A New Glucosyl Flavone with Inhibitory Activity of Cancer Cell Viability and Other Bioactive Constituents from the Traditional Kurdish Plant Plantago loeflingii L.

A new glucosyl flavone, 5,7,2',5'-tetrahydroxyflavone 7-O-ß-d-glucopyranoside, named loeflingiin, together with apigenin 6-C-glucoside (isovitexin), coumarins citropten and isompinellin, triterpenoids betulin and betulinic acid, and a mixture of phytosterols ß-sitosterol, stigmasterol and campesterol were isolated for the first time from the leaves of wild Plantago loeflingii L. (Plantaginaceae) collected in the Iraqi Kurdistan region. The plant is used by local people to treat wounds and as a vulnerary remedy. The structures of isolated compounds were determined by spectroscopic analysis. The activities of isovitexin and loeflingiinon the viability of breast (MCF7), ovarian (BG-1), endometrial (Ishikawa), and mesothelioma (IST-MES1) human cancer cells and two normal cell lines were determined with an MTT assay. Notably, the new 7-O-glucosyl flavone showed effects higher than cisplatin against the Ishikawa and IST-MESI cell lines. The significant biological activities exhibited by all the compounds isolated from P. loeflingii provided scientific evidence to support the use of the plant in the Kurdish traditional medicine.

Melatonin in Chemo/Radiation Therapy; Implications for Normal Tissues Sparing and Tumor Suppression: An Updated Review.

Resistance to therapy and the toxicity of normal tissue are the major problems for efficacy associated with chemotherapy and radiotherapy. Drug resistance is responsible for most cases of mortality associated with cancer. Furthermore, their side effects can decrease the quality of life for surviving patients. An enhancement in the tumor response to therapy and alleviation of toxic effects remain unsolved challenges. One of the interesting topics is the administration of agents with low toxicity to protect normal tissues and/or sensitize cancers to chemo/radiotherapy. Melatonin is a natural body hormone that is known as a multitasking molecule. Although it has antioxidant properties, a large number of experiments have uncovered interesting effects of melatonin that can increase the therapeutic efficacy of chemo/radiation therapy. Melatonin can enhance anticancer therapy efficacy through various mechanisms, cells such as the immune system, and modulation of cell cycle and death pathways, tumor suppressor genes, and also through suppression of some drug resistance mediators. However, melatonin may protect normal tissues through the suppression of inflammation, fibrosis, and massive oxidative stress in normal cells and tissues. In this review, we will discuss the distinct effects of melatonin on both tumors and normal tissues. We review how melatonin may enhance radio/chemosensitivity of tumors while protecting normal tissues such as the lung, heart, gastrointestinal system, reproductive system, brain, liver, and kidney.

Chemical Composition and In Vitro Evaluation of Antioxidant and Antiproliferative Effects of Volatile Oils Hydrodistilled from Onobrychis carduchorum C.C. Towns., a Kurdish Traditional Plant.

The volatile oils hydrodistilled from the aerial parts and roots of O. carduchorum C.C Towns. (Fabaceae) have been chemically characterized for the first time. A total of 43 constituents with an abundance >0.03% were identified and quantified in the two oils by GC/MS and GC/FID analyses. They comprise 38 components (98.58%) of the oil isolated from the aerial parts (OCA) and 34 components (93.33%) of the oil from the roots (OCR). Six constituents, α-pinene (23.11 ± 0.1%), ß-elemene (17.33 ± 0.1%), 1,8-cineole (12.15 ± 0.2%), furfural (7.91 ± 0.1%), terpineol-4-ol (6.32 ± 0.2%), and limonene (4.13 ± 0.1%), accounted for about 75% of the total OCA oil. On the other hand, 1,8-cineole (15.79 ± 0.1%), furfural (10.44 ± 0.1%), ß-elemene (10.14 ± 0.2%), α-terpineol (7.74 ± 0.1%), linalool (7.45 ± 0.1%), and α-pinene (4.76 ± 0.1%) made up about 60% of the OCR oil. The IC50 values of the scavenging activities of the OCA and OCR oils towards the DPPH radical and H2O2 were 79.8 ± 0.5 and 153.3 ± 0.6 µg/mL and 394.09 ± 0.2 and 311.67 ± 0.4 µg/mL, respectively. In addition, in the MTS assay, the OCA and OCR oils showed significant antiproliferative effects against T47D, MDA-MB-453, BG-1, and A549 human cancer cells that were more powerful than those against two normal human cell lines, HEK-293 and HFF-1. The abundant presence of ß-elemene as an antiproliferative component of the two oils suggested the existence of a new chemotype of O. carduchorum.

A Systematic Review of the Chemo/Radioprotective Effects of Melatonin against Ototoxic Adverse Effects Induced by Chemotherapy and Radiotherapy.

BACKGROUND: Although chemotherapy and radiotherapy are effective in cancer treatment, different adverse effects induced by these therapeutic modalities (such as ototoxicity) restrict their clinical use. Co-treatment of melatonin may alleviate the chemotherapy/radiotherapy-induced ototoxicity. OBJECTIVE: In the present study, the otoprotective potentials of melatonin against the ototoxicity induced by chemotherapy and radiotherapy were reviewed. METHODS: According to the PRISMA guideline, a systematic search was carried out to identify all relevant studies on "the role of melatonin against ototoxic damage associated with chemotherapy and radiotherapy" in the different electronic databases up to September 2022. Sixty-seven articles were screened based on a predefined set of inclusion and exclusion criteria. Seven eligible studies were finally included in this review. RESULTS: The in vitro findings showed that cisplatin chemotherapy significantly decreased the auditory cell viability compared to the control group; in contrast, the melatonin co-administration increased the cell viability of cisplatin-treated cells. The results obtained from the distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) tests demonstrated a decreased amplitude of DPOAE and increased values of ABR I-IV interval and ABR threshold in mice/rats receiving radiotherapy and cisplatin; nevertheless, melatonin co-treatment indicated an opposite pattern on these evaluated parameters. It was also found that cisplatin and radiotherapy could significantly induce the histological and biochemical changes in the auditory cells/tissue. However, melatonin co-treatment resulted in alleviating the cisplatin/radiotherapy-induced biochemical and histological changes. CONCLUSION: According to the findings, it was shown that melatonin co-treatment alleviates the ototoxic damage induced by chemotherapy and radiotherapy. Mechanically, melatonin may exert its otoprotective effects via its anti-oxidant, anti-apoptotic, and anti-inflammatory activities and other mechanisms.

A systematic review of the protective effects of silymarin/silibinin against doxorubicin-induced cardiotoxicity.

PURPOSE: Although doxorubicin chemotherapy is commonly applied for treating different malignant tumors, cardiotoxicity induced by this chemotherapeutic agent restricts its clinical use. The use of silymarin/silibinin may mitigate the doxorubicin-induced cardiac adverse effects. For this aim, the potential cardioprotective effects of silymarin/silibinin against the doxorubicin-induced cardiotoxicity were systematically reviewed. METHODS: In this study, we performed a systematic search in accordance with PRISMA guideline for identifying all relevant studies on "the role of silymarin/silibinin against doxorubicin-induced cardiotoxicity" in different electronic databases up to June 2022. Sixty-one articles were obtained and screened based on the predefined inclusion and exclusion criteria. Thirteen eligible papers were finally included in this review. RESULTS: According to the echocardiographic and electrocardiographic findings, the doxorubicin-treated groups presented a significant reduction in ejection fraction, tissue Doppler peak mitral annulus systolic velocity, and fractional shortening as well as bradycardia, prolongation of QT and QRS interval. However, these echocardiographic abnormalities were obviously improved in the silymarin plus doxorubicin groups. As well, the doxorubicin administration led to induce histopathological and biochemical changes in the cardiac cells/tissue; in contrast, the silymarin/silibinin co-administration could mitigate these induced alterations (for most of the cases). CONCLUSION: According to the findings, it was found that the co-administration of silymarin/silibinin alleviates the doxorubicin-induced cardiac adverse effects. Silymarin/silibinin exerts its cardioprotective effects via antioxidant, anti-inflammatory, anti-apoptotic activities, and other mechanisms.

The association of in-utero exposure to polycyclic aromatic hydrocarbons and umbilical liver enzymes.

BACKGROUND: The adverse health influences of polycyclic aromatic hydrocarbons (PAHs) exposures have been examined in several previous research. However, the evidence on the health influences of PAHs exposure during pregnancy and childhood is scarce, with no study on the infant's liver function. Therefore, in this study, the association of in-utero exposure to particulate matter-bound PAHs (PM-bound PAHs) on the umbilical liver enzymes was investigated. METHODS: A total of 450 mother-pair samples were assessed in this cross-sectional study in Sabzevar, Iran (2019-2021). The concentrations of PM-bound PAHs were estimated based on spatiotemporal models at residential addresses. The umbilical cord blood alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) were measured as indicators of infant's liver function. The association of PM-bound PAHs with umbilical liver enzymes was evaluated using multiple linear regression, controlled for relevant covariates. The quantile g-computation (g-comp) was used to investigate the combined impact of the 15 PAHs on liver function biomarkers. RESULTS: Higher levels of total 4-ring PAHs, Dibenzo[a,h]anthrancene, Anthracene, Pyrene, Benzo[a]anthracene, Phenanthrene, Fluorene, Acenaphthylene and Naphthalene were associated with higher umbilical ALP. An increase in total 5-ring PAHs, Benzo[g,h,i]perylene, Benzo[a]pyrene and Chrysene was associated with higher umbilical AST levels. Each 1 ng/m3 increase in exposure to Benzo[g,h,i]perylene was related with 182.21 U/L (95 % CI: 116.11, 248.31, P < 0.01) increase in umbilical GGT. PAHs mixture exposure was positively associated with higher umbilical AST and ALT, while no significant associations were noted for ALP and GGT. We observed a potentially stronger association for girls compared to boys based on umbilical ALT and AST. However, for GGT and ALP, these associations were stronger for boys compared to girls. CONCLUSION: Overall our findings suggested that exposure to PAHs during pregnancy had adverse effects on infant's liver function.

"To be or not to Be": Regulatory T cells in melanoma.

In spite of progresses in the therapy of different malignancies, melanoma still remains as one of lethal types of skin tumor. Melanoma is almost easily treatable by surgery alone with higher overall survival rates when it is diagnosed at early stages. However, survival rates are decreased remarkably upon survival if the tumor is progressed to advanced metastatic stages. Immunotherapeutics have been prosperous in the development of anti-tumor responses in patients with melanoma through promotion of the tumor-specific effector T cells in vivo; nonetheless, suitable clinical outcomes have not been satisfactory. One of the underlying causes of the unfavorable clinical outcomes might stem from adverse effects of regulatory T (Treg) cell, which is a prominent mechanism of tumor cells to escape from tumor-specific immune responses. Evidence shows that a poor prognosis and low survival rate in patients with melanoma can be attributed to a higher Treg cell number and function in these subjects. As a result, to promote melanoma-specific anti-tumor responses, depletion of Treg cells appears to be a promising approach; even though the clinical efficacy of different approaches to attain appropriate Treg cell depletion has been inconsistent. Here in this review, the main purpose is to assess the role of Treg cells in the initiation and perpetuation of melanoma and to discuss effective strategies for Treg cell modulation with the aim of melanoma therapy.

MiRNA-93: a novel signature in human disorders and drug resistance.

miRNA-93 is a member of the miR-106b-25 family and is encoded by a gene on chromosome 7q22.1. They play a role in the etiology of various diseases, including cancer, Parkinson's disease, hepatic injury, osteoarthritis, acute myocardial infarction, atherosclerosis, rheumatoid arthritis, and chronic kidney disease. Different studies have found that this miRNA has opposing roles in the context of cancer. Recently, miRNA-93 has been downregulated in breast cancer, gastric cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, and renal cancer. However, miRNA-93 is up-regulated in a wide variety of malignancies, such as lung, colorectal, glioma, prostate, osteosarcoma, and hepatocellular carcinoma. The aim of the current review is to provide an overview of miRNA-93's function in cancer disorder progression and non-cancer disorders, with a focus on dysregulated signaling pathways. We also give an overview of this miRNA's function as a biomarker of prognosis in cancer and emphasize how it contributes to drug resistance based on in vivo, in vitro, and human studies. Video Abstract.

Relationship between exposure to heavy metals on the increased health risk and carcinogenicity of urinary tract (kidney and bladder).

In today's society, with the continuous development of manufacturing industries and factories related to chemicals, the amount of heavy metals in the inhaled air of humans, water and even food consumption has increased dramatically. The aim of this study was investigation of relationship between exposure to heavy metals on the increased carcinogenicity risk of kidney and bladder. Databases used to for searched were the Springer, Google Scholar, Web of Science, Science Direct (Scopus) and PubMed. At the end after sieve we selected 20 papers. Identify all relevant studies published 2000-2021. The results of this study showed that exposure to heavy metals due to the bio accumulative properties of these metals can cause kidney and bladder abnormalities and provide the basis through various mechanisms for malignant tumors in these organs. Based on result this study, since a limited number of heavy metals including copper, iron, zinc and nickel in very small amounts as micronutrients play a very important role in the function of enzymes and the body cells biological reactions, but exposure to some of them like arsenic, lead, vanadium and mercury will cause irreversible effects on people's health and cause various diseases including cancers of the liver, pancreas, prostate, breast, kidney and bladder. The kidneys, ureter and bladder are the most important organs in the urinary tract on human. According to the result of this study, the duty of this urinary system is to remove toxins, chemicals and heavy metals from the blood, balance electrolytes, excrete excess fluid, produce urine and transfer it to the bladder. This mechanism causes the kidneys and bladder to be highly associated with these toxins and heavy metals, which can lead to various diseases in these two important organs. According to the finding the reducing exposure to heavy metals in various ways can prevent many diseases related to this system and reduce the incidence of kidney and bladder cancers.

Autophagy as a self-digestion signal in human cancers: Regulation by microRNAs in affecting carcinogenesis and therapy response.

Autophagy is defined as a "self-digestion" signal, and it is a cell death mechanism its primary function is degrading toxic agents and aged organelles to ensure homeostasis in cells. The basic leve ls of autophagy are found in cells, and when its levels exceed to standard threshold, cell death induction is observed. Autophagy dysregulation in cancer has been well-documented, and regulation of this pathway by epigenetic factors, especially microRNAs (miRNAs), is interesting and noteworthy. miRNAs are considered short endogenous RNAs that do not encode functional proteins, and they are essential regulators of cell death pathways such as apoptosis, necroptosis, and autophagy. Accumulating data has revealed miRNA dysregulation (upregulation or downregulation) during tumor progression, and their therapeutic manipulation provides new insight into cancer therapy. miRNA/autophagy axis in human cancers has been investigated an exciting point is the dual function of both autophagy and miRNAs as oncogenic and onco-suppressor factors. The stimulation of pro-survival autophagy by miRNAs can increase the survival rate of tumor cells and mediates cancer metastasis via EMT inductionFurthermore, pro-death autophagy induction by miRNAs has a negative impact on the viability of tumor cells and decreases their survival rate. The miRNA/autophagy axis functions beyond regulating the growth and invasion of tumor cells, and they can also affect drug resistance and radio-resistance. These subjects are covered in the current review regarding the new updates provided by recent experiments.

Constructing an Intelligent Model Based on Support Vector Regression to Simulate the Solubility of Drugs in Polymeric Media.

This study constructs a machine learning method to simultaneously analyze the thermodynamic behavior of many polymer-drug systems. The solubility temperature of Acetaminophen, Celecoxib, Chloramphenicol, D-Mannitol, Felodipine, Ibuprofen, Ibuprofen Sodium, Indomethacin, Itraconazole, Naproxen, Nifedipine, Paracetamol, Sulfadiazine, Sulfadimidine, Sulfamerazine, and Sulfathiazole in 1,3-bis[2-pyrrolidone-1-yl] butane, Polyvinyl Acetate, Polyvinylpyrrolidone (PVP), PVP K12, PVP K15, PVP K17, PVP K25, PVP/VA, PVP/VA 335, PVP/VA 535, PVP/VA 635, PVP/VA 735, Soluplus analyzes from a modeling perspective. The least-squares support vector regression (LS-SVR) designs to approximate the solubility temperature of drugs in polymers from polymer and drug types and drug loading in polymers. The structure of this machine learning model is well-tuned by conducting trial and error on the kernel type (i.e., Gaussian, polynomial, and linear) and methods used for adjusting the LS-SVR coefficients (i.e., leave-one-out and 10-fold cross-validation scenarios). Results of the sensitivity analysis showed that the Gaussian kernel and 10-fold cross-validation is the best candidate for developing an LS-SVR for the given task. The built model yielded results consistent with 278 experimental samples reported in the literature. Indeed, the mean absolute relative deviation percent of 8.35 and 7.25 is achieved in the training and testing stages, respectively. The performance on the largest available dataset confirms its applicability. Such a reliable tool is essential for monitoring polymer-drug systems' stability and deliverability, especially for poorly soluble drugs in polymers, which can be further validated by adopting it to an actual implementation in the future.

RETRACTED: The pathogenicity of COVID-19 and the role of pentraxin-3: An updated review study.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. In investigating concerns regarding the contributions of the authors to this article, the editors reached out to the authors for an explanation. In addition to the concerns regarding the contribution of each author, the editors discovered suspicious changes in authorship between the original submission and the revised version of this paper. The names of the authors Ameer A Alameri and Zanko Hassan Jawhar were added to the revised version of the article without explanation and without the exceptional approval by the handling Editor, which is contrary to the journal policy on changes to authorship. The authors were unable to provide a reasonable explanation for either of the issues raised. The editor therefore feels that the findings of the manuscript cannot be relied upon and that the article needs to be retracted.

Estimating the Dissolution of Anticancer Drugs in Supercritical Carbon Dioxide with a Stacked Machine Learning Model.

Synthesizing micro-/nano-sized pharmaceutical compounds with an appropriate size distribution is a method often followed to enhance drug delivery and reduce side effects. Supercritical CO2 (carbon dioxide) is a well-known solvent utilized in the pharmaceutical synthesis process. Reliable knowledge of a drug's solubility in supercritical CO2 is necessary for feasible study, modeling, design, optimization, and control of such a process. Therefore, the current study constructs a stacked/ensemble model by combining three up-to-date machine learning tools (i.e., extra tree, gradient boosting, and random forest) to predict the solubility of twelve anticancer drugs in supercritical CO2. An experimental databank comprising 311 phase equilibrium samples was gathered from the literature and applied to design the proposed stacked model. This model estimates the solubility of anticancer drugs in supercritical CO2 as a function of solute and solvent properties and operating conditions. Several statistical indices, including average absolute relative deviation (AARD = 8.62%), mean absolute error (MAE = 2.86 × 10-6), relative absolute error (RAE = 2.42%), mean squared error (MSE = 1.26 × 10-10), and regression coefficient (R2 = 0.99809) were used to validate the performance of the constructed model. The statistical, sensitivity, and trend analyses confirmed that the suggested stacked model demonstrates excellent performance for correlating and predicting the solubility of anticancer drugs in supercritical CO2.

Mechanisms of cancer stem cells drug resistance and the pivotal role of HMGA2.

Nowadays, the focus of researchers is on perceiving the heterogeneity observed in a tumor. The researchers studied the role of a specific subset of cancer cells with high resistance to traditional treatments, recurrence, and unregulated metastasis. This small population of tumor cells that have stem-cell-like specifications was named Cancer Stem Cells (CSCs). The unique features that distinguish this type of cancer cell are self-renewing, generating clones of the tumor, plasticity, recurrence, and resistance to therapies. There are various mechanisms that contribute to the drug resistance of CSCs, such as CSCs markers, Epithelial mesenchymal transition, hypoxia, other cells, inflammation, and signaling pathways. Recent investigations have revealed the primary role of HMGA2 in the development and invasion of cancer cells. Importantly, HMGA2 also plays a key role in resistance to treatment through their function in the drug resistance mechanisms of CSCs and challenge it. Therefore, a deep understanding of this issue can provide a clearer perspective for researchers in the face of this problem.