Understanding and Targeting the Colon Cancer Pathogenesis: A Molecular Perspective

Abstract Colorectal cancer (CRC) one of the leading cause of cancer-related deaths worldwide. With the presently available knowledge on CRC, it is understood that the underlying is a complex process. The complexity of CRC lies in aberrant activation of several cellular signaling pathways that lead to activation and progression of CRC. In this context, recent studies have pointed towards the role of developmental pathways like; hedgehog (HH), wingless-related integration site (WNT/ß-catenin) and Notch pathways that play a crucial role in maintenance and homeostasis of colon epithelium. Moreover, the deregulation of these signaling pathways has also been associated with the pathogenesis of CRC. Therefore, in the search for better therapeutic options, these pathways have emerged as potential targets. The present review attempts to highlight the role of HH, WNT/ß-catenin and Notch pathways in colon carcinogenesis

Conduction pathway and function of physical signals of moxibustion stimulus / 中国针灸

By reviewing the relevant literature in recent years, this paper analyzes the transformation and conduction of moxibustion physical signals, and explores the action mechanism of moxibustion. It is found that the different molecular targets activated by moxibustion photothermal signal are the keys to transform stimulation signal into biological signal. Photothermal signal transmits signal through neuroendocrine immune system and produces a series of biological reactions, thus regulating the functions of various systems of the body.

Prognostic values of expression of Let-7 family in breast cancer / 局解手术学杂志

Objective To explore the expression of miRLet-7 family members in breast cancer and its correlation with overall survivals (OS), and to find more effective molecular targets for breast cancer prevention and treatment.Methods Kaplan-Meier (KM) plotter online database was used to analyze the correlation among the expression of Let-7 family members (Let-7a, 7b, 7c, 7d, 7e, 7f, 7g, 7i, miR-98, miR-202) correlated with overall survival (OS) and the prognosis and clinical pathological parameters of breast cancer patients, and Hazard ratio (HR), 95％confidence interval (CI), and P value were determined.ResultsThe study showed that the high expression level of Let-7a, Let-7b, Let-7c, Let-7e, Let-7f, Let-7g, miR-98 and the low expression level of miR-202 was associated with better OS for breast cancer patients (P＜0.05).We further assessed the prognostic value of Let-7 in different subtypes and clinical stage.The expression of Let-7a, Let-7b, Let-7f, Let-7g, miR-98, miR-202 was related to clinical stage (P＜0.05).Let-7a, Let-7b, Let-7c, Let-7e, Let-7f, Let-7g, miR-98 and miR-202 was related to lymph node status (P＜0.05).In triple-negative breast cancers (TNBC), with breast cancer subtype, the expression of Let-7b, Let-7c, Let-7g and miR-202 was significantly correlated to overall survival (P＜0.05).Conclusion The Let-7 is significantly correlated with OS in breast cancer patients.The results suggested that members of the Let-7 have different values in predicting the prognosis of breast cancer.Among them, Let-7b, Let-7g and miR-202 are closely related with clinical stage and TNBC, and might promote development of Let-7 as targeted inhibitors for the treatment of breast cancer.

Ursolic acid: An overview on its cytotoxic activities against breast and colorectal cancer cells / 中西医结合学报

Ursolic acid (UA) is a pentacyclic triterpene of the ursane type. As a common chemical constituent among species of the family Lamiaceae, UA possesses a broad spectrum of pharmacological properties. This overview focuses on the anticancer properties of UA against breast cancer (BC) and colorectal cancer (CRC) that are most common among women and men, respectively. In vitro studies have shown that UA inhibited the growth of BC and CRC cell lines through various molecular targets and signaling pathways. There are several in vivo studies on the cytotoxic activity of UA against BC and CRC. UA also inhibits the growth of other types of cancer. Studies on structural modifications of UA have shown that the -OH groups at C3 and at C28 are critical factors influencing the cytotoxic activity of UA and its derivatives. Some needs for future research are suggested. Sources of information were from ScienceDirect, Google Scholar and PubMed.

Tsc1/Tsc2 complex: A molecular target of capsaicin for protection against testicular torsion induced injury in rats / 中草药·英文版

Objective: The detailed knowledge about protective effects of capsaicin (cap)and involved mechanisms against testicular torsion (TT)is still not available completely. Methods: Male Wistar rats were assigned into four major cohorts: (i)sham, (ii)TT, (iii)three subgroups subjected to TT and different doses of cap (100, 500, and 1000 µg/mL), and (iv)three subgroups of healthy animals subjected to various concentrations of cap. The animals were decapitated at 24 h after reperfusion, and the evaluation of protein expression was performed by Western blotting assay. At 72 h after reperfusion, apoptotic cell death and tissue injury were evaluated by TUNEL nuclear and H&E staining, respectively. Results: The results showed that cap administration following TT significantly increased the expression of tuberous sclerosis proteins 1 and 2 (Tsc1/Tsc2)in a dose-dependent manner (P < 0.05). Cap decreased cell apoptosis at highest dose. Likewise, cap contributed to the preservation of tubular morphology and decreased tissue injury at the highest tested concentration (1000 µg/mL). Conclusion: Collectively, our findings demonstrate the validity of cap as a therapeutic agent against TT through targeting Tsc1/Tsc2 in a dose-dependent manner.

Therapeutic role of Ricinus communis L. and its bioactive compounds in disease prevention and treatment

Ricinus communis L. (R. communis), commonly known as castor oil plant, is used as a traditional natural remedy or folkloric herb for the control and treatment of a wide range of diseases around the globe. Various studies have revealed the presence of diverse phytochemicals such as alkaloids, flavonoids, terpenes, saponins, phenolic compounds such as kaempferol, gallic acid, ricin, rutin, lupeol, ricinoleic acid, pinene, thujone and gentisic acid. These phytochemicals have been responsible for pharmacological and therapeutic effects, including anticancer, antimicrobial, insecticidal, antioxidant, anti-diabetic, antinociceptive, anti-inflammatory, bone regenerative, analgesic, and anticonvulsant activity. R. communis harbours phytochemicals which have been shown to target peroxisome proliferator activated receptor (PPAR), nuclear factor NF- κ -B, cytochrome p450, P38 mitogen-activated protein kinases kinase (p38 MAPK), tumor protein P53, B-cell lymphoma-extra-large (Bcl-xL) and vascular endothelial growth factor receptor-2 (VEGFR-2). Considering its wide variety of phytochemicals, its pharmacological activity and the subsequent clinical trials, R. communis could be a good candidate for discovering novel complementary drugs. Further experimental and advanced clinical studies are required to explore the pharmaceutical, beneficial therapeutic and safety prospects of R. communis with its phytochemicals as a herbal and complementary medicine for combating various diseases and disorders.

Progress on the molecular targeted therapy in esophageal cancer / 国际生物医学工程杂志

Esophageal cancer is the eighth most common cancer worldwide and one of the most common malignant tumors in China.Despite the continuous improvement in the methods of comprehensive treatment such as surgery,radiotherapy and chemotherapy,the prognosis and five-year survival rate of patients with esophageal cancer remain poor.Targeted therapy for esophageal cancer inhibits the proliferation and migration of esophageal cancer cells and promotes apoptosis by regulating related signaling pathways.Up to now,a variety of molecular targets and related regulatory mechanisms of esophageal cancer have been discovered,and a variety of targeted therapeutic drugs have been designed,some of which have achieved certain effects in clinical trials.At present,targeted molecular therapeutic targets such as HER-2,VEGFR,EGFR and other targeted therapeutic drugs (monoclonal antibodies and tyrosinase inhibitors) have achieved clinical effects in esophageal cancer treatments.Preliminary progress have been made in the study of some key kinases,such as such as mTOR,AXL,C-MET,AURKA,etc,in various signaling pathways,and the development of the relevant targeted therapeutic agents for esophageal cancer.Meanwhile,esophageal cancer immunotherapy targeting PD-1 shows good prospects,and the immunotherapy drugs,such as Pembrolizumab,have achieved good therapeutic effects.Additionally,new targets for esophageal cancer,such as MMP-9 and COX-2,have been found to be potential targets for esophageal cancer treatments.

Application and significance of molecular targeted nanotechnology in diagnosis and treatment of hepatocellular carcinoma / 中华肝胆外科杂志

Hepatocellular carcinoma (HCC) is one of the most common malignancies.Current radiological examination is quite limited in diagnosing early HCC.Various treatments for HCC have definite indications,and there is still no effective treatment and prevention for recurrence and metastasis.Based on the recent development of molecular targeting nanotechnology for specific molecules in liver cancer cells,early diagnosis and the monitoring of recurrence and metastasis for HCC can be improved,and the specificity of drug in targeting cancer cells and the therapeutic effect on HCC can be significantly enhanced.The article reviewed the application and significance of molecular targeting nanotechnology in HCC diagnosis and treatment.

Inflammatory Bowel Disease: Updates on Molecular Targets for Biologics

Therapy for inflammatory bowel disease (IBD) has changed, with several new agents being evaluated. The era of anti-tumor necrosis factor (anti-TNF) antibody therapy saw remarkable progress in IBD therapy. Some patients, however, do not respond to anti-TNF treatment, or their response decreases over time. This phenomenon highlights the need to identify new molecular targets for therapy in IBD. The targets of new therapeutic molecules in IBD must aim to restore immune dysregulation by the inhibition of proinflammatory cytokines (TNF-α, interleukin [IL]-6, IL-13, IL-17, IL-18, and IL-21) and augmentation of the effect of anti-inflammatory cytokines (IL-10, IL-11, and transforming growth factor β) and to pursue new anti-inflammatory targets, such as regulatory T-cell therapy, Smad7 antisense, Janus-activated kinase inhibition, Toll-like receptor stimulation, leukocyte adhesion, and blockade of T-cell homing via integrins and mucosal addressin cellular adhesion molecule-1. In addition, potential molecular targets could restore mucosal barrier function and stimulate mucosal healing. Despite these potential targets, the value and clinical significance of most new molecules remain unclear, and clinical efficacy and safety must be better defined before their implementation in clinical practice. This article aims to review the promising and emerging molecular targets that could be clinically meaningful for novel therapeutic approaches.

Research progress in anticancer effects and molecular targets of honokiol in experimental therapy / 药学学报

Honokiol (HNK), one of major biological active constituents of Mangnolia officinalis, exerts a wide range of biological functions, such as moderate anticancer effects. It inhibits the growth of lung cancer, gastrointestinal cancer, head and neck squamous cell carcinoma, breast cancer, prostate cancer, ovarian cancer, in vitro and in vivo through multiple potential molecular targets. It modulates apoptosis-associated signaling pathway, inhibits growth factor receptor-mediated signal transduction pathway, blocks nuclear factor-κB signaling pathway, decreases the expression level of androgen receptors, subsides mTOR and STAT3 signaling pathway, and so on. HNK enhances the inhibitory effects of traditional anticancer drugs or targeted antitumor drugs in vitro and in vivo. It reverses multidrug resistances of cancer cells to cisplatin, doxorubicin and paclitaxol. Therefore, HNK plays a role in the augmentation of antitumor effects of cancer drugs and the reversal of multidrug resistance of tumor cells. HNK is a promising biochemical modulator of anti-cancer medicines in the cancer therapy.

Carboplatin: molecular mechanisms of action associated with chemoresistance

Carboplatin is a derivative of cisplatin; it has a similar mechanism of action, but differs in terms of structure and toxicity. It was approved by the FDA in the 1980s and since then it has been widely used in the treatment of several tumor types. This agent is characterized by its ability to generate lesions in DNA through the formation of adducts with platinum, thereby inhibiting replication and transcription and leading to cell death. However, its use can lead to serious inconvenience arising from the development of resistance that some patients acquire during treatment, limiting the scope of its full potential. Currently, the biochemical mechanisms related to resistance are not precisely known. Therefore, knowledge of pathways associated with resistance caused by carboplatin exposure may provide valuable clues for more efficient rational drug design in platinum-based therapy and the development of new therapeutic strategies. In this narrative review, we discuss some of the known mechanisms of resistance to platinum-based drugs, especially carboplatin.

A carboplatina é um derivado da cisplatina, possuindo mecanismo de ação similar, diferindo em estrutura e toxicidade. Este fármaco foi aprovado pelo FDA em meados de 1980 e, desde então, tem sido amplamente usado no tratamento de diversos tipos de tumores. Este agente é caracterizado por sua habilidade em gerar lesões no DNA através da formação de adutos com a platina, inibindo a replicação e a transcrição, levando à morte celular. Entretanto, seu uso pode levar a graves inconvenientes, advindos do desenvolvimento de resistência que alguns pacientes adquirem durante o tratamento, limitando o alcance de seu potencial. Até então, os mecanismos bioquímicos relacionados ao problema da resistência não são precisamente conhecidos. Dessa forma, o conhecimento das vias associadas à resistência causada pela exposição à carboplatina pode prover valiosas informações para o planejamento racional de fármacos com base em platina mais eficiente e para o desenvolvimento de novas estratégias terapêuticas. Nesta revisão narrativa, serão discutidos alguns mecanismos de resistência a fármacos com base em platina, especialmente ao antitumoral carboplatina.

DETECCIÓN IN SILICO DE SEGUNDOS USOS DE MEDICAMENTOS CON POTENCIAL ACCIÓN LEISHMANICIDA / DETECTION IN SILICO OF SECOND USE DRUGS WITH POTENTIAL ANTI-LEISHMANIA ACTIVITY

Actualmente las enfermedades tropicales son objeto de importantes investigaciones en las ciencias biomédicas, debido al impacto global que causa en poblaciones vulnerables. Sin embargo son comúnmente ignoradas por la industria farmacéutica debido a su bajo potencial de rentabilidad económica. Por esta razón, la búsqueda de nuevos tratamientos terapéuticos por medios costo-efectivos es esencial para la lucha contra parásitos tropicales como Leishmania spp. En este trabajo se hizo una búsqueda y selección de medicamentos depositados en bases de datos públicas, y cuyo blanco de acción demostrado son proteínas conocidas. Con estas proteínas blanco de medicamentos, se hizo una búsqueda de ortólogos en el proteoma de Leishmania, con el fin de identificar rápidamente medicamentos que pudieran tener acción también contra este parásito, implementando herramientas in silico, basadas en la Bioinformática. También en el caso de poseer la estructura de las proteínas de interés, se realizó análisis de docking para corroborar la interacción con el medicamento. Empleando esta estrategia, se identificaron y seleccionaron 10 medicamentos que son evaluados actualmente en ensayos in vitro.

Currently, tropical diseases are a major subject of research in biomedical sciences due to its global impact on vulnerable populations. However, these diseases are normally ignored by pharmaceutical companies due to low profitability potential. For that reason, the search of new therapeutic treatments, that are cost-effective, is essential to fight against tropical parasites as Leishmania spp. In this work, a search and selection of drugs with known protein targets, which were deposited in public databases, was conducted. With these target proteins, a search for orthologs in the Leishmania proteome was carried out in order to identify drugs that could also have anti-leishmanial activity. For this purpose bioinformatics tools were implemented. In addition, in the case that Leishmania proteins have its tridimensional structure reported, docking analysis were simulated to corroborate interaction with the drug. At the end, a selection of 10 drugs was identified and is currently being evaluated in in vitro test.

Cancer biomarkers - Current perspectives.

In the recent years, knowledge about cancer biomarkers has increased tremendously providing great opportunities for improving the management of cancer patients by enhancing the efficiency of detection and efficacy of treatment. Recent technological advancement has enabled the examination of many potential biomarkers and renewed interest in developing new biomarkers. Biomarkers of cancer could include a broad range of biochemical entities, such as nucleic acids, proteins, sugars, lipids, and small metabolites, cytogenetic and cytokinetic parameters as well as whole tumour cells found in the body fluid. A comprehensive understanding of the relevance of each biomarker will be very important not only for diagnosing the disease reliably, but also help in the choice of multiple therapeutic alternatives currently available that is likely to benefit the patients. This review provides a brief account on various biomarkers for diagnosis, prognosis and therapeutic purposes, which include markers already in clinical practice as well as various upcoming biomarkers.

The Molecular Targets for the Diagnosis and Treatment of Pancreatic Cancer

Pancreatic cancer is considered an aggressive malignancy that responds poorly to current treatments and therefore has a dismal survival rate. This disease is usually not diagnosed until a late stage, at which point palliative chemotherapy with the purine analogue gemcitabine and/or a fluoropyrimidine or a platinum agent is the standard approach. There are some new data on the molecular and genetic changes that take place in pancreatic cancer, which may facilitate the accuracy of diagnosis and efficacy of treatments. However, translational efforts in clinical practice have increased clinicians' options with a targeted agent, erlotinib, in combination with the standard gemcitabine chemotherapy. Many other novel drugs currently being tested in the field of pharmaco-oncology target various altered biological pathways and molecules. Nevertheless, the lack of clinically significant improvements in treatments is rendering efforts to develop methods of early diagnosis both more urgent and promising. The aim of this review was to summarize the molecular basis of pancreatic carcinogenesis and the latest developments in diagnosis by molecular means, focusing on the results of clinical research into targeted and personalized treatments.

New molecular targets and novel agents for human hepatoma / 中国药理学通报

Current anti-hepatoma agents in clinical aplication have not been proved to be satisfactory. The major obstacles are low efficacy, toxicity, and drug resistance. Identifying new drug targets and discovering new agents accordingly with high efficacies and low toxicities have become the key part of the solution. Recent studies have shown that hyper-methylation of tumor suppressor genes, interaction between hepatocyte growth factor and its receptor, vascular endothelial growth factor and its receptor, as well as cyclooxygenase-2 might be potential targets for hepatomachemotherapy. Indeed, agents acting on these targets have shown to be effective. In addition, other agents such as As 2O3 have also shown their activities against hepatoma.

New molecular targets and novel agents for human hepatoma / 中国药理学通报

Current anti-hepatoma agents in clinical aplication have not been proved to be satisfactory. The major obstacles are low efficacy, toxicity, and drug resistance. Identifying new drug targets and discovering new agents accordin gly with high efficacies and low toxicities have become the key part of the solu tion. Recent studies have shown that hyper-methylation of tumor suppressor gene s, interaction between hepatocyte growth factor and its receptor, vascular endothelial growth factor and its receptor, as well as cyclooxygenase-2 might be potential targets for hepatomachemotherapy. Indeed, agents acting on these targets have shown to be effective. In addition, other agents such as As 2O 3 have also shown th eir activities against hepatoma.