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Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated death. Emerging evidence suggests that autophagy plays a critical role in HCC tumorigenesis, metastasis, and prognosis. Choline is an essential nutrient related to prolonged survival and reduced risk of HCC. However, it remains unclear whether this phenomenon is mediated by autophagy. Methods: Two HCC cell lines (HUH-7 and Hep3B) were used in the present study. Cell growth was evaluated by cell counting kit 8 (CCK-8), colony formation, and in vivo mouse xenografts assays. Cell motility was calculated by wound healing and transwell assays. Autophagosomes were measured by transmission electron microscope (TEM), and autophagy flux was detected by mRFP-GFP-labeled LC3 protein. The mRNA level of genes was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels were detected by Western blotting (WB). Results: We found that choline inhibited the proliferation, migration, and invasion of HCC cells by downregulating autophagy in vitro and in vivo. Upregulated expression of the solute carrier family 5 member 7 (SLC5A7), a specific choline transporter, correlated with better HCC prognosis. We further discovered that choline could promote SLC5A7 expression, upregulate cytoplasm p53 expression to impair the AMPK/mTOR pathway, and attenuate autophagy. Finally, we found that choline acted synergistically with sorafenib to attenuate HCC development in vitro and in vivo. Conclusions: Our findings provide novel insights into choline-mediated autophagy in HCC, providing the foothold for its future application in HCC treatment.
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PURPOSE: Bone metastasis is a significant contributor to morbidity and mortality in advanced prostate cancer, and early diagnosis is challenging due to its insidious onset. The use of machine learning to obtain prognostic information from pathological images has been highlighted. However, there is a limited understanding of the potential of early prediction of bone metastasis through the feature combination method from various sources. This study presents a method of integrating multimodal data to enhance the feasibility of early diagnosis of bone metastasis in prostate cancer. METHODS AND MATERIALS: Overall, 211 patients diagnosed with prostate cancer (PCa) at Gansu Provincial Hospital between January 2017 and February 2023 were included in this study. The patients were randomized (8:2) into a training group (n = 169) and a validation group (n = 42). The region of interest (ROI) were segmented from the three magnetic resonance imaging (MRI) sequences (T2WI, DWI, and ADC), and pathological features were extracted from tissue sections (hematoxylin and eosin [H&E] staining, 10 × 20). A deep learning (DL) model using ResNet 50 was employed to extract deep transfer learning (DTL) features. The least absolute shrinkage and selection operator (LASSO) regression method was utilized for feature selection, feature construction, and reducing feature dimensions. Different machine learning classifiers were used to build predictive models. The performance of the models was evaluated using receiver operating characteristic curves. The net clinical benefit was assessed using decision curve analysis (DCA). The goodness of fit was evaluated using calibration curves. A joint model nomogram was eventually developed by combining clinically independent risk factors. RESULTS: The best prediction models based on DTL and pathomics features showed area under the curve (AUC) values of 0.89 (95% confidence interval [CI], 0.799-0.989) and 0.85 (95% CI, 0.714-0.989), respectively. The AUC for the best prediction model based on radiomics features and combining radiomics features, DTL features, and pathomics features were 0.86 (95% CI, 0.735-0.979) and 0.93 (95% CI, 0.854-1.000), respectively. Based on DCA and calibration curves, the model demonstrated good net clinical benefit and fit. CONCLUSION: Multimodal radiomics and pathomics serve as valuable predictors of the risk of bone metastases in patients with primary PCa.
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Tumeurs osseuses , Apprentissage profond , Tumeurs de la prostate , Mâle , Humains , , Imagerie par résonance magnétique , Tumeurs osseuses/imagerie diagnostique , Algorithmes , Tumeurs de la prostate/imagerie diagnostique , Études rétrospectivesRÉSUMÉ
Dementia, with homocysteine (Hcy) as an important risk factor, is a severe public health problem in the aging society. Betaine serves as a methyl donor and plays an important role in reducing Hcy. However, the effects and mechanisms of betaine on Hcy-induced cognitive impairment remain unclear. Firstly, SD rats were injected with Hcy (400 µg/kg) through vena caudalis, and betaine (2.5 % w/v) was supplemented via drinking water for 14 days. Betaine supplementation could attenuate Hcy-induced cognitive impairment in the Y maze and novel object recognition tests by repairing brain injury. Meanwhile, microglial activation was observed to be inhibited by betaine supplementation using immunofluorescence and sholl analysis. Secondly, HMC3 cells were treated with betaine, which was found to decrease the ROS level, ameliorate cell membrane rupture, reduce the release of LDH, IL-18 and IL-1ß, and attenuate the damage of microglia to neurons. Mechanistically, betaine alleviates cognitive impairment by inhibiting microglial pyroptosis via reducing the expressions of NLRP3, ASC, pro-caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N, IL-18 and IL-1ß. Betaine treatment can increase SAM/SAH ratio, confirming its enhancement on methylation capacity. Furthermore, betaine treatment was found to enhance N6-methyladenosine (m6A) modification of NLRP3 mRNA, and reduced the NLRP3 mRNA stability through increasing the expression of the m6A reader YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Finally, silencing YTHDF2 could reverse the inhibitory effect of betaine on pyroptosis. Our data demonstrated that betaine attenuated Hcy-induced cognitive impairment by suppressing microglia pyroptosis via inhibiting the NLRP3/caspase-1/GSDMD pathway in an m6A-YTHDF2-dependent manner.
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Bétaïne , Dysfonctionnement cognitif , Animaux , Rats , Rat Sprague-Dawley , Bétaïne/pharmacologie , Pyroptose , Interleukine-18 , Microglie , Protéine-3 de la famille des NLR contenant un domaine pyrine/génétique , Caspase-1 , Dysfonctionnement cognitif/induit chimiquement , Dysfonctionnement cognitif/traitement médicamenteux , Homocystéine , Interleukine-1 bêta , InflammasomesRÉSUMÉ
AIMS: FoxO1 is an important target in the treatment of Alzheimer's disease (AD). However, FoxO1-specific agonists and their effects on AD have not yet been reported. This study aimed to identify small molecules that upregulate the activity of FoxO1 to attenuate the symptoms of AD. METHODS: FoxO1 agonists were identified by in silico screening and molecular dynamics simulation. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to assess protein and gene expression levels of P21, BIM, and PPARγ downstream of FoxO1 in SH-SY5Y cells, respectively. Western blotting and enzyme-linked immunoassays were performed to explore the effect of FoxO1 agonists on APP metabolism. RESULTS: N-(3-methylisothiazol-5-yl)-2-(2-oxobenzo[d]oxazol-3(2H)-yl) acetamide (compound D) had the highest affinity for FoxO1. Compound D activated FoxO1 and regulated the expression of its downstream target genes, P21, BIM, and PPARγ. In SH-SY5Y cells treated with compound D, BACE1 expression levels were downregulated, and the levels of Aß1-40 and Aß1-42 were also reduced. CONCLUSIONS: We present a novel small-molecule FoxO1 agonist with good anti-AD effects. This study highlights a promising strategy for new drug discovery for AD.
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Maladie d'Alzheimer , Neuroblastome , Humains , Maladie d'Alzheimer/traitement médicamenteux , Peptides bêta-amyloïdes/métabolisme , Amyloid precursor protein secretases/génétique , Aspartic acid endopeptidases/génétique , Aspartic acid endopeptidases/métabolisme , Régulation négative , Récepteur PPAR gamma/génétiqueRÉSUMÉ
BACKGROUND: Transsphenoidal surgeons should try to avoid internal carotid artery (ICA) injury but also be prepared to manage it. We analyzed our experience with ICA injury during endoscopic transsphenoidal pituitary surgery and present associated risk factors and a management protocol. METHODS: We retrospectively reviewed and analyzed the medical records of 1596 patients who underwent endoscopic transsphenoidal surgery for pituitary tumor resection in our institution from January 2009 to October 2022. RESULTS: Six patients experienced an ICA injury. All received timely and effective hemostasis with immediate direct tamponade followed by endovascular treatment. No serious postoperative complications occurred. CONCLUSIONS: We proposed a treatment plan for ICA injuries encountered during endoscopic transsphenoidal surgery and described our hemostasis process, methods of endovascular treatment, and means of postoperative follow-up in detail.
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Lésions traumatiques de l'artère carotide , Tumeurs de l'hypophyse , Humains , Tumeurs de l'hypophyse/chirurgie , Tumeurs de l'hypophyse/complications , Artère carotide interne/chirurgie , Études rétrospectives , Endoscopie/effets indésirables , Lésions traumatiques de l'artère carotide/étiologie , Lésions traumatiques de l'artère carotide/chirurgieRÉSUMÉ
The number of individuals experiencing mental disorders (e.g., anxiety and depression) has significantly risen in recent years. Therefore, it is essential to seek prevention and treatment strategies for mental disorders. Several gut microbiota, especially Firmicutes and Bacteroidetes, are demonstrated to affect mental health through microbiota-gut-brain axis, and the gut microbiota dysbiosis can be related to mental disorders, such as anxiety, depression, and other mental disorders. On the other hand, dietary components, including probiotics (e.g., Lactobacillus and Bifidobacterium), prebiotics (e.g., dietary fiber and alpha-lactalbumin), synbiotics, postbiotics (e.g., short-chain fatty acids), dairy products, spices (e.g., Zanthoxylum bungeanum, curcumin, and capsaicin), fruits, vegetables, medicinal herbs, and so on, could exert protective effects against mental disorders by enhancing beneficial gut microbiota while suppressing harmful ones. In this paper, the mental disorder-associated gut microbiota are summarized. In addition, the protective effects of dietary components on mental health through targeting the gut microbiota are discussed. This paper can be helpful to develop some dietary natural products into pharmaceuticals and functional foods to prevent and treat mental disorders.
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Microbiome gastro-intestinal , Troubles mentaux , Humains , Anxiété/prévention et contrôle , Dépression/prévention et contrôle , Troubles mentaux/prévention et contrôle , Prébiotiques , Probiotiques , Synbiotiques , Produits biologiquesRÉSUMÉ
Skull base tumors are challenging to treat because of their deep location, complex anatomy, and close proximity to important blood vessels and nerves. Furthermore, some patients with cranial tumors are found to have aneurysms, but there is no consensus on how to evaluate the impact of aneurysms on surgery and how to handle the lesions safely and effectively. We retrospectively reviewed our database to identify all patients with a skull base tumor treated in the Department of Neurosurgery of Beijing Tiantan Hospital affiliated with Capital Medical University from 2019 to 2021. The records of patients with skull base tumors associated with aneurysms were analyzed. The operative methods and postoperative follow-up information were collected. We analyzed a total of 481 patients with skull base tumors, comprising 224 males and 257 females with a mean age of 48 ± 14 years. Twenty-four patients (24/481, 5.0%) were diagnosed with aneurysms. For eight patients, it was considered necessary to perform aneurysm treatment before or during the tumor resection surgery. For the other 16 patients, the recommendation was to monitor the aneurysm or perform elective aneurysm treatment after tumor resection. All patients with both skull base tumors and aneurysms benefited from treatment. No severe postoperative complications occurred. We summarized the final treatment plan for all patients with skull base tumors with aneurysms and proposed a protocol to decrease the surgical risk of patients with skull base tumors associated with aneurysms.
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Anévrysme , Tumeurs de la base du crâne , Mâle , Femelle , Humains , Adulte , Adulte d'âge moyen , Tumeurs de la base du crâne/chirurgie , Études rétrospectives , Résultat thérapeutique , Base du crâne/chirurgieRÉSUMÉ
Kombucha beverage is commonly prepared by black tea infusion fermentation without tea residues, and possesses various health benefits. In this paper, kombucha beverages of two non-Camellia sinensis teas, including vine tea (Ampelopsisgrossedentata) and sweet tea (Rubus suavissimus), were studied for the first time. The antioxidant activities and polyphenol contents of kombucha beverages were evaluated by ferric-reducing antioxidant power assay, Trolox equivalent antioxidant capacity assay, and Folin-Ciocalteu method, respectively. In addition, effects of tea residues on antioxidant capacities of kombucha beverages were evaluated. The results showed that kombucha beverages from vine tea and sweet tea possessed strong antioxidant activities (especially vine tea kombucha), and fermentation with tea residues could significantly increase antioxidant capacities (maximum increase of 38%) and total phenolic content (maximum increase of 55%) of two kombucha beverages compared with those without tea residues. Moreover, the sensory evaluations showed that the sensory evaluation scores of kombucha with tea residues could be improved compared with those without tea residues. Furthermore, the concentrations of several bioactive components in the kombucha beverages were detected by high-performance liquid chromatography. These kombucha beverages could be used for prevention of several diseases with related of oxidative stress.
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Grape (Vitis vinifera L.) is one of the most popular fruits worldwide. It contains various bioactive compounds, such as proanthocyanidins, anthocyanins, flavonols, phenolic acids and stilbenes, the contents of which could vary considerably in grape skin, pulp and seed. Many studies have revealed that grape possesses a variety of health benefits, such as antioxidant, anti-inflammatory, gut-microbiota-modulating, anticancer and cardioprotective effects. Grape is eaten as fresh fruit and is also used as raw material to produce various products, such as wine, grape juice and raisins. Moreover, the byproducts of grape, such as grape pomace and grape seed, have many applications in the food industry. In this paper, the bioactive compounds in grape are briefly summarized based on literature published in recent years. In addition, the health benefits of grape and its bioactive components are discussed, with special attention paid to the underlying mechanisms. Furthermore, the applications of grape in the food industry are elucidated, especially the applications of grape pomace and grape seed. This paper can contribute to understanding the health benefits and mechanisms of grape and its bioactive compounds, as well as the promotion of the use of grape in the food industry.
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The gut microbiota and their metabolites could play an important role in health and diseases of human beings. Short-chain fatty acids (SCFAs) are mainly produced by gut microbiome fermentation of dietary fiber and could also be produced by bacteria of the skin and vagina. Acetate, propionate, and butyrate are three major SCFAs, and their bioactivities have been widely studied. The SCFAs have many health benefits, such as anti-inflammatory, immunoregulatory, anti-obesity, anti-diabetes, anticancer, cardiovascular protective, hepatoprotective, and neuroprotective activities. This paper summarizes health benefits and side effects of SCFAs with a special attention paid to the mechanisms of action. This paper provides better support for people eating dietary fiber as well as ways for dietary fiber to be developed into functional food to prevent diseases.
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Cancer is the leading cause of death in the world. Curcumin is the main ingredient in turmeric (Curcuma longa L.), and is widely used in the food industry. It shows anticancer properties on different types of cancers, and the underlying mechanisms of action include inhibiting cell proliferation, suppressing invasion and migration, promoting cell apoptosis, inducing autophagy, decreasing cancer stemness, increasing reactive oxygen species production, reducing inflammation, triggering ferroptosis, regulating gut microbiota, and adjuvant therapy. In addition, the anticancer action of curcumin is demonstrated in clinical trials. Moreover, the poor water solubility and low bioavailability of curcumin can be improved by a variety of nanotechnologies, which will promote its clinical effects. Furthermore, although curcumin shows some adverse effects, such as diarrhea and nausea, it is generally safe and tolerable. This paper is an updated review of the prevention and management of cancers by curcumin with a special attention to its mechanisms of action.
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Cancer has been a serious public health problem. Berberine is a famous natural compound from medicinal herbs and shows many bioactivities, such as antioxidant, anti-inflammatory, antidiabetic, anti-obesity, and antimicrobial activities. In addition, berberine shows anticancer effects on a variety of cancers, such as breast, lung, gastric, liver, colorectal, ovarian, cervical, and prostate cancers. The underlying mechanisms of action include inhibiting cancer cell proliferation, suppressing metastasis, inducing apoptosis, activating autophagy, regulating gut microbiota, and improving the effects of anticancer drugs. This paper summarizes effectiveness and mechanisms of berberine on different cancers and highlights the mechanisms of action. In addition, the nanotechnologies to improve bioavailability of berberine are included. Moreover, the side effects of berberine are also discussed. This paper is helpful for the prevention and treatment of cancers using berberine.
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Antinéoplasiques , Berbérine , Microbiome gastro-intestinal , Plantes médicinales , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Berbérine/pharmacologie , Berbérine/usage thérapeutique , Humains , Mâle , Obésité/traitement médicamenteuxRÉSUMÉ
Treatment of schwannomas in patients with neurofibromatosis type 2 (NF2) is extremely unsatisfactory, and innovative therapeutic approaches are urgently needed. However, the lack of clinically relevant NF2-associated schwannoma models has severely hampered drug discovery in this rare disease. Here we report the first establishment and characterization of patient-derived xenograft (PDX) and cell line models of NF2-associated schwannoma, which recapitulates the morphological and histopathological features of patient tumors, retain patient NF2 mutations, and maintain gene expression profiles resembling patient tumor profiles with the preservation of multiple key signaling pathways commonly dysregulated in human schwannomas. Using gene expression profiling, we identified elevated PI3K/AKT/mTOR networks in human NF2-associated vestibular schwannomas. Using high-throughput screening of 157 inhibitors targeting the PI3K/AKT/mTOR pathways in vitro, we identified a dozen inhibitors (such as BEZ235, LY2090314, and AZD8055) with significant growth-suppressive effects. Interestingly, we observed that three cell lines displayed differential therapeutic responses to PI3K/AKT/mTOR inhibitors. Furthermore, we demonstrated that two orally bioavailable inhibitors, AZD8055 and PQR309, suppressed NF2-associated schwannoma growth both in vitro and in vivo. In conclusion, our novel patient-derived models of NF2-associated schwannoma closely mimic the phenotypes and genotypes of patient tumors, making them reliable preclinical tools for testing novel personalized therapies. © 2022 The Pathological Society of Great Britain and Ireland.
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Neurinome , Neurofibromatose de type 2 , Lignée cellulaire , Hétérogreffes , Humains , Neurinome/traitement médicamenteux , Neurinome/génétique , Neurofibromatose de type 2/traitement médicamenteux , Neurofibromatose de type 2/génétique , Neurofibromatose de type 2/anatomopathologie , Phosphatidylinositol 3-kinases/métabolisme , Protéines proto-oncogènes c-akt/métabolisme , Sérine-thréonine kinases TOR/génétiqueRÉSUMÉ
Three undescribed azaphilones, phomopsones A-C (1-3) and two known azaphilones (4-5) were isolated from the culture of endophytic fungus Phomopsis sp. CGMCC No.5416 from the stems of Achyranthes bidentata. Their structures were determined by spectroscopic analysis (HRESIMS, 1D and 2D NMR), and the absolute configurations were determined by CD spectroscopy. Compounds 2 and 3 showed significant inhibitory activities against HIV-1 with against HIV-1 with IC50 values of 7.6 and 0.5 µmol/L, respectively. Compounds 2 and 3 also displayed moderate cytotoxicity with CC50 values of 3.2-303 µmol/L against A549, MDA-MB-231 and PANC-1 cell lines. Moreover, compound 3 can induce the early apoptosis of PANC-1 cancer cells with the apoptosis rate of 28.54%.
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Agents antiVIH/pharmacologie , Antinéoplasiques/pharmacologie , Benzopyranes/pharmacologie , Produits biologiques/pharmacologie , Phomopsis (genre)/composition chimique , Pigments biologiques/pharmacologie , Achyranthes/microbiologie , Agents antiVIH/isolement et purification , Antinéoplasiques/isolement et purification , Apoptose , Benzopyranes/isolement et purification , Produits biologiques/isolement et purification , Lignée cellulaire tumorale , Chine , Endophytes/composition chimique , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , Humains , Structure moléculaire , Pigments biologiques/isolement et purification , Tiges de plante/microbiologieRÉSUMÉ
Morindae Officinalis Radix (MOR), the dried root of Morinda officinalis F.C. How (Rubiaceae), is a popular food supplement in southeastern China for bone protection, andrological, and gynecological healthcare. In clinical use, 3-4 year old MOR is commonly used and the xylem is sometimes removed. However, there is no scientific rationale for these practices so far. In this study, metabolomics and glycomics were integrated using multiple chromatographic and mass spectrometric techniques coupled with multivariate statistical analysis to investigate the qualitative and quantitative variations of secondary metabolome and glycome in different growth years (1-7 years) and tissues (xylem and cortex) of MOR. The results showed that various types of bioactive components reached a maximum between 3 and 4 years of growth and that the xylem contained more potentially toxic constituents but less bioactive components than the cortex. This study provides the chemical basis for the common practice of using 3-4 year old MOR with the xylem removed.
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Médicaments issus de plantes chinoises/composition chimique , Morinda/croissance et développement , Racines de plante/composition chimique , Chine , Médicaments issus de plantes chinoises/métabolisme , Glycomique , Métabolomique , Morinda/composition chimique , Morinda/métabolisme , Racines de plante/croissance et développement , Racines de plante/métabolisme , Facteurs temps , Xylème/composition chimique , Xylème/métabolismeRÉSUMÉ
BACKGROUND: The endoscopic transnasal approach has been proven to have advantages on the removal of the tumors in pterygopalatine fossa (PPF) and infratemporal fossa (ITF). Herein, this study aimed to describe a modified approach for resection of the tumors in these areas, both in cadaveric specimen and clinical patients. METHODS: The 20 adult cadaveric specimens and five patients with tumors in PPF and ITF were enrolled in this study. For the cadaveric specimens, ten were simulated anterior transmaxillary approach and ten were performed modified endoscopic transnasal transmaxillary approach. The exposure areas were compared between two groups and main anatomic structure were measured. Surgery was operated in the five patients with tumors of PPF and ITF to verify the experience from the anatomy. Perioperative management, intraoperative findings and postoperative complications were recorded and analyzed. RESULTS: The modified endoscopic transnasal transmaxillary approach provided as enough surgical exposure and high operability to the PPF and ITF as the anterior transmaxillary approach did. The diameter of maxillary artery in the PPF was 3.77â±â0.78âmm (range: 2.06-4.82âmm), the diameter of middle meningeal artery in the ITF was 2.79â±â0.61âmm (range: 1.54-3.78âmm). Four patients who suffered schwannoma got total removal and one of adenocystic carcinoma got subtotal removal. The main complications were facial numbness and pericoronitis of the wisdom tooth. No permanent complication was found. CONCLUSIONS: With the widespread use of neuroendoscopy, the modified endoscopic transnasal transmaxillary approach is feasible and effective for the resection of tumors located in PPF and ITF, which has significant advantages on less trauma and complications to the patients.
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Tumeurs sous-tentorielles/anatomopathologie , Fosse ptérygopalatine/anatomopathologie , Adulte , Femelle , Humains , Tumeurs sous-tentorielles/chirurgie , Mâle , Adulte d'âge moyen , Neuroendoscopie , Soins périopératoires , Complications postopératoires , Fosse ptérygopalatine/chirurgieRÉSUMÉ
BACKGROUND: Lung cancer is a leading cause of cancer-related death worldwide. Cisplatin-based chemotherapy is the standard treatment for lung cancer, but chemoresistance and adverse effects especially cardiotoxicity limit its efficacy. PURPOSE: The efficacy of combination treatment of dendrobine, a plant alkaloid isolated from Dendrobium nobile, with cisplatin was examined as a possible anti-non-small cell lung cancer strategy. METHODS: The cytotoxicity of dendrobine and cisplatin against A549 lung cancer cells was analyzed by MTT and colony formation assays. Apoptosis was measured by annexin V/PI double staining. Apoptosis-related proteins were assessed by western blotting and qPCR analysis. In vivo efficacy was determined using A549 xenograft in nude mice. JNK and Bim inhibition were achieved by siRNA knockdown and/or chemical inhibition. Cardiotoxicity was assessed by serum creatine phosphokinase activity assay. RESULTS: Dendrobine induced apoptotic cell death through mitochondrial-mediated pathway. Combination treatment of dendrobine with cisplatin showed enhanced cytotoxicity through stimulation of JNK/p38 stress signaling pathways and, consequently, the induction of apoptosis involving pro-apoptotic proteins Bax and Bim. In addition, dendrobine attenuated the body weight reduction and cardiotoxicity induced by cisplatin in nude mice. CONCLUSION: The combination treatment showed enhanced anticancer activity toward non-small cell lung cancer cells without aggravating the cardiotoxic effects of cisplatin suggesting that the combination strategy deserves further investigation for human lung cancer treatment.
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Alcaloïdes/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Tumeurs du poumon/traitement médicamenteux , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Cellules A549 , Alcaloïdes/administration et posologie , Animaux , Antinéoplasiques d'origine végétale/administration et posologie , Antinéoplasiques d'origine végétale/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Protéines régulatrices de l'apoptose/métabolisme , Poids/effets des médicaments et des substances chimiques , Carcinome pulmonaire non à petites cellules/anatomopathologie , Lignée cellulaire tumorale , Cisplatine/administration et posologie , Cisplatine/pharmacologie , Femelle , Humains , Tumeurs du poumon/anatomopathologie , Souris de lignée BALB C , Mitochondries/effets des médicaments et des substances chimiques , Mitochondries/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
In a prospective, randomized, three-arms, controlled clinical study, Chinese Herbal Medicine MaZiRenWan (MZRW, also known as Hemp Seed Pill) demonstrates comparable efficacy with Senna for functional constipation (FC) during an 8-week treatment period. Both MZRW and Senna are better than a placebo; relative to Senna and a placebo, MZRW displayed a more sustained effect during the 8-week follow-up period. The characteristic pharmacological mechanism responsible for this observation is still unclear. To explore this, we collected pre- and post-treatment serum samples of 85 FC patients from MZRW/Senna/placebo treatment groups for pharmacometabolomic analysis. An ultrahigh-performance liquid chromatography-mass spectrometer (UPLC-MS) was used for metabolic profiling and quantification. In vivo studies were conducted in constipated C57BL/6J mice to verify the effects and corresponding mechanism(s) of the action of MZRW. Pearson correlation analysis, paired t-test, one-way ANOVA analysis, χ2 test, and Student t-test were used to interpret the clinical and preclinical data. Changes in levels of circulating oleamide and its derivatives negatively correlate with improvement in complete spontaneous bowel movement (CSBM) in the MZRW group (Pearson r = -0.59, p = 0.00057). The same did not hold true for either Senna or placebo groups. Oleamide is a known regulator of intestinal motility. MZRW treatment resulted in reduced levels of circulating oleamide in FC patients. Experimental verification showed that MZRW attenuated oleamide-induced slow intestinal motility in mice. MZRW decreased oleamide levels in serum, ileum, and colon in normal mice, but increased expression of colonic fatty acid amide hydrolase (FAAH). In conclusion, MZRW improved bowel movement in FC by down-regulating oleamide, possibly by enhancing FAAH-mediated degradation. Our findings suggest a novel therapeutic strategy for FC.
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Worldwide, colorectal cancer (CRC) is a deleterious disease causing millions of death annually. 5-Fluorouracil (5-FU) is a first-line chemotherapy for CRC, but chemoresistance and gastrointestinal mucositis limit its efficacy. Polyphenol-rich foods are increasingly popular due to their potential beneficial roles in preventing and treating cancer. Ellagitannins are a group of phenolic compounds commonly found in pomegranate, strawberries, raspberries, etc. The objective of this study was to explore whether ellagitannins from pomegranate (PETs) could ameliorate 5-FU-induced intestinal mucositis and enhance the drug's efficacy against CRC. The results showed that PETs (100 mg/kg) counteracted 5-FU-induced intestinal mucositis in rats. The number of apoptotic cells per crypt was reduced from 1.50 ± 0.21 to 0.85 ± 0.18 ( P < 0.05). Moreover, PETs induced HT-29 CRC cell death through intrinsic apoptosis, as demonstrated by dissipation of mitochondrial membrane potential, increased Bax-to-Bcl-2 ratio, and cleavage of caspase 9 and caspase 3. PETs and 5-FU combination treatments exhibited synergistic cytotoxicity against HT-29 cells with a weighted combination index of 0.3494. PETs (80 µg/mL) and 5-FU (40 µg/mL) treatments for 48 h induced 14.03 ± 0.76% and 16.42 ± 1.15% of HT-29 cells to undergo apoptosis, while the combination treatment further increased apoptosis of cells to 34.00 ± 1.54% ( P < 0.05). Combination treatment of the cells also enhanced S phase cell cycle arrest as compared with PETs or 5-FU monotherapy ( P < 0.05). These results suggest that dietary ellagitannins from pomegranate could alleviate intestinal mucositis in rats induced by 5-FU while enhancing its toxicity against HT-29 cells through potentiation of apoptosis and cell cycle arrest.