Phytotherapy Research最新文献

Oxyberberine (OBB), a natural metabolite of berberine, has been shown to exhibit inhibitory effects on gluconeogenesis in our previous work. This work was designed to investigate the potential effects and underlying mechanisms of OBB on hepatic gluconeogenesis. Our work found that OBB significantly inhibited the expressions of glucose 6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), and decreased the glucose production in palmitic acid-induced HepG2 cells. Then, AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways were confirmed by transcriptomics and network pharmacology analyses. It was shown that AMPK activation may phosphorylate and promote nuclear exclusion of FoxO1 and CRTC2, two key regulators of hepatic gluconeogenesis transcriptional pathways, resulting in the inhibition of gluconeogenesis under OBB administration. Afterwards, AMPK/Akt/FoxO1, AMPK/CRTC2 signaling pathways were evidenced by western blot, immunoprecipitation and confocal immunofluorescence, and the targeted inhibitor (Compound C) and siRNA of AMPK were applied for further mechanism verification. Moreover, it was found that OBB treatment activated AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways to decrease hepatic gluconeogenesis in db/db mice. Similarly, the in vivo inhibitory effects of OBB on gluconeogenesis were also diminished by AMPK inhibition. Our work demonstrated that OBB can inhibit hepatic gluconeogenesis in vitro and in vivo, and its underlying mechanisms were associated with AMPK-mediated suppression of FoxO1 and CRTC2 signaling axes.

Insulin resistance (IR) is a central pathophysiological process underlying numerous chronic metabolic disorders, including type 2 diabetes and obesity. Lycii Cortex, a widely used traditional Chinese herb, has demonstrated potential benefits in preventing and managing diabetes and IR. Whereas, the specific bioactive compounds responsible for these protective effects and their underlying mechanisms of action remain elusive. This study aimed to identify the bioactive components within Lycii Cortex that contribute to its anti-diabetic effects and to elucidate the molecular mechanisms underlying its beneficial actions on insulin resistance. Network pharmacology and molecular docking analyses were employed to identify the potential active compounds in Lycii Cortex and their corresponding target proteins. An in vitro model of IR was established using palmitic acid (PA)-treated HepG2 cells. Cell viability was assessed using the CCK-8 assay, while glucose uptake was evaluated by 2-NBDG staining and extracellular glucose measurement. To validate the in vitro findings, an in vivo model of obesity-induced IR was established using high-fat diet (HFD)-fed mice. The network pharmacology analysis preliminarily identified 13 candidate chemicals and 10 hub LyC and IR-related genes (LIRRGs). Molecular docking analysis demonstrates that Linarin as the potential active component exhibits the greatest potential to target c-FOS for preventing obesity-induced IR. Enrichment analysis suggested that Linarin-targeted pathways are correlated with inflammation. In vitro experimental validation demonstrated that Linarin was capable of protecting against PA-induced IR in HepG2 cells evidenced by improving glucose uptake ability and reducing extracellular glucose content. Additionally, we found that Linarin ablated PA-induced increase in the expression of c-FOS and inflammatory cytokines. Furthermore, in PA-treated cells, silencing c-FOS markedly improved glucose consumption, and reduced inflammation and Arginase 2 (ARG2) expression. Similarly, as exposure to PA, silencing ARG2 also ameliorated glucose uptake and inflammation, while not affecting c-FOS expression. In vivo experiments further showed that Linarin administration remarkably improved glucose tolerance and insulin sensitivity, and reduced the fat mass and body weight in HFD-induced obese mice. In this study, Linarin has been identified as the bioactive compound of Lycii Cortex to ameliorate obesity-related IR and inflammation through the c-FOS/ARG2 signaling cascade. These findings underscore the therapeutic potential of Linarin and provide valuable insights into developing novel intervention strategies for type 2 diabetes therapy.

The current dearth of safe and efficacious pharmaceutical interventions for pulmonary fibrosis (PF) has prompted investigations into alternative treatments. This study aim to investigate the underlying mechanisms of Tanshinone IIA in the treatment of PF. PF was induced in a mouse model by intratracheal infusion of bleomycin (BLM), followed by gavage administration of varying concentrations of Tanshinone IIA. Lung tissue was obtained for pathological slides, proteomic and transcriptomic analyses. The target was predicted and analyzed using network pharmacology. Initially, an in vitro model in A549 cells was established by adding BLM, followed by treatment with varying concentrations of Tanshinone IIA. Subsequently, NAC and the ERK inhibitor, U0126, were individually introduced. Treatment with Tanshinone IIA in vivo decreased lung tissue lesions. Proteomic, transcriptomic, and network pharmacology analyses suggested that Tanshinone IIA may offer therapeutic benefits for PF by mitigating oxidative stress damage via the MAPK signaling pathway. In vitro studies demonstrated that BLM treatment in A549 cells induced exposure of the N-terminal end of the pyroptosis core protein GSDMD, and elevated oxidative stress levels in A549 cells, concomitant with the upregulation of P-ERK protein expression. Subsequent administration of Tanshinone IIA, NAC, and U0126 reduced the number of A549 cells undergoing pyroptosis, decreased oxidative stress levels, and decreased P-ERK protein expression. These findings suggested that Tanshinone IIA potentially delays the progression of PF. The mechanism of action involves the inhibition of oxidative stress and reduced epithelial cell pyroptosis via the MAPK-related pathway. The findings may provide a new reference for treatment of PF.

Inflammation is an essential step for the etiology of multiple diseases. Clinically, due to the limitations of current drugs for the treatment of inflammatory diseases, such as serious side effects and expensive costs, it is urgent to explore novel mechanisms and medicines. Natural products have received extensive attention recently because of their multi-component and multi-target characteristics. Epigenetic modifications are crucial pathophysiological targets for developing innovative therapies for pharmacological interventions. Investigations examining how natural products improving inflammation through epigenetic modifications are emerging. This review state that natural products relieve inflammation via regulating the gene transcription levels through chromosome structure regulated by histone acetylation levels and the addition or deletion of methyl groups on DNA duplex. They could also exert anti-inflammatory effects by modulating the proteins in typical inflammatory signaling pathways by ubiquitin-related degradation and the effect of glycolysis derived free glycosyls. Studies on epigenetic modifications have the potential to facilitate the development of natural products as therapeutic agents. Future research directed at better understanding of how natural products modulate inflammatory processes through less studied epigenetic modifications including neddylation, SUMOylation, palmitoylation and lactylation, may provide new implications. Meanwhile, higher quality preclinical studies and more powerful clinical evidence are still needed to firmly establish the clinical efficacy of the natural products. Trial Registration: ClinicalTrials.gov Identifier: NCT01764204; ClinicalTrials.gov Identifier: NCT05845931; ClinicalTrials.gov Identifier: NCT04657926; ClinicalTrials.gov Identifier: NCT02330276.

Degenerative bone and joint diseases (DBJDs), characterized by osteoporosis, osteoarthritis, and chronic inflammation of surrounding soft tissues, are systemic conditions primarily affecting the skeletal system. Ferroptosis, a programmed cell death pathway distinct from apoptosis, autophagy, and necroptosis. Accumulating evidence suggests that ferroptosis is intricately linked to the pathogenesis of DBJDs, and targeting its regulation could be beneficial in managing these conditions. Natural products, known for their anti-inflammatory and antioxidant properties, have shown unique advantages in preventing DBJDs, potentially through modulating ferroptosis. This article provides an overview of the latest research on ferroptosis, with a focus on its role in the pathogenesis of DBJDs and the therapeutic potential of natural products targeting this cell death pathway, offering novel insights for the prevention and treatment of DBJDs.

The increasing use of red yeast rice (RYR) as a natural supplement to manage blood cholesterol levels is driven by its active compound, monacolin K (MK), which is chemically identical to the statin drug lovastatin (LOV). Despite its growing popularity, concerns persists regarding the safety and efficacy of RYR compared to pure statins. This study aimed to evaluate the phytochemical composition, pharmacological effects, and safety profile of various RYR samples in comparison with LOV. RYR samples with different MK content were analyzed using HPLC-DAD to quantify monacolins and other bioactive compounds. The inhibitory activity on HMG-CoA reductase was assessed through an enzymatic assay, while pharmacokinetic properties were predicted using in vitro simulated digestion and in silico models. In vitro cytotoxicity was evaluated in intestinal, hepatic, renal, and skeletal muscle cell models. Additionally, the transcriptional levels of muscle damage-related target genes were evaluated by qRT-PCR in skeletal muscle cells treated with a selection of RYR samples. Significant variability in the phytochemical composition of RYR samples was observed, particularly in the content of secondary monacolins, triterpenes, and polyphenols. The RYR phytocomplex exhibited superior inhibition of HMG-CoA reductase activity compared to isolated LOV, suggesting synergistic effects between secondary monacolins and other compounds. Molecular insights revealed that RYR samples had a lower impact on muscle cells than LOV, as reflected also by cell viability. These findings suggest that RYR could serve as a safe alternative to purified statins. However, further research is needed to fully elucidate the mechanisms behind the synergistic activity of the phytocomplex and to firmly establish the clinical efficacy of this natural product.

Tetrandrine (TET) is a minimally toxic drug extracted from the root of Stephania tetrandra. We previously demonstrated that TET could ameliorate pulmonary fibrosis (PF) by modulating autophagy. However, the mechanism behind TET's protective effects on PF remains unclear. In this study, we utilized 16S rRNA gene sequencing, nontargeted metabolomic analysis, and network pharmacology to identify changes in lung microbiota and metabolites that mediate alveolar epithelial cell senescence in bleomycin (BLM)-induced PF in mice. Additionally, we employed Western blot analysis, RT-PCR, and immunofluorescence staining to investigate the in vitro and in vivo effects of TET and its influential bacterial metabolites on PF. The TET intervention alleviated PF by regulating the compositions of lung microbial communities (Streptococcus, Micrococcus, Acinetobacter, Altererythrobacter, Atopostipes, Candidatus Cloacimonas, Clostridium sensu stricto 1, Sphingomonas, Listeria, Blautia, and Pseudomonas) and metabolites (3,4-dihydroxyphenylpropionic acid (3,4-DHPPA), 6-Aminonicotinamide, N-acetyl-5-methoxykynuramine, and resiniferatoxin). Through network pharmacological analysis, it was determined that 3,4-DHPPA played a crucial role in alleviating PF by further inhibiting the senescence of alveolar epithelial cells, a finding further validated in ex vivo experiments. TET mitigated BLM-induced PF in murine models through the modulation of lung microbiota composition and metabolism. Specifically, TET augmented the level of the microbiota-derived metabolite, 3,4-DHPPA, which in turn attenuated alveolar epithelial cell senescence.

Cannabidiolic (CBDA) and cannabigerolic (CBGA) acids are naturally occurring compounds from Cannabis sativa plant, previously identified by us as dual PPARα/γ agonists. Since the development of multitarget-directed ligands (MTDL) represents a valuable strategy to alleviate and slow down the progression of multifactorial diseases, we evaluated the potential ability of CBDA and CBGA to also inhibit enzymes involved in the modulation of the cholinergic tone and/or β-amyloid production. A multidisciplinary approach based on computational and biochemical studies was pursued on selected enzymes, followed by behavioral and electrophysiological experiments in an AD mouse model. The β-arrestin assay on GPR109A and qPCR on TRPM7 were also carried out. CBDA and CBGA are effective on both acetyl- and butyryl-cholinesterases (AChE/BuChE), as well as on β-secretase-1 (BACE-1) enzymes in a low micromolar range, and they also prevent aggregation of β-amyloid fibrils. Computational studies provided a rationale for the competitive (AChE) vs. noncompetitive (BuChE) inhibitory profile of the two ligands. The repeated treatment with CBDA and CBGA (10 mg/kg, i.p.) improved the cognitive deficit induced by the β-amyloid peptide. A recovery of the long-term potentiation in the hippocampus was observed, where the treatment with CBGA and CBDA also restored the physiological expression level of TRPM7, a receptor channel involved in neurodegenerative diseases. We also showed that these compounds do not stimulate GPR109A in β-arrestin assay. Collectively, these data broaden the pharmacological profile of CBDA and CBGA and suggest their potential use as novel anti-AD MTDLs.

Lung cancer is a major cause of cancer-related mortality, and radiotherapy is often limited by tumor resistance and side effects. This study explores whether epoxymicheliolide (ECL), a compound from feverfew, can enhance radiotherapy efficacy in lung cancer. We tested ECL on A549 and PC-9 lung cancer cell lines to evaluate its effect on x-ray irradiation. We measured apoptosis, NF-κB pathway inhibition, TGF-β secretion reduction, and epithelial-mesenchymal transition suppression. In vivo, C57BL/6 mice with lung tumors received ECL and radiotherapy. ECL enhanced the antiproliferative effects of x-ray irradiation, induced apoptosis in senescent cells, inhibited the NF-κB pathway, reduced TGF-β levels, and suppressed epithelial-mesenchymal transition. ECL also inhibited tumor growth and improved survival in mice. ECL is a promising adjunct to radiotherapy for lung cancer, improving treatment outcomes by targeting multiple tumor progression mechanisms. It offers potential for enhanced management of lung cancer.