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- Volume 23, Issue 14, 2022
Current Pharmaceutical Biotechnology - Volume 23, Issue 14, 2022
Volume 23, Issue 14, 2022
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Strategy of Virtual Screening based Discovery of HSP90 C-terminal Inhibitors and Network Pharmacological Analysis
Authors: Lihong Li, Man Yang, Chenyao Li, Hongyu Xue, Meiyun Shi and Yajun LiuBackground: HSP90 has been considered an important anticancer target for several decades, but traditional HSP90 N-terminal inhibitors often suffered from organ toxicity and/or drug resistance. Methods: The development of HSP90 C-terminal inhibitors represents a reliable alternative strategy. In view of rare examples of structure-based identification of HSP90 C-terminal inhibitors, we report a virtual screening based strategy for the discovery of HSP90 C-terminal inhibitors as anticancer agents from natural products. Results & Discussion: 13 chemical ingredients from licorice were identified as possible HSP90 inhibitors and 3 of them have been reported as anticancer agents. The binding modes towards HSP90 C-terminus were predicted by molecular docking and refined by molecular dynamics simulation. Conclusion: Further network pharmacological analysis predicted overall possible targets involved in the pathways in cancer and revealed that 8 molecules possibly interact with HSP90. A structure based virtual screening strategy was established for the discovery of HSP90 Cterminal inhibitors.
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Oridonin Induces Oxidative Stress-mediated Cancer Cells Apoptosis via Targeting Thioredoxin Reductase
Authors: Dongzhu Duan, Xiaolu Feng, Dabo Pan, Le Wang, Yanru Wang and Xiaoling WangBackground: Thioredoxin reductase (TrxR) plays vital role in regulating cellular redox balance as well as redox-mediated signal transduction. Accumulating evidence supports that overactivation of TrxR is closely related to tumorigenesis and that targeting TrxR ablation reverses the growth of numerous malignant tumors, making TrxR a promising target for cancer chemotherapy. Thus, the discovery and development of molecules as promising anticancer agents that target TrxR is of great significance. Oridonin was shown to inhibit TrxR activity, but the detailed cellular mechanism is largely unknown. Objective: The study investigated the mechanism of action and underlying inhibitory properties of oridonin on TrxR in HeLa cells. Methods: A covalent docking was performed to reveal the possible interaction between oridonin and TrxR by Schrödinger Software Suite. TrxR activity was determined by 5,5’-dithiobis-2- nitrobenzoic acid reduction assay and endpoint insulin reduction assay. Sulforhodamine B and colony formation assay were employed to assess the viability and growth of cells. Reactive oxygen species level was measured by probe 2’, 7’-dichlorfluorescein diacetate, and dihydroethidium. Hoechst 33342 staining, caspase 3 activation, and fluorescein-5-isothiocyanate-conjugated Annexin V and propidium iodide double staining were used to evaluate apoptosis. Results: Here, we reported the oridonin as a potent inhibitor of TrxR. Inhibition of TrxR results in a decrease of thiols content and total glutathione, elevates reactive oxygen species levels, and finally promotes oxidative stress-mediated apoptosis of cancer cells. Conclusion: Targeting TrxR by oridonin discloses a novel molecular mechanism underlying the biological action of oridonin and sheds light on developing oridonin as a potential tumor therapeutic agent.
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FLG Gene Mutation Up-regulates the Abnormal Tumor Immune Response and Promotes the Progression of Prostate Cancer
Authors: Peng Zhang, Zesheng An, Changhai Sun, Yong Xu and Zhihong ZhangBackground: Prostate Cancer (PCa) ranks sixth with regard to the cause of cancerinduced male diseases worldwide, and inflammation is closely associated with its morbidity, deterioration, and prognosis. Tumor Mutation Burden (TMB) is identified to be the most common biomarker for the prediction of immunotherapy. But it is still unclear about the relationship of gene mutations in PCa with TMB and immune response. Objectives: To study the relationship between gene mutation and anti-tumor immune response in the prostate cancer tumor microenvironment. Methods: In the present work, the PCa somatic mutation data were collected from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) datasets. Results: As a result, 8 genes with high mutation frequency, including TP53, PTEN, TTN, FLG, CTNNB1, SPOP, MUC16, and KMT2C, were discovered to be covered by 4 cohorts from the United States, Canada, the United Kingdom, and China. Overall, the FLG mutation was related to a greater TMB, which predicted the dismal prognostic outcome. Besides, the CIBERSORT algorithm and Gene Set Enrichment Analysis (GSEA) were adopted for analysis, which revealed that FLG mutation remarkably promoted immune response in the context of PCa and accelerated cancer development. To sum up, FLG shows a high mutation frequency in PCa, and is related to the increase in TMB, up-regulation of abnormal immune responses in tumors, and promotion of tumor progression. Conclusion: Therefore, it may be used as a biomarker to predict the abnormal immune responses and provide a therapeutic target for immunotherapy in the treatment of PCa.
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New Advances of CRISPR/Cas9 Technique and its Application in Disease Treatment and Medicinal Plants Research
Authors: He-Fang Wan, Wen-Jing Han, Lei Zhou, Shuo Wang and Chun SuiBackground: Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 technology is widely used in disease treatment and medicinal plant improvements due to its advantages, such as easy operation, low time consumption, and high efficiency. However, potential off-target risks still exist in practical applications and need to be solved urgently. Objectives: This study aimed to review the application progress of CRISPR/Cas9 technology in the field of disease treatment and medicinal agriculture in recent years. Furthermore, the study discusses the ways to reduce the off-target effect of CRISPR/Cas9 technology, providing a reference for the further application of this technology. Methods: CiteSpace software was used to analyze relevant literature data from 2013 to August 2021, and search results were retrieved from Web of Science, PubMed, and CNKI databases. Results: In the field of disease treatment, CRISPR/Cas9 technology has great potential to cure challenging human diseases and has been widely used in drug target development, drug design, and screening. In crop breeding, CRISPR/Cas9 accelerates the improvement of crop varieties and shortens the number of years of crop breeding. By adjusting the length and GC content of sgRNA and changing the concentration of Cas9/sgRNA complex to reduce the off-target effect of CRISPR/Cas9 technology, the target genes can be manipulated more accurately. Conclusion: CRISPR/Cas9 technology is an indispensable and key technology in the field of disease treatment and medicinal plants. With the in-depth study of the off-target effect, CRISPR/Cas9 technology can have broader application prospects in the fields of medicine and medicinal agriculture.
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Xenobots: Applications in Drug Discovery
Authors: Nilay Solanki, Sagar Mahant, Swayamprakash Patel, Mehul Patel, Umang Shah, Alkesh Patel, Hardik Koria and Ashish PatelThis review work discusses the applications of xenobots in drug discovery. These are the world's first tiny robots that are living. Robots are built of metals and other things that benefit humans to solve various issues; however, in this case, small xenobots were built utilizing Xenopus laevis, frog embryonic stem cells in the blastocyte stage. Xenobots were created by combining bioscience, artificial intelligence, and computer science. Artificial intelligence constructs several forms of design in an in vitro, In-silico model, after which software analyzes the structure; the most substantial and most noticeable forms are filtered out. Later in vivo development create the design of the Petri plate using the MMR solution and makes the same form as the in silico approach. Ultimately evaluation done based on the behavior, movement, function, and features of xenobots. Xenobots are employed in medical research, pharmaceutical research to evaluate novel dosage forms, also useful for biotechnological and environmental research. Xenobots can be utilized to cure neurodegenerative disorders such as Alzheimer's, Parkinson's disease, and cancer-related issues because of their selfrepairing properties, which allow them to repair normal damaged cells, and convey drugs to their specific target, and reduce cytotoxicity in mostly malignancy circumstances. In the future, new approaches will be employed to treat chronic illnesses and their complications.
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Strategies Employed to Evade the Host Immune Response and the Mechanism of Drug Resistance in Mycobacterium tuberculosis: In Search of Finding New Targets
Authors: Bashir A. Sheikh, Basharat A. Bhat, Zahoor Ahmad and Manzoor A. MirThe partial effectiveness of the host immune response to M. tuberculosis drives bacteria into a latent state, but it is difficult to eliminate the bacteria completely. Usually, this latent condition of M. tuberculosis is reversible, and reactivation of tuberculosis is the leading cause of the majority of transmission. A number of studies performed on animal models and humans have not yet provided a detailed understanding of the mechanisms or correlates of immunity of M. tuberculosis infection or why there is a significant immunity failure to remove the pathogen. Moreover, the mechanism of resistance involved in drug-resistant M. tuberculosis leads to the emergence of strains of bacteria that show significant resistance to the majority of anti-tuberculosis drugs. We have also provided the recent findings and trends regarding the development of new drug molecules to treat drug and multidrug-resistant tuberculosis and the advancements in immunotherapy in the treatment of drug-resistant tuberculosis. This article provides an in-depth and critical analysis of various strategies employed by the drug-resistant M. tuberculosis to escape the host immune response. This bacterium persists in the host for a longer period of time and leads to the development of tuberculosis infection. Furthermore, we also discussed the new targets for the effective treatment of drug-resistant tuberculosis.
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Review on Natural Bioactive Products as Radioprotective Therapeutics: Present and Past Perspective
Authors: Seema Raj, Romila Manchanda, Meena Bhandari and Md. S. AlamAmong conventional treatment methodologies, surgery, hyperthermia, radiation, and chemotherapy have become integral components of treatment for most cancers. Radiation therapy in the treatment of many malignancies is always the better choice over surgery and chemotherapy. Ionizing radiation produced as a consequence of using these radiations has always been a concern in these treatment methods. Synthetic radio-protectors with their inherent limitations are being used to date to reduce the mortality of these radiations; still, it compromises the clinical efficacy of these administrations. Hence, investigations for alternative methods, including natural resources such as plant and fruit extracts, are being explored to treat radiation-mediated ailments. The present review article endeavors to provide a comprehensive, updated, and chronological account of these promising plants and fruit extracts and their bioactive principles as radio-protectors. We present the merits and demerits of radiation therapy and cell stress generation of reactive oxygen species (ROS) associated with radiation need and availability of radio-protectors. Finally, we discuss green-based bioactive compounds that have radioprotective properties.
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Nanotech-based Food: An Initiative for Alternative Pharmaceuticals
Authors: Riddhi Trivedi and Pravin ShendeNanotechnology opens many avenues in the food sector and offers applications associated with food production, processing, cultivation, and packaging. Nanofood employs nanotechniques like nano-encapsulation to conjugate various phytochemicals, antioxidants, probiotics, minerals, vitamins, etc., into nanovehicles. Food fortification strategies are implemented to incorporate nano-processed substances. Nanofood is mostly used for improving health and as a supplementation in various diseases ranging from liver diseases to neurodegenerative disorders. Here, we focus on recent studies that exhibit comparable results for nanofood and conventional medicines, subsiding the limitations of traditional therapies. Nanofood holds the potential for the management of various health problems and can be used as an alternative to medicine in clinical conditions, like cancers and inflammatory bowel disease. With further advances in nanotechnology and expansion in the scope of the current nanofood industry, in addition to proper regulations set in place, nanofood may offer a wide variety of advantages in terms of safety, long-term stability, etc.
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Study on Single-molecule Biophysics and Biochemistry in Dilute Liquids and Live Cells without Immobilization or Significant Hydrodynamic Flow: The Thermodynamic Single-molecule Demon
Authors: Gerd Baumann and Zeno Foldes-PappSince mathematics provides a way to answer questions about the thermodynamic jitter in a clear, rational manner, with evidence to support it, mathematics is the reliable method necessary to get the best information on the movement of a single molecule / a single particle at the molecular scale in dilute liquids and live cells without immobilization or hydrodynamic flow. The Brownian movement (normal diffusive systems) and generally the thermodynamic jitter (anomalous diffusive systems) are ultimately the direct or indirect cause of every measurement signal at the molecular scale in diffraction limited and unlimited optical systems in dilute liquids and live cells without immobilization or hydrodynamic flow. For example, emitted photons are the epiphenomenon of the underlying process of thermodynamic jitter of single molecules / single particles at the molecular scale. The key question is: How far apart do two molecules / two particles have to be in the time domain so that the required degree of separation between the two individual molecules / the two individual particles can be quantified at the molecular scale in order to distinguish them as separate entities without immobilization or hydrodynamic flow? The Földes-Papp’s limits of the singlemolecule time resolution in dilute liquids and live cells without immobilization or hydrodynamic flow are the exact answers. The diffusive process is complicated and not minimalist. A minimalist model has a third possibility, it may be right but irrelevant.
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Profiling of Biologically Active Metabolites of Spergula fallax L. Using High-resolution UPLC-QTOF-MS
Authors: Taghreed Ibrahim, Mostafa Hegazy and Atef El-HelaBackground: Medicinal plants are recognized to have a wide range of important biological activities, Spergula fallax L. is a well-known plant while phytochemical and biological activities screening of the species are rare. Objective: This study aims to evaluate the antioxidant, anticáncer, antimicrobial, and antiviral activities of the methanol extract (ME) of the aerial parts of Spergula fallax L. and its successive fractions; n-hexane (HF), ethyl acetate (EAF), and n-butanol (BF) fractions and identify their biologically active metabolites. Methods: Ultra-performance liquid chromatography (UPLC) coupled to quadrupole high-resolution time-of-flight mass spectrometry (QTOF-MS) was utilized to establish the metabolic profile of Sergula fallax L. Total phenol and flavonoids content were determined colorimetrically using Folin Ciocalteu and aluminum chloride reagents, respectively. 1,2-diphenyl-1-picrylhydrazyl (DPPH) was utilized for estimation of antioxidant activity, cytotoxic activity was determined on Hep-G2, HCT- 116, and MCF-7 cell lines, and agar diffusion method was used for screening of antimicrobial activity while cytopathic effect inhibition assay was utilized for antiviral assay. Results: Twenty-eight metabolites were identified, flavonoids were predominated (26), it was characterized by the presence of four main aglycones (Apigenin, luteolin, quercetin and kaempferol) with their O and/or C-glycosides based on its MS fragments. ME and EAF significantly scavenged DPPH in a dose-dependent manner with IC50 16.99 and 18.74 μg.mL-1, respectively. Among the tested samples, only ME and EAF showed significant cytotoxic activity against the tested cell lines with IC50 ranging from 5.541- 9.509 μg.mL-1. All tested samples significantly inhibited the growth of the tested bacterial strains with inhibition zone diameters ranging from 11.2- 26.4 mm and showed a wide range of antiviral activity. Conclusion: Generally, S. fallax is potentially bioactive as evident by antioxidant, cytotoxic, antibacterial, and antiviral assays. These activities are correlated with its identified metabolites. The results proved that S. fallax has promising medicinal activities and would be examined in future clinical trials for herbal therapy.
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Ezetimibe Prevents IL-1β-induced Inflammatory Reaction in Mouse Chondrocytes via Modulating NF-κB and Nrf2/HO-1 Signaling Crosstalk
Authors: Qiuyan Weng, Tongzhou Hu, Xiaohan Shen, Jinming Han, Yong Zhang and Jianning LuoBackground: Osteoarthritis is a type of age-related, chronic, and degenerative joint disease. Ezetimibe, a cholesterol absorption inhibitor, is widely used for the treatment of various diseases. However, the role of ezetimibe in osteoarthritis remains unclear. Objectives: This study aimed to explore the anti-inflammation effect of ezetimibe on mouse chondrocytes. Methods: In the present study, ELISA, qPCR and western blot analysis were performed to evaluate the anti-inflammatory effects of ezetimibe. In addition, enzymes that are highly associated with the anabolism and catabolism of the extracellular matrix of the articular cartilage were also evaluated. Results: Treatment with ezetimibe attenuated the IL-1β-induced degradation of the extracellular matrix, including aggrecan and collagen II. Ezetimibe also attenuated the IL-1β-induced expression levels of MMP3, MMP13 and ADAMTS5, thus exerting protective effects against IL-1β- induced extracellular matrix degradation. The complex mechanism of the anti-inflammatory reaction contributed to the activation of the Nrf2/HO-1 pathway and the suppression of the NF-ΚB pathway. Conclusion: On the whole, the present study demonstrates that ezetimibe may be a promising agent for further osteoarthritis therapy.
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Volumes & issues
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Volume 25 (2024)
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Volume 24 (2023)
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Volume 23 (2022)
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Volume 22 (2021)
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Volume 21 (2020)
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Volume 20 (2019)
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Volume 19 (2018)
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Volume 18 (2017)
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Volume 17 (2016)
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Volume 16 (2015)
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Volume 15 (2014)
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Volume 14 (2013)
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Volume 13 (2012)
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Volume 12 (2011)
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Volume 11 (2010)
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Volume 10 (2009)
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Volume 9 (2008)
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Volume 8 (2007)
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Volume 7 (2006)
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Volume 6 (2005)
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Volume 5 (2004)
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Volume 4 (2003)
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Volume 3 (2002)
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Volume 2 (2001)
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Volume 1 (2000)