A review of the literature on the use of CRISPR/Cas9 gene therapy to treat hepatocellular carcinoma.

Noncoding RNAs instruct the Cas9 nuclease to site-specifically cleave DNA in the CRISPR/Cas9 system. Despite the high incidence of hepatocellular carcinoma (HCC), the patient's outcome is poor. As a result of the emergence of therapeutic resistance in HCC patients, clinicians have faced difficulties in treating such tumor. In addition, CRISPR/Cas9 screens were used to identify genes that improve the clinical response of HCC patients. It is the objective of this article to summarize the current understanding of the use of the CRISPR/Cas9 system for the treatment of cancer, with a particular emphasis on HCC as part of the current state of knowledge. Thus, in order to locate recent developments in oncology research, we examined both the Scopus database and the PubMed database. The ability to selectively interfere with gene expression in combinatorial CRISPR/Cas9 screening can lead to the discovery of new effective HCC treatment regimens by combining clinically approved drugs. Drug resistance can be overcome with the help of the CRISPR/Cas9 system. HCC signature genes and resistance to treatment have been uncovered by genome-scale CRISPR activation screening, although this method is not without limitations. It has been extensively examined whether CRISPR can be used as a tool for disease research and gene therapy. CRISPR and its applications to tumor research, particularly in HCC, are examined in this study through a review of the literature.

Cocoa as immunomodulatory agent: an update.

Cocoa is rich in polyphenols, mainly flavonoids, which correlate with several health benefits mediated by their antioxidant, anti-inflammatory and immunomodulatory properties. Cocoa and chocolate consumption have been reported to impact the regulation of the immune system, both in preclinical studies and in human trials. The mechanisms for immunomodulation can involve different effects of cocoa polyphenols on the immune system, acting as anti-inflammatory, antioxidant and anti-allergic agents, as well as the direct influence of cocoa on innate and acquired immunity, with cytokines production and activation of both lymphocyte-dependent and -independent pathways. Cocoa intake has been also correlated to changes in gut microbiota ecology and composition, also affecting the intestinal immune system. This review summarises the updates of the last two decades on cocoa as immunomodulatory agent and explores the health-related benefits of cocoa and chocolate intake.

Biological activities of the aerial and undergound parts of Gymnadenia nigra Rchb.f. (syn. Nigritella nigra (L.) Rchb. f.) from the Italian Alps.

This study investigated the bioactivity of both aerial (GNAR) and underground (GNUG) parts of Gymnadenia nigra Rchb.f. (syn. Nigritella nigra (L.) Rchb. f.) (Orchidaceae). The obtained data proved interesting when the samples were tested in two adrenocortical cancer cell lines (SW13 and H295R). In particular, the GNAR 80% methanol extract distinctly inhibited their viability after 24 h at a concentration of 1 µg/µL by MTT assay and trypan blue dye exclusion method. Cell morphology evaluation by means Wright's staining also showed significant results, particularly in SW13 cells under the effect of both extracts. GNAR extract was able to scavenge the DPPH radical better than GNUG extract. It also was more active in albumin denaturation (a maximum % denaturation equal to 463.0 ± 8.3 vs 77.3 ± 13.3) and protease inhibition (a maximum % inhibition equal to 138.5 ± 7.0 vs 2.1 ± 2.0) tests. The results highlighted an important antitumor activity of G. nigra in vitro that deserves to be further studied.

Validation of miRNAs as diagnostic and prognostic biomarkers, and possible therapeutic targets in medullary thyroid cancers.

Introduction: Medullary thyroid cancer (MTC) is a rare type of neuroendocrine tumor that produces a hormone called calcitonin (CT). Thyroidectomy is the preferred treatment for MTC, as chemotherapy has been shown to have limited effectiveness. Targeted therapy approaches are currently being used for patients with advanced, metastatic MTC. Several studies have identified microRNAs, including miR-21, as playing a role in the development of MTC. Programmed cell death 4 (PDCD4) is a tumor suppressor gene that is an important target of miR-21. Our previous research has shown that high levels of miR-21 are associated with low PDCD4 nuclear scores and high CT levels. The aim of this study was to investigate the potential of this pathway as a novel therapeutic target for MTC. Methods: We used a specific process to silence miR-21 in two human MTC cell lines. We studied the effect of this anti-miRNA process alone and in combination with cabozantinib and vandetanib, two drugs used in targeted therapy for MTC. We analyzed the effect of miR-21 silencing on cell viability, PDCD4 and CT expression, phosphorylation pathways, cell migration, cell cycle, and apoptosis. Results: Silencing miR-21 alone resulted in a reduction of cell viability and an increase in PDCD4 levels at both mRNA and protein levels. It also led to a reduction in CT expression at both mRNA and secretion levels. When combined with cabozantinib and vandetanib, miR-21 silencing did not affect cell cycle or migration but was able to enhance apoptosis. Conclusion: Silencing miR-21, although not showing synergistic activity with TKIs (tyrosine kinase inhibitors), represents a potential alternative worth exploring as a therapeutic target for MTC.

Phytates as a natural source for health promotion: A critical evaluation of clinical trials.

Phytates are a type of organophosphorus compound produced in terrestrial ecosystems by plants. In plant feeds, phytic acid and its salt form, phytate, account for 60%-80% of total phosphorus. Because phytate is a polyanionic molecule, it can chelate positively charged cations such as calcium, iron, and zinc. Due to its prevalence in vegetal tissues and the fact that people consume plants, phytate was first considered a potential health benefit. This updated review aims to summarize the current data on the results of clinical trials of phytates on human health, highlighting both beneficial and undesirable effects. To obtain these updated data, published papers in electronic databases such as PubMed/MedLine, TRIP database, Wiley, Google Scholar, Baidu, and Scopus were searched. Study results have shown that phytate can have beneficial health effects such as antioxidant, anticancer potential and reduction of pathological calcifications in blood vessels and organs; but also, negative effects by reducing the absorption of minerals important for maintaining the homeostasis of the human body. According to these recent results derived from recent clinical studies, phytates may be a potential natural source for health benefits. To improve clinical efficacy and human health benefits, further dose-response studies are needed to determine effective therapeutic doses and potential interactions with conventional drugs.

Phenolic compounds as Nrf2 inhibitors: potential applications in cancer therapy.

Cancer is a leading cause of death worldwide and involves an oxidative stress mechanism. The transcription factor Nrf2 has a crucial role in cytoprotective response against oxidative stress, including cancer growth and progression and therapy resistance. For this reason, inhibitors of Nrf2 are new targets to be studied. Traditional plant-based remedies rich in phytochemicals have been used against human cancers and phenolic compounds are known for their chemopreventive properties. This comprehensive review offers an updated review of the role of phenolic compounds as anticancer agents due to their action on Nrf2 inhibition. In addition, the role of naturally-occurring bioactive anticancer agents are covered in the clinical applications of polyphenols as Nrf2 inhibitors. Video Abstract.

Natural essential oils as a new therapeutic tool in colorectal cancer.

Colorectal cancer (CRC) is the third most revalent type of cancer in the world and the second most common cause of cancer death (about 1 million per year). Historically, natural compounds and their structural analogues have contributed to the development of new drugs useful in the treatment of various diseases, including cancer. Essential oils are natural odorous products made up of a complex mixture of low molecular weight compounds with recognized biological and pharmacological properties investigated also for the prevention and treatment of cancer. The aim of this paper is to highlight the possible role of essential oils in CRC, their composition and the preclinical studies involving them. It has been reviewed the preclinical pharmacological studies to determine the experimental models used and the anticancer potential mechanisms of action of natural essential oils in CRC. Searches were performed in the following databases PubMed/Medline, Web of science, TRIP database, Scopus, Google Scholar using appropriate MeSH terms. The results of analyzed studies showed that EOs exhibited a wide range of bioactive effects like cytotoxicity, antiproliferative, and antimetastatic effects on cancer cells through various mechanisms of action. This updated review provides a better quality of scientific evidence for the efficacy of EOs as chemotherapeutic/chemopreventive agents in CRC. Future translational clinical studies are needed to establish the effective dose in humans as well as the most suitable route of administration for maximum bioavailability and efficacy. Given the positive anticancer results obtained from preclinical pharmacological studies, EOs can be considered efficient complementary therapies in chemotherapy in CRC.

Digestive and gastroprotective effects of Achillea erba-rotta subsp. moschata (Wulfen) I.Richardson (syn. A. moschata Wulfen) (Asteraceae): From traditional uses to preclinical studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Achillea erba-rotta subsp. moschata (Wulfen) I.Richardson (syn. A. moschata Wulfen) (Asteraceae) is an alpine endemic plant whose aerial parts are harvested by the locals mainly for the digestive properties. Despite its widespread use, few studies have been conducted to date to verify its bioactivity. AIM OF THE STUDY: The purpose of the work was to meet the tradition confirming with experimental data the popular belief that the consumption of this species offers beneficial effects to the gastrointestinal system. MATERIALS AND METHODS: Using Soxhlet apparatus, the dried aerial parts of A. erba-rotta subsp. moschata were successively extracted with petroleum ether (PET), dichloromethane (DCM) and methanol (MeOH). The essential oil (EO) was obtained by hydrodistillation using a Clevenger apparatus while infusion (AE) was prepared following the traditional local recipe. Their chemical characterization was performed by various techniques including SPME-GC/MS, GC/MS and HPLC/MS-MS. An in vitro biological screening was carried out. The influence of AE on lipid digestion was monitored by titration of free fatty acids (FFA) during pancreatic lipase activity with the pH-stat method. For all extracts and EO, the anti-Helicobacter pylori activity was assessed by the broth microdilution method, the influence on cell viability was evaluated against NCI-N87, OE21 and Caco-2 cell lines and a preliminary toxicity evaluation was done using Brine Shrimp lethality (BSL) assay. The anti-inflammatory potential was evidenced by interleukin IL-1- induced IL8 expression on Caco-2 cells. RESULTS: AE increased by 15% the FFA releasing compared to the pancreatic lipase alone. PET, DCM and MeOH extracts as well as AE and EO were considered active against the growth of both antimicrobial susceptible and resistant strains of H. pylori with MIC values starting from 16 µg/mL. PET and DCM (IC50 = 89 µg/mL and 96 µg/mL, respectively, against Caco-2 cell line) extracts showed the high effect on cell viability while the EO reduced in 50% of cell viability at 1.48 µL/mL (NCI-N87 cells), 1.42 µL/mL (OE21 cells), and 3.44 µL/mL (Caco-2 cells) corroborating the BSL results. In different degrees, all extracts and EO inhibited the IL-1ß-stimulated IL-8 production in Caco-2 cells. CONCLUSIONS: The obtained data are encouraging and provide a scientific basis for the traditional use of A. erba-rotta subsp. moschata as a digestive agent although they need to be further corroborated by studies involving the investigation of both the in vivo activities and the role of the compounds detected in the extracts.

Anticancer properties of bromelain: State-of-the-art and recent trends.

Bromelain is a key enzyme found in pineapple (Ananas comosus (L.) Merr.); a proteolytic substance with multiple beneficial effects for human health such as anti-inflammatory, immunomodulatory, antioxidant and anticarcinogenic, traditionally used in many countries for its potential therapeutic value. The aim of this updated and comprehensive review focuses on the potential anticancer benefits of bromelain, analyzing the cytotoxic, apoptotic, necrotic, autophagic, immunomodulating, and anti-inflammatory effects in cancer cells and animal models. Detailed information about Bromelain and its anticancer effects at the cellular, molecular and signaling levels were collected from online databases such as PubMed/MedLine, TRIP database, GeenMedical, Scopus, Web of Science and Google Scholar. The results of the analyzed studies showed that Bromelain possesses corroborated pharmacological activities, such as anticancer, anti-edema, anti-inflammatory, anti-microbial, anti-coagulant, anti-osteoarthritis, anti-trauma pain, anti-diarrhea, wound repair. Nonetheless, bromelain clinical studies are scarce and still more research is needed to validate the scientific value of this enzyme in human cancer diseases.

Myricetin: A comprehensive review on its biological potentials.

Myricetin is a critical nutritive component of diet providing immunological protection and beneficial for maintaining good health. It is found in fruits, vegetables, tea, and wine. The families Myricaceae, Polygonaceae, Primulaceae, Pinaceae, and Anacardiaceae are the richest sources of myricetin. Different researchers explored the therapeutic potential of this valuable constituent such as anticancer, antidiabetic, antiobesity, cardiovascular protection, osteoporosis protection, anti-inflammatory, and hepatoprotective. In addition to these, the compound has been tested for cancer and diabetic mellitus during clinical trials. Health benefits of myricetin are related to its impact on different cell processes, such as apoptosis, glycolysis, cell cycle, energy balance, lipid level, serum protein concentrations, and osteoclastogenesis. This review explored the potential health benefits of myricetin with a specific emphasis on its mechanism of action, considering the most updated and novel findings in the field.

Plant Natural Compounds in the Treatment of Adrenocortical Tumors.

Plant natural products are a plethora of diverse and complex molecules produced by the plant secondary metabolism. Among these, many can reserve beneficial or curative properties when employed to treat human diseases. Even in cancer, they can be successfully used and indeed numerous phytochemicals exert antineoplastic activity. The most common molecules derived from plants and used in the fight against cancer are polyphenols, i.e., quercetin, genistein, resveratrol, curcumin, etc. Despite valuable data especially in preclinical models on such compounds, few of them are currently used in the medical practice. Also, in adrenocortical tumors (ACT), phytochemicals are scarcely or not at all used. This work summarizes the available research on phytochemicals used against ACT and adrenocortical cancer, a very rare disease with poor prognosis and high metastatic potential, and wants to contribute to stimulate preclinical and clinical research to find new therapeutic strategies among the overabundance of biomolecules produced by the plant kingdom.

Clinical applications of artificial intelligence and machine learning in cancer diagnosis: looking into the future.

Artificial intelligence (AI) is the use of mathematical algorithms to mimic human cognitive abilities and to address difficult healthcare challenges including complex biological abnormalities like cancer. The exponential growth of AI in the last decade is evidenced to be the potential platform for optimal decision-making by super-intelligence, where the human mind is limited to process huge data in a narrow time range. Cancer is a complex and multifaced disorder with thousands of genetic and epigenetic variations. AI-based algorithms hold great promise to pave the way to identify these genetic mutations and aberrant protein interactions at a very early stage. Modern biomedical research is also focused to bring AI technology to the clinics safely and ethically. AI-based assistance to pathologists and physicians could be the great leap forward towards prediction for disease risk, diagnosis, prognosis, and treatments. Clinical applications of AI and Machine Learning (ML) in cancer diagnosis and treatment are the future of medical guidance towards faster mapping of a new treatment for every individual. By using AI base system approach, researchers can collaborate in real-time and share knowledge digitally to potentially heal millions. In this review, we focused to present game-changing technology of the future in clinics, by connecting biology with Artificial Intelligence and explain how AI-based assistance help oncologist for precise treatment.

Immunophenotypical characterization of paraneoplastic neurological syndrome patients: a multicentric study.

Paraneoplastic neurological syndromes (PNS) are a group of rare and severe immune-mediated disorders that affect the nervous system in patients with cancer. The best way to diagnose a paraneoplastic neurological disorder is to identify anti-onconeural protein antibodies that are specifically associated with various cancers. The aim of this multicentric study was to clinically and immunologically characterize patients with PNS and study their association with cancer. Patients suspected to have PNS were enrolled from various clinical centres and were characterized immunologically. This study population consisted of 112 patients. Onset of PNS was mainly subacute (76 %). PNS patients had various neurological disorders and symptoms. PNS developed before the diagnosis of cancer in 28 definite PNS patients and in six suspected PNS patients. The most frequent autoantibodies detected in PNS patients were anti-Hu and anti-Yo. One definite PNS patient with cerebellar syndrome had anti-Tr antibody and seven patients had atypical antibodies. The literature associates these antibodies with various neurological disorders and cancers. Our observations confirm the important role of autoantibodies in PNS and their importance for the early diagnosis of cancer in PNS patients.

The Wonderful Activities of the Genus Mentha: Not Only Antioxidant Properties.

Medicinal plants and their derived compounds have drawn the attention of researchers due to their considerable impact on human health. Among medicinal plants, mint (Mentha species) exhibits multiple health beneficial properties, such as prevention from cancer development and anti-obesity, antimicrobial, anti-inflammatory, anti-diabetic, and cardioprotective effects, as a result of its antioxidant potential, combined with low toxicity and high efficacy. Mentha species are widely used in savory dishes, food, beverages, and confectionary products. Phytochemicals derived from mint also showed anticancer activity against different types of human cancers such as cervix, lung, breast and many others. Mint essential oils show a great cytotoxicity potential, by modulating MAPK and PI3k/Akt pathways; they also induce apoptosis, suppress invasion and migration potential of cancer cells lines along with cell cycle arrest, upregulation of Bax and p53 genes, modulation of TNF, IL-6, IFN-γ, IL-8, and induction of senescence phenotype. Essential oils from mint have also been found to exert antibacterial activities against Bacillus subtilis, Streptococcus aureus, Pseudomonas aeruginosa, and many others. The current review highlights the antimicrobial role of mint-derived compounds and essential oils with a special emphasis on anticancer activities, clinical data and adverse effects displayed by such versatile plants.

Multivesicular Liposome (Depofoam) in Human Diseases.

Drug development is a key point in the research of new therapeutic treatments for increasing maximum drug loading and prolonged drug effect. Encapsulation of drugs into multivesicular liposomes (DepoFoam) is a nanotechnology that allow delivery of the active constituent at a sufficient concentration during the entire treatment period. This guarantees the reduction of drug administration frequency, a very important factor in a prolonged treatment. Currently, diverse DepoFoam drugs are approved for clinical use against neurological diseases and for post-surgical pain management while other are under development for reducing surgical bleeding and for post-surgical analgesia. Also, on pre-clinical trials on cancer DepoFoam can improve bioavailability and stability of the drug molecules minimizing side effects by site-specific targeted delivery. In the current work, available literature on structure, preparation and pharmacokinetics of DepoFoam are reviewed. Moreover, we investigated approved DepoFoam formulations and preclinical studies with this nanotechnology.

Phytochemical and pharmacological properties of asperuloside, a systematic review.

Plants are a natural source of bioactive compounds such as secondary metabolites. These molecules, also called phytochemicals, are fundamental for plant survival and often show therapeutic properties used for the treatment of human diseases. Asperuloside is a secondary metabolite which belongs to iridoid glycosides and is commonly present in the plant family Rubiaceae. In this review we aim to summarize the scientific knowledge on asperuloside, with a special emphasis on its pharmacological properties as anti-viral, anti-malarial, anti-protozoal, anti-tumorigenic, anti-hypertensive, anti-obesity, immunomodulatory, anti-inflammatory and antioxidant agent. Preclinical studies in animal models suggest that asperuloside has therapeutic potential that could be evaluated in humans. However, despite its tangible phytochemical characteristics, no clinical trial has been performed so far. Thus, we hope that this review will facilitate scientific dissemination of asperuloside pharmacological properties and encourage researchers to evaluate both pharmacokinetic and toxicity of asperuloside in animal models. This will be the first step towards clinical studies in humans.

Plant natural products with anti-thyroid cancer activity.

Thyroid cancer is the most frequent endocrine malignancy, with more than 500,000 cases per year worldwide. Differentiated thyroid cancers are the most common forms with best prognosis, while poorly/undifferentiated ones are rare (2% of all thyroid cancer), aggressive, frequently metastasize and have a worse prognosis. For aggressive, metastatic and advanced thyroid cancer novel antitumor molecules are urgently needed and phytochemical products can be a rational and extensive source, since secondary plant metabolites can guarantee the necessary biochemical variability for therapeutic purpose. Among bioactive molecules that present biological activity on thyroid cancer, resveratrol, curcumin, isoflavones, glucosinolates are the most common and used in experimental model. Most of them have been studied both in vitro and in vivo on this cancer, but rarely in clinical trial. This review summarizes phytochemicals, phytotherapeutics and plant derived compounds used in thyroid cancer.

Statins Reduce Intratumor Cholesterol Affecting Adrenocortical Cancer Growth.

Mitotane causes hypercholesterolemia in patients with adrenocortical carcinoma (ACC). We suppose that cholesterol increases within the tumor and can be used to activate proliferative pathways. In this study, we used statins to decrease intratumor cholesterol and investigated the effects on ACC growth related to estrogen receptor α (ERα) action at the nuclear and mitochondrial levels. We first used microarray to investigate mitotane effect on genes involved in cholesterol homeostasis and evaluated their relationship with patients' survival in ACC TCGA. We then blocked cholesterol synthesis with simvastatin and determined the effects on H295R cell proliferation, estradiol production, and ERα activity in vitro and in xenograft tumors. We found that mitotane increases intratumor cholesterol content and expression of genes involved in cholesterol homeostasis, among them INSIG, whose expression affects patients' survival. Treatment of H295R cells with simvastatin to block cholesterol synthesis decreased cellular cholesterol content, and this affected cell viability. Simvastatin reduced estradiol production and decreased nuclear and mitochondrial ERα function. A mitochondrial target of ERα, the respiratory complex IV (COXIV), was reduced after simvastatin treatment, which profoundly affected mitochondrial respiration activating apoptosis. Additionally, simvastatin reduced tumor volume and weight of grafted H295R cells, intratumor cholesterol content, Ki-67 and ERα, COXIV expression and activity and increase terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. Collectively, these data demonstrate that a reduction in intratumor cholesterol content prevents estradiol production and inhibits mitochondrial respiratory chain-inducing apoptosis in ACC cells. Inhibition of mitochondrial respiration by simvastatin represents a novel strategy to counteract ACC growth.

Nootkatone Inhibits Acute and Chronic Inflammatory Responses in Mice.

Nootkatone (NTK) is a sesquiterpenoid found in essential oils of many species of Citrus (Rutaceae). Considering previous reports demonstrating that NTK inhibited inflammatory signaling pathways, this study aimed to investigate the effects of this compound in mice models of acute and chronic inflammation. Murine models of paw edema induced by carrageenan, dextran, histamine, and arachidonic acid, as well as carrageenan-induced peritonitis and pleurisy, were used to evaluate the effects of NTK on acute inflammation. A murine model of granuloma induced by cotton pellets was used to access the impact of NTK treatment on chronic inflammation. In the acute inflammation models, NTK demonstrated antiedematogenic effects and inhibited leukocyte recruitment, which was associated with decreased vascular permeability, inhibition of myeloperoxidase (MPO), interleukin (IL)1-ß, and tumor necrosis factor (TNF)-α production. In silico analysis suggest that NTZ anti-inflammatory effects may also occur due to inhibition of cyclooxygenase (COX)-2 activity and antagonism of the histamine receptor type 1 (H1). These mechanisms might have contributed to the reduction of granuloma weight and protein concentration in the homogenates, observed in the chronic inflammation model. In conclusion, NTK exerted anti-inflammatory effects that are associated with inhibition of IL1-ß and TNF-α production, possibly due to inhibition of COX-2 activity and antagonism of the H1 receptor. However, further studies are required to characterize the effects of this compound on chronic inflammation.

LncRNAs as Potential Therapeutic Targets in Thyroid Cancer.

Thyroid cancer (TC) is the most common cancer of endocrine system. TC can be subdivided into 4 different entities, papillary, follicular, medullary and anaplastic thyroid cancer. Among them, anaplastic thyroid cancer has the poorest prognosis. Exploring new therapeutic approach may entail favorable prediction as well as increasing overall survival rate of patients. Long non-coding RNAs (lncRNAs), have vast implications in different cancer types. Although they are not transcribed into proteins, they can act as a harness in regulating a plethora of biological functions. They have been implicated in a decisive role in gene expression via modulation of both coding and non-coding RNAs. This article discuss the multi-facet role of lncRNA in thyroid cancer biology.
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