Phytomedicine最新文献

Background: Pimpinellin is a phenylpropanoid compound involved in various physiological and pathological processes in the body. The specific impact of pimpinellin on ulcerative colitis (UC) remains uncertain. Research on pimpinellin by using a dextran sulfate sodium (DSS)-induced UC model can lay the groundwork for future drug screening and various treatment approaches for UC.

Purpose and methods: This research focused on investigating the effects and mechanisms of pimpinellin on DSS-induced UC in mice.

Results: The findings indicated that pimpinellin mitigated DSS-induced shortening of the colon and intestinal barrier damage and notably lowered inflammatory cytokine levels. Mechanistic analysis revealed that pimpinellin boosted the protein expression of intestinal barrier proteins by inhibiting the MAPK/NF-κB signaling pathway. Additionally, pimpinellin enhanced the levels of beneficial gut probiotics (S24-7 and Lactobacillaceae) while reducing the presence of harmful bacteria (Enterobacteriaceae). Further studies indicated that administering 100 mg/kg pimpinellin could significantly alleviate UC by modulating the gut microbiota.

Conclusion: In summary, timely use of pimpinellin can alleviate DSS-induced UC by reducing inflammation, maintaining intestinal barrier integrity, and adjusting gut microbiota. This research broadens the potential pharmaceutical applications of pimpinellin.

Background: Artemisia argyi is a well-known medicinal plant. A. argyi has been widely used in clinical for about 3000 years, owing to its extensive pharmacological activity. Among these, its anti-cancer properties are the most reported activity. However, its pharmacodynamic compounds remain unknown.

Purpose: This study aimed to investigate the potential anti-cancer compounds in A. argyi and reveal its molecular mechanisms and targets.

Methods: Firstly, A. argyi were extracted with 70 % ethanol, yielding A. argyi EtOH (AAE) crude extracts. AAE was extracted with Ethyl acetate and Butanol successively to yield A. argyi EtOAc (AAEA) and A. argyi Butanol (AAB) sub-fraction. And, AAE, AAEA, and AAB were prepared to assess their anti-cancer ability in vitro and in vivo. Then, the natural products were isolated from active sub-fraction via activity-oriented separation and identification. Meanwhile, all the compounds were evaluated the anti-cancer effect. The anti-proliferation mechanism of representative compounds was explored, based on programmed cell death. Moreover, 4D-data-independent (DIA) quantitative proteomic studies were performed to reveal the underlying targets and mechanism of representative compounds. Finally, the pharmacodynamic compound and key target interaction were identified by the evaluation of targets function, molecular docking, surface plasmon resonance (SPR) assay, and small interfering RNA. In addition, the toxicity of pharmacodynamic compounds were evaluated by in vitro and zebrafish model in vivo.

Results: AAEA demonstrated stronger inhibitory effects than AAB on various cancer cell lines in vitro. And, AAEA sub-fraction effectively inhibited the tumor growth in vitro and in vivo. Subsequently, we isolated and identified 47 anti-cancer components from AAEA, especially 23 of which were isolated from A. argyi for the first time. Among them, 8 sesquiterpenes compounds showed strong anti-cancer activity. Moreover, compound 3 (moxartenolide) exhibited stronger induction of apoptosis and ferroptosis. Ultimately, a series of studies based on proteomics revealed that Moxartenolide inhibited cancer cell proliferation through the key enzyme NDUFA4. In addition, toxicological evaluation in vivo and in vitro demonstrated the safety of the candidate drug.

Conclusion: These findings reveal the anti-cancer components of A. argyi based on activity-oriented separation and identification for the first time. Specially, Compound 3 (moxartenolide) inhibited cancer proliferation by inducing apoptosis and ferroptosis via key cell metabolism enzyme NDUFA4. Briefly, it suggests that A. argyi has the potential of anti-cancer drug development.

Background: Changan Granule (CAG) is a drug product developed from a traditional Chinese medicine (TCM) empirical prescription for diarrhea-predominant irritable bowel syndrome (IBS-D). The action mechanism and effective compounds of CAG in the treatment of IBS-D are not well understood.

Purpose: This study aimed to investigate the effectiveness, action mechanism and effective compounds of CAG for treating IBS-D.

Methods: Network pharmacology was used to screen the related pathways and active compounds of CAG in the treatment of IBS-D. Neonatal mother-infant separation, acetic acid enema and colorectal dilation were employed to construct IBS-D model for in vivo study. The effectiveness of CAG was evaluated in accordance with the results of body weight measurement, fecal water content determination, abdominal withdraw reflex test, open field test, sucrose preference test, forced swimming test and hematoxylin-eosin (HE) staining. The protein and mRNA levels of key molecules regulated by CAG were assessed through enzyme-linked immunosorbent assay (ELISA), western blotting, and reverse transcription quantitative polymerase chain reaction (RT-qPCR). The active compounds from CAG screened by network pharmacology were investigated with Caco-2 and RIN-14B cell models in vitro.

Results: Network pharmacological analysis showed that CAG regulated 5-hydroxytryptamine (5-HT) signaling pathway and tetrahydropalmatine, formononetin and corydaline might be the potential effective compounds. The validation experiments showed that CAG restored the decreased body weight, and alleviated intestinal sensitivity, low-grade inflammation, diarrhea, frequent defecation, anxiety and depression of IBS-D rats through regulating the expression levels of 5-HT, tryptophan hydroxylase (TPH)1/2, serotonin transporter (SERT), 5-hydroxytryptamine-3 and -4 receptors (5-HT₃R and 5-HT₄R) in brain-gut axis (BGA). Tetrahydropalmatine and formononetin were confirmed to be the potential effective compounds of CAG in regulating 5-HT signaling pathway.

Conclusion: CAG exhibits therapeutic effect on IBS-D rats through regulating 5-HT signaling pathway in BGA. Tetrahydropalmatine and formononetin are major potential effective compounds. Our findings provide scientific basis for the clinical use and drug development of CAG for IBS-D.

Background: Sarcopenia is currently a life-threatening disease for the elderly. Polygonatum sibiricum polysaccharide (PSP) has anti-oxidative stress and anti-inflammatory effects. However, the effects of PSP on skeletal muscle aging, myoblast differentiation and mitochondrial dysfunction through PI3K/Akt/mTOR signaling pathway has not been explored.

Purpose: To explore the effects and related mechanisms of PSP on muscle aging, myoblast differentiation and mitochondrial dysfunction.

Methods: The chemical components of Polygonatum sibiricum were determined using the UHPLC-MS/MS method. The common targets and biological pathways between PSP and sarcopenia were investigated by network pharmacology analysis. In vitro C2C12 cells experiments were performed to reveal the effects of PSP on muscle aging, myotube differentiation, and mitochondrial damage. In addition, in vivo experiments were designed with the mouse model of D-gal-induced aging to evaluate the ameliorative impact of PSP on the skeletal muscle mass and function.

Results: Polygonatum sibiricum mainly included 466 bioactive components. Polygonatum sibiricum and sarcopenia had 278 common targets by network pharmacology analysis, which were associated with mitochondrial function and PI3K/Akt/mTOR pathway. In vitro experiment indicated that PSP significantly enhanced the viability of C2C12 cells and myotube differentiation by down-regulating p21, p53, p16, MuRF1 and Atrogin-1and up-regulating MyoD, Myogenin, and MyHC. However, the addition of LY294002, PI3K/Akt/mTOR pathway inhibitor, partially reversed the anti-aging and anti-oxidative stress effects of PSP. PSP also significantly improved mitochondrial membrane potential and decreased mitochondrial ROS levels by upregulating the phosphorylation of the PI3K/Akt/mTOR pathway. In vivo experimental data indicated that PSP significantly enhanced muscle strength, endurance, mass of skeletal muscle (quadriceps and gastrocnemius) and cross-sectional area (CSA) of skeletal muscle in D-gal induced aging mice.

Conclusion: PSP exhibits significant ameliorative effects on skeletal muscle aging and atrophy, as well as mitochondrial dysfunction by activating the PI3K/Akt/mTOR signaling pathway. Our study uniquely investigates the effects of PSP on skeletal muscle aging and mitochondrial dysfunction with a specific focus on the PI3K/Akt/mTOR signaling pathway, which highlights the potential of PSP as a novel therapeutic agent for sarcopenia, offering an alternative to current treatment strategies.

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) has a high incidence and mortality rate, representing a significant patient burden. Therefore, treatment strategies that work synergistically with hypothermic therapies are urgently required. Punicalagin (PUN) is a natural and safe polyphenol with anti-inflammatory functions whose excellent water solubility and safety make it an advantageous perinatal medication. However, its underlying mechanisms of action in HIE remain unclear.

Objectives: This study investigated the role and associated mechanism of action PUN in HIE.

Methods: We used the Rice Vannucci method to construct an in vivo HIE model in rats, from which we extracted primary cortical neurons to construct an in vitro oxygen and glucose deprivation/reoxygenation (OGD/R) model. The mechanisms of action of PUN were investigated using transcriptome sequencing, laser speckle contrast imaging, 2,3,5-triphenyltetrazolium chloride-staining, the Morris water maze test, western blotting, qPCR, immunofluorescence, and histochemistry.

Results: HIE rats demonstrated excessive autophagy and inflammation. PUN reduced brain tissue damage and neuronal apoptosis, and improved cerebral blood flow perfusion, learning, and cognitive abilities. PUN attenuated autophagic overexpression following HIE and inhibited the AKT-FOXO4 (forkhead box O4) signaling pathway. The neuroprotective effects of PUN were inhibited by treatment with the AKT signaling pathway and autophagy inhibitor 3-MA. Furthermore, brain tissue damage was significant and PUN was ineffective in siFOXO4 rats.

Conclusions: PUN significantly reduces cerebral infarction, neuroinflammation, and excessive autophagy caused by HIE, thereby exerting short- and long-term neuroprotective effects. Mechanistically, the neuroprotective effect of PUN is mediated by activation of the AKT-FOXO4 pathway. Therefore, PUN may be a potential therapy for HIE.

Background and purpose: Metabolic dysfunction-associated steatohepatitis (MASH) is an inflammatory lipotoxic disorder marked by hepatic steatosis, hepatocyte damage, inflammation, and varying stages of fibrosis. Sappanone A (SA), a flavonoid, exhibits anti-inflammatory and hepatoprotection activities. Nevertheless, the effects of SA on MASH remain ambiguous. We evaluated the effects of SA on hepatocyte lipotoxicity, inflammation, and fibrosis conditions in MASH mice, as well as the underlying mechanisms.

Methods: A conventional murine MASH model fed a methionine-choline-deficient (MCD) diet was utilized to assess the role of SA on MASH in vivo. Drug target prediction and liver transcriptomics were employed to elucidate the potential actions of SA. AML12 cells were applied to further explore the effects and mechanisms of SA in vitro.

Results: The in silico prediction indicated that SA could modulate inflammation, insulin resistance, lipid metabolism, and collagen catabolic process. Treating with SA dose-dependently lessened the elevated levels of serum ALT and AST in mice with diet-triggered MASH, and high-dose SA treatment exhibited a similar effect to silymarin. Additionally, SA treatment significantly reduced lipid deposition, inflammation, and fibrosis subjected to metabolic stress in a dose-dependent manner. Besides, SA mitigated palmitate-triggered lipotoxicity in hepatocytes. Liver transcriptomics further confirmed the aforementioned findings. Of note, mRNA-sequencing analysis and molecular biology experiments demonstrated that SA statistically up-regulated the hepatic expression of major urinary protein 3 (Mup3), thereby facilitating lipid transportation and inhibiting lipotoxicity. Furthermore, Mup3 knockdown in hepatocytes significantly abolished the hepatoprotection provided by SA.

Conclusion: SA alleviates MASH by decreasing lipid accumulation and lipotoxicity in hepatocytes, at least partially by targeting Mup3, and subsequently blocks MASH process. Therefore, SA could be a promising hepatoprotective agent in the context of MASH.

Background: The safety and efficacy of herbal medicines including traditional Chinese medicine (TCM) has been one of the major scientific problems in the medical field. In TCM prescriptions, reasonable herbal combinations bring stronger efficacy and low risk of toxicity. However, the rules and mechanisms for herbal combinations are far from complete understood yet.

Purpose: In this study, we investigated the efficacy-toxicity transformation of the licorice-kansui herbal combination under clinical equivalent doses, and study the inside mechanisms.

Study design: Licorice-kansui or glycyrrhetinic acid-kansuinine A combinations of different combining ratio were given to malignant pleural effusion mice as well as the IEC-6 and S-180 cells.

Methods: The therapeutic and toxic effects were characterized by various indicators; the chemical changes were analyzed by LC-MS method; the role of H₂S was also studied through its inhibitors.

Results: Low-proportion of licorice combined with kansui exerted comparable therapeutic effects to cisplatin, by reducing pleural effusion, promoting respiration, increasing urine volume, protecting lung tissue, and inhibiting tumor cells by inducing oxidative stress and apoptosis. On the other hand, high-proportion of licorice combined with kansui had poor therapeutic effect but induced oxidative stress, inflammation and tissue damages, especially to the small intestine. This efficacy-toxicity transformation was also reproduced by the glycyrrhetinic acid-kansuinine A combination on IEC-6 epithelial cells and S-180 tumor cells. The transformation was not simply caused by the in-solution solubilization effects of licorice during co-decocted with kansui. Furthermore, the therapeutic and toxic effects were both highly related to the hydrogen sulfide level and its anabolic enzymes, cystathionine-gamma-lyase (CSE) or cystathionine beta-synthase (CBS), either in tissues or in-vitro cells. By inhibiting CSE or CBS, all the therapeutic or toxic effects were abolished both in-vivo and in-vitro. Moreover, the intestinal sulfide-reducing bacteria Desulfovibrio and body drug-metabolism were also important variants influencing the efficacy-toxicity transformation of licorice-kansui herbal combination.

Conclusion: This study comprehensively uncovered the rules of licorice-kansui herbal combination, and for the first time confirmed that H₂S plays a crucial role in mediating its efficacy-toxicity transformation. Our study not only supports the reasonable clinical usage of these two herbs but also provide ideas and methods for the study of other herb pairs in TCM prescriptions.

Background: Macrophage-myofibroblast transition (MMT) plays a significant role in the progression of renal fibrosis in chronic kidney disease (CKD), making inhibition of MMT a promising therapeutic strategy. Pyruvate kinase M2 (PKM2) and its metabolite lactate are implicated in the pathogenesis of renal fibrosis; however, the mechanisms through which they contribute to this process remain poorly understood.

Purpose: To investigate the effects of PKM2 inhibition by shikonin on renal fibrosis and the underly mechanisms.

Methods: Mice were subjected to unilateral ureteral obstruction (UUO) to establish a CKD model. Renal fibrosis was assessed using histochemistry and western blotting. The MMT and histone lactylation levels were evaluated by immunofluorescence and western blotting. The interaction between the Tgfb1 promoter and lactylated histone H3 (K18) was examined using chromatin Immunoprecipitation (ChIP).

Results: PKM2 expression was significantly elevated in the renal tubular cells of UUO mouse kidneys, resulting in increased pyruvate and lactate production. Similarly, lactate levels were elevated in TGF-β1-treated TCMK-1 cells and in the serum of CKD patients. In UUO mice, treatment with shikonin, a potent PKM2 inhibitor, effectively reduced lactate production, alleviated renal fibrosis, decreased TGF-β1 expression, and suppressed the MMT process. Mechanistic studies revealed that lactate treatment stimulates Tgfb1 expression in TCMK-1 cells. Consequently, TGF-β1 in conditioned media from lactate-treated TCMK-1 cells promoted M2 macrophage polarization and upregulated fibrotic gene expression in RAW264.7 cells. Pharmacological intervention demonstrated that TGF-β1 activates the Smad3 pathway to drive the MMT process. In TCMK-1 cells, both lactate treatment and PKM2 overexpression induced Tgfb1 expression by promoting histone H3K18 lactylation.

Conclusions: Our findings indicate that PKM2-induced excessive lactate production renal tubular cells contributes to renal fibrosis. Lactate promotes histone lactylation, leading to TGF-β1 expression in these cells, which subsequently activates the Smad3 pathway in macrophages, driving the MMT and fibrosis in the kidney. Therefore, targeting PKM2, as with shikonin treatment, may represent an effective therapeutic strategy for managing renal fibrosis in CKD.