Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

Predicting bioactive compounds and cancer-related molecular targets of lotus seedpod (Receptaculum Nelumbinis) based on network pharmacology and molecular docking

Background:Lotus seedpod(Receptaculum Nelumbinis)is the abundant by-products produced during lotus seed processing,and the sources are usually considered to be wastes and are abandoned outdoors or incinerated.This study aims at predicting its bioactive compounds and cancer-related molecular targets against six cancers,including lung cancer,gastric cancer,liver cancer,breast cancer,ovarian cancer and cervical cancer.Methods:Network pharmacology and molecular docking methods were performed.Results:Network pharmacology results indicated that 14 core compounds(liensinine,tetrandrine,lysicamine,tricin,sanleng acid,cireneol G,ricinoleic acid,linolenic acid,5,7-dihydroxycoumarin,apigenin,luteolin,morin,quercetin and isorhamnetin)and 10 core targets(AKT1,ESR1,HSP90AA1,JUN,MAPK1,MAPK3,PIK3CA,PIK3R1,SRC and STAT3)were screened for lotus seedpod against the six cancers.Molecular docking analysis suggested that the binding abilities between the core compounds and the core targets were mostly strong.GO analysis revealed that the intersected targets between the bioactive compounds of lotus seedpod and the six cancers were significantly related to biological processes,cell compositions and molecular functions.KEGG analysis showed that PI3K-Akt,TNF,Ras,MAPK,HIF-1 and C-type lectin receptor signaling pathways were notably involved in the anti-cancer activities of lotus seedpod against the six cancers.Conclusions:14 core compounds and 10 core targets were screened for lotus seedpod against lung cancer,gastric cancer,liver cancer,breast cancer,ovarian cancer and cervical cancer.This study supports the application of lotus seedpod in treating cancers,and promotes the recycling and the high-value utilization.

Chemotherapy and molecular targeting therapy for recurrent cervical cancer

For patients with primary stage IVB, persistent, or recurrent cervical cancer, chemotherapy remains the standard treatment, although it is neither curative nor associated with long-term disease control. In this review, we summarized the history of treatment of recurrent cervical cancer, and the current recommendation for chemotherapy and molecular targeted therapy. Eligible articles were identified by a search of the MEDLINE bibliographical database for the period up to November 30, 2014. The search strategy included the following any or all of the keywords： ＂uterine cervical cancer＂, ＂chemotherapy＂, and ＂targeted therapies＂. Since cisplatin every 21 days was considered as the historical standard treatment for recurrent cervical cancer, subsequent trials have evaluated and demonstrated activity for other agents including paclitaxel, gemcitabine, topotecan and vinorelbine among others. Accordingly, promising agents were incorporated into phase III trials. To examine the best agent to combine with cisplatin, several landmark phase III clinical trials were conducted by Gynecologic Oncology Group （GOG） and Japan Clinical Oncology Group （JCOG）. Through, GOG204 and JCOG0505, paclitaxel/cisplatin （TP） and paclitaxel/carboplatin （TC） are now considered to be the recommended therapies for recurrent cervical cancer patients. However, the prognosis of patients who are already resistant to chemotherapy, are very poor. Therefore new therapeutic strategies are urgently required. Molecular targeted therapy will be the most hopeful candidate of these strategies. From the results of GOG240, bevacizumab combined with TP reached its primary endpoint of improving overall survival （OS）. Although, the prognosis for recurrent cervical cancer patients is still poor, the results of GOG240 shed light on the usefulness of molecular target agents to chemotherapy in cancer patients. Recurrent cervical cancer is generally considered incurable and current chemotherapy regiments offer only modest gains in OS, particularly for patients with multiple poor prognostic factors. Therefore, it is crucial to consider not only the survival benefit, but also the minimization of treatment toxicity, and maximization of quality of life （QOL）.

Novel molecular targets in hepatocellular carcinoma

Globally,hepatocellular carcinoma(HCC)is a leading cause of cancer and cancerrelated deaths.The therapeutic efficacy of locoregional and systemic treatment in patients with advanced HCC remains low,which results in a poor prognosis.The development of sorafenib for the treatment of HCC has resulted in a new era of molecular targeted therapy for this disease.However,the median overall survival was reported to be barely higher in the sorafenib treatment group than in the control group.Hence,in this review we describe the importance of developing more effective targeted therapies for the management of advanced HCC.Recent investigations of molecular signaling pathways in several cancers have provided some insights into developing molecular therapies that target critical members of these signaling pathways.Proteins involved in the Hedgehog and Notch signaling pathways,Polo-like kinase 1,arginine,histone deacetylases and Glypican-3 can be potential targets in the treatment of HCC.Monotherapy has limited therapeutic efficacy due to the development of inhibitory feedback mechanisms and induction of chemoresistance.Thus,emphasis is now on the development of personalized and combination molecular targeted therapies that can serve as ideal therapeutic strategies for improved management of HCC.

Improving cancer therapy by combining cell biological, physical, and molecular targeting strategies

Successful cancer therapy depends on selective killing of tumor cells while sparing normal cells. Selectivity can be achieved through treatment strategies that target tumor cells. A recent report from the Li laboratory （1） describes an elegant strategy to selectively kill tumor cells by combining several targeting strategies based on cell biological, physical, and molecular （genetic） properties of tumor and normal cells that enhances tumor cell killing in vitro and in an in vivo tumor xenograft model. The idea of using a multiplex targeting approach is reminiscent of strategies in which several antibiotics are used to treat bacterial infections while minimizing the chance that rare antibiotic-resistant mutants will arise within a population.

Quantitative examination of the inhibitory activation of molecular targeting agents in hepatocellular carcinoma patient-derived cell invasion via a novel in vivo tumor model

Background: The outcomes for patients with advanced hepatocellular carcinoma(HCC) receiving sorafenib are far from satisfactory because of treatment resistance to sorafenib. However, the exact mechanism of resistance to sorafenib remains unclear and it is valuable to establish a novel mouse model to quantitatively analyze the inhibition rates of sorafenib on the invasive growth of HCC cells in the liver.Methods: HCC tissue microblocks derived from patients were cultured and mixed with hydrogel drops. Then, hydrogel drops containing microblocks of HCC tissue were attached onto the surface of the livers of nude mice to form lesions or nodules of HCC. The mice received molecular targeting agents through oral administration. Livers with tumor nodules were harvested for H&E staining(hematoxylin-eosin staining) analysis and H&E staining images were quantitatively analyzed using image J software. The invasive growth of HCC cells into the liver was calculated using the depth of the lesions compared with the total thickness of the liver.Results: Microblocks containing cells derived from HCC patients can form lesions in the liver of nude mice. Oral administration of molecular targeting agents inhibited the invasive growth of HCC cells in the liver of nude mice.Conclusions: The model established in this study involves the invasive growth of HCC cells in the liver of nude mice, and the model allows for the quantitative analysis of the inhibitory effect of molecular targeting agents on the invasion of HCC cells in vivo.

Molecular targeted therapy causes hepatic encephalopathy in patients after Transjugular intrahepatic portosystemic shunt(TIPS):A case report and literature review

We report two cases of hepatic encephalopathy caused by molecular targeted drugs after the Transjugular intrahepatic portosystemic shunt(TIPS)procedure in our center.The liver toxicities and anti-angiogenic effects induced by targeted drugs may generate an imbalance in ammonia metabolism,elevating blood ammonia levels.TIPS diverts partial blood supply from the liver,aggravates liver impairment,and shunts ammonia-rich blood from the intestine into the systemic circulation.These may be the mechanisms leading to hepatic encephalopathy caused by molecular targeted drugs following TIPS.When clinicians choose molecular targeted therapy as the second or third targeted therapy for patients who have undergone TIPS,the consequence of drug-induced hepatic encephalopathy should also be considered.

Mechanisms of hepatocellular carcinoma and challenges and opportunities for molecular targeted therapy

The incidence and mortality of hepatocellular carcinoma(HCC) have fallen dramatically in China and elsewhere over the past several decades. Nonetheless, HCC remains a major public health issue as one of the most common malignant tumors worldwide and one of the leading causes of death caused by cancer in China. Hepatocarcinogenesis is a very complex biological process associated with many environmental risk factors and factors in heredity, including abnormal activation of cellular and molecular signaling pathways such as Wnt/β-catenin, hedgehog, MAPK, AKT, and ERK signaling pathways, and the balance between the activation and inactivation of the proto-oncogenes and anti-oncogenes, and the differentiation of liver cancer stem cells. Molecule-targeted therapy, a new approach for the treatment of liver cancer, blocks the growth of cancer cells by interfering with the molecules required for carcinogenesis and tumor growth, making it both specific and selective. However, there is no one drug completely designed for liver cancer, and further development in the research of liver cancer targeted drugs is now almost stagnant. The purpose of this review is to discuss recent advances in our understanding of the molecular mechanisms underlying the development of HCC and in the development of novel strategies for cancer therapeutics.

Molecular targeting agents associated with transarterial chemoembolization or radiofrequency ablation in hepatocarcinoma treatment

Hepatocellular carcinoma(HCC)is the fifth most common cause of cancer in the world.According to Barcelona Clinic Liver Cancer modified criteria,patients with early stage disease are candidate to radiofrequency ablation(RFA),while patients with intermediate stage HCC are usually treated by transarterial chemoembolization(TACE).TACE and RFA induce a transient devascularisation effect followed by strong neoangiogenic stimulus.In fact,after these procedures,it has been demonstrated an up-regulation of pro-angiogenic and growth factors such as vascular endothelial growth factor-A,which might contribute to accelerated progression in patients with incomplete response.Several studies have demonstrated that MAP-kinase and AKT pathways,in addition to neo-angiogenesis,have an important role in the development of HCC.In advanced HCC,anti-angiogenic therapy and tyrosine kinases inhibitors showed potential clinical benefit.Actually,a number of clinical studies are ongoing testing these agents in combination with TACE or RFA.In this paper,we have reviewed the most recent preclinical and clinical results of such trials.

Molecular targeting to treat gastric cancer

Trastuzumab that targets human epidermal growth factor receptor 2(HER2) protein is the only approved molecular targeting agent for treating gastric cancer in Japan and the outcomes have been favorable. However,trastuzumab is effective for only 10% to 20% of the population with gastric cancer that expresses HER2 protein. Molecular targeting therapy with bevacizumab against vascular endothelial growth factors(VEGF) and with cetuximab and panitumumab against the epidermal growth factors pathway that have been approved for treating colorectal cancer are not considered effective for treating gastric cancer according to several clinical trials. However,ramucirumab that targets VEGF receptor-2 prolonged overall survival in a large phase Ⅲ clinical trial and it might be an effective molecular targeting therapy for gastric cancer. The significance of molecular targeting therapy for gastric cancer remains controversial. A large-scale randomized clinical trial of novel molecular targeting agents with which to treat gastric cancer is needed.

Molecular targeted therapy for hepatocellular carcinoma:Current and future

Hepatocellular carcinoma(HCC)is one of the most frequent tumors worldwide.The majority of HCC cases occur in patients with chronic liver disease.Despite regular surveillance to detect small HCC in these patients,HCC is often diagnosed at an advanced stage.Because HCC is highly resistant to conventional systemic therapies,the prognosis for advanced HCC patients remains poor.The introduction of sorafenib as the standard systemic therapy has unveiled a new direction for future research regarding HCC treatment.However,given the limited efficacy of the drug,a need exists to look beyond sorafenib.Many molecular targeted agents that inhibit different pathways involved in hepatocarcinogenesis are under various phases of clinical development,and novel targets are being assessed in HCC.This review aims to summarize the efforts to target molecular components of the signaling pathways that are responsible for the development and progression of HCC and to discuss perspectives on the future direction of research.

Emerging molecular targets and therapy for cholangiocarcinoma

Cholangiocarcinoma(CCA) is a rare cancer arising from the biliary tree with a poor prognosis and limited therapeutic options. Recent large scale molecular characterisation studies have identified recurrent genetic alterations in CCA which may be amenable to therapeutic targeting. In this review we explore the genomic landscape of CCA and examine results from trials of molecularly targeted agents and immunotherapy in this disease. Challenges in CCA diagnosis, treatment and trial design are discussed and we reflect on future directions which may lead to improved outcomes for CCA patients.

Anti-psoriasis molecular targets and active components discovery of Optimized Yinxieling Formula via affinity-purified strategy

Psoriasis,a prevalent inherited skin condition,involves an inflammatory response as a key pathogenic mechanism.The Optimized Yinxieling Formula(OYF),rooted in traditional Chinese medicine,is extensively utilized in clinical settings to treat psoriasis.Although previous studies have demonstrated OYF’s significant anti-inflammatory effects in psoriasis,its potential molecular targets and active components remain unexplored.This study aimed to unveil the anti-psoriasis molecular targets and active components of OYF.Our findings indicated that OYF extract markedly reduced the production of several inflammatory mediators,including IL-23,nitric oxide,TNF-α,and IL-1β,in LPS-induced RAW264.7 cells.We synthesized OYF extract-crosslinked beads to isolate pharmacological targets from RAW264.7 lysates using an affinity purification strategy,known as Target Fishing.The enriched target proteins were subsequently identified via LC-MS/MS,followed by bioinformatics analysis to map the psoriasis-associated pathway-gene network.We identified a total of 76 potential target proteins,which were highly associated with mRNA transcription mechanisms.In particular,pathway-gene network analysis revealed that the IL-23 inflammatory pathway was involved in the anti-psoriasis effect of OYF extract.We further utilized a target protein-based affinity capture strategy,combined with LC-MS and SPR analysis,to globally screen OYF’s active components,focusing on the mRNA transcription regulator,fused in sarcoma(FUS).This process led to the identification of umbelliferone,vanillic acid,protocatechuic acid,gentisic acid,and echinacoside as key compounds targeting FUS to inhibit IL-23 expression.Additionally,we formulated a compound cocktail(CpdC),which significantly reduced psoriasis area and severity index(PASI)scores and the expressions of IL-23 and Ki67 in an imiquimod(IMQ)-induced psoriasis mouse model.Collectively,our study elucidates the primary molecular targets and active components of OYF,offering novel insights for psoriasis treatment.

Clinical efficacies,underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management

Diabetic nephropathy(DN) has been recognized as a severe complication of diabetes mellitus and a dominant pathogeny of end-stage kidney disease,which causes serious health problems and great financial burden to human society worldwide.Conventional strategies,such as renin-angiotensinaldosterone system blockade,blood glucose level control,and bodyweight reduction,may not achieve satisfactory outcomes in many clinical practices for DN management.Notably,due to the multi-target function,Chinese medicine possesses promising clinical benefits as primary or alternative therapies for DN treatment.Increasing studies have emphasized identifying bioactive compounds and molecular mechanisms of reno-protective effects of Chinese medicines.Signaling pathways involved in glucose/lipid metabolism regulation,antioxidation,anti-inflammation,anti-fibrosis,and podocyte protection have been identified as crucial mechanisms of action.Herein,we summarize the clinical efficacies of Chinese medicines and their bioactive components in treating and managing DN after reviewing the results demonstrated in clinical trials,systematic reviews,and meta-analyses,with a thorough discussion on the relative underlying mechanisms and molecular targets reported in animal and cellular experiments.We aim to provide comprehensive insights into the protective effects of Chinese medicines against DN.

Network pharmacology-based prediction and verification of the molecular targets and pathways for schisandrin against cerebrovascular disease

AIM: To illuminate the molecular targets for schisandrin against cerebrovascular disease based on the combined methods of network pharmacology prediction and experimental verification. METHOD: A protein database was established through constructing the drug-protein network from literature mining data. The protein-protein network was built through an in-depth exploration of the relationships between the proteins. The computational platform was implemented to predict and extract the sensitive sub-network with significant P-values from the protein-protein network. Then the key targets and pathways were identified from the sensitive sub-network. The most related targets and pathways were also confirmed in hydrogen peroxide(H2O2)-induced PC12 cells by Western blotting. RESULTS: Twelve differentially expressed proteins(gene names: NFKB1, RELA, TNFSF10, MAPK1, CHUK, CASP8, PIGS2, MAPK14, CREB1, IFNG, APP, and BCL2) were confirmed as the central nodes of the interaction network(45 nodes, 93 edges). The NF-κB signaling pathway was suggested as the most related pathway of schisandrin for cerebrovascular disease. Furthermore, schisandrin was found to suppress the expression and phosphorylation of IKKα, as well as p50 and p65 induced by H2O2 in PC12 cells by Western blotting. CONCLUSION: The computational platform that integrates literature mining data, protein-protein interactions, sensitive sub-network, and pathway results in identification of the NF-κB signaling pathway as the key targets and pathways for schisandrin.

Delineation on Therapeutic Significance of Transporters as Molecular Targets of Drugs

Transporters are membrane proteins mediating permeation of organic and inorganic solutes through the plasma membrane and membranes of intracellular organella.They play essential roles in the epithelial absorption and cellular uptake of nutrients as well as absorption,distribution,metabolism,and excretion of drugs.Because transporters contribute to determining the distribution of compounds in the body in concert with metabolic/synthetic enzymes,the drugs that affect the functions of transporters are expected to alter the distribution of compounds in the body and to ameliorate disrupted homeostasis.In this context,drugs targeting transporters have been used clinically.Such drugs include antidepressants targeting monoamine transporters,diuretics targeting inorganic ion transporters of renal tubules,and uricosuric agents targeting renal urate transporters.Now new transporter-targeting drugs designed based on post-genome drug development strategy have been in the process of clinical trials or basic/clinical researches.For example,the inhibitors of renal Na+/glucose cotransporter SGLT2 have been proved for their efficacy in the treatment of diabetes mellitus.The cancer L-type amino acid transporter 1(LAT1) has been considered as a target of cancer diagnosis and therapeutics.The transporter-targeting drugs are expected to provide new rationale in the therapeutics of various diseases.

Molecular targets for modulating the protein translation vital to proteostasis and neuron degeneration in Parkinson’s disease

Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body formation in affected brain areas.The detailed pathogenic mechanisms underlying the selective loss of dopaminergic neurons in PD are unclear,and no drugs or treatments have been developed to alleviate progressive dopaminergic neuron degeneration in PD.However,the formation ofα-synuclein-positive protein aggregates in Lewy body has been identified as a common pathological feature of PD,possibly stemming from the consequence of protein misfolding and dysfunctional proteostasis.Proteostasis is the mechanism for maintaining protein homeostasis via modulation of protein translation,enhancement of chaperone capacity and the prompt clearance of misfolded protein by the ubiquitin proteasome system and autophagy.Deregulated protein translation and impaired capacities of chaperone or protein degradation can disturb proteostasis processes,leading to pathological protein aggregation and neurodegeneration in PD.In recent years,multiple molecular targets in the modulation of protein translation vital to proteostasis and dopaminergic neuron degeneration have been identified.The potential pathophysiological and therapeutic significance of these molecular targets to neurodegeneration in PD is highlighted.

Hyaluronic acid-based dual-responsive nanomicelles mediated mutually synergistic photothermal and molecular targeting therapies

Precise clinical treatment of triple-negative breast cancer(TNBC)is an obstacle in clinic.Nanotechnology-assisted photothermal therapy(PTT)is a superior treatment modality for TNBC in terms of precision.However,thermoresistance arising from PTT and insufficient drug release from nanocarriers decrease the efficacy of PTT.AT13387 is a novel HSP90 inhibitor that can weaken thermoresistance and undergoing clinic II phase study,showing satisfactory antitumour activity through molecularly targeted therapy(MTT).Whereas,it has poor solubility.Hence hyaluronic acid and stearic acid were connected by hydrazone bonds and disulfide bonds,forming an amphipathic copolymer that could self-assembled into nanomicelles,followed by encapsulating Cypate and AT13387.These nanomicelles exhibited great features,including achieving mutually synergistic PTT/MTT for overcoming thermoresistance and promoting translocation of drugs,increasing the solubility of Cypate and AT13387,showing a pH/redox dual response that contributes to drug release,and having the ability of active targeting.Thus,the nanomicelles developed in this study may be a promising strategy for the precise treatment of TNBC.

Erlotinib Analogue-substituted Zinc（Ⅱ） Phthalocyanines for Small Molecular Target-based Photodynamic Cancer Therapy

＂Smart＂ targeted photosensitizer conjugated with small molecule target-based anticancer drug which has a sim- ple chemical structure and high stability, is a new promising targeted therapeutic strategy. We herein extended this strategy and reported a novel series of zinc（II） phthalocyanine-erlotinib analogue conjugates with different periph- eral substituted positions and lengths of the linker. Having erlotinib analogue as the targeting moiety, all conjugates exhibited high specificity and potent affinity to HepG2 cancer cells and kept high photodynamic activity （ICs0 = 3.7 -- 16.7 nmol/L）. Structure-activity relationships of these conjugates were assessed by investigating their photophys- ical/photochemical properties, targeting intracellular uptake and in vitro phototoxicity. The results suggested that a-substituted conjugates showed slightly higher photodynamic activity than ,8-substituted ones. In conclusion, we have developed a series of promising anticancer agents with high tumor selectivity and anticancer activity for targeted photodynamic therapy.