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1.
ACS Synth Biol ; 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34990118

RESUMO

Bacteroides is the most abundant genus in the human gut microbiome and has been increasingly used as model organisms for studying the function and ecology of the gut microbiome. However, genome editing tools for such commensal gut microbes are still lacking. Here we developed a versatile, highly efficient CRISPR/Cas-based genome editing tool that allows markerless gene deletion and insertion in human gut Bacteroides species. We constructed multiple CRISPR/Cas systems in all-in-one Bacteroides-E. coli shuttle plasmids and systematically evaluated the genome editing efficiency in Bacteroides thetaiotaomicron, including the mode of Cas protein expression (constitutive, inducible), different Cas proteins (FnCas12a, SpRY, SpCas9), and sgRNAs. Using the anhydrotetracycline (aTc)-inducible CRISPR/FnCas12a system, we successfully deleted large genomic fragments up to 50 kb to study the function of metabolic gene clusters. Furthermore, we demonstrated that CRISPR/FnCas12a can be broadly applied to engineer multiple human gut Bacteroides species, including Bacteroides fragilis, Bacteroides ovatus, Bacteroides uniformis, and Bacteroides vulgatus. We envision that CRISPR/Cas-based genome editing tools for Bacteroides will greatly facilitate mechanistic studies of the gut commensal and the development of engineered live biotherapeutics.

2.
Pharmacol Ther ; : 108050, 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34864132

RESUMO

KRAS mutations are one of the most frequent activating alterations in carcinoma. Recent efforts have witnessed a revolutionary strategy for KRAS G12C inhibitors with exhibiting conspicuous clinical responses across multiple tumor types, providing new impetus for renewed drug development and culminating in sotorasib with approximately 6-month median progression-free survival in KRAS G12C-driven lung cancer. However, diverse genomic and histological mechanisms conferring resistance to KRAS G12C inhibitors may limit their clinical efficacy. Herein, we first briefly discuss the recent resistance looms for KRAS G12C inhibitors, focusing on their clinical trials. We then comprehensively interrogate and underscore our current understanding of resistance mechanisms and the necessity of incorporating genomic analyses into the clinical investigation to further decipher resistance mechanisms. Finally, we highlight the future role of novel treatment strategies especially rational identification of targeted combinatorial approaches in tackling drug resistance, and propose our views on including the application of robust biomarkers to precisely guide combination medication regimens.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34956388

RESUMO

Background: Compound Taxus chinensis capsule (CTCC), an antitumor Chinese patent medicine, has been commonly prescribed as an adjunctive agent to chemotherapy for the management of non-small-cell lung cancer (NSCLC); however, the effects of CTCC added to chemotherapy for NSCLC patients have never been comprehensively evaluated or summarized. Purpose: To assess the synergistic effects of CTCC and chemotherapy on NSCLC. Study Design. Evidence-based study, systematic review, and quantitative meta-analysis. Methods: This systematic review and meta-analysis was implemented in accordance with the PRISMA (Preferred Reported Items for Systematic Review and Meta-Analysis) guidelines. Eight databases including China National Knowledge Infrastructure, SINOMED, China Biomedical Literature Database, Wanfang Database, VIP, PubMed, Cochrane Library, and EMBASE were searched for relevant RCTs from their inception until May 24, 2021, and hand-searching was also carried out to identify additional studies. All randomized controlled trials (RCTs) that compared CTCC combined with chemotherapy versus chemotherapy alone were included in our study. The Cochrane Risk-of-Bias tool was used to determine the risk of bias and methodological quality of the included RCTs. Review Manager 5.3 software was used for comprehensive analysis. The primary outcome measure for this study was the disease control rate (DCR), and the secondary outcomes included the objective response rate (ORR), adverse reactions, and quality of life (QOL). Results: Six RCTs with a total sample size of 410 were finally included. The pooled data showed that, compared with chemotherapy alone, CTCC combined with chemotherapy significantly improved DCR (RR = 1.15, 95% CI: 1.06-1.25, P = 0.006), ORR (RR = 1.38, 95% CI: 1.18-1.63, P < 0.00001), and QOL (MD = 8.69, 95% CI: 7.26-10.13, P < 0.006) and reduced the incidence of total adverse reactions (RR = 0.48, 95% CI: 0.38-0.60, P < 0.00001). The subgroup analyses indicated that CTCC plus chemotherapy significantly improved gastrointestinal reactions (P = 0.004), leukopenia (P = 0.0009), thrombocytopenia (P = 0.01), rash (P = 0.002), and fever (P = 0.007). Conclusion: Based on the available evidence, compared with chemotherapy alone, CTCC used as an adjunctive agent to chemotherapy for NSCLC can improve the clinical efficacy and quality of life and decrease the likelihood of adverse reactions, suggesting that CTCC might be an effective and safe adjunctive medicine to chemotherapy for NSCLC. However, considering the relatively small sample size and the inherent imperfections of the included randomized controlled trials, more high-quality clinical trials with longer follow-up time are needed to further assess the efficacy and safety of this combined treatment regimen.

4.
Front Pharmacol ; 12: 764351, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899321

RESUMO

PGAM1 is overexpressed in a wide range of cancers, thereby promoting cancer cell proliferation and tumor growth, so it is gradually becoming an attractive target. Recently, a series of inhibitors with various structures targeting PGAM1 have been reported, particularly anthraquinone derivatives. In present study, the structure-activity relationships and binding mode of a series of anthraquinone derivatives were probed using three-dimensional quantitative structure-activity relationships (3D-QSAR), molecular docking, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, r2 = 0.97, q2 = 0.81) and comparative molecular similarity indices analysis (CoMSIA, r2 = 0.96, q2 = 0.82) techniques were performed to produce 3D-QSAR models, which demonstrated satisfactory results, especially for the good predictive abilities. In addition, molecular dynamics (MD) simulations technology was employed to understand the key residues and the dominated interaction between PGAM1 and inhibitors. The decomposition of binding free energy indicated that the residues of F22, K100, V112, W115, and R116 play a vital role during the ligand binding process. The hydrogen bond analysis showed that R90, W115, and R116 form stable hydrogen bonds with PGAM1 inhibitors. Based on the above results, 7 anthraquinone compounds were designed and exhibited the expected predictive activity. The study explored the structure-activity relationships of anthraquinone compounds through 3D-QSAR and molecular dynamics simulations and provided theoretical guidance for the rational design of new anthraquinone derivatives as PGAM1 inhibitors.

5.
Front Med (Lausanne) ; 8: 731106, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34970556

RESUMO

Background: The use of extracorporeal membrane oxygenation (ECMO) to support critically ill patients with cardiorespiratory dysfunction has increased over the last decades. However, hemorrhagic complications occur frequently during ECMO support, and this has a significant impact on morbidity and mortality. Thus, this study aimed to identify the risk factors for hemorrhage in patients receiving ECMO. Methods: Our retrospective study included 60 patients, who were admitted to the Taihe Hospital in Shiyan City, Hubei Province, China from February 2017 to October 2020. About 18 patients developed hemorrhagic complications, and 42 patients did not demonstrate such complications. Data regarding patient demography, laboratory tests, and clinical manifestations prior to ECMO were collected to analyze their clinical features. Univariable and multivariable logistic analyses were used to explore the risk factors for hemorrhage in adults on ECMO. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of the binary logistic model. The amount of blood transfusions was compared between the two groups, and the activated partial thromboplastin time (APTT), platelet count, and hemoglobin level before the initiation of ECMO. Results: Logistic analysis showed that a longer duration of ECMO support, higher APTT, and lower platelet count prior to ECMO were independent risk factors for hemorrhage in adults on ECMO. In addition, we found that the cannula site was the most common bleeding site. Most bleeding events occurred within the first 3 days of ECMO therapy. After the ECMO initiation, APTT was prolonged while the platelet count and hemoglobin levels were decreased. The amount of blood transfusion was significantly higher in the hemorrhage group than in the non-hemorrhage group. Conclusions: Clinicians should evaluate the risk of hemorrhage based on the coagulation function of patients, underlying disease, and the duration of ECMO support. In the first 3 days during ECMO support, special attention should be given to the cannula site, mucosal, and dermal regions, and digestive tract to detect any signs of hemorrhage. Moreover, increasing the platelet count transfusion threshold and accurately determining the amount of blood transfusion required may prevent bleeding events.

6.
Phytomedicine ; : 153786, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34785104

RESUMO

BACKGROUND: Lung cancer has become the principal cause of cancer-related deaths. Emodin is a Chinese herb-derived compound extracted from the roots of Rheum officinale that exhibits numerous pharmacological characteristics. Secretory phospholipase A2-IIa (sPLA2-IIa) is overexpressed in cancers and plays an important role in cancer development. PURPOSE: This study aims to investigate the anti-tumor mechanism of emodin in non-small-cell lung cancer (NSCLC). METHODS: MTT assay was applied to detect the sensitivity of emodin to NSCLC cell line. Flow cytometry was used to examine the effect of emodin on cell cycle distribution and evaluate ROS level and apoptosis. Western blot analysis was utilised to examine the expression levels of sPLA2-IIa, PKM2, and AMPK and its downstream pathways induced by emodin. Enzyme inhibition assay was applied to investigate the inhibitory effect of emodin on sPLA2-IIa. The anticancer effect of emodin was also detected using an in vivo model. RESULTS: Emodin significantly inhibited NSCLC proliferation in vivo and in vitro and was relatively less cytotoxic to normal lung cell lines. Most importantly, emodin inhibited the proliferation of KRAS mutant cell lines by decreasing the expression of sPLA2-IIa and NF-κB pathways. Emodin also inhibited mTOR and AKT and activated the AMPK pathway. Furthermore, emodin induced apoptosis, increased the reactive oxygen species (ROS) level, and arrested the cell cycle. CONCLUSION: Emodin exhibited a novel anti-tumor mechanism of inhibiting the proliferation of KRAS mutant cell lines by decreasing the expression levels of sPLA2-IIa and NF-κB pathways. Hence, emodin can potentially serve as a therapeutic target in NSCLC.

7.
Phytomedicine ; : 153831, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34794861

RESUMO

BACKGROUND: Currently, the identification of accurate biomarkers for the diagnosis of patients with early-stage lung cancer remains difficult. Fortunately, metabolomics technology can be used to improve the detection of plasma metabolic biomarkers for lung cancer. In a previous study, we successfully utilised machine learning methods to identify significant metabolic markers for early-stage lung cancer diagnosis. However, a related research platform for the investigation of tumour metabolism and drug efficacy is still lacking. HYPOTHESIS/PURPOSE: A novel methodology for the comprehensive evaluation of the internal tumour-metabolic profile and drug evaluation needs to be established. METHODS: The optimal location for tumour cell inoculation was identified in mouse chest for the non-traumatic orthotopic lung cancer mouse model. Microcomputed tomography (micro-CT) was applied to monitor lung tumour growth. Proscillaridin A (P.A) and cisplatin (CDDP) were utilised to verify the anti-lung cancer efficacy of the platform. The top five clinically valid biomarkers, including proline, L-kynurenine, spermidine, taurine and palmitoyl-L-carnitine, were selected as the evaluation indices to obtain a suitable lung cancer mouse model for clinical metabolomics research by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: The platform was successfully established, achieving 100% tumour development rate and 0% surgery mortality. P.A and CDDP had significant anti-lung cancer efficacy in the platform. Compared with the control group, four biomarkers in the orthotopic model and two biomarkers in the metastatic model had significantly higher abundance. Principal component analysis (PCA) showed a significant separation between the orthotopic/metastatic model and the control/subcutaneous/KRAS transgenic model. The platform was mainly involved in arginine and proline metabolism, tryptophan metabolism, and taurine and hypotaurine metabolism. CONCLUSION: This study is the first to simulate clinical metabolomics by comparing the metabolic phenotype of plasma in different lung cancer mouse models. We found that the orthotopic model was the most suitable for tumour metabolism. Furthermore, the anti-tumour drug efficacy was verified in the platform. The platform can very well match the clinical reality, providing better lung cancer diagnosis and securing more precise evidence for drug evaluation in the future.

8.
Comput Struct Biotechnol J ; 19: 5455-5465, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603638

RESUMO

The key step for SARS-CoV-2 to infect human cells is the membrane fusion triggered by the binding of the viral extracellular Spike protein to the human extracellular receptor, the angiotensin-converting enzyme 2 (ACE2). Although the Cryo-electron microscopy (Cryo-EM) uncovered the static atomic details of ACE2 homodimers, there is still a lack of research on the kinetic and thermodynamic properties of these full-length structures. This information is helpful to understand and interpret the role of ACE2 in the cell entry of SARS-CoV-2. In order to obtain this information, we performed microsecond-scale conventional and accelerated molecular dynamics (MD) simulations of full-length all-atomic systems of the RBD-ACE2 complex, the normal and torsional conformations of the apo-ACE2 homodimer. The comparative analysis of these systems showed that there were differences in their allosteric signal pathways and motion trends. These results may be helpful to further explore the cell entry mechanism of SARS-CoV-2. Moreover, the binding free energy and hydrogen bond distribution analysis of RBD-ACE2 binding interface provided the binding motifs that may be critical to allosteric signal transmission and RBD binding. These multi-conformational binding motifs can be used as targets or templates for the inhibitor design of the cell entry of SARS-CoV-2.

9.
Phys Chem Chem Phys ; 23(34): 18404-18413, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34612381

RESUMO

As a human mitotic kinase, haspin is considered as a promising target for various diseases including cancers. However, no inhibitors targeting haspin have entered clinical trials presently. 5-iTU (5-iodotubercidin) is a useful and classical chemical probe for the investigation of haspin activity, but its inhibitory mechanism remains unclear. In this study, integrated molecular dynamics (MD) of conventional MD, extended adaptive biasing force (eABF), random acceleration MD and well-tempered metadynamics were applied to investigate the thermodynamic and kinetic features of 5-iTU and three derivatives targeting haspin. To emphasize the importance of gatekeeper Phe605, two haspin mutants (F605Y and F605T) were also built. The results showed that the binding affinity of 5-iTU and haspin was highest in all wild type (WT) systems, relying on the strong halogen aromatic π interaction between 5-iTU and gatekeeper Phe605. Gatekeeper mutations, because of damage to this interaction, led to the rearrangement of water distributions at the binding site and the decrease of 5-iTU residence times. Additionally, compared with the smaller 5-fTU, 5-iTU dissociated from WT haspin with more difficulty through distinct unbinding pathways. These findings will provide crucial guidance for the design and development of novel haspin inhibitors and the rational modification of existing inhibitors.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/farmacologia , Termodinâmica , Tubercidina/análogos & derivados , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cinética , Conformação Molecular , Inibidores de Proteínas Quinases/química , Tubercidina/química , Tubercidina/farmacologia
10.
Oncol Lett ; 22(5): 787, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34594428

RESUMO

Lung cancer is the most common type of cancer with the highest mortality rate worldwide. Non-small cell lung cancer (NSCLC) accounts for ~85% of the total number of lung cancer cases. In the past two decades, immunotherapy has become a more promising treatment method than traditional treatments (surgery, radiotherapy and chemotherapy). Immunotherapy has been shown to improve the survival rate of patients and to have a superior effect when controlling lung cancer than traditional therapy. However, only a small number of patients can benefit from immunotherapy, and not all patients who qualify experience long-term benefits. In the clinic, the objective response rate of programmed cell death protein 1 treatment without the prior screening of patients is only 15-20%. Immunotherapy is associated with both opportunities and challenges for patients with NSCLC. The current challenges of immunotherapy include the lack of accurate biomarkers, inevitable resistance and insufficient understanding of immune checkpoints. In previous years, several methods for overcoming the challenges posed by immunotherapy have been proposed, but combination therapy is the most suitable choice. A large number of studies have shown that the combination of drugs can significantly improve their efficacy, compared with monotherapy, and that some therapeutic combinations have been approved by the Food and Drug Administration for the treatment of NSCLC. Traditional Chinese medicine (TCM) is a traditional medical practice in China that can play an important role in immunotherapy. Most agents used in TCM originate from plants, and have the advantages of low toxicity and multiple targets. In addition, TCM includes a unique class of drugs that can improve autoimmunity. Therefore, TCM may be a promising treatment method for all types of cancer.

11.
Pharmacol Res ; 171: 105574, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34419228

RESUMO

Currently, conventional methods of treating non-small cell lung cancer (NSCLC) have many disadvantages. An alternative effective therapy with minimal adverse reactions is urgently needed. Weijing decoction (WJD), which is a classic ancient Chinese herbal prescription, has been used successfully to treat pulmonary system diseases containing lung cancer in the clinic. However, the key active component and target of Weijing decoction are still unexplored. Therefore, for the first time, our study aims to investigate the pharmacological treatment mechanism of Weijing decoction in treating NSCLC via an integrated model of network pharmacology, metabolomics and biological methods. Network pharmacology results conjectured that Tricin is a main bioactive component in this formula which targets PRKCA to suppress cancer cell growth. Metabolomics analysis demonstrated that sphingosine-1-phosphate, which is regulated by sphingosine kinase 1 and sphingosine kinase 2, is a differential metabolite in plasma between the WJD-treated group and the control group, participating in the sphingolipid signaling. In vitro experiments demonstrated that Tricin had vital effects on the proliferation, pro-apoptosis, migration and colony formation of Lewis lung carcinoma cells. Through a series of validation assays, Tricin inhibited the tumor growth mainly by suppressing PRKCA/SPHK/S1P signaling and antiapoptotic signaling. On the other hand, Weijing formula could inhibit the tumor growth and prolong the survival time. A high dosage of Tricin was much more potent in animal experiments. In conclusion, we confirmed that Weijing formula and its primary active compound Tricin are promising alternative treatments for NSCLC patients.

12.
Pharmacol Res ; 172: 105804, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34450309

RESUMO

Bromodomain-containing proteins include bromodomain and extra-terminal (BET) and non-BET families. Due to the conserved bromodomain (BD) module between BD-containing proteins, and especially BETs with each member having two BDs (BD1 and BD2), the high degree of structural similarity makes BD-selective inhibitors much difficult to be designed. However, increasing evidences emphasized that individual BDs had distinct functions and different cellular phenotypes after pharmacological inhibition, and selectively targeting one of the BDs could result in a different efficacy and tolerability profile. This review is to summarize the pioneering progress of BD-selective inhibitors targeting BET and non-BET proteins, focusing on their structural features, biological activity, therapeutic application and experimental/theoretical mechanisms. The present proteolysis targeting chimeras (PROTAC) degraders targeting BDs, and clinical status of BD-selective inhibitors were also analyzed, providing a new insight into future direction of bromodomain-selective drug discovery.

13.
Chem Biol Drug Des ; 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34288496

RESUMO

Lung cancer is the leading cause of cancer death. Pyronaridine, a synthetic drug of artemisinin, has been used in China for over 30 years for the treatment of malaria, but its effect on non-small cell lung cancer (NSCLC) cells is rarely reported. In this study, we determined the efficacy of pyronaridine in four different NSCLC cell lines and explored its mechanism in H1975. The data showed that pyronaridine could upregulate the expression of TNF-related apoptosis-inducing ligand (TRAIL)-mediated death receptor 5 to promote cellular apoptosis. Meanwhile, the JNK (c-Jun N-terminal kinase) level was detected to be significantly increased after treating with pyronaridine. We used JNK inhibitor and found that it could partially inhibit cell apoptosis. The results showed that epidermal growth factor receptor (EGFR), PI3K, and AKT were downregulated after the treatment of pyronaridine. In summary, pyronaridine can selectively kill NSCLC by regulating TRAIL-mediated apoptosis and downregulating the protein level of EGFR. It is a promising anticancer drug for NSCLC.

14.
Pharmacol Res ; 169: 105656, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33964470

RESUMO

Non-small cell lung cancer (NSCLC) is one of the most frequently diagnosed cancers and the leading causes of cancer death worldwide. Therefore, new therapeutic agents are urgently needed to improve patient outcomes. Plumbagin (PLB), a natural sesquiterpene present in many Chinese herbal medicines, has been reported for its anti-cancer activity in various cancer cells. In this study, the effects and underlying mechanisms of PLB on the tumorigenesis of NSCLC were investigated. PLB dose-dependently inhibited the growth of NSCLC cell lines. PLB promoted ROS production, activated the endoplasmic reticulum (ER) stress pathway, and induced cell apoptosis, accompanied by the decreased expression level of ADP-ribosylation factor 1 (ARF1) in NSCLC cancer cells, and those effects of PLB could be reversed by the pretreatment with N-acetyl-L-cysteine (NAC). More importantly, the calcium chelator (BM) significantly reversed PLB-induced cell apoptosis. Furthermore, PLB significantly inhibited the growth of both H1975 xenograft and LLC1 tumors and exhibited antitumor activity by enhancing the number and the effector function of CD8+ T cells in KRASLA2 mice model and the LLC1 xenograft. Our findings suggest that PLB exerts potent antitumor activity against NSCLC in vitro and in vivo through ARF1 downregulation and induction of antitumor immune response, indicating that PLB is a new novel therapeutic candidate for the treatment of patients with NSCLC.

15.
BMC Cancer ; 21(1): 531, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33971846

RESUMO

BACKGROUND: Cervical cancer continues to be one of the leading causes of cancer deaths among females in low and middle-income countries. In this study, we aimed to assess the independent prognostic value of clinical and potential prognostic factors in progression-free survival (PFS) in cervical cancer. METHODS: We conducted a retrospective study on 92 cervical cancer patients treated from 2017 to 2019 at the Zhuhai Hospital of Traditional Chinese and Western Medicine. Tumor characteristics, treatment options, progression-free survival and follow-up information were collected. Kaplan-Meier method was used to assess the PFS. RESULTS: Results showed that the number of retrieved lymph nodes had a statistically significant effect on PFS of cervical cancer patients (P = 0.002). Kaplan-Meier survival curve analysis showed that cervical cancer patients with initial symptoms age 25-39 had worse survival prognoses (P = 0.020). And the using of uterine manipulator in laparoscopic treatment showed a better prognosis (P < 0.001). A novel discovery of our study was to verify the prognostic values of retrieved lymph nodes count combining with FIGO staging system, which had never been investigated in cervical cancer before. According to the Kaplan-Meier survival curve analysis and receiver operating characteristic (ROC) curve analysis, significant improvements were found after the combination of retrieved lymph nodes count and FIGO stage in predicting PFS for cervical cancer patients (P < 0.001, AUC = 0.826, 95% CI: 0.689-0.962). CONCLUSION: Number of retrieved lymph nodes, initial symptoms age, uterine manipulator, and retrieved lymph nodes count combining with FIGO staging system could be potential prognostic factors for cervical cancer patients.


Assuntos
Neoplasias do Colo do Útero/mortalidade , Adulto , Idoso , Feminino , Humanos , Excisão de Linfonodo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia
16.
Gut ; 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006584

RESUMO

OBJECTIVE: Programmed death 1 and its ligand 1 (PD-1/PD-L1) immunotherapy is promising for late-stage lung cancer treatment, however, the response rate needs to be improved. Gut microbiota plays a crucial role in immunotherapy sensitisation and Panax ginseng has been shown to possess immunomodulatory potential. In this study, we aimed to investigate whether the combination treatment of ginseng polysaccharides (GPs) and αPD-1 monoclonal antibody (mAb) could sensitise the response by modulating gut microbiota. DESIGN: Syngeneic mouse models were administered GPs and αPD-1 mAb, the sensitising antitumour effects of the combination therapy on gut microbiota were assessed by faecal microbiota transplantation (FMT) and 16S PacBio single-molecule real-time (SMRT) sequencing. To assess the immune-related metabolites, metabolomics analysis of the plasma samples was performed. RESULTS: We found GPs increased the antitumour response to αPD-1 mAb by increasing the microbial metabolites valeric acid and decreasing L-kynurenine, as well as the ratio of Kyn/Trp, which contributed to the suppression of regulatory T cells and induction of Teff cells after combination treatment. Besides, the microbial analysis indicated that the abundance of Parabacteroides distasonis and Bacteroides vulgatus was higher in responders to anti-PD-1 blockade than non-responders in the clinic. Furthermore, the combination therapy sensitised the response to PD-1 inhibitor in the mice receiving microbes by FMT from six non-responders by reshaping the gut microbiota from non-responders towards that of responders. CONCLUSION: Our results demonstrate that GPs combined with αPD-1 mAb may be a new strategy to sensitise non-small cell lung cancer patients to anti-PD-1 immunotherapy. The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.

17.
PLoS One ; 16(4): e0249276, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33793632

RESUMO

Aconitine (AC) is the primary bioactive and secondary metabolite alkaloidin of Aconitum species which is accounted for more than 60% of the total diester-diterpenoid alkaloids in Aconite. To evaluate the analgesic effects of AC, 4 different pain models including hot plate assay, acetic acid writhing assay, formalin and CFA induced pain models were adopted in this study. In hot plate experiment, AC treatment at concentration of 0.3 mg/kg and 0.9 mg/kg improved the pain thresholds of mice similar to the positive drug aspirin at the concentration of 200 mg/kg (17.12% and 20.27% VS 19.21%). In acetic acid writhing experiment, AC significantly reduced the number of mice writhing events caused by acetic acid, and the inhibition rates were 68% and 76%. These results demonstrated that AC treatment revealed significant analgesic effects in both acute thermal stimulus pain model and chemically-induced visceral pain model. The biphasic nociceptive responses induced by formalin were significantly inhibited after AC treatment for 1h or 2h. The inhibition rates were 33.23% and 20.25% of AC treatment for 1h at 0.3 mg/kg and 0.9 mg/kg in phase I. In phase II, the inhibition rates of AC and aspirin were 36.08%, 32.48% and 48.82% respectively, which means AC showed similar analgesic effect to non-steroidal anti-inflammatory compounds. In the chronic CFA-induced nociception model, AC treatment also improved mice pain threshold to 131.33% at 0.3 mg/kg, which was similar to aspirin group (152.03%). Above all, our results verified that AC had obviously analgesic effects in different mice pain models.


Assuntos
Aconitina/uso terapêutico , Analgésicos/uso terapêutico , Dor/tratamento farmacológico , Ácido Acético/toxicidade , Animais , Aspirina/uso terapêutico , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/patologia , Feminino , Formaldeído/toxicidade , Adjuvante de Freund/toxicidade , Temperatura Alta , Camundongos , Camundongos Endogâmicos C57BL , Dor/induzido quimicamente , Dor/patologia , Limiar da Dor
18.
Cell Death Discov ; 7(1): 42, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33649292

RESUMO

Golgi membrane protein 1 (GOLM1) was implicated in carcinogenesis of multiple types of cancer. However, Phosphoproteome landscapes of GOLM1 overexpression in lung cancer remain largely unknown. In this study, using data from the Cancer Genome Atlas (TCGA) and phosphoproteome, we systematically evaluated the feature of GOLM1 and studied its prognostic value in non-small cell lung cancer (NSCLC). The proliferation, migration, and invasion capacities in PC9 cell with GOLM1 overexpression were determined using Trans-well system assay. Tumor engrafts was visualized in mice models and confirmed by ex vivo. An increased expression of GOLM1 had shorter overall survival (OS) in patients with NSCLC in TCGA database. GOLM1 in single gene set enrichment analysis (GSEA) related to adherent's junction, cell cycle, and pathway in cancer. Overexpression of GOLM1 in GOLM1OE PC9 cells promoted cell proliferation, migration, and invasion. Decreased migration and invasion potential were also observed in knockdown of GOLM1 in GOLM1KD PC9 cells in migration assay. An increased expression of GOLM1 could significantly increase the growth of tumor in xenograft mice models. phosphoproteome analysis showed 239 upregulated and 331 downregulated Phosphorylated proteins in GOLM1OE PC9 cells. Overexpression of GOLM1 in GSEA was significantly related to P53 in MAPK signaling pathway. Overexpression of GOLM1enhanced the phosphorylation of P53 protein at site S315 but inhibited the formation of P53 tetramers. These results indicate that overexpression GOLM1 enhances non-small-cell carcinoma aggressiveness through inhibited the formation of P53 tetramer.

19.
J Cancer ; 12(8): 2285-2294, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33758606

RESUMO

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) significantly improve the outcome of non-small-cell lung cancer (NSCLC) patients with EGFR mutations, however, most TKI-treated patients will develop resistance to TKIs. ß-elemene, extracted from Curcuma aromatica Salisb., has been widely used to treat various malignant tumors, including TKI-resistant NSCLC, but, the effects and the molecular mechanisms remain unclear. In this study, the NCI-H1975 cell line harboring double mutations L858R/T790M was treated with varying concentrations of ß-elemene and/or erlotinib. The effects of ß-elemene on cell proliferation, migration, apoptosis, and the expression of relevant proteins of NCI-H1975 cells were evaluated. The results revealed that ß­elemene significantly inhibited the growth, colony formation capacity, wound healing ability of NCI-H1975 cells, and improved the sensitivity of NCI-H1975 cells to erlotinib. Compared with erlotinib alone, ß-elemene plus erlotinib significantly promoted the apoptosis of NCI-H1975 cells, accompanied by the down-regulated expression of P-mTOR, P-EGFR, CHOP proteins and up-regulated expression of P-AMPKα and Bax proteins. Taken together, these findings demonstrate that ß-elemene suppresses the proliferation and migration of TKI-resistant H1975 cells, and enhances the antitumor activity of erlotinib by inducing apoptosis through AMPK and MAPK pathways in TKI-resistant H1975 lung cancer cells, indicating that ß-elemene is a promising anti-cancer therapeutic candidate for TKI-resistant NSCLC.

20.
Brief Bioinform ; 22(5)2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-33418562

RESUMO

Machine-learning (ML)-based scoring functions (MLSFs) have gradually emerged as a promising alternative for protein-ligand binding affinity prediction and structure-based virtual screening. However, clouds of doubts have still been raised against the benefits of this novel type of scoring functions (SFs). In this study, to benchmark the performance of target-specific MLSFs on a relatively unbiased dataset, the MLSFs trained from three representative protein-ligand interaction representations were assessed on the LIT-PCBA dataset, and the classical Glide SP SF and three types of ligand-based quantitative structure-activity relationship (QSAR) models were also utilized for comparison. Two major aspects in virtual screening campaigns, including prediction accuracy and hit novelty, were systematically explored. The calculation results illustrate that the tested target-specific MLSFs yielded generally superior performance over the classical Glide SP SF, but they could hardly outperform the 2D fingerprint-based QSAR models. Although substantial improvements could be achieved by integrating multiple types of protein-ligand interaction features, the MLSFs were still not sufficient to exceed MACCS-based QSAR models. In terms of the correlations between the hit ranks or the structures of the top-ranked hits, the MLSFs developed by different featurization strategies would have the ability to identify quite different hits. Nevertheless, it seems that target-specific MLSFs do not have the intrinsic attributes of a traditional SF and may not be a substitute for classical SFs. In contrast, MLSFs can be regarded as a new derivative of ligand-based QSAR models. It is expected that our study may provide valuable guidance for the assessment and further development of target-specific MLSFs.


Assuntos
Bases de Dados de Proteínas , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Proteínas/química , Ligantes , Relação Quantitativa Estrutura-Atividade
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