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Novel drug discovery from the active ingredients of traditional Chinese medicine is the most distinctive feature and advantageous field of China, which has provided an unprecedented opportunity. However, there are still problems such as unclear functional substance basis, action targets and mechanism, which greatly hinder the clinical transformation of active ingredients in traditional Chinese medicine. Based on the analysis of the current status and progress of innovative drug research and development in China, this paper aimed to explore the prospect and difficulties of the development of natural active ingredients from traditional Chinese medicine, and to explore the efficient discovery of trace active ingredients in traditional Chinese medicine, and obtain drug candidates with novel chemical structure, unique target/mechanism and independent intellectual property rights, in order to provide a new strategy and a new model for the development of natural medicine with Chinese characteristics.
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Medicine, Chinese Traditional , Drugs, Chinese Herbal/chemistry , Research , Drug Discovery , ChinaABSTRACT
Gastric cancer (GC) is one of the most common malignant tumors worldwide, and most of the patients are diagnosed at the advanced stage. Most of the treating options are comprehensive treatment, in which immunotherapy plays more and more important role. Melanoma antigen-associated gene-A (MAGE-A) family is a kind of cancer testis antigens. Except in germ cells of testis and trophoblast cells of placenta, MAGE-A family is highly expressed in cancerous tissues and participates in a variety of biological processes, such as cancer cell proliferation, differentiation and metastasis. In addition, cancer testis antigen also possesses good immunogenicity, which can induce humoral and cellular immune responses, is a good target for immunotherapy, and has good application value in the diagnosis, treatment and prognosis of GC. A variety of targeted therapeutic drugs based on MAGE-A are in phase I or II clinical trials, it has good safety and potential clinical application value. With the continuous progress of clinical trials and basic research on MAGE-A targets in GC, it is expected to provide a theoretical basis for clinical transformation and immunotherapy of MAGE-A in the future.
Subject(s)
Male , Humans , Stomach Neoplasms/therapy , Antigens, Neoplasm/genetics , Melanoma , Immunotherapy , PrognosisABSTRACT
Small cell lung cancer （SCLC） accounts for about 15% in lung cancer and is highly malignant， heterogeneous and invasive. Etoposide combined with platinum-based chemotherapy is the basis of standard first-line treatment for extensive-stage SCLC， but suffers from the problem of susceptibility to drug resistance and relapse. In recent years， the emergence of new immunological drugs and novel cytotoxic drugs has improved the survival of SCLC patients to a certain extent， especially bringing therapeutic hope to patients with relapsed/refractory SCLC. In this paper， we review the current clinical drug regimens and the new progress of potential target drug therapeutic regimens for the treatment of SCLC. At present， the first-， second- and third-line schemes of SCLC include etoposide+carboplatin， atezolizumab+etoposide+platinum， adebrelimab， topotecan， docetaxel， etc.； the current drug targets for the treatment of SCLC mainly focus on topoisomerase Ⅱ/Ⅰ， DNA， the immune checkpoint molecules programmed death-1/programmed death-ligand 1， tubulin， etc. The potential target drug therapeutic options include alisertib+ paclitaxel， rovalpituzumab， APG-1252， etc.， and mainly focus on DNA damage response pathways and immune pathways， which can achieve the prolongation of patient survival by exerting anti-tumor effects through aurora kinase A and other potential targets.
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@#The human gut microbiota regulates many host pathophysiological processes including metabolic, inflammatory, immune and cellular responses. In recent years, the incidence and mortality of lung cancer have increased rapidly, which is one of the biggest challenges in the field of cancer treatment today, especially in non-small cell lung cancer. Animal models and clinical studies have found that the gut microbiota of non-small cell lung cancer patients is significantly changed compared with the healthy people. The gut microbiota and metabolites can not only play a pro-cancer or tumor suppressor role by regulating immune, inflammatory responses and so on, but also be related with radiotherapy and chemotherapy of non-small cell lung cancer and the resistance of immunotherapy. Therefore, gut microbiota and related metabolites can be both potential markers for early diagnosis and prognosis in patients with non-small cell lung cancer and novel therapeutic targets for targeted drugs. This study will review the latest research progress of effect of gut microbiota on non-small cell lung cancer, and provide a new diagnosis and treatment ideas for non-small cell lung cancer.
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Resumen Introducción: las guías de práctica clínica en diabetes mellitus (DM) establecen objetivos clínicos precisos sobre el buen manejo de la enfermedad, pero poco se sabe sobre el adecuado cumplimiento en nuestro medio. El sobrepeso y el sedentarismo han generado estigmas de síndrome metabólico en la población con DM1. Objetivos: evaluar el cumplimiento en cinco de dichos criterios: HbA1c <7%, c-LDL ≤100 mg/dl, actividad física ≥3 veces/ semana, tensión arterial sistólica (TAS) <140 mm Hg y no tabaquismo, y su asociación con insulinorresistencia determinada por la tasa estimada de disposición de glucosa (TeDG). Materiales y métodos: en 415 DM1 ≥18 años, 52% mujer y una edad de 34,8±13,9 años, se evaluó HbA1c, c-LDL, frecuencia semanal de actividad física (AF) estructurada, TAS y tabaquismo actual. Se determinó el grado de asociación a género, edad, antigüedad de la DM, nivel de educación, cobertura médica, índice de masa corporal (IMC) y sensibilidad a la insulina medida a través de la TeDG. Las variables cualitativas se analizaron por test de chi. y las cuantitativas por test de ANOVA I con post hoc por test de Tukey. Un valor de p<0,05 se consideró estadísticamente significativo. En todos los casos se utilizó un intervalo de confianza del 95%. Resultados: el 94,8% presentó TAS <140 mm Hg, el 82,2% no tabaquismo actual, el 56,5% c-LDL ≤100 mg/dL, el 39% AF ≥3 veces/semana y el 20,3% HbA1c <7%. Solo 26 pacientes (6,2%) alcanzaron en forma combinada los cinco objetivos analizados. El cumplimiento de dichos objetivos se asoció a nivel de educación secundaria o mayor (p=0,002) y cobertura de salud con obra social o prepaga (p=0,002). Hubo asociación significativa entre la TeDG en quienes cumplieron los cinco objetivos (p=0,02) y en forma individual en cuatro de ellos (TAS, c-LDL, HbA1c y AF). Conclusiones: de los 415 pacientes evaluados, el 6,2% cumplió los cinco objetivos. Solo el control de la TAS, no fumar y un c-LDL <100 mg/dL lo cumplió la mayoría de los pacientes. Una HbA1c <7% fue el objetivo individual que presentó menor grado de cumplimiento.
Abstract Introduction: the clinical practice guidelines in diabetes mellitus (DM) establish precise clinical objectives for the good management of the disease, but little is known about adequate compliance in our environment. Being overweight and sedentary have generated stigmas of metabolic syndrome in the population with DM1. Objectives: to evaluate the compliance with 5 of these criteria: HbA1c <7%, c-LDL ≤100 mg/dL, physical activity (PA) ≥3 times/week, systolic blood preasure (SBP) <140 mm Hg, and no smoking and its association with insulin resistance determined by the estimated glucose disposition rate (eGDR). Materials and methods: in 415 DM1 ≥18 years, 52% women, age 34.8±13.9 years, HbA1c, c-LDL, weekly frequency of structured PA, SBP, and current smoking were evaluated. The degree of association with gender, age, age of DM, level of education, medical coverage, BMI, and insulin sensitivity measured through eGDR was determined. Qualitative variables were analyzed by chi-square test and quantitative variables by ANOVA I test and analysis post hoc by Tukey's test for multiple comparisons. A value of p<0.05 was considered statistically significant. A 95% confidence interval was used in all cases. Results: systolic BP <140 mm Hg presented 94.8%, current non-smoking 82.2%, c-LDL ≤ 100 mg/dL 56.5%, physical activity (PA) ≥3 times a week 39% and HbA1c <7% 20.3%. Only 26 patients (6.2%) achieved the 5 objectives analyzed in combination. The fulfillment of the 5 objectives was associated at the level of ≥ secondary education (p=0.002) and health coverage with social welfare or prepaid (p=0.002). There was a significant association between TeDG in those who fulfilled the 5 objectives (p=0.02) and individually in 4 of them (SPB, c-LDL, HbA1c, and PA). Conclusions: of the 415 patients evaluated in our study, only 6.2% met the 5 criteria under consideration. Only control of SBP, non-smoking and c-LDL <100 were complied with by the majority of the patients. HbA1c <7% was the individual objective with the lowest degree of compliance.
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Neddylation,a novel post-translational modification of proteins, is overactivated in digestive system tumors and can be used as a potential anti-tumor molecular target. Targeting Neddylation pathway plays an anti-tumor role by inducing cell cycle arrest, apoptosis, senescence and autophagy of digestive system tumor cells, as well as enhancing the sensitivity of digestive system tumor cells to the radiotherapy and chemotherapy. Targeting Neddylation pathway and its inhibnitor MLN4924 can act as poential targets against digestive system tumors.
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Objective:To study the expression and clinical significance of collagen type Ⅰ alpha 2 chain (COL1A2) in glioma , and its effect on the migration and invasion of glioma cell lines.Methods:Through in-depth mining of the data related to COL1A2 in the Oncomine database, meta-analysis of its expression in different types of tumors, different grades and different molecular types of glioma, and then through the Chinese glioma genome map project (Chinese Glioma Genome Atlas, CGGA) database to explore the relationship between its expression level and the prognosis of glioma patients. The COL1A2 gene was functionally annotated by gene ontology (GO) and Pathway analysis. The annotation content includes cell components, biological processes, molecular functions and related signal pathways.Results:A total of 426 research results on COL1A2 in different types of tumors were collected in the Oncomine database, 114 of which were statistically different, 103 studies with increased COL1A2 expression, and 11 studies with decreased expression; the analysis shows there were 22 studies on high expression of COL1A2 in tumors, and no studies on low expression. Analysis of different grades of glioma and different molecular types of glioma Compared with the control group, COL1A2 was highly expressed in various types of glioma. Through the analysis of the gene chip data of the CGGA database, it was found that in glioblastoma, low expression levels of COL1A2 were significantly associated with an improved prognosis in patients with glioma ( P<0.05). Next, through GO and Pathway annotations, it was found that COL1A2 was involved in the biological processes of NAD metabolic salvage pathway, cell and cell signal transduction, circadian rhythm regulation and so on. Finally, through the construction of overexpression and knockdown cell lines in glioblastoma cell lines U87 and T98, scratch experiments and transwell cell function experiments confirmed that COL1A2 can significantly promote the migration and invasion of glioblastoma cell lines. Conclusions:Low expression levels of COL1A2 were significantly associated with improved prognosis in patients with glioma. Knockdown and overexpression of COL1A2 on glioblastoma cell lines U87 and T98 manifested that COL1A2 can promote glioblastoma cell lines migration and invasion ability. Based on the above results, COL1A2 may be used as an indicator for judging the prognosis of glioblastoma and as a potential biological target for therapy.
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ObjectiveTo conduct a systematic review of the susceptibility gene polymorphism sites of primary knee osteoarthritis (PKO). MethodsThe literature on genetic susceptibility and gene polymorphisms of PKO were retrieved from PubMed, Web of Science, CNKI, Wanfang Data, and China Biomedical Literature Database from establishment of the library to December, 2020, and systematically reviewed. ResultsA total of 42 papers on the polymorphism sites of human PKO susceptibility genes were included, involving cellular signaling pathways related to PKO pathogenesis, including inflammatory response, receptor signaling pathway, transcription factor signaling pathway, bone-related signaling pathway, etc. Multiple gene polymorphism sites located in inflammatory factor genes, chemokine genes, Toll-like receptor genes, transcription factor genes, obesity-related genes, and bone-related genes. ConclusionInflammatory factor genes and bone-associated allele polymorphisms are likely to be related to PKO susceptibility.
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@#Diabetic retinopathy(DR)is a kind of multi-factor mediated diseases, currently accepted DR environment that is caused by chronic high blood glucose metabolic abnormalities caused by, but it is regulated by the genetic factors, is considered to be a classic case of complex diseases, can be attributed to genetic factors, environmental factors and the interaction of the results. Genetic studies on the occurrence and development of DR have achieved some results, but the specific pathogenic genes and their pathogenesis are still not clear. In this study, potential DR susceptibility genes and their polymorphisms have been identified so far, so as to provide reference for further study of DR pathogenic genes and their pathogenesis.
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Systemic lupus erythematosus (SLE) is a chronic and autoimmunity-mediated diffuse connective tissue disease. The mainstay of treatments for SLE mainly relies on corticosteroids and immunosuppressants, which have a series of unavoidable side effects. Therefore, it is of fundamental importance to search novel therapeutic targets for better treatment with favorable efficacy and minor side effects. Recent studies shed light on potential therapeutic targets for SLE, mainly covering the followings: B-cell/plasmocyte-related targets [B cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), CD20, CD22, CD19/FcγRIIb, Bruton tyrosine kinase (Btk), and proteasome], T cell-related targets [calcineurin, mammalian target of rapamycin (mTOR), regulatory factor X1 (RFX1), and Rho kinase], macrophage-related targets (macrophage migration inhibitory factor), intracellular signaling molecules, cytokines (cereblon, histone deacetylase 6, Janus activated kinase/signal transducer and activator of transcription), co-stimulating factors (CD28/B7, CD40/CD154), IgE autoantibody, and gut microbiome. Among them, belimumab (a humanized monoclonal antibody against B-lymphocyte stimulator) and telitacicept (a recombinant human B-lymphocyte stimulator receptor-antibody fusion protein) have been sequentially approved for the clinical treatment of SLE in China. A variety of new targeted-therapy drugs are in the Phase 2 or Phase 3 clinical trials,among which anifrolumab (a human monoclonal antibody against type I interferon receptor subunit 1) has completed a Phase 3 clinical trial with good responses achieved, although its incidence of herpes zoster is higher than that in the control group. The research progress in both molecular mechanisms and new drug development for different therapeutic targets have greatly promoted our better and in-depth understanding of the pathogenesis of SLE, and have also reflected the complexity and heterogeneity of the disease. Successful development and clinical application of more novel therapies would no doubt usher in a new era of individualized treatment for SLE in the future.
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Humans , Antibodies, Monoclonal/therapeutic use , B-Lymphocytes , Graft vs Host Disease , Immunosuppressive Agents , Lupus Erythematosus, Systemic/drug therapyABSTRACT
@#Oral lichen planus (OLP) is a chronic inflammatory disease of the mucosa, some of which will develop into oral squamous cell carcinoma (OSCC). However, the pathogenesis of OLP remains unknown, but autoimmunity has been suggested as a potential cause. MicroRNAs (miRNAs), which are small noncoding RNAs, have been reported to be involved in a series of physiological events as well as the progression of diseases. The evidence indicates that miRNAs may be highly related to both the initiation and malignant progression of OLP. MiR-146a, miR-26b, miR-155, miR-19a and miR-125a are able to trigger OLP by regulating autoimmunity, and miR-137, miR-125b, and miR-27b may accelerate the carcinogenesis of OLP. These miRNAs may be potential targets for prognosis and treatment. Subsequent studies are expected to focus on a more comprehensive exploration of the role of miRNAs in OLP (including specific action pathways and other OLP-related miRNAs), as well as the potential for miRNAs to predict the treatment outcome of OLP. This review provides an updated summary of the roles of miRNAs in OLP to provide new ideas and approaches to OLP research.
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The incidence of non-alcohol fatty liver disease (NAFLD) is increasing year by year, and the relevant cardiovascular events have become a major problem in chronic diseases management. The activation of innate immunity is closely related to the development of NAFLD. The immune cells include Kupffer cells, neutrophils, dendritic cells, and natural killer T cells, which acts through the activation of innate immunity-related signals mediated by pattern recognition receptors.
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Humans , Immunity, Innate , Kupffer Cells , Liver , Non-alcoholic Fatty Liver DiseaseABSTRACT
Resumen: Las dianas terapéuticas para el control en el dolor postoperatorio son cada vez más conocidas. Entre ellas se encuentran las implicadas en canales de voltaje, iónicos, transportadores, ligadas a proteínas G, de reconocimiento molecular, peptídicos, neutróficos, enzimáticos, citoquínicos, celular, epigenético y genético. Además, podemos dividir a las dianas terapéuticas en tres grandes grupos dependiendo de su injerencia: las que actúan en el dolor agudo, aquéllos que irrumpirán en la generación de dolor crónico y los enfocados a la hiperalgesia. Claro está que casi todos están implicados en el mecanismo de los tres grupos de dolor, aunque infieren de manera más concisa en uno de ellos.
Abstract: The therapeutic targets for control in postoperative pain are increasingly well known. Among them are those involved in voltage, ion, transporter, G-protein, molecular recognition, peptide, neutrophic, enzymatic, cytokinic, cellular, epigenetic and genetic channels. We can also divide the therapeutic targets into three large groups depending on their interference; those that act in acute pain, those that will break into the chronic pain generation and those focused on hyperalgesia. Of course, almost everyone is involved in the mechanism of the three pain groups although they infer more concisely in one of them.
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Long non-coding RNAs (LncRNAs) are non-coding RNAs with a length of more than 200 bp. Cellular senescence is a stable proliferative stagnation state, which is irreversible and may be caused by a variety of factors, such as telomere shortening, oncogene induction or oxidative stress. Multiple factors are involved in cellular senescence, in which p53/p21 and pl6/Rb are major regulators of cellular senescence in different cell types. Cellular aging has been extensively studied as a powerful tumor suppressor mechanism to counter the emergence of oncogenes. In this review, the mechanism of action and therapeutic targets of LncRNAs in senescent cells are explored in depth.
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ABSTRACT The hemoflagellate protozoan, Trypanosoma cruzi, mainly transmitted by triatomine insects through blood transfusion or from mother-to-child, causes Chagas' disease. This is a serious parasitic disease that occurs in Latin America, with considerable social and economic impact. Nifurtimox and benznidazole, drugs indicated for treating infected persons, are effective in the acute phase, but poorly effective during the chronic phase. Therefore, it is extremely urgent to find innovative chemotherapeutic agents and/or effective vaccines. Since piplartine has several biological activities, including trypanocidal activity, the present study aimed to evaluate it on two T. cruzi strains proteome. Considerable changes in the expression of some important enzymes involved in parasite protection against oxidative stress, such as tryparedoxin peroxidase (TXNPx) and methionine sulfoxide reductase (MSR) was observed in both strains. These findings suggest that blocking the expression of the two enzymes could be potential targets for therapeutic studies.
Subject(s)
Piperidones/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/chemistry , Plant Extracts/pharmacology , Proteins/analysis , Reference Values , Mass Spectrometry , Trypanosoma cruzi/metabolism , Electrophoresis, Gel, Two-Dimensional , Reproducibility of Results , Oxidative Stress , ProteomicsABSTRACT
Molecular pathology is playing an increasingly important role in the treatment and overall management of patients with colorectal carcinoma. Three distinct genetic pathways have been identified that play a role in carcinogenesis: the chromosomal instability pathway, the microsatellite instability pathway, and the CpG island methylator phenotype pathway. Certain genetic mutations, some of which overlap with the aforementioned pathways, can also indicate that a carcinoma patient has a genetic predisposition syndrome, such as familial adenomatous polyposis, Lynch syndrome, and hamartomatous polyposis syndromes. A variety of advanced methods, including next-generation sequencing, are available to test for these and other mutations, such as targetable mutations that may allow tailoring of a treatment regimen to a patient's specific cancer (e.g., KRAS and BRAF mutations). The possible future role of testing circulating tumor cells is also addressed. New mutations and syndromes continue to be discovered, ensuring that our knowledge of colorectal carcinoma and our ability to treat it will advance in the future (AU)
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Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Neoplastic Syndromes, Hereditary , Colorectal Neoplasms/genetics , Chromosomal Instability , Pathology, Molecular , CarcinogenesisABSTRACT
Tumor cell energy metabolism is dependent on glycolysis and oxidative phosphorylation.Tumor cells,because of its rapid growth,often show increased intake of glucose and other nutrients,increased glycolysis and so on.In recent years,the study on energy metabolism of tumor cells has received extensive attention.This paper summarizes the required nutrients,regulatory networks and therapeutic targets in the energy metabolism of tumor cells,and provides important reference for future research and clinical treatment.
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Objective@#To investigate differentially expressed genes associated with liver cancer using bioinformatics methods, and to screen out molecular markers for early diagnosis of liver cancer and potential molecular targets for immunotherapy.@*Methods@#The microarray data associated with liver cancer were downloaded from Gene Expression Omnibus. JMP software was used for correlation analysis of GSE datasets, Limma program in R language was used to screen out differentially expressed genes, and the Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis were performed for differentially expressed genes. A protein-protein interaction (PPI) network was also established for analysis. An analysis of specific expression associated with liver cancer was performed with reference to RNA-seq transcriptome data for other tumors obtained from TCGA to further identify specific differentially expressed genes in liver cancer, and a survival curve analysis was performed for patients with liver cancer.@*Results@#A total of 92 differentially expressed genes were identified, with 21 upregulated genes and 71 downregulated genes. Through the GO, KEGG, and PPI analyses, RNA-seq data verified that only glypican 3 (GPC3) was upregulated in liver cancer, and MBL2, SDS, SLCO1B3, TDO2, SAA4, and SPP2 were downregulated.@*Conclusions@#GPC3 might act as a target for immunotherapy, and other molecular markers may become molecular markers for early detection of liver cancer and potential targets for immunotherapy.
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Long non-coding RNAs ( lncRNAs) are a class of RNA molecules which are unable to codify proteins. They express abnormally in tumor cells including prostate cancer cells and play a significant role in development of tumor. Some lncRNAs have been proven to affect physiological processes of prostate cells and act as tumor suppressor or activator and could be regulated through several methods. Thus, lncRNAs have the potential to be therapeutic targets of prostate cancer. This review introduces expressed abnormally ln-cRNAs in prostate cancer and their functions and mechanisms in prostate cancer.
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Nonalcoholic fatty liver disease(NAFLD) is a kind of metabolic liver injury, which is closely associated with insulin resistance and genetic susceptibility. Traditional Chinese herbs used in the treatment of nonalcoholic fatty liver disease are widely investigated in recent years. A series of recent studies show that the effects of the active components in traditional Chinese herbs on NAFLD are associated with activating AMPK signaling pathway, improving insulin resistance, modulating the activity and expression of peroxisome proliferator-activated receptor γ, antioxidant and anti-inflammatory activities and regulating intestinal flora. In this review, the potential therapeutic targets of the active components from traditional Chinese herbs for NAFLD would be summarized to provide a new thought for further research and clinical treatment of nonalcoholic fatty liver disease.