leaves and roots. The findings of this study will facilitate a comprehensive understanding of the N-deficient tea plants and provide a valuable reference for the optimized N nutrient management and the sustainable development in the tea plantations.